bluuebunny/crossref_metadata_2025_split huggingface dataset:
Damage-induced pyroptosis drives endogenous thymic regeneration via induction of Foxn1 by purinergic receptor activation
Authors: Kinsella Sinéad , Evandy Cindy A. , Cooper Kirsten , Cardinale Antonella , Iovino Lorenzo , deRoos Paul , Hopwo Kayla S. , Smith Colton W. , Granadier David , Sullivan Lucas B. , Velardi Enrico , Dudakov Jarrod A. 
Published: January 2023

ABSTRACTEndogenous thymic regeneration is a crucial process that allows for the renewal of immune competence following stress, infection or cytoreductive conditioning. Fully understanding the molecular mechanisms driving regeneration will uncover therapeutic targets to enhance regeneration. We previously demonstrated that high levels of homeostatic apoptosis suppress regeneration and that a reduction in the presence of damage-induced apoptotic thymocytes facilitates regeneration. Here we identified that cell-specific metabolic remodeling after ionizing radiation steers thymocytes towards mitochondrial-driven pyroptotic cell death. We further identified that a key damage-associated molecular pattern (DAMP), ATP, stimulates the cell surface purinergic receptor P2Y2 on cortical thymic epithelial cells (cTECs) acutely after damage, enhancing expression ofFoxn1, the critical thymic transcription factor. Targeting the P2Y2 receptor with the agonist UTPγS promotes rapid regeneration of the thymusin vivofollowing acute damage. Together these data demonstrate that intrinsic metabolic regulation of pyruvate processing is a critical process driving thymus repair and identifies the P2Y2 receptor as a novel molecular therapeutic target to enhance thymus regeneration.SUMMARYThymocytes rapidly and transiently undergo pyroptosis after acute thymic damage and promote regeneration.Damage-induced redirection of pyruvate acutely enhances mitochondrial OXPHOS in thymocytes.Elevated mitochondrial ROS promotes pyroptosis in thymocytes after acute insult by driving caspase 1 cleavage.Extracellular ATP release promotesFoxn1expression in cTECs via activation of P2Y2Therapeutic targeting of the P2Y2 receptor promotes thymic regeneration.
Emergence and maintenance of stable coexistence during a long-term multicellular evolution experiment
Authors: Pineau Rozenn M. , Demory David , Libby Eric , Lac Dung T. , Day Thomas C. , Bravo Pablo , Yunker Peter J. , Weitz Joshua S. , Bozdag G. Ozan , Ratcliff William C. 
Published: January 2023

AbstractThe evolution of multicellular life spurred evolutionary radiations, fundamentally changing many of Earth’s ecosystems. Yet little is known about how early steps in the evolution of multicellularity transform eco-evolutionary dynamics, e.g., via niche expansion processes that may facilitate coexistence. Using long-term experimental evolution in the snowflake yeast model system, we show that the evolution of multicellularity drove niche partitioning and the adaptive divergence of two distinct, specialized lineages from a single multicellular ancestor. Over 715 daily transfers, snowflake yeast were subject to selection for rapid growth in rich media, followed by selection favoring larger group size. Both small and large cluster-forming lineages evolved from a monomorphic ancestor, coexisting for over ~4,300 generations. These small and large sized snowflake yeast lineages specialized on divergent aspects of a trade-off between growth rate and survival, mirroring predictions from ecological theory. Through modeling and experimentation, we demonstrate that coexistence is maintained by a trade-off between organismal size and competitiveness for dissolved oxygen. Taken together, this work shows how the evolution of a new level of biological individuality can rapidly drive adaptive diversification and the expansion of a nascent multicellular niche, one of the most historically-impactful emergent properties of this evolutionary transition.
Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress
Authors: Bueschke Nikolaus , Amaral-Silva Lara , Hu Min , Alvarez Alvaro , Santin Joseph M. 
Published: January 2023

