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, Pask Gm, Slone Jd, Millar Jg, Das P, Moreira Ja, Zhou X, Bello J, Berger Sl, Bonasio R, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 8; https://doi.org/10.3410/f.728772247.793537478

Abstract:
Eusocial insects use cuticular hydrocarbons as components of pheromones that mediate social behaviours, such as caste and nestmate recognition, and regulation of reproduction. In ants such as Harpegnathos saltator, the queen produces a pheromone which suppresses the development of workers' ovaries and if she is removed, workers can transition to a reproductive state known as gamergate. Here we functionally characterize a subfamily of odorant receptors (Ors) with a nine-exon gene structure that have undergone a massive expansion in ants and other eusocial insects. We deorphanize 22 representative members and find they can detect cuticular hydrocarbons from different ant castes, with one (HsOr263) that responds strongly to gamergate extract and a candidate queen pheromone component. After systematic testing with a diverse panel of hydrocarbons, we find that most Harpegnathos saltator Ors are narrowly tuned, suggesting that several receptors must contribute to detection and discrimination of different cuticular hydrocarbons important in mediating eusocial behaviour.Cuticular hydrocarbons (CHC) mediate the interactions between individuals in eusocial insects, but the sensory receptors for CHCs are unclear. Here the authors show that in ants such as H. saltator, the 9-exon subfamily of odorant receptors (HsOrs) responds to CHCs, and ectopic expression of HsOrs in Drosophila neurons imparts responsiveness to CHCs.
Christian Schmahl, , Fertuck Ea, Roepke S, Dziobek I, Miano A
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 8; https://doi.org/10.3410/f.727006525.793533983

Abstract:
This study assessed the instability of romantic partner trustworthiness perceptions as a possible underlying mechanism of unstable relationships in borderline personality disorder (BPD). Based on recent empirical findings of difficulties in maintaining trust in economic games and negatively biased facial trust perceptions in BPD individuals, the authors hypothesized that trustworthiness attributions with regard to a romantic partner...
, , Ron-Harel N, Juneja Vr, Sen, Maleri S, Sungnak W, Kuchroo Vk, Haining Wn, Haigis M, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 17; https://doi.org/10.3410/f.726814966.793537559

Abstract:
Interleukin (IL)-21 is a key regulator of T follicular helper (Tfh) cell development in germinal centers and represents a major cytokine secreted by Tfh cells that critically regulates the differentiation of memory B cells and plasma cells. IL-21 can also influence another small population of cells in the germinal center, known as T follicular regulatory (Tfr) cells, which negatively regulate Tfh-directed germinal center responses....
, , Herman Ei, Lainez B, Esplugues E, Flavell R, Craft J, Weinstein Js, Licona-Limon P
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 17; https://doi.org/10.3410/f.726696313.793537557

Abstract:
Interleukin (IL)-21 is a key regulator of T follicular helper (Tfh) cell development in germinal centers and represents a major cytokine secreted by Tfh cells that critically regulates the differentiation of memory B cells and plasma cells. Tfh cells appear to be heterogeneous with regard to their cytokine profiles and their anatomical location. For example, when IL-4-IL-21 double reporter mice were infected with Nippostrongylus ...
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 15; https://doi.org/10.3410/f.725439655.793537554

Abstract:
Using interleukin (IL)-2 to preferentially expand regulatory T (Treg) cells constitutes an area of intense focus related to autoimmune disease. This article showed that providing low doses of IL-2 to patients with systemic lupus erythematosus (SLE) can increase the percentage of circulating Treg cells and may prove clinically beneficial. This Recommendation is of an article referenced in an F1000 ...
, , Tomala J, Luca Vc, Jude Km, Dong S, Ring Am, Votavova P, Pepper M, Garcia Kc, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 42; https://doi.org/10.3410/f.725506812.793537553

Abstract:
It is possible to modulate interleukin (IL)-2 signaling by efforts to diminish the expression of CD25 in conventional T cells, deplete CD25 high regulatory T (Treg) cells, or to increase the availability of IL-2, either locally or systemically. The effects of complexes of IL-2 and IL-2-specific antibodies have also been studied. One monoclonal antibody binds with high affinity to human IL-2 at the CD25-binding epitope, thus preventing...
, , Meguri Y, Iwamoto M, Yagita H, Koreth J, Kim Ht, Alyea Ep, Armand P, Cutler Cs, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 129; https://doi.org/10.3410/f.727261561.793537556

Abstract:
Using interleukin (IL)-2 to preferentially expand regulatory T (Treg) cells constitutes an area of intense focus related to autoimmune disease. For example, providing low doses of IL-2 to patients with systemic lupus erythematosus (SLE) can increase the percentage of circulating Treg cells and may prove clinically beneficial. An initial study in which patients with SLE were given low-dose IL-2 reported an increase in the number...
, , Hufford Mm, Olson, Kaplan Mh
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 15; https://doi.org/10.3410/f.725426077.793537561

Abstract:
Interleukin (IL)-2 and IL-21 can drive alternative and sometimes opposing differentiation programs in a range of cell types, including stimulatory and inhibitory germinal center populations. Another example of opposing actions for these cytokines is in the differentiation of IL-9-producing T helper type 9 (Th9) cells. This article provides a useful guide to these cells, which were initially characterized as a population generated...
Warren J Leonard, Rosanne Spolski, Rajagopalan A, Berezhnoy A, Schrand B, Puplampu-Dove Y, Gilboa E
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 25; https://doi.org/10.3410/f.727377816.793537552

