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Found 36319 matches. Displaying 41-50
Halford B
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Proteomics path paver is using organic chemistry to glean information on immune system proteins

CHEMICAL & ENGINEERING NEWS 2021 AUG 16; 99(30):48-49
Rowan DJ, Yasir S, Chen ZME, Mounajjed T, Damgard SE, Cummins L, Zhang LZ, Whitcomb E, Falck V, Simon SM, Singhi AD, Torbenson MS
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Morphologic and Molecular Findings in Myxoid Hepatic Adenomas

Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59 +/- 12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS-mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS, CDKN1B (encodes p27), and RNF123. In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.
Muecksch F, Weisblum Y, Barnes CO, Schmidt F, Schaefer-Babajew D, Wang ZJ, Lorenzi JCC, Flyak AI, DeLaitsch AT, Huey-Tubman KE, Hou SR, Schiffer CA, Gaebler C, Da Silva J, Poston D, Finkin S, Cho A, Cipolla M, Oliveira TY, Millard KG, Ramos V, Gazumyan A, Rutkowska M, Caskey M, Nussenzweig MC, Bjorkman PJ, Hatziioannou T, Bieniasz PD
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Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations

IMMUNITY 2021 AUG 10; 54(8):1853-1868.e7
Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
Bor WL, Zheng KL, Tavenier AH, Gibson CM, Granger CB, Bentur O, Lobatto R, Postma S, Coller BS, van 't Hof AWJ, Ten Berg JM
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Pharmacokinetics, pharmacodynamics, and tolerability of subcutaneous administration of a novel glycoprotein IIb/IIIa inhibitor, RUC-4, in patients with ST-segment elevation myocardial infarction

EUROINTERVENTION 2021 AUG; 17(5):E401-410
Background: Pre-hospital platelet inhibition in patients with ST-segment elevation myocardial infarction (STEMI) may improve outcomes. RUC-4 is a novel, second-generation glycoprotein IIb/IIIa inhibitor designed for first-point-of-medical-contact treatment for STEMI by subcutaneous injection. Aims: The open-label, phase 2A, CEL-02 trial aimed to assess the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of RUC-4 in STEMI patients undergoing primary PCI (pPCI). Methods: A total of 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before pPCI in escalating doses (0.075 mg/kg [n = 8], 0.090 mg/kg [n = 9], or 0.110 mg/kg [n = 10]). Results: The primary PD endpoint of high-grade (>= 77%) inhibition of the VerifyNow iso-TRAP assay at 15 minutes was met in 3/8, 7/8, and 7/8 patients in the three cohorts with a dose-response relationship (mean inhibition [min -max] of 77.5% [65.7%-90.6%], 87.5% [73.8%-93.1%], and 91.7% [76.4%-99.3%], respectively; ptrend = 0.002). Fifty percent (50%) inhibition remained after 89.1 (38.0-129.7), 104.2 (17.6-190.8), and 112.4 (19.7-205.0) minutes. Injection site reactions or bruising were observed in 1 (4%) and 11 (41%) patients, respectively. Mild access-site haematomas occurred in 6 (22%), and severe access-site haematomas occurred in 2 patients (7%). No thrombocytopaenia was observed within 72 hours post dose. Conclusions: In patients with STEMI, a single subcutaneous dose of RUC-4 at 0.075, 0.090, and 0.110 mg/kg showed dose-response high-grade inhibition of platelet function within 15 minutes.
Dubin C, Del Duca E, Guttman-Yassky E
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The IL-4, IL-13 and IL-31 pathways in atopic dermatitis

Introduction: Atopic dermatitis (AD) is the most common inflammatory skin disease. It has a complex pathophysiology, with a combination of immune dysregulation and intrinsic barrier defects driving cutaneous inflammation and allergic symptomatology. The IL-4, IL-13 and IL-31 inflammatory pathways have been identified as hallmark features in the pathogenesis of the disease, contributing uniquely and synergistically to immune and barrier abnormalities as well as the key symptoms, such as pruritis. Novel therapeutics that target these pathways have been under development to find treatments for AD. Areas covered: This review discusses the IL-4, IL-13 and IL-31 pathways in AD. We will also detail novel targeted therapeutics that have recently been or are currently in clinical trials for AD. A literature search was conducted by querying Scopus, Google Scholar, PubMed, and up to January 2021 using combinations of the search terms 'IL-4' 'IL-13' 'IL-31' 'atopic dermatitis' 'immune pathway' 'biologics' 'novel therapeutics' 'JAK/STAT inhibitors.' Expert opinion: The complex pathophysiology of AD advocates for innovation. Novel minimally invasive sampling modalities such as tape stripping will allow for a broader characterization of the immunomechanisms behind AD pathophysiology. This will allow for the continued development of a personalized medicine approach to treat AD.
Kanzaki N, Yamashita T, Lee JS, Shih PY, Ragsdale EJ, Shinya R
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Tokorhabditis n. gen. (Rhabditida, Rhabditidae), a comparative nematode model for extremophilic living

