C reactive protein impairs adaptive immunity in immune cells of patients with melanoma.

J Immunother Cancer. 2020 Apr;8(1):

Authors: Yoshida T, Ichikawa J, Giuroiu I, Laino AS, Hao Y, Krogsgaard M, Vassallo M, Woods DM, Stephen Hodi F, Weber J

Abstract
BACKGROUND: High C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma.
METHODS: The effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay.
RESULTS: In vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients.
CONCLUSIONS: These findings suggest that high levels of CRP induce an immunosuppressive milieu in melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer.
TRIAL REGISTRATION NUMBER: NCT01783938 and NCT02983006.

PMID: 32303612 [PubMed - as supplied by publisher]

Robust production of uniform human cerebral organoids from pluripotent stem cells.

Life Sci Alliance. 2020 May;3(5):

Authors: Sivitilli AA, Gosio JT, Ghoshal B, Evstratova A, Trcka D, Ghiasi P, Hernandez JJ, Beaulieu JM, Wrana JL, Attisano L

Abstract
Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human-specific cortical development and pathophysiology in an experimentally tractable system. Although diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we have directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent hCOs and achieve a success rate of >80%. These hCOs include both a radial glial stem cell compartment and electrophysiologically competent mature neurons. Moreover, we show using immunofluorescence microscopy and single-cell profiling that individual organoids display reproducible cell type compositions that are conserved upon extended culture. We expect that application of this method will provide new insights into brain development and disease processes.

PMID: 32303588 [PubMed - as supplied by publisher]

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/18

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30 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/17

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23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/17

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44 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/16

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42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/16

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28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/15

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48 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Type VI secretion system delivers a cell-wall amidase to target bacterial competitors.

Mol Microbiol. 2020 Apr 12;:

Authors: Wang T, Hu Z, Du X, Shi Y, Dang J, Lee M, Hesek D, Mobashery S, Wu M, Liang H

Abstract
The human pathogen Pseudomonas aeruginosa harbors three paralogous zinc proteases annotated as AmpD, AmpDh2, and AmpDh3, which turn over the cell wall and cell-wall-derived muropeptides. AmpD is cytoplasmic and plays a role in recycling of cell-wall muropeptides, with a link to antibiotic resistance. AmpDh2 is a periplasmic soluble enzyme with the former anchored to the inner leaflet of the outer membrane. We document herein that the type VI secretion system locus II (H2-T6SS) of P. aeruginosa delivers AmpDh3 (but not AmpD or AmpDh2) to the periplasm of a prey bacterium upon contact. AmpDh3 hydrolyzes the cell-wall peptidoglycan of the prey bacterium, which leads to its killing, thereby providing a growth advantage for P. aeruginosa in bacterial competition. We also document that the periplasmic protein PA0808, heretofore of unknown function, affords self-protection from lysis by AmpDh3. Cognates of the AmpDh3-PA0808 pair are widely distributed across Gram-negative bacteria. Taken together, these findings underscore the importance of their function as an evolutionary advantage and that of the H2-T6SS as the means for manifestation of the effect.

PMID: 32279364 [PubMed - as supplied by publisher]

Generation of an induced pluripotent stem cell line SYSUi-004-A from a child of microcephaly with TYW1 mutations.

Stem Cell Res. 2020 Apr 07;45:101783

Authors: Sun C, Zhou P, Yuan S, Guo R, Zhang Z, Xu Q, Han D, He L, Tang H, Xu K, Hu H, Li N

Abstract
We generated an induced human pluripotent stem cell line from a child with microcephaly carrying compound heterozygous mutations of TYW1 inherited from healthy parents. This iPS cell line showed typical embryonic stem cell-like morphology, expressed pluripotent markers that comparable to human embryonic stem cells. Moreover, these cells have the ability to differentiate into three germ layers and maintain a normal karyotype.

PMID: 32279010 [PubMed - as supplied by publisher]

Stress in groups: Lessons from non-traditional rodent species and housing models.