Abstract:
Because interleukin (IL)-2 drives CD8+ T cells toward an ‘effector’ phenotype, which confers poor anti-tumor performance in some models, reducing IL-2 signaling favors the production of memory CD8+ T cells. A new strategy for reducing IL-2 signaling is to conjugate IL2Ra siRNAs to a 4-1BB-binding oligonucleotide aptamer. Since 4-1BB is expressed on activated CD8+ T cells, this approach was designed to decrease IL-2 signaling...
, , Zhang X, Wei Y, Jia R, Xu C, Hou Z, Leong Ya, Zhu L, Ye H, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 22; https://doi.org/10.3410/f.726619783.793537555

Abstract:
Using interleukin (IL)-2 to preferentially expand regulatory T (Treg) cells constitutes an area of intense focus related to autoimmune disease. For example, providing low doses of IL-2 to patients with systemic lupus erythematosus (SLE) can increase the percentage of circulating Treg cells and may prove clinically beneficial. This study in which patients with SLE were given low-dose IL-2 reported an increase in the number of Treg...
, , Liu Sm, Cañete Pf, Warren J, Hughes We, Vogelzang A, Webster K, Craig Me, Uzel G, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 8; https://doi.org/10.3410/f.727416724.793537560

Abstract:
While interleukin (IL)-2 enhances the survival of FoxP3+ regulatory T (Treg) cells, IL-21 diminishes IL-2 production by conventional T cells and thereby lowers Treg cell numbers. As a result, one would predict that humans depleted of IL-21 would have increased Treg cells. This study showed that, in fact, IL21R-deficient patients have high numbers of both Treg cells and T follicular regulatory (Tfr)-like cells in their peripheral...
, , Gurish Mf, Marshall Jl, Slowikowski K, Fonseka Cy, Liu Y, Donlin Lt, Henderson La, Mizoguchi F, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 542; https://doi.org/10.3410/f.727254238.793537558

Abstract:
Interleukin (IL)-21 is a key regulator of T follicular helper (Tfh) cell development in germinal centers and represents a major cytokine secreted by Tfh cells that critically regulates the differentiation of memory B cells and plasma cells. Interestingly, high production of IL-21 has been detected in populations of Tfh and Tfh-like cells that are external to germinal centers, and these cells can also regulate B cell activation and...
, , Renga G, Oikonomou V, Galosi C, Pariano M, Iannitti Rg, Pucillo Ce, Zelante T, Renauld Jc, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 8; https://doi.org/10.3410/f.727212422.793537562

Abstract:
Interleukin (IL)-2 and IL-21 can drive alternative and sometimes opposing differentiation programs in a range of cell types, including stimulatory and inhibitory germinal center populations. This study reported that IL-2 contributes to the pathogenic role of IL-9 in lung disease and inflammation in cystic fibrosis through a self-amplifying circuit involving IL-2. In this circuit, lung epithelial damage resulted in the release...
Daniela Wenzel, Jia Jm, Chowdary Pd, Gao X, Ci B, Li W, Mulgaonkar A, Plautz Ej, Hassan G, Kumar A, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 14; https://doi.org/10.3410/f.727097241.793537489

Abstract:
The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.
, Terashima A, Okamoto K, Nakashima T, Akira S, Ikuta K, Takayanagi H
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 44; https://doi.org/10.3410/f.726432916.793537138

Abstract:
Sepsis is a host inflammatory response to severe infection associated with high mortality that is caused by lymphopenia-associated immunodeficiency. However, it is unknown how lymphopenia persists after the accelerated lymphocyte apoptosis subsides. Here we show that sepsis rapidly ablated osteoblasts, which reduced the number of common lymphoid progenitors (CLPs). Osteoblast ablation or inducible deletion of interleukin-7 (IL-7) in osteoblasts recapitulated the lymphopenic phenotype together with a lower CLP number without affecting hematopoietic stem cells (HSCs). Pharmacological activation of osteoblasts improved sepsis-induced lymphopenia. This study demonstrates a reciprocal interaction between the immune and bone systems, in which acute inflammation induces a defect in bone cells resulting in lymphopenia-associated immunodeficiency, indicating that bone cells comprise a therapeutic target in certain life-threatening immune reactions.Copyright © 2016 Elsevier Inc. All rights reserved.
, Tetreau G, Pinaud S, Portet A, Galinier R, Gourbal B, Duval D
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 8; https://doi.org/10.3410/f.731739267.793537480

