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Article ; Online: Inferring the T cell repertoire dynamics of healthy individuals.

Bensouda Koraichi, Meriem / Ferri, Silvia / Walczak, Aleksandra M / Mora, Thierry

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 4, Page(s) e2207516120

Abstract: ... Here, we learn the parameters that underlie the clonal dynamics of the T cell repertoire in healthy ...

Abstract	The adaptive immune system is a diverse ecosystem that responds to pathogens by selecting cells with specific receptors. While clonal expansion in response to particular immune challenges has been extensively studied, we do not know the neutral dynamics that drive the immune system in the absence of strong stimuli. Here, we learn the parameters that underlie the clonal dynamics of the T cell repertoire in healthy individuals of different ages, by applying Bayesian inference to longitudinal immune repertoire sequencing (RepSeq) data. Quantifying the experimental noise accurately for a given RepSeq technique allows us to disentangle real changes in clonal frequencies from noise. We find that the data are consistent with clone sizes following a geometric Brownian motion and show that its predicted steady state is in quantitative agreement with the observed power-law behavior of the clone-size distribution. The inferred turnover time scale of the repertoire increases with patient age and depends on the clone size in some individuals.
MeSH term(s)	Humans ; T-Lymphocytes ; Ecosystem ; Bayes Theorem ; Clone Cells ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2207516120
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Article ; Online: Application of optical coherence tomography in decision-making of post-thrombectomy adjunctive treatments.

Li, Di / Tang, Tao / Hu, Teng / Walczak, Piotr / Gandhi, Dheeraj / Li, Shen

Journal of neurointerventional surgery

2022 Volume 15, Issue 6, Page(s) 616–618

Abstract: An adult patient with acute basilar artery occlusion underwent mechanical thrombectomy. After complete reperfusion, a 70% residual stenosis of the proximal basilar artery was observed. Intravascular optical coherence tomography (OCT) identified lipid ... ...

Abstract	An adult patient with acute basilar artery occlusion underwent mechanical thrombectomy. After complete reperfusion, a 70% residual stenosis of the proximal basilar artery was observed. Intravascular optical coherence tomography (OCT) identified lipid plaques with an intact fibrous cap and thrombus in the culprit lesion, indicating plaque erosion was the mechanism of in situ thrombosis. Adjunctive antiplatelet therapy rather than rescue interventions was pursued for its beneficial effects in acute coronary syndrome caused by plaque erosion. The patient had a 90-day modified Rankin Scale score of 0. OCT enables precise evaluation of vessel characteristics following thrombectomy, so may improve outcomes through subsequent tailored treatments.
MeSH term(s)	Adult ; Humans ; Tomography, Optical Coherence/methods ; Plaque, Atherosclerotic/complications ; Acute Coronary Syndrome/etiology ; Acute Coronary Syndrome/pathology ; Thrombectomy/adverse effects ; Thrombosis/pathology ; Coronary Vessels ; Coronary Angiography
Language	English
Publishing date	2022-07-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2514982-9
ISSN	1759-8486 ; 1759-8478
ISSN (online)	1759-8486
ISSN	1759-8478
DOI	10.1136/jnis-2022-019195
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Article: Drug-drug interaction database for safe prescribing of systemic antifungal agents.

Niazi-Ali, Saarah / Atherton, Graham T / Walczak, Marcin / Denning, David W

Therapeutic advances in infectious disease

2021 Volume 8, Page(s) 20499361211010605

Abstract: Introduction: A drug-drug interaction (DDI) describes the influence of one drug upon another or the change in a drug's effect on the body when the drug is taken together with a second drug. A DDI can delay, decrease or enhance absorption or metabolism ... ...

