Escherichia coli is generally used as model bacteria to define microbial cell factories for many products and to investigate regulation mechanisms. E. coli exhibits phospholipids, ...lipopolysaccharides, colanic acid, flagella and type I fimbriae on the outer membrane which is a self-protective barrier and closely related to cellular morphology, growth, phenotypes and stress adaptation. However, these outer membrane associated molecules could also lead to potential contamination and insecurity for fermentation products and consume lots of nutrients and energy sources. Therefore, understanding critical insights of these membrane associated molecules is necessary for building better microbial producers. Here the biosynthesis, function, influences, and current membrane engineering applications of these outer membrane associated molecules were reviewed from the perspective of synthetic biology, and the potential and effective engineering strategies on the outer membrane to improve fermentation features for microbial cell factories were suggested.
Background Remnant cholesterol (RC) has been reported to promote atherosclerotic cardiovascular disease. Yet little is known regarding the RC-related residual risk in patients with myocardial ...infarction (MI) with nonobstructive coronary arteries. Methods and Results A total of 1179 patients with MI with nonobstructive coronary arteries were enrolled and divided according to median level of RC calculated as non-high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol. The primary end point was a composite of major adverse cardiovascular events (MACEs), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, and receiver-operating characteristic analyses were used. Patients with higher median level of RC had a significantly higher incidence of MACEs (16.9% versus 11.5%;
=0.009) over the median follow-up of 41.7 months. High RC levels were significantly associated with an increased risk of MACEs after adjustment for multiple clinically relevant variables (per 1 SD increase, hazard ratio, 0.61; 95% CI, 1.12-2.31;
=0.009). Elevated RC also contributed to residual risk beyond conventional lipid parameters. Moreover, RC had an area under the curve of 0.61 for MACE prediction. When adding RC to the Thrombolysis in Myocardial Infarction risk score, the combined model yielded a significant improvement in discrimination for MACEs. Conclusions Elevated RC was closely associated with poor outcomes after MI with nonobstructive coronary arteries independent of traditional risk factors, indicating the utility of RC for risk stratification and a rationale for targeted RC-lowering trials in patients with MI with nonobstructive coronary arteries.
Stem cells play critical roles both in the development of cancer and therapy resistance. Although mesenchymal stem cells (MSCs) can actively migrate to tumor sites, their impact on chimeric antigen ...receptor modified T cell (CAR-T) immunotherapy has been little addressed. Using an in vitro cell co-culture model including lymphoma cells and macrophages, here we report that CAR-T cell-mediated cytotoxicity was significantly inhibited in the presence of MSCs. MSCs caused an increase of CD4
T cells and Treg cells but a decrease of CD8
T cells. In addition, MSCs stimulated the expression of indoleamine 2,3-dioxygenase and programmed cell death-ligand 1 which contributes to the immune-suppressive function of tumors. Moreover, MSCs suppressed key components of the NLRP3 inflammasome by modulating mitochondrial reactive oxygen species release. Interestingly, all these suppressive events hindering CAR-T efficacy could be abrogated if the stanniocalcin-1 (STC1) gene, which encodes the glycoprotein hormone STC-1, was knockdown in MSC. Using xenograft mice, we confirmed that CAR-T function could also be inhibited by MSC in vivo, and STC1 played a critical role. These data revealed a novel function of MSC and STC-1 in suppressing CAR-T efficacy, which should be considered in cancer therapy and may also have potential applications in controlling the toxicity arising from the excessive immune response.
There is a complex regulatory network of nitrogen metabolism in
, and many details of this regulatory network have not been revealed. This study explored the global regulation of nitrogen metabolism ...in
from an epigenetic perspective. Comparative transcriptome analysis of
S288C treated with 30 nitrogen sources identified nine chromatin regulators (CRs) that responded significantly to different nitrogen sources. Functional analysis showed that among the CRs identified, Ahc1p and Eaf3p promoted the utilization of non-preferred nitrogen sources through global regulation of nitrogen metabolism. Ahc1p regulated nitrogen metabolism through amino acid transport, nitrogen catabolism repression (NCR), and the Ssy1p-Ptr3p-Ssy5p signaling sensor system. Eaf3p regulated nitrogen metabolism via amino acid transport and NCR. The regulatory mechanisms of the effects of Ahc1p and Eaf3p on nitrogen metabolism depended on the function of their histone acetyltransferase complex ADA and NuA4. These epigenetic findings provided new insights for a deeper understanding of the nitrogen metabolism regulatory network in
.