Abstract:
Detection of pathogens by all living organisms is the primary step needed to implement a coherent and efficient immune response. This implies a mediation by different soluble and/or membrane-anchored proteins related to innate immune receptors called PRRs (pattern-recognition receptors) to trigger immune signaling pathways. In most invertebrates, their roles have been inferred by analogy to those already characterized in vertebrate homologs. Despite the induction of their gene expression upon challenge and the presence of structural domains associated with the detection of pathogen-associated molecular patterns in their sequence, their exact role in the induction of immune response and their binding capacity still remain to be demonstrated. To this purpose, we developed a fast interactome approach, usable on any host-pathogen couple, to identify soluble proteins capable of directly or indirectly detecting the presence of pathogens. To investigate the molecular basis of immune recognition specificity, different pathogens (Gram-positive bacterium, Micrococcus luteus; Gram-negative, Escherichia coli; yeast, Saccharomyces cerevisiae; and metazoan parasites, Echinostoma caproni or Schistosoma mansoni) were exposed to hemocyte-free hemolymph from the gastropod Biomphalaria glabrata. Twenty-three different proteins bound to pathogens were identified and grouped into three different categories based on their primary function. Each pathogen was recognized by a specific but overlapping set of circulating proteins in mollusk's hemolymph. While known PRRs such as C-type lectins were identified, other proteins not known to be primarily involved in pathogen recognition were found, including actin, tubulin, collagen, and hemoglobin. Confocal microscopy and specific fluorescent labeling revealed that extracellular actin present in snail hemolymph was able to bind to yeasts and induce their clotting, a preliminary step for their elimination by the snail immune system. Aerolysin-like proteins (named biomphalysins) were the only ones involved in the recognition of all the five pathogens tested, suggesting a sentinel role of these horizontally acquired toxins. These findings highlight the diversity and complexity of a highly specific innate immune sensing system. It paves the way for the use of such approach on a wide range of host-pathogen systems to provide new insights into the specificity and diversity of immune recognition by innate immune systems.
Lisa J Lapidus, Singh R, Hassan Mi, Islam A, Ahmad F
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 10; https://doi.org/10.3410/f.725536299.793536718

Abstract:
The denatured states of proteins have always attracted our attention due to the fact that the denatured state is the only experimentally achievable state of a protein, which can be taken as initial reference state for considering the in vitro folding and defining the native protein stability. It is known that heat and guanidinium chloride (GdmCl) give structurally different states of RNase-A, lysozyme, α-chymotrypsinogen A and α-lactalbumin. On the contrary, differential scanning calorimetric (DSC) and isothermal titration calorimetric measurements, reported in the literature, led to the conclusion that heat denatured and GdmCl denatured states are thermodynamically and structurally identical. In order to resolve this controversy, we have measured changes in the far-UV CD (circular dichroism) of these heat-denatured proteins on the addition of different concentrations of GdmCl. The observed sigmoidal curve of each protein was analyzed for Gibbs free energy change in the absence of the denaturant (ΔG0X→D) associated with the process heat denatured (X) state ↔ GdmCl denatured (D) state. To confirm that this thermodynamic property represents the property of the protein alone and is not a manifestation of salvation effect, we measured urea-induced denaturation curves of these heat denatured proteins under the same experimental condition in which GdmCl-induced denaturation was carried out. In this paper we report that (a) heat denatured proteins contain secondary structure, and GdmCl (or urea) induces a cooperative transition between X and D states, (b) for each protein at a given pH and temperature, thermodynamic cycle connects quantities, ΔG0N→X (native (N) state ↔ X state), ΔG0X→D and ΔG0N→D (N state ↔ D state), and (c) there is not a good enthalpy difference between X and D states, which is the reason for the absence of endothermic peak in DSC scan for the transition, X state ↔ D state.
Lisa J Lapidus, Ozenne V, Noel Jk, Heidarsson Po, Brander S, Poulsen Fm, Jensen, Kragelund Bb, Blackledge M, Danielsson J
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 426; https://doi.org/10.3410/f.718171116.793536719

Abstract:
The unfolded state of globular proteins is not well described by a simple statistical coil due to residual structural features, such as secondary structure or transiently formed long-range contacts. The principle of minimal frustration predicts that the unfolded ensemble is biased toward productive regions in the conformational space determined by the native structure. Transient long-range contacts, both native-like and non-native-like, have previously been shown to be present in the unfolded state of the four-helix-bundle protein acyl co-enzyme binding protein (ACBP) as seen from both perturbations in nuclear magnetic resonance (NMR) chemical shifts and structural ensembles generated from NMR paramagnetic relaxation data. To study the nature of the contacts in detail, we used paramagnetic NMR relaxation enhancements, in combination with single-point mutations, to obtain distance constraints for the acid-unfolded ensemble of ACBP. We show that, even in the acid-unfolded state, long-range contacts are specific in nature and single-point mutations affect the free-energy landscape of the unfolded protein. Using this approach, we were able to map out concerted, interconnected, and productive long-range contacts. The correlation between the native-state stability and compactness of the denatured state provides further evidence for native-like contact formation in the denatured state. Overall, these results imply that, even in the earliest stages of folding, ACBP dynamics are governed by native-like contacts on a minimally frustrated energy landscape. Copyright © 2013 Elsevier Ltd. All rights reserved.
Greg Gibson, Rask-Andersen M, Karlsson T, Ek We, Johansson Å
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 13; https://doi.org/10.3410/f.730774144.793537491

Abstract:
Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.
Lisa J Lapidus, Parui S, Manna Rn, Jana B
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 120; https://doi.org/10.3410/f.726664650.793536720

Abstract:
Despite their routine use as protein denaturants, the comprehensive understanding of the molecular mechanisms by which urea and guanidinium chloride (GdmCl) disrupts proteins' structure is still lacking. Here, we use steered molecular dynamics simulations along with the umbrella sampling technique to elucidate the mechanism of unfolding of chicken villin headpiece (HP-36) in these two denaturants. We find that while urea denatures protein predominantly by forming hydrogen bonds with the protein backbone, GdmCl commences unfolding by weakening of the hydrophobic interactions present in the core. The potential of mean force calculation indicates the reduction of hydrophobic interactions between two benzene moieties in 6 M GdmCl as compared to 6 M urea. We observe a near parallel orientation between the guanidinium cation and aromatic side chains of the HP-36 suggesting π-cation type stacking interactions which play a crucial role in weakening of the hydrophobic interaction. We use QM/MM optimization calculations to estimate the energetics of this π-cation interaction. Additionally, the consistency of the unfolding paths between high temperature (400 K) unfolding simulations and steered molecular dynamics simulations strengthens the proposed molecular mechanism of unfolding further.
Lisa J Lapidus, Graziano G, Pica A
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 105; https://doi.org/10.3410/f.726584577.793536721

