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Meier, C.

Publications and source records attributed to Meier, C..

6 recordsLinked to original sources

Continental-scale relationships of fine root and soil carbon stocks hold in grasslands but not forests

Increasing root carbon inputs into soils has been proposed as a solution to increasing soil organic carbon (SOC). However, while fine root carbon (FRC) inputs can increase SOC accrual in soils, FRC can also enhance SOC loss by stimulating microbial respiration and cause a net loss of SOC through priming. It remains unclear how SOC varies as a function of FRC at broad spatial scales and across ecosystems and depths. Here, we tested the relationship of SOC and FRC using data from 43 sites across the US National Ecological Observatory Network (NEON). We found that total stocks of SOC and FRC in the top 2 meters of soil were positively related with an across-ecosystem slope of 7 {+/-} 3 kg SOC m-2 per kg FRC m-2. However, grassland sites primarily drove this relationship. Grasslands had 15 {+/-} 2 kg SOC m-2 per kg FRC m-2, which is double the across-ecosystem slope. We used deviations from the standardized 1:1 relationship between FRC and SOC to infer whether ecosystems were net priming (indicated by observed SOC being lower than the 1:1 line) or SOC accruing (higher SOC than the 1:1 line). Grassland soils and especially their deep soil layers (>30 cm) showed primarily SOC accrual with increasing fine root abundance. Meanwhile, forest soils had high variability in whether increasing fine roots were associated with net SOC priming or accrual across both shallow and deeper soil layers. We found that in grasslands, FRC inputs are strongly related to SOC accrual, especially at depth and at sites with high moisture and clay content. In contrast, SOC-FRC relationships in forests remain difficult to characterize. Nevertheless, deep grassland soils may serve as optimal environments in which increasing FRC could lead to meaningful increases in SOC stocks.

ecology↗

Membrane-permeable 5-fluorodeoxyuridine triphosphate derivatives inhibit the proliferation of Plasmodium falciparum

Malaria tropica remains a major global health challenge, requiring new therapeutic strategies against Plasmodium falciparum. While nucleoside analogues are effective against viruses and cancer, their use against P. falciparum is limited by the parasites lack of nucleoside kinases. To overcome this, we tested cell-permeable derivatives of 5-fluorodeoxyuridine triphosphate (cpFdUTP) for anti-parasitic activity in infected human red blood cells. cpFdUTP rapidly and potently inhibited P. falciparum proliferation, arresting development at the trophozoite-to-schizont transition by stalling DNA replication, as revealed by a P. falciparum nuclear cycle sensor line. Although cpFdUTP also impaired human cell growth, supplementation with thymidine or cell-permeable deoxythymidine triphosphate (cpdTTP) selectively rescued human cells while maintaining P. falciparum inhibition. This identifies a potential therapeutic window for cpFdUTP in combination with thymidine, outlining a novel approach for malaria treatment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/640175v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b20ddaorg.highwire.dtl.DTLVardef@1ab6497org.highwire.dtl.DTLVardef@15932e2org.highwire.dtl.DTLVardef@11b9e61_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

WCRC-25: A novel luminal Invasive Lobular Carcinoma cell line model

Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin (CDH1). Few ILC cell line models are available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a CDH1 Q706* truncating mutation, together with mutations in FOXA1, CTCF, BRCA2 and TP53, which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical genome mapping revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/AKT signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities. Financial supportThe work was in part supported by a Susan G Komen Leadership Grant to SO (SAC160073) and NCI R01 CA252378 (SO/AVL). AVL and SO are Komen Scholars, Hillman Foundation Fellows and supported by BCRF. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. This research was also supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Finally, partial support was provided by the Magee-Womens Research Institute and Foundation, The Shear Family Foundation, and The Metastatic Breast Cancer Network.

cancer biology↗

Backtracking of influenza polymerase upon consecutive incorporation of nucleoside analogue T1106 directly observed by high resolution cryo-electron microscopy

The broad-spectrum antiviral pseudobase T705, a fluorinated pyrazinecarboxamide, is incorporated via its triphosphate form into nascent viral RNA by viral RNA-dependent RNA polymerases. Since it mimics guanine or adenine it can act as a mutagen, whereas consecutive incorporation leads to chain termination. Here we examine the structural basis for incorporation and stalling for the case of influenza polymerase, using T1106-TP, the nucleotide form of T1105, the de-fluoro analogue of T705. We used a specially designed template that allows single T1106-MP incorporation at a defined site followed by consecutive T1106-MP incorporation and stalling four nucleotides later, as demonstrated by biochemical analysis. A high-resolution cryoEM structure of influenza A/H7N9 polymerase, stalled after transcribing this template, revealed that the entire product-template duplex has backtracked by five nucleotides. Consequently, the singly incorporated T1106-MP resides at the +1 position and forms an unexpected wobble base-pair with a U in the template. The relative stability of the canonical and wobble T1106:U base-pairs in different contexts is investigated by molecular dynamics simulations. Using a different template and influenza B polymerase we also observe stalling after double incorporation of T1106-MP and structural analysis showed again that backtracking occurs, this time by four nucleotides. These results show that, at least in early elongation, consecutive T1106-MP incorporation into the product destabilises the proximal end of the product-template duplex, promoting irreversible backtracking until a more favourable overall configuration is achieved. These results give new insight into the unusual mechanism of chain termination by pyrazinecarboxamide base analogues.

molecular biology↗

Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects cognitive behavior

Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition (E/I). Yet, the molecular and cellular mechanisms that form the E/I balance are just beginning to emerge. Here, using conditional GABAB receptor-deficient mice we identified a GABA/TNF-related cytokine (TNFSF12)-mediated bidirectional communication pathway between Parvalbumin-positive (PV+) fast spiking interneurons and oligodendrocyte precursor cells (OPCs) that determines the density and function of interneurons in the developing medial prefrontal cortex (mPFC). Interruption of the GABAergic signaling to OPCs resulted in reduced myelination and hypoactivity of interneurons, strong changes of cortical network activities and impaired cognitive behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct brain functions.

neuroscience↗

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. Here we show that Favipiravir exerts an antiviral effect as a nucleotide analogue through a combination of chain termination, slowed RNA synthesis and lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

biochemistry↗