Abstract	Introduction: A drug-drug interaction (DDI) describes the influence of one drug upon another or the change in a drug's effect on the body when the drug is taken together with a second drug. A DDI can delay, decrease or enhance absorption or metabolism of either drug. Several antifungal agents have a large number of potentially deleterious DDIs. Methods: The antifungal drug interactions database https://antifungalinteractions.org/was first launched in 2012 and is updated regularly. It is available as web and app versions to allow information on potential drug interactions with antifungals with a version for patients and another for health professionals. A new and updated database and interface with apps was created in 2019. This allows clinicians and patients to rapidly check for DDIs. The database is fully referenced to allow the user to access further information if needed. Currently DDIs for fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, terbinafine, amphotericin B, caspofungin, micafungin and anidulafungin are cross-referenced against 2398 other licensed drugs, a total of nearly 17,000 potential DDIs. Results: The database records 541 potentially severe DDIs, 1129 moderate and 1015 mild DDIs, a total of 2685 (15.9%). Conclusion: As the online database and apps are free to use, we hope that widespread acceptance and usage will reduce medical misadventure and iatrogenic harm from unconsidered DDIs.
Language	English
Publishing date	2021-04-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2728410-4
ISSN	2049-937X ; 2049-9361
ISSN (online)	2049-937X
ISSN	2049-9361
DOI	10.1177/20499361211010605
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Article ; Online: Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.

Vringer, Esmee / Heilig, Rosalie / Riley, Joel S / Black, Annabel / Cloix, Catherine / Skalka, George / Montes-Gómez, Alfredo E / Aguado, Aurore / Lilla, Sergio / Walczak, Henning / Gyrd-Hansen, Mads / Murphy, Daniel J / Huang, Danny T / Zanivan, Sara / Tait, Stephen Wg

The EMBO journal

2024 Volume 43, Issue 6, Page(s) 904–930

Abstract: Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging ... ...

Abstract	Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.
MeSH term(s)	Humans ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Ubiquitin/metabolism ; Mitochondrial Membranes/metabolism ; Mitochondria/metabolism ; Apoptosis/physiology ; Inflammation/metabolism
Chemical Substances	NF-kappa B ; Ubiquitin
Language	English
Publishing date	2024-02-09
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/s44318-024-00044-1
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Article ; Online: A transfer-learning approach to predict antigen immunogenicity and T-cell receptor specificity.

Bravi, Barbara / Di Gioacchino, Andrea / Fernandez-de-Cossio-Diaz, Jorge / Walczak, Aleksandra M / Mora, Thierry / Cocco, Simona / Monasson, Rémi

eLife

2023 Volume 12

Abstract: Antigen immunogenicity and the specificity of binding of T-cell receptors to antigens are key ... underlie the antigen's probability of triggering a response, and on the other hand the T-cell receptor's ... to existing sequence-based predictors of antigen immunogenicity and T-cell receptor specificity. ...

Abstract	Antigen immunogenicity and the specificity of binding of T-cell receptors to antigens are key properties underlying effective immune responses. Here we propose diffRBM, an approach based on transfer learning and Restricted Boltzmann Machines, to build sequence-based predictive models of these properties. DiffRBM is designed to learn the distinctive patterns in amino-acid composition that, on the one hand, underlie the antigen's probability of triggering a response, and on the other hand the T-cell receptor's ability to bind to a given antigen. We show that the patterns learnt by diffRBM allow us to predict putative contact sites of the antigen-receptor complex. We also discriminate immunogenic and non-immunogenic antigens, antigen-specific and generic receptors, reaching performances that compare favorably to existing sequence-based predictors of antigen immunogenicity and T-cell receptor specificity.
MeSH term(s)	T-Cell Antigen Receptor Specificity ; Learning ; Amino Acids ; Cell Membrane ; Mitochondrial Membranes
Chemical Substances	Amino Acids
Language	English
Publishing date	2023-09-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.85126
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Article ; Online: Quantifying changes in the T cell receptor repertoire during thymic development.

Camaglia, Francesco / Ryvkin, Arie / Greenstein, Erez / Reich-Zeliger, Shlomit / Chain, Benny / Mora, Thierry / Walczak, Aleksandra M / Friedman, Nir

eLife

2023 Volume 12

Abstract: ... the self. During maturation in the thymus, T cells are selected through the binding properties ... of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and ... repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter ...

Abstract	One of the feats of adaptive immunity is its ability to recognize foreign pathogens while sparing the self. During maturation in the thymus, T cells are selected through the binding properties of their antigen-specific T-cell receptor (TCR), through the elimination of both weakly (positive selection) and strongly (negative selection) self-reactive receptors. However, the impact of thymic selection on the TCR repertoire is poorly understood. Here, we use transgenic Nur77-mice expressing a T-cell activation reporter to study the repertoires of thymic T cells at various stages of their development, including cells that do not pass selection. We combine high-throughput repertoire sequencing with statistical inference techniques to characterize the selection of the TCR in these distinct subsets. We find small but significant differences in the TCR repertoire parameters between the maturation stages, which recapitulate known differentiation pathways leading to the CD4
MeSH term(s)	Mice ; Animals ; T-Lymphocytes ; Thymus Gland/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Mice, Transgenic ; Cell Differentiation
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-01-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.81622
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Article: International Survey of Perfusion Practice for Pediatric and Congenital Heart Surgery: 2021 Results.