Abstract:
It has long been known that proteins generally unfold at temperatures higher than the basal temperature of the organism in which it evolved. This article, together with {1,2}, helpfully summarizes current knowledge on thermophilic protein stability, highlighting that the melting temperatures of proteins from thermophilic organisms are typically higher than their homologs from mesophilic organisms. This Recommendation...
Lisa J Lapidus, Fossat Mj, Dao Tp, Jenkins K, Dellarole M, Yang Y, McCallum Sa, Garcia Ae, Barrick D, Roumestand C, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 111; https://doi.org/10.3410/f.727082876.793536723

Abstract:
A complete description of the pathways and mechanisms of protein folding requires a detailed structural and energetic characterization of the conformational ensemble along the entire folding reaction coordinate. Simulations can provide this level of insight for small proteins. In contrast, with the exception of hydrogen exchange, which does not monitor folding directly, experimental studies of protein folding have not yielded such structural and energetic detail. NMR can provide residue specific atomic level structural information, but its implementation in protein folding studies using chemical or temperature perturbation is problematic. Here we present a highly detailed structural and energetic map of the entire folding landscape of the leucine-rich repeat protein, pp32 (Anp32), obtained by combining pressure-dependent site-specific 1H-15N HSQC data with coarse-grained molecular dynamics simulations. The results obtained using this equilibrium approach demonstrate that the main barrier to folding of pp32 is quite broad and lies near the unfolded state, with structure apparent only in the C-terminal region. Significant deviation from two-state unfolding under pressure reveals an intermediate on the folded side of the main barrier in which the N-terminal region is disordered. A nonlinear temperature dependence of the population of this intermediate suggests a large heat capacity change associated with its formation. The combination of pressure, which favors the population of folding intermediates relative to chemical denaturants; NMR, which allows their observation; and constrained structure-based simulations yield unparalleled insight into protein folding mechanisms.Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Lisa J Lapidus, Wirth Aj, Liu Y, Prigozhin Mb, Schulten K, Gruebele M
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 137; https://doi.org/10.3410/f.725503366.793536724

Abstract:
The unimolecular folding reaction of small proteins is now amenable to a very direct mechanistic comparison between experiment and simulation. We present such a comparison of microsecond pressure and temperature jump refolding kinetics of the engineered WW domain FiP35, a model system for β-sheet folding. Both perturbations produce experimentally a faster and a slower kinetic phase, and the "slow" microsecond phase is activated. The fast phase shows differences between perturbation methods and is closer to the downhill limit by temperature jump, but closer to the transiently populated intermediate limit by pressure jump. These observations make more demands on simulations of the folding process than just a rough comparison of time scales. To complement experiments, we carried out several pressure jump and temperature jump all-atom molecular dynamics trajectories in explicit solvent, where FiP35 folded in five of the six simulations. We analyzed our pressure jump simulations by kinetic modeling and found that the pressure jump experiments and MD simulations are most consistent with a 4-state kinetic mechanism. Together, our experimental and computational data highlight FiP35's position at the boundary where activated intermediates and downhill folding meet, and we show that this model protein is an excellent candidate for further pressure jump molecular dynamics studies to compare experiment and modeling at the folding mechanism level.
Ryan Hibbs, Saotome K, Singh Ak, Yelshanskaya Mv, Sobolevsky Ai
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 534; https://doi.org/10.3410/f.726421942.793537497

Abstract:
Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca(2+)-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca(2+) uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca(2+) permeation remain obscure. Here we report the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared with other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular 'skirt' involved in allosteric modulation. In the K(+) channel-like transmembrane domain, Ca(2+) selectivity is determined by direct coordination of Ca(2+) by a ring of aspartate side chains in the selectivity filter. On the basis of crystallographically identified cation-binding sites at the pore axis and extracellular vestibule, we propose a Ca(2+) permeation mechanism. Our results provide a structural foundation for understanding the regulation of epithelial Ca(2+) uptake and its role in pathophysiology.
Wilbert Aronow, Ridker Pm, Everett Bm, Thuren T, MacFadyen Jg, Chang Wh, Ballantyne C, Fonseca F, Nicolau J, Koenig W, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 377; https://doi.org/10.3410/f.729280216.793537475

Abstract:
BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).
Steve Brown, Kalbassi S, Bachmann So, Cross E, Roberton Vh, Baudouin Sj
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 4; https://doi.org/10.3410/f.728373443.793537476

Abstract:
In most mammals, including humans, the postnatal acquisition of normal social and nonsocial behavior critically depends on interactions with peers. Here we explore the possibility that mixed-group housing of mice carrying a deletion of Nlgn3, a gene associated with autism spectrum disorders, and their wild-type littermates induces changes in each other's behavior. We have found that, when raised together, male Nlgn3 knockout mice and their wild-type littermates displayed deficits in sociability. Moreover, social submission in adult male Nlgn3 knockout mice correlated with an increase in their anxiety. Re-expression of Nlgn3 in parvalbumin-expressing cells in transgenic animals rescued their social behavior and alleviated the phenotype of their wild-type littermates, further indicating that the social behavior of Nlgn3 knockout mice has a direct and measurable impact on wild-type animals' behavior. Finally, we showed that, unlike male mice, female mice lacking Nlgn3 were insensitive to their peers' behavior but modified the social behavior of their littermates. Altogether, our findings show that the environment is a critical factor in the development of behavioral phenotypes in transgenic and wild-type mice. In addition, these results reveal that the social environment has a sexually dimorphic effect on the behavior of mice lacking Nlgn3, being more influential in males than females.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 95; https://doi.org/10.3410/f.727879026.793537484

