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Found 35417 matches. Displaying 81-90
Many bacteria can cause pyogenic lesions in humans. Most of these bacteria are harmless in most individuals, but they, nevertheless, cause significant morbidity and mortality worldwide. The inherited and acquired immunodeficiencies underlying these pyogenic infections differ between bacteria. This short review focuses on two emblematic pyogenic bacteria: pneumococcus (Streptococcus pneumoniae) and Staphylococcus, both of which are Gram-positive encapsulated bacteria. We will discuss the contribution of human genetic studies to the identification of germline mutations of the TLR and IL-1R pathways.
Wagner M, Levy J, Jung-Klawitter S, Bakhtiari S, Monteiro F, Maroofian R, Bierhals T, Hempel M, Elmaleh-Berges M, Kitajima JP, Kim CA, Salomao JG, Amor DJ, Cooper MS, Perrin L, Pipiras E, Neu A, Doosti M, Karimiani EG, Toosi MB, Houlden H, Jin SC, Si YC, Rodan LH, Venselaar H, Kruer MC, Kok F, Hoffmann GF, Strom TM, Wortmann SB, Tabet AC, Opladen T
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Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

GENETICS IN MEDICINE 2020 JUN; 22(6):1061-1068
Purpose TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
Multicellular eukaryotes emerged late in evolution from an ocean of viruses, bacteria, archaea, and unicellular eukaryotes. These macroorganisms are exposed to and infected by a tremendous diversity of microorganisms. Those that are large enough can even be infected by multicellular fungi and parasites. Each interaction is unique, if only because it operates between two unique living organisms, in an infinite diversity of circumstances. This is neatly illustrated by the extraordinarily high level of interindividual clinical variability in human infections, even for a given pathogen, ranging from a total absence of clinical manifestations to death. We discuss here the idea that the determinism of human life-threatening infectious diseases can be governed by single-gene inborn errors of immunity, which are rarely Mendelian and frequently display incomplete penetrance. We briefly review the evidence in support of this notion obtained over the last two decades, referring to a number of focused and thorough reviews published by eminent colleagues in this issue of Human Genetics. It seems that almost any life-threatening infectious disease can be driven by at least one, and, perhaps, a great many diverse monogenic inborn errors, which may nonetheless be immunologically related. While the proportions of monogenic cases remain unknown, a picture in which genetic heterogeneity is combined with physiological homogeneity is emerging from these studies. A preliminary sketch of the human genetic architecture of severe infectious diseases is perhaps in sight.
Algazi AP, Twitty CG, Tsai KK, Le M, Pierce R, Browning E, Hermiz R, Canton DA, Bannavong D, Oglesby A, Francisco M, Fong L, Pittet MJ, Arlauckas SP, Garris C, Levine LP, Bifulco C, Ballesteros-Merino C, Bhatia S, Gargosky S, Andtbacka RHI, Fox BA, Rosenblum MD, Daud AI
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Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma

CLINICAL CANCER RESEARCH 2020 JUN; 26(12):2827-2837
Purpose: Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL). Patients and Methods: Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progressionfree survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done. Results: The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFN gamma feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses. Conclusions: The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.
Scopino K, Williams E, Elsayed A, Barr WA, Krizanc D, Thayer KM, Weir MP
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A Ribosome Interaction Surface Sensitive to mRNA GCN Periodicity

BIOMOLECULES 2020 JUN; 10(6):? Article 849
A longstanding challenge is to understand how ribosomes parse mRNA open reading frames (ORFs). Significantly, GCN codons are over-represented in the initial codons of ORFs of prokaryote and eukaryote mRNAs. We describe a ribosome rRNA-protein surface that interacts with an mRNA GCN codon when next in line for the ribosome A-site. The interaction surface is comprised of the edges of two stacked rRNA bases: the Watson-Crick edge of 16S/18S rRNA C1054 and the adjacent Hoogsteen edge of A1196 (Escherichia coli 16S rRNA numbering). Also part of the interaction surface, the planar guanidinium group of a conserved Arginine (R146 of yeast ribosomal protein Rps3) is stacked adjacent to A1196. On its other side, the interaction surface is anchored to the ribosome A-site through base stacking of C1054 with the wobble anticodon base of the A-site tRNA. Using molecular dynamics simulations of a 495-residue subsystem of translocating ribosomes, we observed base pairing of C1054 to nucleotide G at position 1 of the next-in-line codon, consistent with previous cryo-EM observations, and hydrogen bonding of A1196 and R146 to C at position 2. Hydrogen bonding to both of these codon positions is significantly weakened when C at position 2 is changed to G, A or U. These sequence-sensitive mRNA-ribosome interactions at the C1054-A1196-R146 (CAR) surface potentially contribute to the GCN-mediated regulation of protein translation.
Netea MG, Dominguez-Andres J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, Joosten LAB, van der Meer JWM, Mhlanga MM, Mulder WJM, Riksen NP, Schlitzer A, Schultze JL, Benn CS, Sun JSC, Xavier RJ, Latz E
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Defining trained immunity and its role in health and disease

