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Zheng, F.

Publications and source records attributed to Zheng, F..

43 records · Page 3Linked to original sources
bioRxiv2020

Ratio of the interferon-γ signature to the immunosuppression signature predicts anti-PD-1 therapy response in melanoma

Immune checkpoint inhibitor (ICI) treatments produce clinical benefit in many patients. However, better pretreatment predictive biomarkers for ICI are still needed to help match individual patients to the treatment most likely to be of benefit. Existing gene expression profiling (GEP)-based biomarkers for ICI are primarily focused on measuring a T cell-inflamed tumour microenvironment that contributes positively to the response to ICI. Here, we identified an immunosuppression signature (IMS) through analysing RNA sequencing data from a combined discovery cohort (n = 120) consisting of three publicly available melanoma datasets. Using the ratio of an established IFN-{gamma} signature and IMS led to consistently better prediction of the ICI therapy outcome compared to a collection of nine published GEP signatures from the literature on a newly generated internal validation cohort (n = 55) and three published datasets of metastatic melanoma treated with anti-PD-1 (n = 48) and anti-CTLA-4 (n = 42) as well as in patients with gastric cancer treated with antiPD-1 (n = 45), demonstrating the potential utility of IMS as a predictive/prognostic biomarker that complements existing GEP signatures for immunotherapy.

immunology↗
bioRxiv2020

Dicistronic tRNA-mRNA transcripts in grapevine (Vitis vinifera) display distinct, regional expression patterns that correlate with tRNA expression

Transfer RNAs (tRNA) are crucial adaptor molecules between messenger RNA (mRNA) and amino acids. Recent evidence in plants suggests that dicistronic tRNA-like structures also act as mobile signals for mRNA transcripts to move between distant tissues. Co-transcription is not a common feature in the plant nuclear genome and, in the few cases where polycistronic transcripts have been found, they include non-coding RNA species such as small nucleolar RNAs and microRNAs. It is not known, however, the extent to which dicistronic transcripts of tRNA and mRNAs are expressed in field-grown plants, or the factors contributing to their expression. We analysed tRNA-mRNA dicistronic transcripts in the major horticultural crop grapevine (Vitis vinifera) using a novel pipeline developed to identify dicistronic transcripts from high-throughput RNA sequencing data. We identified dicistronic tRNA-mRNA in leaf and berry samples from 22 commercial vineyards. Of the 124 tRNA genes that were expressed in both tissues, 18 tRNA were expressed forming part of 19 dicistronic tRNA-mRNAs. The presence and abundance of dicistronic molecules was tissue and geographic sub-region specific. In leaves, the expression patterns of dicistronic tRNA-mRNAs significantly correlated with tRNA expression, suggesting that their transcriptional regulation might be linked. We also found evidence of syntenic genomic arrangements of tRNAs and protein coding genes between grapevine and Arabidopsis thaliana, and widespread prevalence of dicistronic tRNA-mRNA transcripts among vascular land plants but no evidence of these transcripts in nonvascular lineages. This suggests that the appearance of plant vasculature and tRNA-mRNA occurred concurrently during the evolution of land plants.

plant biology↗
bioRxiv2020

Pyridoxal Kinase Inhibition by Artemisinins Downregulates Inhibitory Neurotransmission

The anti-malarial artemisinins have also been implicated in the regulation of various other cellular pathways. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin-B6 (also known as pyridoxal 5-phosphate, PLP), in complex with artesunate at 2.4-[A] resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter {gamma}-aminobutyric acid (GABA), define how artemisinins interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.

neuroscience↗
bioRxiv2020

Klp2 and Ase1 synergize to maintain meiotic spindle stability during metaphase I

The spindle apparatus segregates bi-oriented sister chromatids during mitosis but mono-oriented homologous chromosomes during meiosis I. It has remained unclear if similar molecular mechanisms operate to regulate spindle dynamics during mitosis and meiosis I. Here, we employed live-cell microscopy to compare the spindle dynamics of mitosis and meiosis I in fission yeast cells and demonstrated that the conserved kinesin-14 motor Klp2 plays a specific role in maintaining metaphase spindle length during meiosis I, but not during mitosis. Moreover, the maintenance of metaphase spindle stability during meiosis I requires the synergism between Klp2 and the conserved microtubule crosslinker Ase1 as the absence of both proteins causes exacerbated defects in metaphase spindle stability. The synergism is not necessary for regulating mitotic spindle dynamics. Hence, our work reveals a new molecular mechanism underlying meiotic spindle dynamics and provides insights into understanding differential regulation of meiotic and mitotic events.

cell biology↗
bioRxiv2019

Clinical Significance of C4d Deposition in Renal Tissues from Patients with Primary Sj&oumlgren's Syndrome--A Preliminary Study

ObjectivesTo evaluate renal expression of C4d, a complement component in the classical/mannose binding lectin (MBL) pathway, in patients with primary Sjogrens syndrome (pSS)-associated renal impairments. MethodsWe retrospectively reviewed the clinical and pathological data from 39 patients with pSS presenting with renal impairments. C4d was examined in paraffin-embedded biopsy tissues using immunohistochemistry. Glomerular C4d positive was defined when >75% glomeruli were globally stained. Tubulointerstitial C4d (TI-C4d) were scored semi-quantitatively as 0 (absent), 1 (spotty or weak), 2 (patchy) and 3 (diffuse). A TI-C4d score [≥]2 was considered TI-C4d positive and included in the TI-C4d+ group and vice versa. Peritubular capillary (PTC) C4d was scored as 0 (absent), 1 (0[~]10%, minimal), 2 (10%[~]50%, focal), and 3 (>50%, diffuse). ResultsGlomerular C4d deposition was observed in all 8 patients with pSS-related membranous nephropathy (MN) without obvious C1q deposition. Two of 5 patients with mesangial proliferative glomerulonephritis and 1 of 2 patients with IgA nephropathy had mild mesangial C4d deposition. Sixteen patients (6 glomerular dominant and 10 tubulointerstitial dominant) presented TI-C4d score [≥]2. Patients in the TI-C4d+ group exhibited a higher serum creatinine level at the time of renal biopsy (TI-C4d+ 132.5 [89.7, 165.5] vs. TI-C4d- 83.0 [70.7, 102.0] mol/L, P=0.008). PTC C4d was observed in 12 patients, with each of minimal, focal and diffuse staining being noted in 4 patients. ConclusionsThe MBL pathway of complement activation was potentially involved in pSS-related MN. Tubulointerstitial C4d might be a pathological marker of severe renal injury in patients with pSS-related renal impairments.