Abstract:
Local protein synthesis in known to be essential for several neuronal processes such as dendrite formation or axon steering. However, it had not previously been shown that local translation is also important for axon branching. In this beautiful study, the authors report a method that allows them to simultaneously visualize RNA trafficking and axon branching in vivo. Thanks to this very challenging technical advance, they are...
Gottfried Otting, Cigler M, Müller Tg, Horn-Ghetko D, Von Wrisberg Mk, Fottner M, Goody Rs, Itzen A, Müller Mp, Lang K
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 56; https://doi.org/10.3410/f.731430647.793537477

Abstract:
The characterization of low-affinity protein complexes is challenging due to their dynamic nature. Here we present a method to stabilize transient protein complexes in vivo by generating a covalent and conformationally flexible bridge between the interaction partners. A highly active pyrrolysyl tRNA synthetase mutant directs the incorporation of unnatural amino acids bearing bromoalkyl moieties (BrCnK) into proteins. We demonstrate for the first time that low-affinity protein complexes between BrCnK-containing proteins and their binding partners can be stabilized in vivo in bacterial and mammalian cells. Using this approach we determined the crystal structure of a transient GDP-bound complex between a small G-protein and its nucleotide exchange factor. We envision that this approach will prove valuable as a general tool for validating and characterizing protein-protein interactions in vitro and in vivo.© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Mehdi Mollapour, , Washburn Hr, Sheffler-Collins Si, Xia Nl, Henderson N, Tillu Dv, Hassler S, Spellman Ds, Zhang G, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 15; https://doi.org/10.3410/f.727819393.793537149

Abstract:
This work shows that the receptor tyrosine kinase ephrin B2 receptor (EphB2) becomes phosphorylated on its extracellular portion upon stimulation of EphB2 with its cognate ligand ephrin B. The phosphorylation site is Y504 inside the highly conserved fibronectin type III domain and is widely conserved in other ephrin receptors and other proteins with such a domain. This phosphorylation occurs at the neuronal cell surface. It requires...
Andrea Ricci Maccarini, Alfonso Gianluca Gucciardo, Flavio Pieri, Jarecke J, Yang C, Teal Cr, Street Rl, Stuckey H, Haidet P
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 5; https://doi.org/10.3410/f.731430416.793537340

Abstract:
This article is very seminal because, in our opinion, it could open many avenues to further research on this theme. In effect, jazz is a performing art with both medical and general benefits. The authors seem to demonstrate that one of these benefits is increased improvisational communication skills, useful not only for generic people but above all for medical doctors in their ordinary and specialist practices.
, Li Lx, Fan Lx Li Lx, Zhou Jx, Grantham Jj, Calvet JP, Sage J, Li X
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 127; https://doi.org/10.3410/f.727709383.793535576

Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.
, Martínez-Sáez N, Sun S, Oldrini D, Sormanni P, Boutureira O, Carboni F, Compañón I, Deery M, Vendruscolo M, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature; https://doi.org/10.3410/f.731518500.793537383

Abstract:
Here we show that a four-membered oxygen ring - oxetane - can be readily grafted into native peptides and proteins through site-selective bis-alkylation of cysteine residues present as disulfides under mild and biocompatible conditions. The selective installation of the oxetane graft enhances stability and activity, as demonstrated for a range of biologically relevant cyclic peptides, including somatostatin, proteins and antibodies, such as a Fab arm of the antibody Herceptin® and a designed antibody DesAb-A against the human Amyloid- peptide. Markedly, oxetane grafting of the genetically detoxified diphtheria toxin CRM197 improves significantly the immunogenicity of this protein in mice, which illustrates the general utility of this strategy to modulate the stability and biological activity of therapeutic proteins containing disulfides in their structures.© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
, Jie Li, Mu R, Tat J, Zamudio R, Zhang Y, Yates Jr, Kumagai A, Dunphy Wg, Reed Si
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 37; https://doi.org/10.3410/f.727840200.793537370

Abstract:
CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication.Copyright © 2017 American Society for Microbiology.
Susan Kalisz, Austen Ej, Rowe L, Stinchcombe Jr, Forrest Jrk
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 215; https://doi.org/10.3410/f.727521636.793534299

Abstract:
Decades of observation in natural plant populations have revealed pervasive phenotypic selection for early flowering onset. This consistent pattern seems at odds with life-history theory, which predicts stabilizing selection on age and size at reproduction. Why is selection for later flowering rare? Moreover, extensive evidence demonstrates that flowering time can and does evolve. What maintains ongoing directional selection for early flowering? Several non-mutually exclusive processes can help to reconcile the apparent paradox of selection for early flowering. We outline four: selection through other fitness components may counter observed fecundity selection for early flowering; asymmetry in the flowering-time-fitness function may make selection for later flowering hard to detect; flowering time and fitness may be condition-dependent; and selection on flowering duration is largely unaccounted for. In this Viewpoint, we develop these four mechanisms, and highlight areas where further study will improve our understanding of flowering-time evolution.© 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.
, Sczyrba A, Hofmann P, Belmann P, Koslicki D, Janssen S, Dröge J, Gregor I, Majda S, Fiedler J, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 14; https://doi.org/10.3410/f.731537511.793537446