Neurosci Biobehav Rev. 2020 Apr 09;:

Authors: Beery AK, Holmes MM, Lee W, Curley JP

Abstract
A major feature of life in groups is that individuals experience social stressors of varying intensity and type. Social stress can have profound effects on health, social behavior, and ongoing relationships. Relationships can also buffer the experience of exogenous stressors. Social stress has most commonly been investigated in dyadic contexts in mice and rats that produce intense stress. Here we review findings from studies of diverse rodents and non-traditional group housing paradigms, focusing on laboratory studies of mice and rats housed in visible burrow systems, prairie and meadow voles, and mole-rats. We argue that the use of methods informed by the natural ecology of rodent species provides novel insights into the relationship between social stress, behavior and physiology. In particular, we describe how this ethologically inspired approach reveals how individuals vary in their experience of and response to social stress, and how ecological and social contexts impact the effects of stress. Social stress induces adaptive changes, as well as long-term disruptive effects on behavior and physiology.

PMID: 32278793 [PubMed - as supplied by publisher]

Photosynthesis, Respiration and Growth:A Carbon and Energy Balancing Act for Alternative Oxidase.

Mitochondrion. 2020 Apr 09;:

Authors: Vanlerberghe GC, Dahal K, Alber NA, Chadee A

Abstract
This review summarizes knowledge of alternative oxidase, a mitochondrial electron transport chain component that lowers the ATP yield of plant respiration. Analysis of mutant and transgenic plants has established that alternative oxidase activity supports leaf photosynthesis. The interaction of alternative oxidase respiration with chloroplast metabolism is important under conditions that challenge energy and/or carbon balance in the photosynthetic cell. Under such conditions, alternative oxidase provides an extra-chloroplastic means to optimize the status of chloroplast energy pools (ATP, NADPH) and to manage cellular carbohydrate pools in response to changing rates of carbon fixation and carbon demand for growth and maintenance. Transcriptional and post-translational mechanisms ensure that alternative oxidase can respond effectively when carbon and energy balance are being challenged. This function appears particularly significant under abiotic stress conditions such as water deficit, high salinity, or temperature extremes. Under such conditions, alternative oxidase respiration positively affects growth and stress tolerance, despite it lowering the energy yield and carbon use efficiency of respiration. In part, this beneficial effect relates to the ability of alternative oxidase respiration to prevent excessive reactive oxygen species generation in both mitochondria and chloroplasts. Recent evidence suggests that alternative oxidase respiration is an interesting target for crop improvement.

PMID: 32278748 [PubMed - as supplied by publisher]

Systems metabolomics: from metabolomic snapshots to design principles.

Curr Opin Biotechnol. 2020 Apr 08;63:190-199

Authors: Damiani C, Gaglio D, Sacco E, Alberghina L, Vanoni M

Abstract
Metabolomics is a rapidly expanding technology that finds increasing application in a variety of fields, form metabolic disorders to cancer, from nutrition and wellness to design and optimization of cell factories. The integration of metabolic snapshots with metabolic fluxes, physiological readouts, metabolic models, and knowledge-informed Artificial Intelligence tools, is required to obtain a system-level understanding of metabolism. The emerging power of multi-omic approaches and the development of integrated experimental and computational tools, able to dissect metabolic features at cellular and subcellular resolution, provide unprecedented opportunities for understanding design principles of metabolic (dis)regulation and for the development of precision therapies in multifactorial diseases, such as cancer and neurodegenerative diseases.

PMID: 32278263 [PubMed - as supplied by publisher]

Sexually dimorphic phrase organization in the song of the indris (Indri indri).

Am J Primatol. 2020 Apr 11;:e23132

Authors: Zanoli A, De Gregorio C, Valente D, Torti V, Bonadonna G, Randrianarison RM, Giacoma C, Gamba M

Abstract
Animal acoustic communication often takes the form of complex sequences, composed of multiple distinct acoustic units, which can vary in their degree of stereotypy. Studies of sequence variation may contribute to our understanding of the structural flexibility of primates' songs, which can provide essential ecological and behavioral information about variability at the individual, population, and specific level and provide insights into the mechanisms and drivers responsible for the evolutionary change of communicative traits. Several methods have been used for investigating different levels of structural information and sequence similarity in acoustic displays. We studied intra and interindividual variation in the song structuring of a singing primate, the indri (Indri indri), which inhabits the montane rain forests of Madagascar. Indri groups emit duets and choruses in which they combine long notes, short single units, and phrases consisting of a variable number of units (from two to six) with slightly descending frequency. Males' and females' contributions to the song differ in the temporal and frequency structure of song units and repertoire size. We calculated the similarity of phrase organization across different individual contributions using the Levenshtein distance, a logic distance that expressed the minimum cost to convert a sequence into another and can measure differences between two sequences of data. We then analyzed the degree of similarity within and between individuals and found that: (a) the phrase structure of songs varied between reproductive males and females: female structuring of the song showed a higher number of phrases if compared to males; (b) male contributions to the song were overall more similar to those of other males than were female contributions to the song of other females; (c) male contributions were more stereotyped than female contributions, which showed greater individual flexibility. The picture emerging from phrase combinatorics in the indris is in agreement with previous findings of rhythmic features and song repertoire size of the indris, which also suggested that female songs are potentially less stereotyped than those of males.

