bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluorescent peptomer substrates for differential degradation by metalloproteases
Authors: Austin Mariah J. , Schunk Hattie C. , Watkins Carolyn M. , Ling Natalie R. , Chauvin Jeremy M. , Morton Logan D. , Rosales Adrianne M. 
Published: September 2022

AbstractProteases, especially MMPs, are attractive biomarkers given their central role in both physiological and pathological processes. Distinguishing MMP activity with degradable substrates, however, is a difficult task due to overlapping substrate specificity profiles. Here, we developed a system of peptomers (peptide-peptoid hybrids) to probe the impact of non-natural residues on MMP specificity for a MMP peptide consensus sequence. Peptoids are non-natural, N-substituted glycines with a large side chain diversity. Given the presence of a hallmark proline residue in the P3 position of MMP consensus sequences, we hypothesized that peptoids may offer N-substituted alternatives to generate differential interactions with MMPs. To investigate this hypothesis, peptomer substrates were exposed to five different MMPs, as well as bacterial collagenase, and monitored by fluorescence resonance energy transfer and liquid chromatography-mass spectrometry to determine the rate of cleavage and the composition of degraded fragments, respectively. We found that peptoid residues are well-tolerated in the P3 and P3’ substrate sites and that the identity of the peptoid in these sites displays moderate influence on the rate of cleavage. However, peptoid residues were even better tolerated in the P1 substrate site where activity was more strongly correlated with sidechain identity than sidechain position. All MMPs explored demonstrated similar trends in specificity for the peptomers but exhibited different degrees of variability in proteolytic rate. These kinetic profiles served as “fingerprints” for the proteases and yielded separation by multivariate data analysis. To further demonstrate practical application of this tunability in degradation kinetics, peptomer substrates were tethered into hydrogels and released over distinct timescales. Overall, this work represents a significant step toward the design of probes that maximize differential MMP behavior and presents design rules to tune degradation kinetics with peptoid substitutions, which has promising implications for diagnostic and prognostic applications using array-based sensors.
The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice
Authors: Amand Mathieu , Adams Philipp , Schober Rafaela , Iserentant Gilles , Servais Jean-Yves , Moutschen Michel , Seguin-Devaux Carole 
Published: September 2022

AbstractBackgroundHIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1 β and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice.MethodsNSG mice were engrafted with human CD34+hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA.ResultsExpression of caspase-1, NLRP3 and IL1-β was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at D24 in lymph node and bone marrow (FC 1.49 and 1.64, p<0.05) and coincides with increased IL-18 levels in plasma (6.89 vs. 83.19 pg/ml, p=0.004). AIM2 and IFI16 expression correlated with increased viral load in tissues (p<0.005 for the spleen) and loss of CD4+T cells percentage in blood (p<0.0001 for the spleen). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs. 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4+T cells (44.3% vs 36,7%, p=0.01) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice.Discussionwe report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.
Differential scanning fluorimetry as a measure of functionality of refolded anti-malarial antibody fragments
Authors: Valiyaparambil Ashwathi , Jagannath Deepak K , Viswanath Vysakh K , Kumar Naveen , Shukla Jay Prakash , Pradhan Sabyasachi , Lakshminarasimhan Anirudha 
Published: September 2022