AbstractBrain energy stress leads to neuronal hyperexcitability followed by a rapid loss of function and cell death. In contrast, the frog brainstem switches into a state of extreme metabolic resilience that allows them to maintain motor function during hypoxia as they emerge from hibernation. NMDA receptors (NMDARs) are Ca2+-permeable glutamate receptors that contribute to the loss of homeostasis during hypoxia. Therefore, we hypothesized that hibernation leads to plasticity that reduces the role of NMDARs within neural networks to improve function during energy stress. To test this, we assessed a circuit with a large involvement of NMDAR synapses, the brainstem respiratory network of female bullfrogs,Lithobates catesbeianus. Contrary to our expectations, hibernation did not alter the role of NMDARs in generating network output, nor did it affect the amplitude, kinetics, and hypoxia sensitivity of NMDAR currents. Instead, hibernation strongly reduced NMDAR Ca2+permeability and enhanced desensitization during repetitive stimulation. Under severe hypoxia, the normal NMDAR profile caused network hyperexcitability within minutes, which was mitigated by blocking NMDARs. After hibernation, the modified complement of NMDARs protected against hyperexcitability, as disordered output did not occur for at least one hour in hypoxia. These findings uncover state-dependence in the plasticity of NMDARs, whereby multiple changes to receptor function improve neural performance during energy stress without interfering with its normal role during healthy activity.Significance StatementNeural circuits lose homeostasis during severe energy stress, and NMDA-glutamate receptors play a major role in this response. In contrast, frogs have the remarkable capacity to use plasticity that improves circuit function from minutes to hours during hypoxia, likely as an adaptation to survive emergence from hibernation. We found this occurs, in part, through modification of NMDA receptors that renders them less permeable to Ca2+and more likely to desensitize during high activity states. These NMDA receptor modifications do not influence normal network function but protect against hyperexcitability caused by hypoxia. This work points to endogenous plasticity mechanisms that improve network function during energy stress without altering circuit function when the brain is well-oxygenated.
Myxosortases process MYXO-CTERM and other bacterial C-terminal protein-sorting signals that have invariant Cys residues
Authors: Haft Daniel H 
Published: January 2023

AbstractThe LPXTG protein-sorting signal, found in surface proteins of various Gram-positive pathogens, was the founding member of a growing panel of prokaryotic small C-terminal sorting domains. Sortase A (SrtA) cleaves LPXTG, exosortases (XrtA and XrtB) cleave the PEP-CTERM sorting signal, archaeosortase A (ArtA) cleaves PGF-CTERM, and rhombosortase (RrtA) cleaves GlyGly-CTERM domains. Three sorting signal domains without previously known processing proteases are the MYXO-CTERM, JDVT-CTERM, and SYNERG-CTERM domains. These exhibit the standard tripartite architecture of short signature motif, then a hydrophobic transmembrane segment, then an Arg-rich cluster. Each has an invariant cysteine in its signature motif. Here, we show computational evidence that these three Cys-containing sorting signals are processed by corresponding subfamilies of glutamic-type intramembrane proteases, related to type II CAAX-processing proteases found in eukaryotes. We name these sorting enzymes generally as myxosortases, and identify MXAN_2755 from Myxococcus xanthus as MrtX (myxosortase X). Additional myxosortases families MrtC and MrtP have radically different N-terminal domains, suggesting most myxosortases act as bifunctional enzymes. Myxosortase-like processing enzymes are identified also for the JDVT-CTERM (MrtJ) and SYNERG-CTERM (MrtS). This work establishes a major new family of protein-sorting housekeeping enzymes for the surface attachment of proteins on bacterial outer membranes.
Fusidic acid-based drug combinations exhibit enhanced activity againstMycobacterium tuberculosis
Authors: Omollo Charles , Moosa Atica , Chibale Kelly , Warner Digby F. 
Published: January 2023