pathology↗
bioRxiv2018

Characterizing Activity and Thermostability of GH5 Cellulase Chimeras from Mesophilic and Thermophilic Parents

Cellulases from glycoside hydrolase (GH) family 5 are key enzymes in the degradation of diverse polysaccharide substrates and are used in industrial enzyme cocktails to break down biomass. The GH5 family shares a canonical ({beta})8-barrel structure, where each ({beta}) module is essential for the enzyme stability and activity. Despite their shared topology, the thermostability of GH5 enzymes can vary significantly, and highly thermostable variants are often sought for industrial applications. Based on a previously characterized thermophilic GH5 cellulase from Talaromyces emersonii (TeEgl5A, with an optimal temperature of 90{degrees}C), we created ten hybrid enzymes with the mesophilic cellulase from Prosthecium opalus (PoCel5) to determine which elements are responsible for enhanced thermostability. Five of the expressed hybrid enzymes exhibit enzyme activity. Two of these hybrids exhibited pronounced increases in the temperature optima (10 and 20{degrees}C), T50 (15 and 19{degrees}C), Tm (16.5 and 22.9{degrees}C), and extended half life, t1/2 (~240- and 650-fold at 55{degrees}C) relative to the mesophilic parent enzyme, and demonstrated improved catalytic efficiency on selected substrates. The successful hybridization strategies were validated experimentally in another GH5 cellulase from Aspergillus nidulans (AnCel5), which demonstrated a similar increase in thermostability. Based on molecular dynamics simulations (MD) of both PoCel5 and TeEgl5A parent enzymes as well as their hybrids, we hypothesize that improved hydrophobic packing of the interface between 2 and 3 is the primary mechanism by which the hybrid enzymes increase their thermostability relative to the mesophilic parent PoCel5.\n\nIMPORTANCEThermal stability is an essential property of enzymes in many industrial biotechnological applications, as high temperatures improve bioreactor throughput. Many protein engineering approaches, such as rational design and directed evolution, have been employed to improve the thermal properties of mesophilic enzymes. Structure-based recombination has also been used to fuse TIM-barrel fragments and even fragments from unrelated folds, to generate new structures. However, there are not many research on GH5 cellulases. In this study, two GH5 cellulases, which showed TIM-barrel structure, PoCel5 and TeEgl5A with different thermal properties were hybridized to study the roles of different ({beta}) motifs. This work illustrates the role that structure guided recombination can play in helping to identify sequence function relationships within GH5 enzymes by supplementing natural diversity with synthetic diversity.

bioengineering↗
bioRxiv2018

Comparison of Generally Recognized as Safe Organic Acids for Disinfecting Fresh-cut Lettuce

In this study, we aimed to determine the organic acids (acetic, lactic, citric, malic, propionic, succinic, and tartaric acids; 1% and 0.5%, w/w or v/v) that were most effective for fresh-cut lettuce disinfection based on analysis of quality (i.e., color, electrolyte leakage, and sensory quality) and microbial examination. The results showed that these acids did not negatively affect the color quality (i.e., L*, a*, b*, whiteness index, and sensory color). Additionally, 0.5% lactic acid led to the lowest electrolyte leakage (0.83%), which was not significantly different (p > 0.05) from that of distilled water (0.46%). Lactic acid (1%) did not affect the sensory quality and led to the highest microbial reduction (1.45 log reduction in aerobic plate counts [APCs]; 2.31 log reduction in molds and yeasts [M&Y]) and was therefore recommended as the primary choice for lettuce disinfection. Malic acid (0.5%), with a 1.07% electrolyte leakage rate, 0.73 log reduction in APCs, and 1.40 log reduction in M&Y, was better than the other six acids (0.5%) and was recommended as a pH regulator and a potential synergistic agent for oxidizing sanitizers. Acetic acid (1%) negatively affected the sensory quality and led to the highest electrolyte leakage (2.90%). Microbial analysis showed that propionic acid (0.5% and 1%) was ineffective for disinfection of lettuce (p > 0.05); thus, acetic and propionic acids were not recommended. Our results provide insights into the choice of sanitizers and formula design in food safety.\n\nIMPORTANCESince chlorine is forbidden in several countries, generally recognized as safe organic acids are used in minimal processing industries and in household sanitizers. The disinfection efficacy of organic acids has been studied when used alone or with oxidizing sanitizers. However, since different antibacterial mechanisms, contact time, fresh produce, and concentration have been reported, the acids most effective for single fresh produce disinfection, especially that of lettuce, an important salad vegetable, are not known. Moreover, in developing countries, because of imperfections in field management, cold chain transportation, and minimal processing industry development, the demand for low-cost household sanitizers is greater than that for minimally processed fresh produce. In this work, microbial load in lettuce was determined after disinfecting with seven GRAS organic acids. The changes in quality were also determined. These results provide insights into the choice of minimal processing sanitizers and a formula design for household sanitizers.

microbiology↗