AbstractTransmission blocking monoclonal antibodies, 4B7 and 1245, targeting Pfs25, have been demonstrated to block the developmental stages of the malarial parasite inside the mosquitoes. In this work, anti-Plasmodium antibody fragments of 4B7 and 1245, designated as diabodies, were expressed in bacteria and refolded using a standardized method, with a yield of 0.1 and 0.4 mg per litre of culture, respectively. Dimeric species was detected for 4B7-Db, but not for 1245-Db, using glutaraldehyde cross-linking experiment. The quality of the purified refolded fraction was assessed with differential scanning fluorimetry (DSF). Refolded 4B7-Db, with a melting temperature of 59°C, recognized Pfs25 expressed on the surface of ookinete and zygote stages of Plasmodium in an immunofluorescence-based assay, whereas, 1245-Db, exhibiting a skewed melt profile, showed weak recognition. Further, refolded 4B7-Db recognized the linear epitope, on purified Pfs25 protein, both in the denatured and native state. Differential scanning fluorimetry can be potentially employed as a qualitative measure of functionality, to evaluate refolded proteins, with applicability for antibody engineering in passive immunization.
Population structure and evolution of Salmonella enterica serotype Typhi in Zimbabwe before a typhoid conjugate vaccine immunization campaign
Authors: Thilliez Gaetan , Mashe Tapfumanei , Chaibva Blessmore V. , Robertson Valerie , Bawn Matt , Tarupiwa Andrew , Takawira Faustinos Tatenda , Kock Marleen M. , Midzi Stanley , Mwamakamba Lusubilo W. , Matheu Jorge , Kingsley Robert A. , Ehlers Marthie M. 
Published: September 2022

AbstractBackgroundThe continued emergence of Salmonella enterica serovar Typhi (S. Typhi) with ever increasing antimicrobial resistance (AMR), necessitates the use of vaccines in endemic countries. A typhoid fever outbreak in Harare, Zimbabwe in 2018 from a multidrug resistant S. Typhi with additional resistance to ciprofloxacin was the catalyst for the introduction of a typhoid conjugate vaccine program. To investigate the historic emergence and evolution of AMR of endemic S. Typhi in Zimbabwe and determined the population structure, gene flux and sequence polymorphisms of strains isolated prior to mass typhoid vaccination to provide a baseline for future evaluation of the effect of the vaccination program.MethodsWe determined the population structure, gene flux and sequence polymorphisms and reconstructed the evolution of AMR. The S. Typhi population structure was investigated in the context the genome sequence of 1904 strains isolated from 65 countries to reconstruct spread of endemic strains into Zimbabwe.FindingsThe population structure of S. Typhi in Zimbabwe is dominated by multidrug resistant genotype 4.3.1.1 (H58) that spread to Zimbabwe from neighboring countries around 2009. Evolution of AMR within Zimbabwe included acquisition of an IncN plasmid carrying a qnrS gene and a mutation in the quinolone resistance determining region of gyrA gene, both implicated in resistance to quinolone antibiotics. A minority population of antimicrobial susceptible S. Typhi genotype 3.3.1 strains was detected in typhoid cases.InterpretationThe currently dominant S. Typhi population is genotype 4.3.1.1 that spread to Zimbabwe and acquired additional AMR though acquisition of a plasmid and mutation of the gyrA gene. This study provides a baseline for future evaluation of the impact of the Typhoid Conjugate Vaccine program in Harare.FundingRAK and GT were supported by Bill and Melinda Gates Foundation project OPP1217121 and the BBSRC Institute Strategic Programme BB/R012504/1 and its constituent project BBS/E/F/000PR10348.
MHC-II expressing neutrophils circulate in blood and milk during mastitis and show high microbicidal activity
Authors: Rambault Marion , Gilbert Florence B. , Roussel Philippe , Tessier Alexia , David Valérie , Germon Pierre , Winter Nathalie , Remot Aude 
Published: September 2022