ABSTRACTTuberculosis (TB) imposes a major burden on global public health which is exacerbated by the escalating number of multidrug-resistant (MDR)-TB cases. There is consequently an urgent need for new anti-TB drugs and combination regimens. We have investigated the natural product antibiotic fusidic acid (FA) for repurposing againstMycobacterium tuberculosis, the causative agent of TB. Here, we report the results of synergy screens combining FA with a panel of approved anti-TB agents. Checkerboard and time-kill kinetics assays identified seven compounds from different chemical classes that synergized with FA in inhibiting the growth ofM. tuberculosis in vitro: rifampicin (RIF), a rifamycin and frontline anti-TB drug; the macrolides, erythromycin (ERY), clarithromycin (CLR), and roxythromycin (ROX); the oxazolidinone, linezolid (LZD); the aminoglycoside, streptomycin (STR); and the aminocyclitol, spectinomycin (SPC). Among these, the strongest synergies were observed where FA was combined with SPC and ERY. Moreover, the FA-RIF combination was cidal, while all other FA combinations were bacteriostatic. These results providein vitroevidence of the potential utility of FA-containing combinations againstM. tuberculosis.
Novel keto-alkyl-pyridinium antifungal molecules active in models of in vivoCandida albicansvascular catheter infection and ex vivoCandida aurisskin colonization
Authors: Beattie Sarah R. , Esan Taiwo , Zarnowski Robert , Eix Emily , Nett Jeniel E. , Andes David R. , Hagen Timothy , Krysan Damian J. 
Published: January 2023

AbstractNew antifungal therapies are needed for both systemic, invasive infections as well as superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to non-systemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2-16 µg/mL) against medically important yeasts and moulds, including clinical isolates resistant to azoles and/or echinocandins. Furthermore, these keto-alkyl-pyridinium agents retain substantial activity against biofilm phase yeast and have direct activity against hyphalA. fumigatus. Although their toxicity precludes use in systemic infections, we found that the keto-alkyl-pyridinium molecules reduceC. albicansfungal burden in a rat model of vascular catheter infection and reduceCandida auriscolonization in a porcine ex vivo model. These initial pre-clinical data suggest that molecules of this class may warrant further study and development.
Platelet activation with the Aeson Bioprosthetic Total Artificial Heart: insight from aspirin treatment and outcomes
Authors: Smadja David M. , Peronino Christophe , Jilet Léa , Ivak Peter , Pya Yuri , Philippe Aurélien , Latremouille Christian , Gustafsson Finn , Ramjankhan Faiz Z. , Roussel Jean Christian , Vincentelli André , Flecher Erwan , Gaussem Pascale , Jansen Piet , Netuka Ivan 
Published: January 2023

AbstractIntroductionThe Aeson bioprosthetic total artificial heart (A-TAH) is a pulsatile and autoregulated device. The aim of this study was to evaluate the level of platelet activation secondary to A-TAH implantation.MethodsWe examined the level of platelet activation markers in adult patients receiving A-TAH support (n=16) during clinical follow-up by quantifying sP-selectin (sP-sel) and sCD40L in plasma.ResultsThe cumulative duration of A-TAH support was 3587 days. Before implantation, sCD40L was 2684.6 pg/mL (954.0-16706.1) and remained steady after implantation [3305.8 pg/mL (1234.2-12327.5), 3300.5 pg/mL (1041.5-8370.1), and 2560.0 pg/mL (1325.5-14039.5), respectively, at <3 months, 3–6 months and >6 months; non-significant difference along time-period]. sP-sel was 33997.0 pg/mL (16019.6-73377.6) and remained steady after implantation [33580.1 pg/mL (13979.8-53395.2), 33204.9 pg/mL (15332.6-67263.4), and 34684.5 pg/mL (14084.9-49206.0), respectively, at <3 months, 3–6 months and >6 months; non-significant difference along time-period]. Levels sP-sel and sCD40L analysed according to aspirin or heparin use did not change. Finally, no relation existed between pericardial effusion and aspirin use according to timing of aspirin start and drain removal.ConclusionsWe demonstrated that A-TAH does not induce significant platelet activation. Absence of relationship between aspirin and platelet activation levels or pericardial effusion may support potential for withdrawal of antiplatelet therapy after A-TAH implantation in the future.
A rare gain of function HCN4 gene mutation is responsible for inappropriate sinus tachycardia in a Spanish family
Authors: Cámara-Checa Anabel , Perin Francesca , Rubio-Alarcón Marcos , Dago María , Crespo-García Teresa , Rapún Josu , Marín María , Cebrián Jorge , Bermúdez-Jiménez Francisco , Monserrat Lorenzo , Tamargo Juan , Caballero Ricardo , Jiménez-Jáimez Juan , Delpón Eva 
Published: January 2023