Co-production of polyhydroxyalkanoate (PHA) and amino acids makes bacteria effective microbial cell factories by secreting amino acids outside while accumulating PHA granules inside. ...Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is one of the PHAs with biocompatibility and fine mechanical properties, but its production is limited by the low level of intracellular propionyl-CoA.
L-Isoleucine producing Corynebacterium glutamicum strain WM001 were analyzed by genome and transcriptome sequencing. The results showed that the most over-expressed genes in WM001 are relevant not only to L-isoleucine production but also to propionyl-CoA accumulation. Compared to the wild-type C. glutamicum ATCC13869, the transcriptional levels of the genes prpC2, prpD2, and prpB2, which are key genes relevant to propionyl-CoA accumulation, increased 2
, 2
, and 2
-folds in WM001, respectively; and the intracellular level of propionyl-CoA increased 16.9-fold in WM001. When the gene cluster phaCAB for PHA biosynthesis was introduced into WM001, the recombinant strain WM001/pDXW-8-phaCAB produced 15.0 g/L PHBV with high percentage of 3-hydroxyvalerate as well as 29.8 g/L L-isoleucine after fed-batch fermentation. The maximum 3-hydroxyvalerate fraction in PHBV produced by WM001/pDXW-8-phaCAB using glucose as the sole carbon source could reach 72.5%, which is the highest reported so far.
Genome and transcriptome analysis showed that C. glutamicum WM001 has potential to accumulate L-isoleucine and propionyl-CoA pool. This was experimentally confirmed by introducing the phaCAB gene cluster into WM001. The recombinant strain WM001/pDXW-8-phaCAB produced high levels of PHBV with high 3-hydroxyvalerate fraction as well as L-isoleucine. Because of its high level of intracellular propionyl-CoA pool, WM001 might be used for producing other propionyl-CoA derivatives.
In metabolic engineering, unbalanced microbial carbon distribution has long blocked the further improvement in yield and productivity of high-volume natural metabolites. Current studies mostly focus ...on regulating desired biosynthetic pathways, whereas few strategies are available to maximize L-threonine efficiently. Here, we present a strategy to guarantee the supply of reduced cofactors and actualize L-threonine maximization by regulating cellular carbon distribution in central metabolic pathways. A thermal switch system was designed and applied to divide the whole fermentation process into two stages: growth and production. This system could rebalance carbon substrates between pyruvate and oxaloacetate by controlling the heterogenous expression of pyruvate carboxylase and oxaloacetate decarboxylation that responds to temperature. The system was tested in an L-threonine producer Escherichia coli TWF001, and the resulting strain TWF106/pFT24rp overproduced L-threonine from glucose with 111.78% molar yield. The thermal switch system was then employed to switch off the L-alanine synthesis pathway, resulting in the highest L-threonine yield of 124.03%, which exceeds the best reported yield (87.88%) and the maximum available theoretical value of L-threonine production (122.47%). This inducer-free genetic circuit design can be also developed for other biosynthetic pathways to increase product conversion rates and shorten production cycles.
•A strategy was exploited to dynamically regulate carbon distribution in E. coli.•The redox metabolism was rebalanced to appropriately reduce the cofactor supply.•A thermal switch system was designed for improving E. coli industrial production.•Significant threonine production was gained using the system.•Maximum threonine yield was obtained by switching off the alanine synthesis pathway.
Low triiodothyronine syndrome (LT3S), frequently seen in patients with acute myocardial infarction (AMI), has been regarded as a predictor of poor outcomes after AMI. However, little is known about ...the prognostic value of LT3S in euthyroid patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).
A total of 1162 MINOCA patients were enrolled and divided into LT3S and no-LT3S groups. LT3S was defined as decreased free T3 (fT3 < 2.36 pg/mL) with normal values of thyroid-stimulating hormone. The primary endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, propensity score matching (PSM), and receiver-operating characteristic analyses were performed.