AbstractBovine mastitis are mainly caused by bacterial infection. They are responsible for economic losses and have an impact on the health and welfare of animals. The increase in the somatic cell count in milk during mastitis is mainly due to the influx of neutrophils which have a crucial role in the elimination of pathogens. For a long time, these first line defenders has been view as microbes’ killers with limited role in the orchestration of the immune response. However, their role is more complex and we recently characterized a MHC-II expressing neutrophil subset with regulatory capacities in cattle. In this study, we questioned the implication of different neutrophils subsets in the mammary gland immunity during clinical and subclinical mastitis. Here, we described for the first time that, in blood as in milk, neutrophils are a heterogeneous population and encompass at least two subsets distinguishable with their expression of MHC-II. We observed higher bactericidal capacities of milk MHC-IIpos neutrophils as compared to their classical counterparts, due to a higher production of ROS and phagocytosis ability. MHC-IIpos neutrophils are enriched in milk during a subclinical mastitis as compared to blood. Moreover, we observed a positive and highly significant correlation between MHC-IIpos neutrophils and T lymphocytes present in milk during subclinical mastitis. To conclude, our study could open the way to the discovery of new biomarkers of mastitis inflammation.
Risk factors and spatiotemporal analysis of classical swine fever in Ecuador
Authors: Acosta Alfredo , Dietze Klaas , Baquero Oswaldo , Vizzotto Osowski Germana , Imbacuan Christian , Burbano Lidia Alexandra , Ferreira Fernando , Depner Klaus 
Published: September 2022

1.AbstractClassical swine fever (CSF) is one of the most important re-emergent swine diseases worldwide. Despite concerted control efforts in the Andean countries, the disease remains endemic in several areas, limiting production and trade opportunities. In this study, we aim to determine herd-level risk factors and spatiotemporal implications associated with CSF. We analysed passive surveillance datasets and vaccination programmes from 2014 to 2020; Then, structured a herd-level case-control study using a multivariable logistic model containing 339 cases, and a spatiotemporal Bayesian model, considering 115 thousand premises, 2.3 million annual vaccine doses and a population of 1.6 million pigs distributed in 1,006 parishes. Our results showed that the risk factors that increased the odds of CSF occurrence were swill feeding (OR 9.28), time of notification (OR 2.18), animal entry in the last 30 days (OR 2.08), lack of CSF vaccination (OR 1.88), age of animals between 3-6 months (OR 1.58) and being in the coastal region (OR 1.87). Spatiotemporal models showed that the vaccination campaign reduced the risk by 33% while temperature increased the risk by 17%. The calculated priority index aims to facilitate the intervention process that should be focused on a couple of provinces, mainly in Morona Santiago and Los Rios as well as in specific parishes around the country. Our findings provide insight and understanding of the risk factors associated with CSF in Ecuador, which stands for the Andean region; even though the results are specific for the implementation of risk-based surveillance for CSF, data and methods could be valuable for the prevention and control of diseases such as African swine fever, or porcine reproductive and respiratory syndrome. In conclusion, the results highlight the complexity of the CSF control programme, the need to inform decision-makers, involve stakeholders and implement better strategies to update continental health policies to eradicate swine diseases.
Enhanced Effector Activity of Mediator Kinase Module Deficient CAR-T Cells
Authors: Freitas Katherine A. , Belk Julia A. , Sotillo Elena , Daniel Bence , Sandor Katalin , Klysz Dorota , Duong Vandon T. , Burdsall Kylie , Xu Peng , Malipatlolla Meena , Donovan Micah G. , Weber Evan W. , Majzner Robbie G. , Chang Howard Y. , Espinosa Joaquin M. , Satpathy Ansuman T. , Mackall Crystal L. 
Published: September 2022

