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Koschitzky M, Navrazhina K, Garshick MS, Gonzalez J, Han JS, Garcet S, Krueger JG
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Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris

Psoriasis increases the risk of cardiovascular disease (CVD). Biomarkers for cardiovascular (CV) risk stratification in psoriasis are lacking, and the effects of psoriasis biologics on CV risk reduction remain unclear. The goal of this study was to identify biomarkers of CV risk in psoriasis blood that are reduced by ustekinumab. We quantified 276 inflammatory and CV-related serum proteins with Olink's multiplex assay in 10 psoriasis patients (vs. 18 healthy controls) and after 12 weeks of ustekinumab treatment. For each protein down-regulated after treatment, the literature was reviewed for studies assessing the protein's association with CVD. Data were collected from each study to calculate CV risk thresholds for each protein, which were compared with protein levels in psoriasis patients before and after treatment. Our results showed that 43 out of 276 proteins were down-regulated after treatment, 25 of which were initially up-regulated at baseline (vs. controls, all p-values <= 0.1). 8 down-regulated proteins were initially elevated above thresholds associated with enhanced CV risk in the literature (myeloperoxidase, C-X-C motif chemokine 10, E-selectin, interleukin-6, cystatin B, von Willebrand factor, tumor necrosis factor receptor 1 and N-terminal prohormone brain natriuretic peptide). Treatment lowered these proteins to below their risk thresholds, except for IL-6, which was lowered but remained at its risk threshold despite successful psoriasis skin treatment. In summary, 12 weeks of ustekinumab treatment reduced serum proteins present at levels associated with CV risk in psoriasis patients. Further studies can evaluate these proteins as potential ustekinumab-modulated biomarkers of CV risk in psoriasis and the impact of ustekinumab on CV risk reduction.
Cohen JE, Huillet TE
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Taylor's Law for Some Infinitely Divisible Probability Distributions from Population Models

In a family of random variables, Taylor's law or Taylor's power law of fluctuation scaling is a variance function that gives the variance sigma(2) > 0 of a random variable (rv) X with expectation mu > 0 as a power of mu: sigma(2) = A mu(b) for finite real A > 0, b that are the same for all rvs in the family. Equivalently, TL holds when log sigma(2) = a + b log mu, a = log A, for all rvs in some set. Here we analyze the possible values of the TL exponent b in five families of infinitely divisible two-parameter distributions and show how the values of b depend on the parameters of these distributions. The five families are Tweedie-Bar-Lev-Enis, negative binomial, compound Poisson-geometric, compound geometric-Poisson (or Polya-Aeppli), and gamma distributions. These families arise frequently in empirical data and population models, and they are limit laws of Markov processes that we exhibit in each case.
Haselwandtera CA, Guoc YR, Fuc Z, MacKinnon R
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Quantitative prediction and measurement of Piezo's membrane footprint

Piezo proteins are mechanosensitive ion channels that can locally curve the membrane into a dome shape [Y. R. Guo, R. MacKinnon, eLife 6, e33660 (2017)]. The curved shape of the Piezo dome is expected to deform the surrounding lipid bilayer membrane into a membrane footprint, which may serve to amplify Piezo's sensitivity to applied forces [C. A. Haselwandter, R. MacKinnon, eLife 7, e41968 (2018)]. If Piezo proteins are embedded in lipid bilayer vesicles, the membrane shape deformations induced by the Piezo dome depend on the vesicle size. We employ here membrane elasticity theory to predict, with no free parameters, the shape of such Piezo vesicles outside the Piezo dome, and show that the predicted vesicle shapes agree quantitatively with the corresponding measured vesicle shapes obtained through cryoelectron tomography, for a range of vesicle sizes [W. Helfrich, Z. Naturforsch. C 28, 693-703 (1973)]. On this basis, we explore the coupling between Piezo and membrane shape and demonstrate that the features of the Piezo dome affecting Piezo's membrane footprint approximately follow a spherical cap geometry. Our work puts into place the foundation for deducing key elastic properties of the Piezo dome from membrane shape measurements and provides a general framework for quantifying how proteins deform bilayer membranes.
Richard JC, Frobert E, Destras G, Yonis H, Mezidi M, Dhelft F, Trouillet-Assant S, Bastard P, Gervais A, Danjou W, Aubrun F, Roumieu F, Josset L, Labaune JM, Bal A, Simon B, Casanova JL, Lina B, Picaud JC, Dupont C, Huissoud C, Bitker L
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Virological and clinical features of acute respiratory failure associated with COVID-19 in pregnancy: a case-control study

