Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Tetramerization of upstream stimulating factor USF2 requires the elongated bent leucine zipper of the bHLH-LZ domain.

Upstream stimulating factors (USFs), including USF1 and USF2, are key components of the transcription machinery that recruit coactivators and histone-modifying enzymes. Using the classic basic helix-loop-helix leucine zipper (bHLH-LZ) domain, USFs bind the E-box DNA and form tetramers that promote DNA looping for transcription initiation. The structural basis by which USFs tetramerize and bind DNA, however, remains unknown. Here, we report the crystal structure of the complete bHLH-LZ domain of USF2 in complex with E-box DNA. We observed that the leucine zipper (LZ) of USF2 is longer than that of other bHLH-LZ family transcription factors and that the C-terminus of USF2 forms an additional α-helix following the LZ region (denoted as LZ-Ext). We also found the elongated LZ-Ext facilitates compact tetramer formation. In addition to the classic interactions between the basic region and DNA, we show a highly conserved basic residue in the loop region, Lys271, participates in DNA interaction. Together, these findings suggest that USF2 forms a tetramer structure with a bent elongated LZ-Ext region, providing a molecular basis for its role as a key component of the transcription machinery.

Effects of Latilactobacillus sakei LZ217 on Gastric Mucosal Colonization, Metabolic Interference, and Urease Expression in Helicobacter pylori Infection.

Emerging evidence suggests differential antagonism of lactic acid-producing bacteria (LAB) to Helicobacter pylori, posing challenges to human health and food safety due to unclear mechanisms. This study assessed 21 LAB strains from various sources on H. pylori growth, urease activity, and coaggregation. Composite scoring revealed that Latilactobacillus sakei LZ217, derived from fresh milk, demonstrates strong inhibitory effects on both H. pylori growth and urease activity. L. sakei LZ217 significantly reduced H. pylori adherence of gastric cells in vitro, with inhibition ratios of 47.62%. Furthermore, in vivo results showed that L. sakei LZ217 alleviated H. pylori-induced gastric mucosa damage and inflammation in mice. Metabolomic exploration revealed metabolic perturbations in H. pylori induced by L. sakei LZ217, including reduced amino acid levels (e.g., isoleucine, leucine, glutamate, aspartate, and phenylalanine) and impaired carbohydrate and nucleotide synthesis, contributing to the suppression of ureA (28.30%), ureE (84.88%), and ureF (59.59%) expressions in H. pylori. This study underscores the efficacy of LAB against H. pylori and highlights metabolic pathways as promising targets for future interventions against H. pylori growth and colonization.

An Iterative Scale Purification Procedure on lz for the Detection of Aberrant Responses.

Many person-fit statistics have been proposed to detect aberrant response behaviors (e.g., cheating, guessing). Among them, lz is one of the most widely used indices. The computation of lz assumes the item and person parameters are known. In reality, they often have to be estimated from data. The better the estimation, the better lz will perform. When aberrant behaviors occur, the person and item parameter estimations are inaccurate, which in turn degrade the performance of lz. In this study, an iterative procedure was developed to attain more accurate person parameter estimates for improved performance of lz. A series of simulations were conducted to evaluate the iterative procedure under two conditions of item parameters, known and unknown, and three aberrant response styles of difficulty-sharing cheating, random-sharing cheating, and random guessing. The results demonstrated the superiority of the iterative procedure over the non-iterative one in maintaining control of Type-I error rates and improving the power of detecting aberrant responses. The proposed procedure was applied to a high-stake intelligence test.

Lossy Compression of Individual Sequences Revisited: Fundamental Limits of Finite-State Encoders.

We extend Ziv and Lempel's model of finite-state encoders to the realm of lossy compression of individual sequences. In particular, the model of the encoder includes a finite-state reconstruction codebook followed by an information lossless finite-state encoder that compresses the reconstruction codeword with no additional distortion. We first derive two different lower bounds to the compression ratio, which depend on the number of states of the lossless encoder. Both bounds are asymptotically achievable by conceptually simple coding schemes. We then show that when the number of states of the lossless encoder is large enough in terms of the reconstruction block length, the performance can be improved, sometimes significantly so. In particular, the improved performance is achievable using a random-coding ensemble that is universal, not only in terms of the source sequence but also in terms of the distortion measure.

CD169+ subcapsular sinus macrophage-derived microvesicles are associated with light zone follicular dendritic cells.