ABSTRACTBackgroundIn a family with inappropriate sinus tachycardia (IST) we identified a novel mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here we clinically study the family and functionally analyze the p.V240M variant.MethodsMacroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels.ResultsAll p.V240M mutation carriers exhibited IST (mean heart rate 113[7] bpm, n=9), that in adults, was accompanied by cardiomyopathy. IHCN4generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels. The variant, which lies in the N-terminal HCN domain, increased single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers.ConclusionsThe p.V240M gain-of-function variant increases Ifduring diastole, which explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4 which stabilizes the channels in the closed state.FundingMinisterio de Ciencia e Innovación (PID2020-118694RB-I00); Comunidad Autónoma de Madrid (P2022/BMD-7229), European Structural and Investment Funds); and Instituto de Salud Carlos III (CIBERCV; CB16/11/00303).
Evaluation of the Curitiba University intern medical students’ hability in breaking bad news in a OSCE test
Authors: Silva Thiago Ribeiro E , De Lara João Paulo Zanardini , Prado Oliveira Leonardo Ajuz Do , Baggio Lucas , Freitas Matheus Pisa , Ribeiro E Silva Rodrigo , Baptista João Pedro Ribeiro , Takimura Marcos , Okamoto Cristina Terumy 
Published: January 2023

ABSTRACTObjectiveBreaking bad news (BBN) has a big influence in patients’ lives, but still a lot of health care providers struggle when doing it with efficiency and empathy.MethodsThis study is a prospective cohort that evaluated the knowledge and the evolution of fifth year medical students in breaking bad news, and investigated which factors had a positive or negative influence on their scores. Two simulations were conducted during the year in the model of Objective Structured Clinical Examination (OSCE), the students’ scores were acquired through a checklist based on the SPIKES protocol. Posteriorly, an online questionnaire was filled by the students, containing objective and open questions relevant to the BBN scenario.ResultsParticipated in this study 85 undergraduates, in the first OSCE 52% (n = 44) scored above the minimum institutional average, in the second OSCE 59% (n = 50) scored above the minimum institutional average. Comparing both activities there were isolated differences between isolated items at the checklist, but without statistical significance. The factor that had a positive influence for scoring higher was having previous experience in BBN, during the second OSCE the group that had experience scored an average of 3,11 points, the other group had an average of 2,57 only (p = 0,012).ConclusionThe performance was median, and no score evolution was observed between the activities. Previous experience was the more important factor for a better score.ILUSTRATIONS’ LISTTable 1 Number of students’ right scores, per criteria in both of simulations
Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults
Authors: Pozarickij Alfred , Gan Wei , Lin Kuang , Clarke Robert , Fairhurst-Hunter Zammy , Koido Masaru , Kanai Masahiro , Okada Yukinori , Kamatani Yoichiro , Guo Yu , Bennett Derrick , Du Huaidong , Chen Yiping , Yang Ling , Avery Daniel , Yu Min , Yu Canqing , Valle Dan Schmidt , Lv Jun , Chen Junshi , Peto Richard , Collins Rory , Li Liming , Chen Zhengming , Millwood Iona Y , Walters Robin G 
Published: January 2023

AbstractElevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, harbouring 81 novel associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated strong causal associations of specific BP traits with CVD, including systolic BP with intracranial haemorrhage, and pulse pressure with carotid plaque. The findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their role in disease risk.
Immunogenicity, Safety and Effectiveness of COVID-19 Pfizer-BioNTech (BNT162b2) mRNA Vaccination in Immunocompromised Adolescents and Young Adults: A systematic Review and Meta-Analyses
Authors: Katoto Patrick DMC , Kakubu Mireille AM , Tamuzi Jacques L. , Brand Amanda S. , Ayuk Adaeze , Byamungu Liliane N. , Wiysonge Charles S. , Gray Glenda 
Published: January 2023