Objective: Pregnancy is a risk factor for acute respiratory failure (ARF) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We hypothesised that SARS-CoV-2 viral load in the respiratory tract might be higher in pregnant intensive care unit (ICU) patients with ARF than in non-pregnant ICU patients with ARF as a consequence of immunological adaptation during pregnancy. Design: Single-centre, retrospective observational case- control study. Setting: Adult level 3 ICU in a French university hospital. Participants: Eligible participants were adults with ARF associated with coronavirus disease 2019 (COVID-19) pneumonia. Main outcome measure: The primary endpoint of the study was viral load in pregnant and non-pregnant patients. Results: 251 patients were included in the study, including 17 pregnant patients. Median gestational age at ICU admission amounted to 28 + 3/7 weeks (interquartile range [IQR], 26 + 1/7 to 31 + 5/7 weeks). Twelve patients (71%) had an emergency caesarean delivery due to maternal respiratory failure. Pregnancy was independently associated with higher viral load (-4.6 +/- 1.9 cycle threshold; P < 0.05). No clustering or over-represented mutations were noted regarding SARS-CoV-2 sequences of pregnant women. Emergency caesarean delivery was independently associated with a modest but significant improvement in arterial oxygenation, amounting to 32 +/- 12 mmHg in patients needing invasive mechanical ventilation. ICU mortality was significantly lower in pregnant patients (0 v 35%; P < 0.05). Age, Simplified Acute Physiology Score (SAPS) II score, and acute respiratory distress syndrome were independent risk factors for ICU mortality, while pregnancy status and virological variables were not. Conclusions: Viral load was substantially higher in pregnant ICU patients with COVID-19 and ARF compared with non-pregnant ICU patients with COVID-19 and ARF. Pregnancy was not independently associated with ICU mortality after adjustment for age and disease severity.
Wang ZJ, Zhou PC, Muecksch F, Cho ALC, Ben Tanfous T, Canis M, Witte L, Johnson B, Raspe R, Schmidt F, Bednarski E, Da Silva J, Ramos V, Zong S, Turroja M, Millard KG, Yao KH, Shimeliovich I, Dizon J, Kaczynska A, Jankovic M, Gazumyan A, Oliveira TY, Caskey M, Gaebler C, Bieniasz PD, Hatziioannou T, Nussenzweig MC
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Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans

JOURNAL OF EXPERIMENTAL MEDICINE 2022 SEP 23; 219(12):? Article e20221006
Wang et al. analyze memory B cell and antibody responses in SARS-CoV-2 mRNA vaccines to breakthrough infections with Delta or Omicron BA.1 variants. Breakthrough infection after two or three doses of mRNA vaccination was comparable to three doses of vaccination in eliciting broad and potent memory B cells. The findings provide insights on broad and strain-specific memory responses after mRNA vaccination with Wuhan-Hu-1. Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
Daza-Cajigal V, Albuquerque AS, Young DF, Ciancanelli MJ, Moulding D, Angulo I, Jeanne-Julien V, Rosain J, Minskaia E, Casanova JL, Boisson-Dupuis S, Bustamante J, Randall RE, McHugh TD, Thrasher AJ, Burns SO
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Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria

FRONTIERS IN IMMUNOLOGY 2022 SEP 9; 13(?):? Article 888427
Purpose Janus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-alpha/beta and IFN-gamma), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control. Methods We investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA. Results Partial JAK1 deficiency impairs IFN-gamma -dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-alpha responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts. Conclusion Our data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-gamma responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-alpha responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.
Silva KDA, Nunes JPS, Andrieux P, Brochet P, Almeida RR, Takara ACKK, Pereira NB, Abel L, Cobat A, Zaniratto RCF, Levy D, Bydlowski SP, Cecconello I, Seguro FCBD, Kalil J, Chevillard C, Cunha-Neto E
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Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-gamma Stimulus