Abstract:
Methods for assembly, taxonomic profiling and binning are key to interpreting metagenome data, but a lack of consensus about benchmarking complicates performance assessment. The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from ∼700 newly sequenced microorganisms and ∼600 novel viruses and plasmids and representing common experimental setups. Assembly and genome binning programs performed well for species represented by individual genomes but were substantially affected by the presence of related strains. Taxonomic profiling and binning programs were proficient at high taxonomic ranks, with a notable performance decrease below family level. Parameter settings markedly affected performance, underscoring their importance for program reproducibility. The CAMI results highlight current challenges but also provide a roadmap for software selection to answer specific research questions.
, Constanze Mittermeier, Constanze Hermanns, Guey B, Gulen Mf, Wolter K, Kang Tw, Schmacke Na, Bridgeman A, Rehwinkel J, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 19; https://doi.org/10.3410/f.727857070.793537467

Abstract:
We would recommend this article because it convincingly shows that the cyclic GMP-AMP synthase (cGAS) signalling pathway affects cellular senescence. The authors figure out that the activation of the cGAS-STING pathway occurs through the recognition of cytosolic chromatin fragments in senescent cells arising due to the decreased expression of the nuclear envelope component lamin B1. The activated cGAS-STING pathway then in turn...
, , Rieger S, Kuklik-Roos C, Martin De, Maier Kc, Harth-Hertle Ml, Grüning B, Backofen R, Blum H, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 13; https://doi.org/10.3410/f.731602619.793537436

Abstract:
This substantial body of work describes the interaction between the viral protein EBNA2 and the host cell protein early B cell factor 1 (EBF1). The interaction of EBNA2 with the cellular transcription factor CBF1 is known to be required for transcriptional programming that occurs early upon infection of primary B cells. Using CBF1 deficient cell lines, the authors identify cellular genes regulated in a CBF1-independent manner...
Tahir Hussain, Zha D, Cheng H, Li W, Wu Y, Li X, Zhang L, Feng Yh, Wu X
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature; https://doi.org/10.3410/f.730774563.793537470

Abstract:
Abnormal expression and dysfunction of adiponectin and the cognate receptors are involved in diabetes and diabetic kidney disease (DKD), whereas angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) alleviate diabetic albuminuria and prevent development of DKD through upregulation of adiponectin expression. Here we report that high glucose stimulates expression of angiotensin II (AngII) receptors (AT1 and AT2) in renal proximal tubular epithelial cells (NRK-52E). These receptors underwent hetero-dimerization with adiponectin receptor AdipoR1 and AdipoR2, respectively. High glucose inhibited the dimerization between AT1 and AT2. Interestingly, these hetero-dimers instigated tubulointerstitial injury by inhibiting the cytoprotective action of the adiponectin receptors. These modes of receptor-receptor hetero-dimerization may contribute to high glucose-induced renal tubulointerstitial injury and could be potential therapeutic targets.Copyright © 2017. Published by Elsevier Inc.
Wendy Gibson, Wiedemar N, Graf Fe, Zwyer M, Ndomba E, Kunz Renggli C, Cal M, Schmidt Rs, Wenzler T, Mäser P
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 107; https://doi.org/10.3410/f.731433905.793537440

Abstract:
Suramin is one of the first drugs developed in a medicinal chemistry program (Bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense. Cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with T. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. Here we show that forward selection for suramin resistance in T. brucei spp. cultures is fast, highly reproducible and linked to antigenic variation. Bloodstream-form trypanosomes are covered by a dense coat of variant surface glycoprotein (VSG), which protects them from their mammalian hosts' immune defenses. Each T. brucei genome contains over 2000 different VSG genes, but only one is expressed at a time. An expression switch to one particular VSG, termed VSGSur , correlated with suramin resistance. Reintroduction of the originally expressed VSG gene in resistant T. brucei restored suramin susceptibility. This is the first report of a link between antigenic variation and drug resistance in African trypanosomes.© 2017 The Authors. Molecular Microbiology Published by John Wiley & Sons Ltd.
, Vigneron A, Alsop Eb, Lomans Bp, Kyrpides Nc, Head Im, Tsesmetzis N
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 11; https://doi.org/10.3410/f.727626479.793537464