SCIENTIFIC REPORTS 2021 AUG 13; 11(1):? Article 16470
Life in extreme environments is typically studied as a physiological problem, although the existence of extremophilic animals suggests that developmental and behavioral traits might also be adaptive in such environments. Here, we describe a new species of nematode, Tokorhabditistufae, n. gen., n. sp., which was discovered from the alkaline, hypersaline, and arsenic-rich locale of Mono Lake, California. The new species, which offers a tractable model for studying animal-specific adaptations to extremophilic life, shows a combination of unusual reproductive and developmental traits. Like the recently described sister group Auanema, the species has a trioecious mating system comprising males, females, and self-fertilizing hermaphrodites. Our description of the new genus thus reveals that the origin of this uncommon reproductive mode is even more ancient than previously assumed, and it presents a new comparator for the study of mating-system transitions. However, unlike Auanema and almost all other known rhabditid nematodes, the new species is obligately live-bearing, with embryos that grow in utero, suggesting maternal provisioning during development. Finally, our isolation of two additional, molecularly distinct strains of the new genus-specifically from non-extreme locales-establishes a comparative system for the study of extremophilic traits in this model.
Alexander RG, Mintz RJ, Custodio PJ, Macknik SL, Vaziri A, Venkatakrishnan A, Gindina S, Martinez-Conde S
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Gaze mechanisms enabling the detection of faint stars in the night sky

EUROPEAN JOURNAL OF NEUROSCIENCE 2021 AUG; 54(4):5357-5367 Article 15335
For millennia, people have used "averted vision" to improve their detection of faint celestial objects, a technique first documented around 325 BCE. Yet, no studies have assessed gaze location during averted vision to determine what pattern best facilitates perception. Here, we characterized averted vision while recording eye-positions of dark-adapted human participants, for the first time. We simulated stars of apparent magnitudes 3.3 and 3.5, matching their brightness to Megrez (the dimmest star in the Big Dipper) and Tau Ceti. Participants indicated whether each star was visible from a series of fixation locations, providing a comprehensive map of detection performance in all directions. Contrary to prior predictions, maximum detection was first achieved at similar to 8 degrees from the star, much closer to the fovea than expected from rod-cone distributions alone. These findings challenge the assumption of optimal detection at the rod density peak and provide the first systematic assessment of an age-old facet of human vision.
Okazaki A, Horpaopan S, Zhang QR, Randesi M, Ott J
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Genotype Pattern Mining for Pairs of Interacting Variants Underlying Digenic Traits

GENES 2021 AUG; 12(8):? Article 1160
Some genetic diseases ("digenic traits") are due to the interaction between two DNA variants, which presumably reflects biochemical interactions. For example, certain forms of Retinitis Pigmentosa, a type of blindness, occur in the presence of two mutant variants, one each in the ROM1 and RDS genes, while the occurrence of only one such variant results in a normal phenotype. Detecting variant pairs underlying digenic traits by standard genetic methods is difficult and is downright impossible when individual variants alone have minimal effects. Frequent pattern mining (FPM) methods are known to detect patterns of items. We make use of FPM approaches to find pairs of genotypes (from different variants) that can discriminate between cases and controls. Our method is based on genotype patterns of length two, and permutation testing allows assigning p-values to genotype patterns, where the null hypothesis refers to equal pattern frequencies in cases and controls. We compare different interaction search approaches and their properties on the basis of published datasets. Our implementation of FPM to case-control studies is freely available.
Bosch B, De Jesus MA, Poulton NC, Zhang WZ, Engelhart CA, Zaveri A, Lavalette S, Ruecker N, Trujillo C, Wallach JB, Li SQ, Ehrt S, Chait BT, Schnappinger D, Rock JM
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Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis

CELL 2021 AUG 19; 184(17):4579-4592.e24 Article e24
Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability'' is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomicsmethod to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes. We identified highly vulnerable genes in various processes, including novel targets unexplored for drug discovery. Equally important, we identified invulnerable essential genes, potentially explaining failed drug discovery efforts. Comparison of vulnerability between the reference and a hypervirulent Mtb isolate revealed incomplete conservation of vulnerability and that differential vulnerability can predict differential antibacterial susceptibility. Our results quantitatively redefine essential bacterial processes and identify high-value targets for drug development.
Eberhardt KA, Sarfo FS, Klupp EM, Dompreh A, Di Cristanziano V, Kuffour EO, Boateng R, Norman B, Phillips RO, Aepfelbacher M, Feldt T
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Intestinal Colonization with Tropheryma whipplei-Clinical and Immunological Implications for HIV Positive Adults in Ghana

MICROORGANISMS 2021 AUG; 9(8):? Article 1781
Background: Recent studies demonstrated higher prevalence rates of Tropheryma whipplei (T. whipplei) in HIV positive than in HIV negative subjects. However, associations with the immune status in HIV positive participants were conflicting. Methods: For this cross-sectional study, stool samples of 906 HIV positive and 98 HIV negative individuals in Ghana were tested for T. whipplei. Additionally, sociodemographic parameters, clinical symptoms, medical drug intake, and laboratory parameters were assessed. Results: The prevalence of T. whipplei was 5.85% in HIV positive and 2.04% in HIV negative participants. Within the group of HIV positive participants, the prevalence reached 7.18% in patients without co-trimoxazole prophylaxis, 10.26% in subjects with ART intake, and 12.31% in obese participants. Frequencies of clinical symptoms were not found to be higher in HIV positive T. whipplei carriers compared to T. whipplei negative participants. Markers of immune activation were lower in patients colonized with T. whipplei. Multivariate regression models demonstrated an independent relationship of a high CD4+ T cell count, a low HIV-1 viral load, and an obese body weight with the presence of T. whipplei. Conclusions: Among HIV positive individuals, T. whipplei colonization was associated with a better immune status but not with clinical consequences. Our data suggest that the withdrawal of co-trimoxazole chemoprophylaxis among people living with HIV on stable cART regimen may inadvertently increase the propensity towards colonization with T. whipplei.