Follicular dendritic cells (FDCs) are a specialized type of stromal cells that exclusively reside in B-cell follicles. When inflammation occurs, the FDC network is reorganized to support germinal center (GC) polarization into the light zone (LZ) and dark zone (DZ). Despite the indispensable role of FDCs in supporting humoral responses, the FDC regulatory requirements remain incompletely defined. In this study, we unexpectedly observed an accumulation of CD169+ subcapsular sinus macrophage (SSM)-derived microvesicles (MVs) in the B-cell zone, which were tightly associated with the FDC network. Interestingly, a selective deposition of CD169+ MVs was detected in both GC LZ FDCs in secondary follicles and on predetermined LZ FDCs in primary follicles. The ablation of CD169+ MVs, resulting from SSM depletion, resulted in significantly decreased expression of LZ-related genes in FDCs. In addition, we found that CD169+ MVs could colocalize with fluorescently tagged antigen-containing immune complexes (ICs), supporting a possible role of CD169+ MVs in transporting antigens to the FDC network. Thus, our data reveal intimate crosstalk between FDCs and SSMs located outside B-cell follicles via SSM-released MVs, providing a novel perspective on the mechanisms underlying the regulation of FDC maturation and polarization.

Study of the Impact of Data Compression on the Energy Consumption Required for Data Transmission in a Microcontroller-Based System.

As the number of Internet of Things (IoT) devices continues to rise dramatically each day, the data generated and transmitted by them follow similar trends. Given that a significant portion of these embedded devices operate on battery power, energy conservation becomes a crucial factor in their design. This paper aims to investigate the impact of data compression on the energy consumption required for data transmission. To achieve this goal, we conduct a comprehensive study using various transmission modules in a severely resource-limited microcontroller-based system designed for battery power. Our study evaluates the performance of several compression algorithms, conducting a detailed analysis of computational and memory complexity, along with performance metrics. The primary finding of our study is that by carefully selecting an algorithm for compressing different types of data before transmission, a significant amount of energy can be saved. Moreover, our investigation demonstrates that for a battery-powered embedded device transmitting sensor data based on the STM32F411CE microcontroller, the recommended transmission module is the nRF24L01+ board, as it requires the least amount of energy to transmit one byte of data. This module is most effective when combined with the LZ78 algorithm for optimal energy and time efficiency. In the case of image data, our findings indicate that the use of the JPEG algorithm for compression yields the best results. Overall, our research underscores the importance of selecting appropriate compression algorithms tailored to specific data types, contributing to enhanced energy efficiency in IoT devices.

The regulation function of intestinal microbiota by folate-producing Lactiplantibacillus plantarum LZ227.

BACKGROUND: Folic acid is a class of B vitamins that have the function of improving intestinal microbiota. RESULT: Lactiplantibacillus plantarum LZ227, which is a highly folate-producing strain, was used as the research object, and the folic acid produced by LZ227 was further identified by liquid chromatography-mass spectrometry, and the structural diversity, community composition, abundance difference, and short-chain fatty acids content in fermentation broth were studied by the manure slurry fermentation model. The results showed that the folic acid produced by LZ227 was 5-methyltetrahydrofolate. CONCLUSION: LZ227 can increase the intestinal microbial diversity in the folate-free state, regulate the intestinal flora, increase the abundance of Firmicutes in the intestinal flora, and inhibit the abundance of Bacteroidetes. LZ227 can inhibit the growth of Alistipes, Parabacteroides, and Bacteroides in the intestine. LZ227 significantly reduced the acetic acid content and significantly increased the butyric acid content in the folate-free case. © 2023 Society of Chemical Industry.

A Universal Random Coding Ensemble for Sample-Wise Lossy Compression.

We propose a universal ensemble for the random selection of rate-distortion codes which is asymptotically optimal in a sample-wise sense. According to this ensemble, each reproduction vector, x^, is selected independently at random under the probability distribution that is proportional to 2-LZ(x^), where LZ(x^) is the code length of x^ pertaining to the 1978 version of the Lempel-Ziv (LZ) algorithm. We show that, with high probability, the resulting codebook gives rise to an asymptotically optimal variable-rate lossy compression scheme under an arbitrary distortion measure, in the sense that a matching converse theorem also holds. According to the converse theorem, even if the decoder knew the ℓ-th order type of source vector in advance (ℓ being a large but fixed positive integer), the performance of the above-mentioned code could not have been improved essentially for the vast majority of codewords pertaining to source vectors in the same type. Finally, we present a discussion of our results, which includes among other things, a clear indication that our coding scheme outperforms the one that selects the reproduction vector with the shortest LZ code length among all vectors that are within the allowed distortion from the source vector.

A Hybrid Data-Differencing and Compression Algorithm for the Automotive Industry.

We propose an innovative delta-differencing algorithm that combines software-updating methods with LZ77 data compression. This software-updating method relates to server-side software that creates binary delta files and to client-side software that performs software-update installations. The proposed algorithm creates binary-differencing streams already compressed from an initial phase. We present a software-updating method suitable for OTA software updates and the method's basic strategies to achieve a better performance in terms of speed, compression ratio or a combination of both. A comparison with publicly available solutions is provided. Our test results show our method, Keops, can outperform an LZMA (Lempel-Ziv-Markov chain-algorithm) based binary differencing solution in terms of compression ratio in two cases by more than 3% while being two to five times faster in decompression. We also prove experimentally that the difference between Keops and other competing delta-creator software increases when larger history buffers are used. In one case, we achieve a three times better performance for a delta rate compared to other competing delta rates.