Here a group of leaders in the field define our current understanding of 'trained immunity', which refers to the memory-type responses that occur in the innate immune system. The authors discuss our current understanding of the key epigenetic and metabolic processes involved in trained immunity and consider its relevance in immune-mediated diseases and cancer. Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
Shukla N, Paul M, Halley M, Lowes MA, Hester V, Aguilar C, Guilbault S, Long TS, Taylor A, Thompson AC, Yannuzzi CA, Linos E, Naik HB
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Identifying barriers to care and research in hidradenitis suppurativa: findings from a patient engagement event

Sagi Y, Medrihan L, George K, Barney M, McCabe KA, Greengard P
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Emergence of 5-HT5A signaling in parvalbumin neurons mediates delayed antidepressant action

MOLECULAR PSYCHIATRY 2020 JUN; 25(6):1191-1201
The behavioral response to antidepressants is closely associated with physiological changes in the function of neurons in the hippocampal dentate gyrus (DG). Parvalbumin interneurons are a major class of GABAergic neurons, essential for DG function, and are involved in the pathophysiology of several neuropsychiatric disorders. However, little is known about the role(s) of these neurons in major depressive disorder or in mediating the delayed behavioral response to antidepressants. Here we show, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1 beta channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants.
Kuroda M, Halfmann PJ, Hill-Batorski L, Ozawa M, Lopes TJS, Neumann G, Schoggins JW, Rice CM, Kawaoka Y
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Identification of interferon-stimulated genes that attenuate Ebola virus infection

The West Africa Ebola outbreak was the largest outbreak ever recorded, with over 28,000 reported infections; this devastating epidemic emphasized the need to understand the mechanisms to counteract virus infection. Here, we screen a library of nearly 400 interferon-stimulated genes (ISGs) against a biologically contained Ebola virus and identify several ISGs not previously known to affect Ebola virus infection. Overexpression of the top ten ISGs attenuates virus titers by up to 1000-fold. Mechanistic studies demonstrate that three ISGs interfere with virus entry, six affect viral transcription/replication, and two inhibit virion formation and budding. A comprehensive study of one ISG (CCDC92) that shows anti-Ebola activity in our screen reveals that CCDC92 can inhibit viral transcription and the formation of complete virions via an interaction with the viral protein NP. Our findings provide insights into Ebola virus infection that could be exploited for the development of therapeutics against this virus. Here, Kuroda et al. screen a library of nearly 400 interferon-stimulated genes (ISGs) and identify several ISGs that inhibit Ebola virus entry, viral transcription/replication, or virion formation. The study provides insights into interactions between Ebola and the host cells.
Abt I, Adamczyk L, Aggarwal R, Aushev V, Behnke O, Behrens U, Bertolin A, Bloch I, Brock I, Brook NH, Brugnera R, Bruni A, Bussey PJ, Caldwell A, Capua M, Catterall CD, Chwastowski J, Ciborowski J, Ciesielski R, Cooper-Sarkar AM, Corradi M, Dementiev RK, Dusini S, Ferrando J, Foster B, Gallo E, Gangadharan D, Garfagnini A, Geiser A, Gladilin LK, Golubkov YA, Grzelak G, Gwenlan C, Hochman D, Jomhari NZ, Kadenko I, Kananov S, Karshon U, Kaur P, Klanner R, Klein U, Korzhavina IA, Kovalchuk N, Kowalski H, Kuprash O, Kuze M, Levchenko BB, Levy A, Lohr B, Longhin A, Lukina OY, Makarenko I, Malka J, Masciocchi S, Nagano K, Nam JD, Onderwaater J, Onishchuk Y, Paul E, Pidhurskyi I, Polini A, Przybycien M, Quintero A, Ruspa M, Saxon DH, Schneekloth U, Schorner-Sadenius T, Selyuzhenkov I, Shchedrolosiev M, Shcheglova LM, Skillicorn IO, Slominski W, Solano A, Stanco L, Stefaniuk N, Stopa P, Surrow B, Sztuk-Dambietz J, Tassi E, Tokushuku K, Turcato M, Turkot O, Tymieniecka T, Verbytskyi A, Abdullah WATW, Wichmann K, Wing M, Yamada S, Yamazaki Y, Zarnecki AF, Zawiejski L, Zenaiev O
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Study of proton parton distribution functions at high x using ZEUS data

PHYSICAL REVIEW D 2020 JUN 26; 101(11):? Article 112009
At large values of x, the parton distribution functions (PDFs) of the proton are poorly constrained and there are considerable variations between different global fits. Data at such high x have already been published by the ZEUS Collaboration, but not yet used in PDF extractions. A technique for comparing predictions based on different PDF sets to the observed number of events in the ZEUS data is presented. It is applied to compare predictions from the most commonly used PDFs to published ZEUS data at high Bjorken x. A wide variation is found in the ability of the PDFs to predict the observed results. A scheme for including the ZEUS high-x data in future PDF extractions is discussed.