AbstractAdoptive T cell immune therapies mediate impressive clinical benefit in a fraction of patients, but anti-tumor effects are often limited by inadequate T cell potency. To identify genes limiting T cell effector function, we conducted genome-wide CRISPR knock-out screens in human primary CAR-T cells. The top hits were MED12 and CCNC, components of the cyclin-dependent kinase (CDK) module of the Mediator complex, an evolutionarily conserved regulator of gene transcription. MED12 or CCNC deficient CAR-T cells manifest increased expansion, cytokine production, metabolic fitness, effector function, anti-tumor activity and reduced terminal effector differentiation. Chemical inhibition of CDK8/19 kinase activity recapitulated some features of genetic loss of MED12, including increased T cell expansion. MED12 deficient CAR-T cells showed widespread but selective increases in chromatin accessibility, MED1 chromatin occupancy, and H3K27 acetylation at enhancers used by transcription factors playing a critical role in T cell fate, including several STAT and AP1 family members. The most pronounced enhancement was observed for STAT5 which manifested as increased sensitivity to IL-2 in MED12 deficient T cells. These results link Mediator induced transcriptional coactivation with T cell effector programming and identify the CDK module as a target for enhancing the potency of anti-tumor T cell responses.One Sentence SummaryThe Mediator kinase module is a primary regulator of T cell differentiation, and genetic or small molecule-based inhibition of this module enhances effector T cell potency.
Parity modulates impact of BMI and Gestational Weight Gain on gut microbiota in human pregnancy
Authors: Kennedy Katherine M. , Plagemann Andreas , Sommer Julia , Hofmann Marie , Henrich Wolfgang , Barrett Jon F.R. , Surette Michael G. , Atkinson Stephanie , Braun Thorsten , Sloboda Deborah M. 
Published: September 2022

AbstractPregnancy requires maternal adaptations to support fetal growth: whether these adaptations include temporal shifts in the gut microbiome is still unclear. We investigated the maternal gut microbiome longitudinally over the course of pregnancy and the impact of pre-pregnancy BMI (pBMI) and GWG. We also determined whether parity modulated observed associations. We show that the gut microbiota of participants with higher pBMI changed less over the course of pregnancy in primiparous, but not multiparous participants. This suggests that previous pregnancies may have persistent impacts on maternal adaptations to pregnancy. This ecological memory appears to be passed to the next generation, as parity modulated the impact of maternal GWG on the infant gut microbiome. This work supports a role for the gut microbiome in maternal adaptations to pregnancy and highlights the need for longitudinal sampling and accounting for parity as key considerations for studies of the microbiome in pregnancy and infants.
Modular Streaming Pipeline of Eye/Head Tracking Data Using Tobii Pro Glasses 3
Authors: Nasrabadi Hamed Rahimi , Alonso Jose-Manuel 
Published: September 2022

AbstractHead-mounted tools for eye/head tracking are increasingly used for assessment of visual behavior in navigation, sports, sociology, and neuroeconomics. Here we introduce an open-source python software (TP3Py) for collection and analysis of portable eye/head tracking signals using Tobii Pro Glasses 3. TP3Py’s modular pipeline provides a platform for incorporating user-oriented functionalities and comprehensive data acquisition to accelerate the development in behavioral and tracking research. Tobii Pro Glasses 3 is equipped with embedded cameras viewing the visual scene and the eyes, inertial measurement unit (IMU) sensors, and video-based eye tracker implemented in the accompanying unit. The program establishes a wireless connection to the glasses and, within separate threads, continuously leverages the received data in numerical or string formats accessible for saving, processing, and graphical purposes. Built-in modules for presenting eye, scene, and IMU data to the experimenter have been adapted as well as communicating modules for sending the raw signals to stimulus/task controllers in live fashion. Closed-loop experimental designs are limited due to the 140ms time delay of the system, but this limitation is compensated by the portability of the eye/head tracking. An offline data viewer has been also incorporated to allow more time-consuming computations. Lastly, we demonstrate example recordings involving vestibulo-ocular reflexes, saccadic eye movements, optokinetic responses, or vergence eye movements to highlight the program’s measurement capabilities to address various experimental goals. TP3Py has been tested on Windows with Intel processors, and Ubuntu operating systems with Intel or ARM (Raspberry Pie) architectures.
Hippocampal-cortical functional connectivity during memory encoding and retrieval
Authors: Raud Liisa , Sneve Markus H. , Vidal-Piñeiro Didac , Sørensen Øystein , Folvik Line , Ness Hedda T. , Mowinckel Athanasia M. , Grydeland Håkon , Walhovd Kristine B. , Fjell Anders M. 
Published: September 2022