Abstract:
Subsurface petroleum reservoirs are an important component of the deep biosphere where indigenous microorganisms live under extreme conditions and in isolation from the Earth's surface for millions of years. However, unlike the bulk of the deep biosphere, the petroleum reservoir deep biosphere is subject to extreme anthropogenic perturbation, with the introduction of new electron acceptors, donors and exogenous microbes during oil exploration and production. Despite the fundamental and practical significance of this perturbation, there has never been a systematic evaluation of the ecological changes that occur over the production lifetime of an active offshore petroleum production system. Analysis of the entire Halfdan oil field in the North Sea (32 producing wells in production for 1-15 years) using quantitative PCR, multigenic sequencing, comparative metagenomic and genomic bins reconstruction revealed systematic shifts in microbial community composition and metabolic potential, as well as changing ecological strategies in response to anthropogenic perturbation of the oil field ecosystem, related to length of time in production. The microbial communities were initially dominated by slow growing anaerobes such as members of the Thermotogales and Clostridiales adapted to living on hydrocarbons and complex refractory organic matter. However, as seawater and nitrate injection (used for secondary oil production) delivered oxidants, the microbial community composition progressively changed to fast growing opportunists such as members of the Deferribacteres, Delta-, Epsilon- and Gammaproteobacteria, with energetically more favorable metabolism (for example, nitrate reduction, H2S, sulfide and sulfur oxidation). This perturbation has profound consequences for understanding the microbial ecology of the system and is of considerable practical importance as it promotes detrimental processes such as reservoir souring and metal corrosion. These findings provide a new conceptual framework for understanding the petroleum reservoir biosphere and have consequences for developing strategies to manage microbiological problems in the oil industry.
, , Sun C, Landman Sl, Oosenbrug T, Koppejan Hj, Kwakkenbos Mj, Hoeben Rc, Paludan Sr, Ressing Me, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 91; https://doi.org/10.3410/f.731602800.793537435

Abstract:
This work aims to identify unique aspects of B cell biology which make them important targets for persistent viral infection. The authors identified B cells as being deficient in the essential component of the cytosolic DNA-sensing machinery stimulator of interferon genes (STING). However, reconstitution of these cells with STING did not enable B cells to respond to cytosolic DNA; further research into the precise deficiency is...
, , Van Meeteren J, Twisk Jw, De Laat Fa, Beckerman H, Stam Hj, Bussmann Jb, Blikman Lj, De Groot V, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 23; https://doi.org/10.3410/f.727640385.793537365

Abstract:
Blikman et al. studied 86 patients with multiple sclerosis (MS) who had significant fatigue to determine the effectiveness of energy conservation management on fatigue and participation. The authors reported the results from a single-blinded randomised control trial of 86 patients with all types of MS (relapsing and progressive) who suffered from significant fatigue as defined by the fatigue domain of the CISr20. Patient-reported...
, , Kedia S, Fernandes G, Rahman Mm, Chattarji S
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 6; https://doi.org/10.3410/f.727670505.793537424

Abstract:
Electrophysiology has been aiding our understanding of neural network mechanisms and behavior for a long time now. And scientists like Prof Chattarji have been exploring new dimensions with this technology to make our understanding about the brain and why and how it behaves in certain conditions more vivid. In the present work, the authors offer findings for a new framework spanning multiple levels of neural organization...
Jean-Pierre Changeux, Lynagh T, Romero-Rojo Jl, Lund C, Pless Sa
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 60; https://doi.org/10.3410/f.731386882.793537432

Abstract:
A growing body of evidence links certain aspects of nonsteroidal anti-inflammatory drug (NSAID) pharmacology with acid-sensing ion channels (ASICs), a small family of excitatory neurotransmitter receptors implicated in pain and neuroinflammation. The molecular basis of NSAID inhibition of ASICs has remained unknown, hindering the exploration of this line of therapy. Here, we characterized the mechanism of inhibition, explored the molecular determinants of sensitivity, and sought to establish informative structure-activity relationships, using electrophysiology, site-directed mutagenesis, and voltage-clamp fluorometry. Our results show that ibuprofen is an allosteric inhibitor of ASIC1a, which binds to a crucial site in the agonist transduction pathway and causes conformational changes that oppose channel activation. Ibuprofen inhibits several ASIC subtypes, but certain ibuprofen derivatives show some selectivity for ASIC1a over ASIC2a and vice versa. These results thus define the NSAID/ASIC interaction and pave the way for small-molecule drug design targeting pain and inflammation.
Peter John Lee, Nielsen Rv, Fomsgaard Js, Siegel H, Martusevicius R, Nikolajsen L, Dahl Jb, Mathiesen O
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 158; https://doi.org/10.3410/f.727188281.793537463

Abstract:
Perioperative handling of surgical patients with opioid dependency represents an important clinical problem. Animal studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance. We hypothesized that intraoperative ketamine would reduce immediate postoperative opioid consumption compared with placebo in chronic pain patients with opioid dependency undergoing lumbar spinal fusion surgery. Primary outcome was morphine consumption 0 to 24 hours postoperatively. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours postoperatively (visual analogue scale), adverse events, and persistent pain 6 months postoperatively. One hundred fifty patients were randomly assigned to intraoperative S-ketamine bolus 0.5 mg/kg and infusion 0.25 mg·kg·h or placebo. Postoperatively, patients received their usual opioids, paracetamol and IV patient-controlled analgesia with morphine. In the final analyses, 147 patients were included. Patient-controlled analgesia IV morphine consumption 0 to 24 hours postoperatively was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV, mean difference 42 mg (95% confidence interval -59 to -25), P PMID: 28067693
Janice Fletcher, Shanti Balasubramaniam, Kölker S, Hoffmann Gf, Ebrahimi-Fakhari D, Saffari A
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 40; https://doi.org/10.3410/f.727602479.793537439

Abstract:
This article reviews the emerging evidence linking mitochondrial dysfunction in the pathogenesis and progression of neurodegeneration in select lysosomal storage diseases (LSDs), including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann-Pick disease type C and the neuronal ceroid lipofuscinosis. Experimental therapies aimed at restoring mitochondrial function...
, Fujii Y, Tanaka H, Konno N, Ogasawara Y, Hamashima N, Tamura S, Hasegawa S, Hayasaki Y, Okajima K, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 114; https://doi.org/10.3410/f.727965070.793537471