PMID: 32277718 [PubMed - as supplied by publisher]

Ranking network mechanisms by how they fit diverse experiments and deciding on E. coli's ammonium transport and assimilation network.

NPJ Syst Biol Appl. 2019 Apr 12;5(1):14

Authors: Maeda K, Westerhoff HV, Kurata H, Boogerd FC

Abstract
The complex ammonium transport and assimilation network of E. coli involves the ammonium transporter AmtB, the regulatory proteins GlnK and GlnB, and the central N-assimilating enzymes together with their highly complex interactions. The engineering and modelling of such a complex network seem impossible because functioning depends critically on a gamut of data known at patchy accuracy. We developed a way out of this predicament, which employs: (i) a constrained optimization-based technology for the simultaneous fitting of models to heterogeneous experimental data sets gathered through diverse experimental set-ups, (ii) a 'rubber band method' to deal with different degrees of uncertainty, both in experimentally determined or estimated parameter values and in measured transient or steady-state variables (training data sets), (iii) integration of human expertise to decide on accuracies of both parameters and variables, (iv) massive computation employing a fast algorithm and a supercomputer, (v) an objective way of quantifying the plausibility of models, which makes it possible to decide which model is the best and how much better that model is than the others. We applied the new technology to the ammonium transport and assimilation network, integrating recent and older data of various accuracies, from different expert laboratories. The kinetic model objectively ranked best, has E. coli's AmtB as an active transporter of ammonia to be assimilated with GlnK minimizing the futile cycling that is an inevitable consequence of intracellular ammonium accumulation. It is 130 times better than a model with facilitated passive transport of ammonia.

PMID: 32277071 [PubMed - as supplied by publisher]

Development of IFN-Stimulated Gene Expression from Embryogenesis through Adulthood, with and without Constitutive MDA5 Pathway Activation.

J Immunol. 2020 Apr 10;:

Authors: Bankers L, Miller C, Liu G, Thongkittidilok C, Morrison J, Poeschla EM

Abstract
Pathogen-associated molecular patterns (e.g., dsRNA) activate expression of IFN-stimulated genes (ISGs), which protect hosts from infection. Although transient ISG upregulation is essential for effective innate immunity, constitutive activation typically causes harmful autoimmunity in mice and humans, often including severe developmental abnormalities. We have shown that transgenic mice expressing a picornavirus RNA-dependent RNA polymerase (RdRP) outside the viral context (RdRP mice) exhibit constitutive, MDA5-dependent, and quantitatively dramatic upregulation of many ISGs, which confers broad viral infection resistance. Remarkably, RdRP mice never develop autoinflammation, interferonopathy, or other discernible abnormalities. In this study, we used RNA sequencing and other methods to analyze ISG expression across five time points from fetal development to adulthood in wild-type and RdRP mice. In RdRP mice, the proportion of upregulated ISGs increased during development, with the most dramatic induction occurring 2 wk postnatally. The amplified ISG profile is then maintained lifelong. Molecular pathways and biological functions associated with innate immune and IFN signaling are only activated postnatally, suggesting constrained fetal responsiveness to innate immune stimuli. Biological functions supporting replication of viruses are only inhibited postnatally. We further determined that the RdRP is expressed at low levels and that blocking Ifnar1 reverses the amplified ISG transcriptome in adults. In conclusion, the upregulated ISG profile of RdRP mice is mostly triggered early postnatally, is maintained through adulthood, and requires ongoing type I IFN signaling to maintain it. The model provides opportunities to study the systems biology of innate immunity and to determine how sustained ISG upregulation can be compatible with robust health.

PMID: 32277054 [PubMed - as supplied by publisher]

38 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

32 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

33 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2020/04/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.