AbstractMemory encoding and retrieval are critical sub-processes of episodic memory. While the hippocampus is involved in both, its connectivity with the neocortex during memory processing in humans has been elusive. This is partially due to variations in demands in common memory tasks, which inevitably recruit cognitive processes other than episodic memory. Conjunctive analysis of data from different tasks with the same core elements of encoding and retrieval can reduce the intrusion of patterns related to subsidiary perceptual and cognitive processing. Leveraging data from two large-scale functional resonance imaging studies with different episodic memory tasks (514 and 237 participants), we identified core hippocampal-cortical networks active during memory processing. Anterior and posterior hippocampus had distinct connectivity profiles, which were stable across resting state and memory tasks. Whereas no encoding-specific connectome emerged across tasks, during retrieval hippocampal connectivity was increased with areas known to be active during recollection, including medial prefrontal, inferior parietal, and parahippocampal cortices. This indicates that the stable functional connectivity of the hippocampus along its longitudinal axis is superposed by increased functional connectivity with the recollection network during retrieval, while encoding connectivity likely reflects contextual factors.
Elongation of Very Long Chain Fatty Acids Like- 3 (Elovl3) is activated by ZHX2 and is a regulator of cell cycle progression
Authors: Creasy Kate Townsend , Ren Hui , Jiang Jieyun , Peterson Martha L. , Spear Brett T. 
Published: September 2022

AbstractZinc fingers and homeoboxes 2 (ZHX2) functions as a tumor suppressor in several models of hepatocellular carcinoma (HCC), presumably through its control of target genes. Previous microarray data suggested that Elongation of Very Long Chain Fatty Acids 3 (Elovl3), a member of the Elovl family which synthesize very long chain fatty acids (VLCFAs), is a putative ZHX2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids, which are often dysregulated in diseases, including HCC. Since several previously identified ZHX2 targets become dysregulated in HCC, we investigated the relationship between ZHX2 and Elovl3 in liver damage and HCC. Here, using mouse and cell models, we demonstrate that Zhx2 positively regulates Elovl3 expression in the liver and that male-biased hepatic Elovl3 expression is established between 4-8 weeks of age in mice. Elovl3 is dramatically repressed in mouse models of liver regeneration and HCC and the reduced Elovl3 levels in the regenerating liver are associated with changes in hepatic very long chain fatty acids. Human hepatoma cell lines with forced Elovl3 expression have lower rates of cell growth; analysis of synchronized cells indicate that this reduced proliferation correlates with cells stalling in S-phase. Taken together, these data indicate that Elovl3 expression helps regulate cellular proliferation, possibly through control of VLCFAs, and its repression may be a contributing factor to HCC and explain, in part, the function of ZHX2 as a suppressor of HCC progression.
Metabolic integration of spectral and chemical cues mediating plant responses to competitors and herbivores
Authors: Chautá Alexander , Kessler André 
Published: September 2022

AbstractLight quality and chemicals in a plant’s environment can provide crucial information about the presence and nature of antagonists, such as competitors and herbivores. Here we evaluate the roles of three sources of information - shifts in the red:far red (FR) ratio of light reflected off of potentially competing neighbors, induced metabolic changes to damage by insect herbivores, and induced changes to volatile organic compounds emitted from herbivore–damaged neighboring plants - to affect metabolic responses in the tall goldenrod, Solidago altissima. We address the hypothesis, that plants integrate the information available about competitors and herbivory to optimize metabolic responses to interacting stressors by exposing plants to the different types of environmental information in isolation and combination. We found strong interactions between the exposure to decreased Red:FR light ratios and damage on the induction of secondary metabolites (volatile and non-volatile) in the receiver plants. Similarly, the perception of VOCs emitted from neighboring plants was altered by the simultaneous exposure to spectral cues from neighbors. These results suggest that plants integrate spectral and chemical environmental cues to change the production and perception of volatile and non-volatile compounds and highlight the role of plant context-dependent metabolic responses in mediating population and community dynamics.HighlightPlants integrate spectral and chemical environmental cues to differentially induce production of volatile and non-volatile compounds