BIOMEDICINES 2022 SEP; 10(9):? Article 2215
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 8 million people, and around 1/3 develop chronic cardiac (CCC) or digestive disease (megaesophagus/megacolon), while the majority remain asymptomatic, in the indeterminate form of Chagas disease (ASY). Most CCC cases in families with multiple Chagas disease patients carry damaging mutations in mitochondrial genes. We searched for exonic mutations associated to chagasic megaesophagus (CME) in genes essential to mitochondrial processes. We performed whole exome sequencing of 13 CME and 45 ASY patients. We found the damaging variant MRPS18B 688C > G P230A, in five out of the 13 CME patients (one of them being homozygous; 38.4%), while the variant appeared in one out of 45 ASY patients (2.2%). We analyzed the interferon (IFN)-gamma-induced nitro-oxidative stress and mitochondrial function of EBV-transformed lymphoblastoid cell lines. We found the CME carriers of the mutation displayed increased levels of nitrite and nitrated proteins; in addition, the homozygous (G/G) CME patient also showed increased mitochondrial superoxide and reduced levels of ATP production. The results suggest that pathogenic mitochondrial mutations may contribute to cytokine-induced nitro-oxidative stress and mitochondrial dysfunction. We hypothesize that, in mutation carriers, IFN-gamma produced in the esophageal myenteric plexus might cause nitro-oxidative stress and mitochondrial dysfunction in neurons, contributing to megaesophagus.
Rapaport F, Seier K, Neelamraju Y, Hassane D, Baslan T, Gildea DT, Haddox S, Lee T, Murdock HM, Sheridan C, Thurmond A, Wang L, Carroll M, Cripe LD, Fernandez H, Mason CE, Paietta E, Roboz GJ, Sun ZX, Tallman MS, Zhang YM, Gonen M, Levine R, Melnick AM, Kleppe M, Garrett-Bakelman FE
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Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group's clinical trial E3999

BLOOD CANCER JOURNAL 2022 SEP 23; 12(9):? Article 137
Du J, Vandavasi VG, Molloy KR, Yang H, Massenburg LN, Singh A, Kwansa AL, Yingling YG, O'Neill H, Chait BT, Kumar M, Nixon BT
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Evidence for Plant-Conserved Region Mediated Trimeric CESAs in Plant Cellulose Synthase Complexes br

BIOMACROMOLECULES 2022 SEP 12; 23(9):3663-3677
Higher plants synthesize cellulose using membrane bound, six-lobed cellulose synthase complexes, each lobe containing trimeric cellulose synthases (CESAs). Although molecular biology reports support heteromeric trimers composed of different isoforms, a homomeric trimer was reported for in vitro studies of the catalytic domain of CESA1 of Arabidopsis (AtCESA1CatD) and confirmed in cryoEM structures of fulllength CESA8 and CESA7 of poplar and cotton, respectively. In both structures, a small portion of the plant-conserved region (PCR) forms the only contacts between catalytic domains of the monomers. We report inter-subunit lysine-crosslinks that localize to the small P-CR, negative-stain EM structure, and modeling data for homotrimers of AtCESA1CatD. Molecular dynamics simulations for AtCESA1CatD trimers based on the CESA8 cryoEM structure were stable and dependent upon a small set of residue contacts. The results suggest that homomeric CESA trimers may be important for the synthesis of primary and secondary cell walls and identify key residues for future mutagenic studies.
Poulton NC, Azadian ZA, DeJesus MA, Rock JM
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Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis

Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB. One promising drug target in Mtb is the arabinogalactan biosynthetic enzyme DprE1, and there have been over a dozen unique chemical scaffolds identified which inhibit the activity of this protein. Among the most promising lead compounds are the benzothiazinones BTZ043 and PBTZ169, both of which are currently in or have completed phase IIa clinical trials. Due to the potential clinical utility of these drugs, we sought to identify potential synergistic interactions and new mechanisms of resistance using a genome-scale CRISPRi chemical-genetic screen with PBTZ169. We found that knockdown of rv0678, the negative regulator of the mmpS5/L5 drug efflux pump, confers resistance to PBTZ169. Mutations in rv0678 are the most common form of resistance to bedaquiline and there is already abundant evidence of these mutations emerging in bedaquiline-treated patients. We confirmed that rv0678 mutations from clinical isolates confer low level cross-resistance to BTZ043 and PBTZ169. While it is yet unclear whether rv0678 mutations would render benzothiazinones ineffective in treating TB, these results highlight the importance of monitoring for clinically prevalent rv0678 mutations during ongoing BTZ043 and PBTZ169 clinical trials.