AbstractPeople with weak immune systems are more likely to develop severe COVID-19, less likely to be included in vaccine controlled studies but more likely to be under-vaccinated. We review post-marketing studies to examine the immunogenicity, safety and effectiveness of BNT162b2 vaccine in immunocompromised adolescents and young adults (AYA). We searched more than three international databases from 2020 to 30 May 2022 and used the ROBINS-I for bias assessment. Random effect model was used to estimate pooled proportion, log RR, and mean difference. Egger’s regression and Begg’s rank correlation were used to examine publication bias. 47 full texts were reviewed, and nine were included. Conditions studied were rheumatic diseases, diabetes mellitus, Down syndrome, solid tumours, neurodisability, and cystic fibrosis. Eight studies used cohort designs and one used cross-sectional designs. Europe led most of the investigations. Most studies had unclear risk of bias and none could rule out selection bias, ascertainment bias, or selective outcome reporting. The overall estimated proportion of combined local and systemic reactions after the first BNT162b2 vaccination was 30%[95% CI: 17-42%] and slightly rose to 32% [95% CI: 19-44%] after the second dose. Rheumatic illnesses had the highest rate of AEFI (40%[95% CI: 16-65%]), while cystic fibrosis had the lowest (27%[95% CI: 17%-38%]). Hospitalizations for AEFIs were rare. Healthy controls exhibited higher levels of neutralizing antibodies and measured IgG than immunocompromised AYA, although pooled estimations did not demonstrate a statistically significant difference after primary dose. BNT162b2 is safe and effective in immunocompromised AYA, with no significant difference to healthy controls. However, current evidence is low to moderate due to high RoB. Our research advocates for improving methodology in studies including specific AYA population.
Adaptive robustness through incoherent signaling mechanisms in a regenerative brain
Authors: Bray Samuel R. , Wyss Livia S. , Chai Chew , Lozada Maria E. , Wang Bo 
Published: January 2023

SummaryAnimal behavior emerges from collective dynamics of interconnected neurons, making it vulnerable to connectome damage. Paradoxically, many organisms maintain significant behavioral output after large-scale neural injury. Molecular underpinnings of this extreme robustness remain largely unknown. Here, we develop a quantitative behavioral analysis pipeline to measure previously uncharacterized long-lasting latent memory states in planarian flatworms during whole-brain regeneration. By combining >20,000 animal trials with neural population dynamic modeling, we show that long-range volumetric peptidergic signals allow the planarian to rapidly reestablish latent states and restore coarse behavior after large structural perturbations to the nervous system, while small-molecule neuromodulators gradually refine the precision. The different time and length scales of neuropeptide and small-molecule transmission generate incoherent patterns of neural activity which competitively regulate behavior and memory. Controlling behavior through opposing communication mechanisms creates a more robust system than either alone and may serve as a generic approach to construct robust neural networks.
Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype
Authors: Fitzpatrick Amanda , Iravani Marjan , Mills Adam , Vicente David , Alaguthurai Thanussuyah , Roxanis Ioannis , Turner Nicholas C. , Haider Syed , Tutt Andrew N.J. , Isacke Clare M. 
Published: January 2023

AbstractBreast cancer leptomeningeal metastasis (BCLM), where tumour cells grow along the lining of the brain and spinal cord, is a devastating development for patients. Investigating this metastatic site is hampered by difficulty in accessing tumour material. Here, we utilise cerebrospinal fluid (CSF) cell-free DNA (cfDNA) and CSF disseminated tumour cells (DTCs) to explore the clonal evolution of BCLM and heterogeneity between leptomeningeal and extracranial metastatic sites. Somatic alterations with potential therapeutic actionability were detected in 81% (17/21) of BCLM cases, with 19% detectable in CSF cfDNA only. BCLM was enriched in genomic aberrations in adherens junction and cytoskeletal genes, revealing a lobular-like breast cancer phenotype. CSF DTCs were cultured in 3D to establish BCLM patient-derived organoids, and used for the successful generation of BCLMin vivomodels. These data reveal that BCLM possess a unique genomic aberration profile and highlights potential cellular dependencies in this hard-to-treat form of metastatic disease.