Biology subjects

Pechuan, X.

Publications and source records attributed to Pechuan, X..

4 recordsLinked to original sources

bioRxiv2022

Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity

Tumor-associated macrophages are composed of distinct populations arising from monocytes or tissue macrophages, with a poorly understood link to disease pathogenesis. Here, we demonstrate that mouse monocyte migration was supported by glutaminyl-peptide cyclotransferase-like (QPCTL), an enzyme that mediates N-terminal modification of several subtrates, including the monocyte-chemoattractants CCL2 and CCL7, protecting them from proteolytic inactivation. Knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth and reshaped myeloid cell infiltration, with loss of monocyte-derived populations with immunosuppressive and pro-angiogenic profiles. Antibody blockade of the receptor CSF1R, which more broadly eliminates tissue macrophages, reversed tumor growth inhibition in Qpctl-/- mice, and prevented lymphocyte infiltration. Modulation of QPCTL synergized with anti-PD-L1 to expand CD8+ T cells and limit tumor growth. QPCTL inhibition constitutes an effective approach for myeloid cell-targeted cancer immunotherapy.

immunology↗

bioRxiv2021

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused [~]40 million cases and over 648,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African-American (AA) patients in some areas, yet targeted studies within this demographic are scant. Multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed low viral load, yet pronounced and persistent pulmonary neutrophilia with advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS), including exacerbated production of IL-8, IL-1{beta}, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Circulating S100A12+/IFITM2+ mature neutrophils are recruited via the IL-8/CXCR2 axis, which emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19. Graphical AbstractThe lung pathology due to severe COVID-19 is marked by a perpetual pathogenic neutrophilia, leading to acute respiratory distress syndrome (ARDS) even in the absence of viral burden. Circulating mature neutrophils are recruited to the airways via IL-8 (CXCL8)/CXCR2 chemotaxis. Recently migrated neutrophils further differentiate into a transcriptionally active and hyperinflammatory state, with an exacerbated expression of IL-8 (CXCL8), IL-1{beta} (IL1B), CCL3, CCL4, neutrophil elastase (NE), and myeloperoxidase (MPO) activity. Airway neutrophils and recruited inflammatory monocytes further increase their production of IL-8 (CXCL8), perpetuating lung neutrophilia in a feedforward loop. MdCs and T cells produce IL-1{beta} and TNF, driving neutrophils reprogramming and survival. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/446468v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@81fd3aorg.highwire.dtl.DTLVardef@181e63org.highwire.dtl.DTLVardef@172fedcorg.highwire.dtl.DTLVardef@ba55a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Evolutionary contingency’s impact on laboratory evolution of Escherichia coli under fluctuating environments

1The adaptation of biological organisms to fluctuating environments is one major determinant of their structural and dynamical complexity. Organisms have evolved devoted adaptations to ensure the robust performance of physiological functions under environmental fluctuations. To further our understanding of particular adaptation strategies to different environmental fluctuations, we perform laboratory evolution experiments of Escherichia coli under three temperature fluctuation regimes alternating between 15{degrees}C and 43{degrees}C. Two of these regimes are determined by the populations growth, while the third regime switches stochastically. To address evolutionary contingencies, the experiments are performed on two lineages departing from different genetic backgrounds. The two lineages display distinct evolutionary trajectories, demonstrating dependency on the starting strains genetic background. Several genes exhibit a high degree of parallelism, suggesting their potential adaptive nature. The growth increase of the representative clones from each final population relative to their ancestor at 15{degrees}C and 43{degrees}C demonstrated no correlation between both temperatures, insinuating an absence of a strong trade-off between these two temperatures. Some had a growth rate decrease at 15{degrees}C unless exposed to a 43{degrees}C epoch, indicating some degree of internalization of the structure of the environment fluctuations. The phenotypic response of the evolved clones at 15{degrees}C and 43{degrees}C was assessed by a phenotype array method. The resulting responses reveal a general tendency to move closer to the phenotypic response of our starting strains at the optimum of 37{degrees}C. This observation expands the documented restorative responses, even when facing complex environmental conditions.\n\n2 Author SummaryLaboratory evolution experiments have been widely employed to test hypotheses from evolutionary theory. To assess the dynamics of adaptation under environmental fluctuations, we evolved 24 Escherichia coli populations under different regimes of temperature switching between 15{degrees}C and 43{degrees}C for about 600 generations. At the final point of the evolution experiment, the evolved populations were genome sequenced and clones were isolated and sequenced for phenotypic characterization. Fitness measurements revealed adaptation to both environmental conditions and some strains internalized the environmental fluctuation. Array phenotypic measurements showed that the majority of evolved strains tended to restore the phenotypic signature of the perturbed environments to that of the optimal temperature condition. This observation expands the documented restorative responses, even when facing complex environmental conditions.

evolutionary biology↗

bioRxiv2019

The Process Pathway Model of bacterial growth

The growth profile of microorganisms in an enclosed environment, such as a bioreactor or flask, is a well studied and characterized system. Despite a long history of examination, there are still many competing mathematical models used to describe an output of the microorganisms, namely the number of bacteria as a function of time. However, these descriptions are either purely phenomenological and give no intuition as to the biological mechanisms underlying the growth curves, or extremely complex and become computationally unfeasible at the population level. In this paper, we develop the Process Pathway Model by modifying a model of sequential processes, which was first used to model robustness in metabolic pathways, and demonstrate that the Process Pathway Model encapsulates many features and temperature dependence of bacterial growth. We verify the predictions of the model against growth data for multiple species of microorganisms, and confirm that the model generates accurate predictions on temperature dependence of bacterial growth. The model has five free parameters, and the simplifying assumptions used to build the model are built upon biologically realistic notions. The Process Pathway Model accurately models a microorganisms growth profile at an intermediate level of complexity that is computationally feasible. This model can be used as both an conceptual model for thinking about systems of bacterial growth, as well as a computational model that operates at level of complexity that is amenable to large scale simulation. This balance in accuracy and intuitiveness was accomplished by using realistic biological assumptions to simplify the underlying biology, which may point the way forward for future models of this type.

systems biology↗