Walczak, Ashley B / Voss, Jordan M / Dreher, Molly / Matte, Gregory S / Fonseca, Rachel / Gupta, Rajeev / Averina, Tatiana / Xin, Xin Li / Groom, Robert

The journal of extra-corporeal technology

2023 Volume 54, Issue 4, Page(s) 291–317

Abstract: The conduct of cardiopulmonary bypass in neonatal, infant, and pediatric patients continuously evolves as new devices and innovative techniques are introduced. Since 1989, periodic pediatric perfusion surveys have been conducted to ascertain practice ... ...

Abstract	The conduct of cardiopulmonary bypass in neonatal, infant, and pediatric patients continuously evolves as new devices and innovative techniques are introduced. Since 1989, periodic pediatric perfusion surveys have been conducted to ascertain practice patterns involving demographics, equipment, and perfusion techniques. The goal of this current project is to provide an updated perspective on international pediatric and congenital perfusion practice since the last survey conducted in 2016. In July 2021, a 100-question perfusion survey was distributed to 284 pediatric cardiac surgery centers using a secure web browser-based data application. Each center was given a unique survey hyperlink to ensure one response per institution and to monitor the response rate. Centers were given 1 month to complete the survey and electronic reminders were sent weekly to nonrespondents. After the survey was closed, information from completed surveys was exported to a software program for analysis. Responses were received from 153 of 284 pediatric centers for a response rate of 54%. Sixty respondents (39%) were from North American (NA) centers while 93 respondents (61%) were from non-North American (NNA) centers. The vast majority of centers use a roller head arterial pump (93%), hollow fiber oxygenators with open reservoirs (86%), and integrated arterial line filters (73%). The use of modified ultrafiltration was reported by 76% of centers. Ninety-two percent of centers reported the use of selective antegrade cerebral perfusion for aortic arch repairs. The N + 1 staffing model was most prevalent (52%), followed by two perfusionists per case (33%). Periodic surveys continue to be a useful modality in assessing regional variation in pediatric perfusion practice. This survey marked the first time the majority of responses came from non-North American institutions. Identifying these practice patterns may aid in the development of, and adherence to, regional standards and guidelines. This would foster the reduction of variation in practice and potentially improve patient safety.
MeSH term(s)	Infant ; Infant, Newborn ; Child ; Humans ; Perfusion/methods ; Surveys and Questionnaires ; Cardiopulmonary Bypass/methods ; Cardiac Surgical Procedures ; Heart Defects, Congenital/surgery
Language	English
Publishing date	2023-02-05
Publishing country	France
Document type	Journal Article
ZDB-ID	390977-3
ISSN	0022-1058
ISSN	0022-1058
DOI	10.1182/ject-2200012
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Article ; Online: Does the Use of Psychotropic Medication Adversely Affect the Outcomes of Hip Arthroscopy?

Youlo, Sylvester T / Walczak, Brian E / Keene, James S

The American journal of sports medicine

2018 Volume 46, Issue 14, Page(s) 3423–3428

Abstract: Background: Over the past decade, the use of psychotropic medications (PTMs) in the United States has doubled, and currently 20% of adults are taking 1 or more of these antidepressant, antianxiety, antipsychotic, or mood-altering medications. To date, ... ...

