Skip to main content

Publications search

Found 37387 matches. Displaying 161-170
Deep D, Gudjonson H, Brown CC, Rose SA, Sharma R, Iza YAP, Hong SH, Hemmers S...
Show All Authors

Precursor central memory versus effector cell fate and naive CD4+ ...

JOURNAL OF EXPERIMENTAL MEDICINE 2024 SEP 25; 221(10):? Article e20231193
Upon antigenic stimulation, naive CD4(+) T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4(+) T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naive CD4(+) T cells. Unexpectedly, our studies revealed heterogeneity among naive CD4(+) T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naive CD4(+) T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naive CD4(+) T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naive T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.
Candeias C, Almeida ST, Paulo AC, Simoes AS, Ferreira B, Cruz AR, Queirós M, ...
Show All Authors

Streptococcus pneumoniae carriage, serotypes, genotypes, and antimicrobial re...

VACCINE 2024 SEP 17; 42(22):? Article 126219
Streptococcus pneumoniae carriage studies are crucial to monitor changes induced by use of pneumococcal conjugate vaccines and inform vaccination policies. In this cross-sectional study, we examined changes within the pneumococcal population following introduction of PCV13 in 2015 in the National Immunization Program (NIP), in Portugal. In 2018-2020 (NIP-PCV13), we obtained 1450 nasopharyngeal samples from children <= 6 years attending day-care. We assessed serotypes, antimicrobial resistance, and genotypes (MLST and GPSC) and compared findings with earlier periods: 2009-2010 (pre-PCV13), 2011-2012 (early-PCV13), and 2015-2016 (late-PCV13). Pneumococcal carriage prevalence remained stable at 60.2 %. Carriage of PCV13 serotypes was 10.7 %, markedly reduced compared to pre-PCV13 period (47.6 %). The most prevalent PCV13 serotypes were 19F, 3, and 19A all showing a significant decreasing trend compared to the pre-PCV13 period (from 7.1 % to 4.7 %, 10.1 % to 1.8 %, and 14.1 % to 1.8 %, respectively), a notable observation given the described limited effectiveness of PCV13 against serotype 3. Non-vaccinated children and children aged 4-6 years were more likely to carry PCV13 serotypes (2.5-fold, 95 %CI [1.1-5.6], and 2.9-fold, 95 %CI [1.3-6.8], respectively). The most prevalent non-PCV13 serotypes were 15B/C, 11A, 23B, 23A, and NT, collectively accounting for 51.9 % of all isolates. In total, 30.5 % of all pneumococci were potentially covered by PCV20. Resistance to penicillin (lowlevel) and macrolides increased significantly, from 9.3 % and 13.4 %, respectively, in the late-PCV13 period, to approximately 20 % each, mostly due to lineages expressing non-PCV13 serotypes, nearing pre-PCV13 levels. An expansion of lineages traditionally associated with PCV13 serotypes, like CC156-GPSC6 (serotype 14) and CC193-GPSC11 (serotype 19F), but now predominantly expressing non-PCV13 serotypes (11A, 15B/C, and 24F for GPSC6; and 15A and 21 for GPSC11) was noted. These findings indicate that the pneumococcal population is adapting to the pressures conferred by PCV13 and antimicrobial use and indicate the need to maintain close surveillance.
Ng H, Begum M, Chua GNL, Liu SX
Show All Authors

In Situ Nucleosome Assembly for Single-Molecule Correlative Force and ...

JOVE-JOURNAL OF VISUALIZED EXPERIMENTS 2024 SEP; ?(211):? Article e66579
Nucleosomes constitute the primary unit of eukaryotic chromatin and have been the focus of numerous informative single-molecule investigations regarding their biophysical properties and interactions with chromatin-binding proteins. Nucleosome reconstitution on DNA for these studies typically involves a salt dialysis procedure that provides precise control over the placement and number of nucleosomes formed along a DNA tether. However, this protocol is time-consuming and requires a substantial amount of DNA and histone octamers as inputs. To offer an alternative strategy, an in situ nucleosome reconstitution method for single-molecule force and fluorescence microscopy that utilizes the histone chaperone Nap1 is described. This method enables users to assemble nucleosomes on any DNA template without the need for strong nucleosome positioning sequences, adjust nucleosome density on demand, and use fewer reagents. In situ nucleosome formation occurs within seconds, offering a simpler experimental workflow and a convenient transition into single-molecule measurements. Examples of two downstream assays for probing nucleosome mechanics and visualizing the behavior of individual proteins on chromatin are further described.
Rodrigues FS, Karoutas A, Ruhland S, Rabas N, Rizou T, Di Blasio S, Ferreira ...
Show All Authors

Bidirectional activation of stem-like programs between metastatic cancer and ...

DEVELOPMENTAL CELL 2024 SEP 23; 59(18):?
A key step for metastatic outgrowth involves the generation of a deeply altered microenvironment (niche) that supports the malignant behavior of cancer cells. The complexity of the metastatic niche has posed a significant challenge in elucidating the underlying programs driving its origin. Here, by focusing on early stages of breast cancer metastasis to the lung in mice, we describe a cancer-dependent chromatin remodeling and activation of developmental programs in alveolar type 2 (AT2) cells within the niche. We show that metastatic cells can prime AT2 cells into a reprogrammed multilineage state. In turn, this cancer-induced reprogramming of AT2 cells promoted stem-like features in cancer cells and enhanced their initiation capacity. In conclusion, we propose the concept of "reflected stemness" as an early phenomenon during metastatic niche initiation, wherein metastatic cells reprogram the local tissue into a stem-like state that enhances intrinsic cancer-initiating potential, creating a positive feedback loop where tumorigenic programs are amplified.
Braunscheidel KM, Voren G, Fowler CD, Lu Q, Kuryatov A, Cameron MD, Ibañez-Ta...
Show All Authors

SR9883 is a novel small-molecule enhancer of α4β2*nicotinic acetylcholine rec...