Patients with LT3S (prevalence of 17.5%) had a significantly higher incidence of MACE (19.6% vs. 12.9%; p = .013) than patients without during the median follow-up of 41.7 months. LT3S was closely associated with an increased risk of MACE even after multivariable adjustment (HR 1.50, 95% CI: 1.03-2.18, p = .037). After PSM, 197 pairs of patients with or without LT3S were identified, and LT3S remained a robust risk factor of worse outcomes (HR 1.53, 95% CI: 1.02-2.65, p = .042). Moreover, LT3S had an area under the curve (AUC) of 0.60 for predicting MACE. When adding LT3S to the thrombolysis in myocardial infarction (TIMI) risk score, the combined model yielded a significant improvement in discrimination for MACE.
LT3S was independently associated with poor outcomes after MINOCA. Routine assessment of LT3S may provide valuable prognostic information in this specific population.
Hyperuricemia (HUA) has been proved as a predictor of worse outcomes in patients with coronary artery disease. Here, we investigated the prognostic value of HUA in a distinct population with ...myocardial infarction with nonobstructive coronary arteries (MINOCA).
A total of 1179 MINOCA patients were enrolled and divided into HUA and non-HUA groups. HUA was defined as a serum uric acid level ≥ 420 μmol/L in men or ≥ 357 μmol/L in women. The primary study endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, and receiver-operating characteristic analyses were performed.
Patients with HUA (prevalence of 23.5%) had a significantly higher incidence of MACE (18.7% vs. 12.8%; p = 0.015) than patients without during the median follow-up of 41.7 months. HUA was closely associated with an increased risk of MACE even after multivariable adjustment (hazard ratio 1.498, 95% confidence interval: 1.080 to 2.077; p = 0.016). HUA remained a robust risk factor of MACE after propensity score matching analysis. Moreover, HUA showed an area under the curve (AUC) of 0.59 for predicting MACE. Incorporation of HUA to the thrombolysis in myocardial infarction (TIMI) score yielded a significant improvement in discrimination for MACE.
HUA was independently associated with poor prognosis after MINOCA. Routine assessment of HUA may facilitate risk stratification in this specific population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
This paper presents a reflective-type phase shifter (RTPS) capable of full 360° phase shift range with low-loss and compact for 5.47-5.85 GHz WLAN wireless backhaul. Intuitive and concise analyses of ...common reflective loads, including single-element single-tunable (SEST), dual-element single-tunable (DEST) and there-element single-tunable (TEST), are analyzed, elaborating their limitations. The four-elements dual-tunable (FEDT) load technique is proposed to increase the phase shift range. In addition, the influence factors of phase shift step and insertion loss (IL) are comprehensively discussed. Measurement results show that the proposed RTPS provides a phase shift range greater than 360°, a phase shift step less than 15°, an IL less than 2.3 dB in the entire frequency band. Meanwhile, the size of this RTPS is just only 9.5×8.2 mm 2 . Compared to other RTPS, this design has the advantages of low IL, compact size, wide-band, high precision, and easy to control.
Thyroid function is closely involved in cardiovascular diseases. The free triiodothyronine (fT3) to free thyroxine (fT4) ratio has been reported as a risk factor for coronary artery disease, but its ...prognostic value in euthyroid patients with myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear.
A total of 1162 euthyroid patients with MINOCA were enrolled and divided according to decreased tertiles of fT3/fT4 ratio. The study endpoint was major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan-Meier, Cox regression, and receiver-operating characteristic analyses were performed.
Patients with lower fT3/fT4 tertile levels had a significantly higher incidence of MACE (10.0%, 13.9%, 18.2%; p=0.005) over the median follow-up of 41.7 months. The risk of MACE increased with the decreasing fT3/fT4 tertiles even after multivariate adjustment (tertile1 as reference, tertile2: HR 1.58, 95% CI: 1.05-2.39, p=0.030; tertile3: HR 2.06, 95% CI: 1.17-3.11, p=0.006). Lower level of fT3/fT4 ratio remained a robust predictor of MACE in overall (HR 1.64, 95% CI: 1.18-2.29, p=0.003) and in subgroups. When adding fT3/fT4 ratio area under the curve (AUC) 0.61 into the thrombolysis in myocardial infarction (TIMI) risk score (AUC 0.69), the combined model (AUC 0.74) yielded a significant improvement in discrimination for MACE (ΔAUC 0.05, p=0.023).
Low level of fT3/fT4 ratio was strongly associated with a poor prognosis in euthyroid patients with MINOCA. Routine assessment of fT3/fT4 ratio may facilitate risk stratification in this specific population.
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