Abstract	Background: Over the past decade, the use of psychotropic medications (PTMs) in the United States has doubled, and currently 20% of adults are taking 1 or more of these antidepressant, antianxiety, antipsychotic, or mood-altering medications. To date, however, the incidence of PTM use in patients undergoing hip arthroscopy and the results of hip arthroscopy in these patients have not been reported. Purpose: To determine the prevalence of PTM use in patients undergoing hip arthroscopy and to compare the outcomes of patients taking PTMs versus those of patients not taking PTMs. Study design: Cohort study; Level of evidence, 3. Methods: Medical records of 880 consecutive patients who underwent hip arthroscopy performed by the senior author were reviewed and data were collected, including the number and types of PTMs that these patients were taking at the time of their hip arthroscopy. All hips were assessed with the Byrd modified Harris Hip Score (mHHS) preoperatively; 709 patients (81%) had scores obtained at 12 months and 669 patients (76%) at 24 months after surgery. Demographic data and mHHS of patients taking psychotropic medications (PTM group) were compared with those of patients not taking PTMs (NPTM group). Results: Four hundred twenty-two (48%) of the 880 patients studied were taking PTMs at the time of their hip arthroscopy; significant differences between the PTM and NPTM groups were average age (48 vs 35 years, respectively), and the high percentage of females (53%) and low percentage of males (38%) in the PTM group. Preoperative scores for the PTM and NPTM groups were similar (41 vs 42 points, respectively), but postoperative scores of the PTM group were significantly lower at 6 months (72 vs 89 points), 12 months (77 vs 91 points), and 24 months (79 vs 88 points) after surgery ( P = .01). In contrast, the scores of the subgroups of PTM and NPTM adolescents obtained at 3 months (92.5 vs 88.9 points), 6 months (92.1 vs 90.3 points), 12 months (89.5 vs 92.1 points), and 24 months (90.3 vs 90.1 points) after surgery did not significantly differ. Conclusion: The incidence of PTM use in this series of patients with hip arthroscopy was triple that reported for US adults (48% vs 17%, respectively) and adolescents (23% vs 6.3%), and the PTM group had significantly lower 12- and 24-month mHHS results than the NPTM group. These results suggest that (1) patients undergoing hip arthroscopy who are taking PTMs are at significantly higher risk for poor outcomes and (2) their use of PTMs should be identified and addressed before proceeding with hip arthroscopy.
MeSH term(s)	Adolescent ; Adult ; Arthroscopy/adverse effects ; Female ; Hip Joint/surgery ; Humans ; Male ; Middle Aged ; Postoperative Complications ; Psychotropic Drugs/therapeutic use ; Retrospective Studies ; Treatment Outcome
Chemical Substances	Psychotropic Drugs
Language	English
Publishing date	2018-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	197482-8
ISSN	1552-3365 ; 0363-5465
ISSN (online)	1552-3365
ISSN	0363-5465
DOI	10.1177/0363546518801881
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Article ; Online: An Extremum Principle for Smooth Problems

Dariusz Idczak / Stanisław Walczak

Games, Vol 11, Iss 56, p

2020 Volume 56

Abstract: ... The proof of this principle is based on a simple generalization of the Fermat’s theorem, the smooth-convex ...

Abstract	We derive an extremum principle. It can be treated as an intermediate result between the celebrated smooth-convex extremum principle due to Ioffe and Tikhomirov and the Dubovitskii–Milyutin theorem. The proof of this principle is based on a simple generalization of the Fermat’s theorem, the smooth-convex extremum principle and the local implicit function theorem. An integro-differential example illustrating the new principle is presented.
Keywords	extremum principle ; Fermat’s theorem ; local implicit function theorem ; Technology ; T ; Social Sciences ; H
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Cost and benefits of clustered regularly interspaced short palindromic repeats spacer acquisition.

Bradde, Serena / Mora, Thierry / Walczak, Aleksandra M

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2019 Volume 374, Issue 1772, Page(s) 20180095

Abstract: Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas-mediated immunity in bacteria allows bacterial populations to protect themselves against pathogens. However, it also exposes them to the dangers of auto-immunity by developing ... ...

Abstract	Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas-mediated immunity in bacteria allows bacterial populations to protect themselves against pathogens. However, it also exposes them to the dangers of auto-immunity by developing protection that targets its own genome. Using a simple model of the coupled dynamics of phage and bacterial populations, we explore how acquisition rates affect the probability of the bacterial colony going extinct. We find that the optimal strategy depends on the initial population sizes of both viruses and bacteria. Additionally, certain combinations of acquisition and dynamical rates and initial population sizes guarantee protection, owing to a dynamical balance between the evolving population sizes, without relying on acquisition of viral spacers. Outside this regime, the high cost of auto-immunity limits the acquisition rate. We discuss these optimal strategies that minimize the probability of the colony going extinct in terms of recent experiments. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
MeSH term(s)	Bacteria/genetics ; Bacteriophages/genetics ; CRISPR-Cas Systems/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Models, Biological
Language	English
Publishing date	2019-03-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2018.0095
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