FRONTIERS IN MOLECULAR NEUROSCIENCE 2024 SEP 5; 17(?):? Article 1459098
Background Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents.Methods 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) was used as a starting point for medical chemistry efforts to develop novel small molecule enhancers of alpha 4 beta 2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of alpha 4/alpha 4 and alpha 4/alpha 5 subunits.Results The NS9283 derivative SR9883 enhanced the effect of nicotine on alpha 4 beta 2* nAChR stoichiometries containing low-affinity agonist binding sites, with EC50 values from 0.2-0.4 mu M. SR9883 had no effect on alpha 3 beta 2* or alpha 3 beta 4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg-1) and oral (10-20 mg kg-1) administration and penetrated into the brain. When administered alone, SR9883 (5-10 mg kg-1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg-1) decreased responding for intravenous nicotine infusions (0.03 mg kg-1 per infusion) but had no effect on responding for food rewards in rats.Conclusions These data suggest that SR9883 is useful for investigating behavioral processes regulated by certain alpha 4 beta 2* nAChR stoichiometries. SR9883 and related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.
Le Pen J, Paniccia G, Kinast V, Moncada-Velez M, Ashbrook AW, Bauer M, Hoffma...
Show All Authors

A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier...

PLOS BIOLOGY 2024 SEP; 22(9):? Article e3002767
Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently. Interferons (IFNs) have a role in the regulation of virus-host interactions. This study uses genome-wide CRISPR knockout screen data to identify 28 genes that impact SARS-CoV-2 infection, including PLSCR1, which restricts spike-mediated SARS-CoV-2 entry independently of its IFN-related role.
El Kettani A, Ouair H, Marnissi F, El Bakkouri J, Chevalier R, Lorenzo L, Kho...
Show All Authors

Case Report of Two Independent Moroccan Families with Syndromic Epidermodyspl...

VIRUSES-BASEL 2024 SEP; 16(9):? Article 1415
Epidermodysplasia verruciformis (EV) is a rare genodermatosis caused by beta-human papillomaviruses (HPV) in immunodeficient patients. EV is characterized by flat warts and pityriasis-like lesions and might be isolated or syndromic, associated with some other infectious manifestations. We report here three patients from two independent families, with syndromic EV for both of them. By whole exome sequencing, we found that the patients carry new homozygous variants in STK4, both leading to a premature stop codon. STK4 deficiency causes a combined immunodeficiency characterized by a broad infectious susceptibility to bacteria, viruses, and fungi. Auto-immune manifestations were also reported. Deep immunophenotyping revealed multiple cytopenia in the three affected patients, in particular deep CD4(+) T cells deficiency. We report here the fourth and the fifth cases of the syndromic EV due to STK4 deficiency.
Short B
Show All Authors

Grammotoxin increases its toxic behavior

JOURNAL OF GENERAL PHYSIOLOGY 2024 SEP 25; 156(10):? Article e202413665
This JGP study reveals that in addition to voltage-gated Ca2+ and K+ channels, omega-grammotoxin-SIA also inhibits voltage-gated Na+ channel currents.
Hayrapetyan A, Tumasyan A, Adam W, Andrejkovic JW, Arnold B, Bergauer H, Berg...
Show All Authors

Performance of the CMS electromagnetic calorimeter in pp collisions at √s<...

JOURNAL OF INSTRUMENTATION 2024 SEP; 19(9):? Article P09004
The operation and performance of the Compact Muon Solenoid (CMS) electromagnetic calorimeter (ECAL) are presented, based on data collected in pp collisions at root s = 13 TeV at the CERN LHC, in the years from 2015 to 2018 (LHC Run 2), corresponding to an integrated luminosity of 151 fb(-1). The CMS ECAL is a scintillating lead-tungstate crystal calorimeter, with a silicon strip preshower detector in the forward region that provides precise measurements of the energy and the time-of-arrival of electrons and photons. The successful operation of the ECAL is crucial for a broad range of physics goals, ranging from observing the Higgs boson and measuring its properties, to other standard model measurements and searches for new phenomena. Precise calibration, alignment, and monitoring of the ECAL response are important ingredients to achieve these goals. To face the challenges posed by the higher luminosity, which characterized the operation of the LHC in Run 2, the procedures established during the 2011-2012 run of the LHC have been revisited and new methods have been developed for the energy measurement and for the ECAL calibration. The energy resolution of the calorimeter, for electrons from Z boson decays reaching the ECAL without significant loss of energy by bremsstrahlung, was better than 1.8%, 3.0%, and 4.5% in the vertical bar eta vertical bar intervals [ 0.0, 0.8], [0.8, 1.5], [1.5, 2.5], respectively. This resulting performance is similar to that achieved during Run 1 in 2011-2012, in spite of the more severe running conditions.
Karaaslan BG, Rosain J, Bustamante J, Kiykim A
Show All Authors

Interferon Gamma in Sickness Predisposing to Mycobacterial Infectious ...

BALKAN MEDICAL JOURNAL 2024 SEP; 41(5):326-332
In recent decades, the prevalence of inborn errors of immunity has increased, necessitating the development of more effective treatment and care options for these highly morbid conditions. Due to these "experiments of nature," the complicated nature of the immune system is being revealed. Based on the functional and molecular tests, targeted therapies are now being developed which offer a more effective approach and reduce damage. This study aimed to investigate a key cytokine of the cellular immune response, interferon-gamma (IFN-gamma), gamma ), which is linked to Mendelian susceptibility to Mycobacterial disease, and its potential as a therapeutic option for IFN-gamma gamma deficiency.