Abstract:
Living organisms detect changes in temperature using thermosensory molecules. However, these molecules and/or their mechanisms for sensing temperature differ among organisms. To identify thermosensory molecules in plants, we investigated chloroplast positioning in response to temperature changes and identified a blue-light photoreceptor, phototropin, that is an essential regulator of chloroplast positioning. Based on the biochemical properties of phototropin during the cellular response to light and temperature changes, we found that phototropin perceives temperature based on the temperature-dependent lifetime of the photoactivated chromophore. Our findings indicate that phototropin perceives both blue light and temperature and uses this information to arrange the chloroplasts for optimal photosynthesis. Because the photoactivated chromophore of many photoreceptors has a temperature-dependent lifetime, a similar temperature-sensing mechanism likely exists in other organisms. Thus, photoreceptors may have the potential to function as thermoreceptors.
Chris Waters, Commichau Fm, Gibhardt J, Halbedel S, Gundlach J, Stülke J
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 26; https://doi.org/10.3410/f.731603148.793537473

Abstract:
Bacteria use second-messenger molecules to adapt to their environment. Several second messengers, among them cyclic di-AMP (c-di-AMP), have been discovered and intensively studied. Interestingly, c-di-AMP is essential for growth of Gram-positive bacteria such as Bacillus subtilis, Listeria monocytogenes, and Staphylococcus aureus. Many studies demonstrated that perturbation of c-di-AMP metabolism affects the integrity of the bacterial cell envelope. Therefore, it has been assumed that the nucleotide is essential for proper cell envelope synthesis. In this Opinion paper, we propose that the cell envelope phenotypes caused by perturbations of c-di-AMP metabolism can be interpreted differently: c-di-AMP might indirectly control cell envelope integrity by modulating the turgor, a physical variable that needs to be tightly adjusted. We also discuss open questions related to c-di-AMP metabolism that need to be urgently addressed by future studies.Copyright © 2017 Elsevier Ltd. All rights reserved.
, Beach Jm, Rajeswaran J, Parodi Fe, Kuramochi Y, Brier C, Blackstone E, Eagleton Mj
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature; https://doi.org/10.3410/f.731602528.793537421

Abstract:
OBJECTIVE: Repair options for complex abdominal and thoracoabdominal aortic aneurysms (TAAAs) are evolving with increased experience and availability of less invasive endovascular techniques. Identifying risk factors for mortality after fenestrated and branched endovascular aortic repair (F/B-EVAR) could improve patient selection and facilitate decision making regarding who may benefit from prophylactic F/B-EVAR. METHODS: We evaluated 1091 patients in a prospective investigational device exemption trial who underwent F/B-EVAR from August 2001 to June 2015 for complex aortic aneurysms (CAAs). Multivariable analysis of risk factors for death was performed using a nonproportional hazards model and a nonparametric analysis using random survival forest technology. RESULTS: Operative mortality after F/B-EVAR was low (3.7%), with high CAA-related survival at 30 day and 5 years (96.8% and 94.0%, respectively). All-cause 5-year survival, however, was 46.2% and older age, heart failure, chronic obstructive pulmonary disease, renal disease, anemia, and coagulation disorders were risk factors. Risk was highest for those undergoing type I/II TAAA repairs and those with larger aneurysms. CONCLUSIONS: Patients with multiple comorbidities and those undergoing type I or II TAAA repair are at greatest risk of mortality; however, in this high-risk population, F/B-EVAR offers greater survival compared with that reported for the natural history of untreated aneurysms. Operative and early mortality is lower than the best-reported open repair outcomes, even in this high-risk population, suggesting a potential benefit in extending the use of F/B-EVAR to low-to-average risk CAA patients. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Yukishige Ito, Roversi P, Marti L, Caputo At, Alonzi Ds, Hill Jc, Dent Kc, Kumar A, Levasseur, Lia A, et al.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Volume 114; https://doi.org/10.3410/f.727838964.793537433

Abstract:
Glycoproteins traversing the eukaryotic secretory pathway begin life in the endoplasmic reticulum (ER), where their folding is surveyed by the 170-kDa UDP-glucose:glycoprotein glucosyltransferase (UGGT). The enzyme acts as the single glycoprotein folding quality control checkpoint: it selectively reglucosylates misfolded glycoproteins, promotes their association with ER lectins and associated chaperones, and prevents premature secretion from the ER. UGGT has long resisted structural determination and sequence-based domain boundary prediction. Questions remain on how this single enzyme can flag misfolded glycoproteins of different sizes and shapes for ER retention and how it can span variable distances between the site of misfold and a glucose-accepting N-linked glycan on the same glycoprotein. Here, crystal structures of a full-length eukaryotic UGGT reveal four thioredoxin-like (TRXL) domains arranged in a long arc that terminates in two β-sandwiches tightly clasping the glucosyltransferase domain. The fold of the molecule is topologically complex, with the first β-sandwich and the fourth TRXL domain being encoded by nonconsecutive stretches of sequence. In addition to the crystal structures, a 15-Å cryo-EM reconstruction reveals interdomain flexibility of the TRXL domains. Double cysteine point mutants that engineer extra interdomain disulfide bridges rigidify the UGGT structure and exhibit impaired activity. The intrinsic flexibility of the TRXL domains of UGGT may therefore endow the enzyme with the promiscuity needed to recognize and reglucosylate its many different substrates and/or enable reglucosylation of N-linked glycans situated at variable distances from the site of misfold.
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