Structural basis for the dimerization mechanism of human transcription factor E3.

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) is a member of the microphthalmia (MiT/TFE) transcription factor family. Dysregulation of TFE3 due to chromosomal abnormalities is associated with a subset of human renal cell carcinoma. Little structural information of this key transcription factor has been reported. In this study, we determined the crystal structure of the helix-loop-helix leucine zipper (HLH-Lz) domain of human TFE3 to a resolution of 2.6 Å. The HLH-Lz domain is critical for the dimerization and function of TFE3. Our structure showed that the conserved HLH region formed a four-helix bundle structure with a predominantly hydrophobic core, and the leucine zipper region contributed to the function of TFE3 by promoting dimer interaction and providing partner selectivity. Together, our results elucidated the dimerization mechanism of this important transcription factor, providing the structural basis for the development of inhibiting strategies for treating TFE3 dysregulated diseases.

LZ205, a newly synthesized flavonoid compound, exerts anti-inflammatory effect by inhibiting M1 macrophage polarization through regulating PI3K/AKT/mTOR signaling pathway.

Macrophage polarization is involved in the process of inflammation. Regulation of macrophage polarization is considered to be an effective method for the treatment of various inflammatory diseases. In our study, we investigated the potential molecular mechanism of the flavonoid compound LZ205, which exhibits anti-inflammatory property. Results showed that LZ205 significantly reduced M1 macrophage-associated proinflammatory cytokines secretion by regulating PI3K/AKT/mTOR signaling pathway without affecting M2 macrophage-associated cytokines mRNA levels. In vivo studies showed that LZ205 significantly inhibited M1 macrophages polarization in DSS-induced colitis and alum-induced murine peritonitis. Consistent with in vitro studies, LZ205 significantly blocked expression of PI3K, p-AKT and p-mTOR in colon tissues and peritoneal macrophages. Taken together, LZ205 exerts anti-inflammatory effect by inhibiting M1 macrophage polarization via regulating PI3K/AKT/mTOR signaling pathway.

Miz-1 and Max compete to engage c-Myc: implication for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1.

c-Myc is a basic helix-loop-helix leucine zipper (b-HLH-LZ) transcription factor deregulated in the majority of human cancers. As a heterodimer with Max, another b-HLH-LZ transcription factor, deregulated and persistent c-Myc accumulates at transcriptionally active promoters and enhancers and amplifies transcription. This leads to the so-called transcriptional addiction of tumor cells. Recent studies have showed that c-Myc transcriptional activities can be reversed by its association with Miz-1, a POZ transcription factor containing 13 classical zinc fingers. Although evidences have led to suggest that c-Myc interacts with both Miz-1 and Max to form a ternary repressive complex, earlier evidences also suggest that Miz-1 and Max may compete to engage c-Myc. In such a scenario, the Miz-1/c-Myc complex would be the entity responsible for the inhibition of c-Myc transcriptional amplification. Considering the implications of the Miz-1/c-Myc interaction, it is highly important to solve this duality. While two potential c-Myc interacting domains (hereafter termed MID) have been identified in Miz-1 by yeast two-hybrid, with the b-HLH-LZ as a bait, the biophysical characterization of these interactions has not been reported so far. Here, we report that the MID located between the 12th and 13th zinc finger of Miz-1 and the b-HLH-LZ of Max compete to form a complex with the b-HLH-LZ of c-Myc. Our results support the notion that the repressive action of Miz-1 on c-Myc does not rely on the formation of a ternary complex. The implications of these observations for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1 are discussed. Proteins 2017; 85:199-206. © 2016 Wiley Periodicals, Inc.

Novel vitamin B12-producing Enterococcus spp. and preliminary in vitro evaluation of probiotic potentials.

Vitamin B12 is an essential nutrient required for crucial metabolic processes in humans. Vitamin B12-producing lactic acid bacteria (LAB) have been attracting increased attentions currently because of the generally recognized as safe (GRAS) status. Most of recent studies focused on Lactobacillus, and little is known about B12-producing Enterococcus. In the present study, five Enterococcus strains isolated from infant feces were identified as vitamin B12 producers. Among them, Enterococcus faecium LZ86 had the highest B12 production (499.8 ± 83.7 µg/L), and the B12 compound from LZ86 was identified as the biological active adenosylcobalamin, using reversed phase high-performance liquid (RP-HPLC) chromatogram. We examined basic probiotic and safety properties of E. faecium LZ86 and found that it was able to survive harsh environmental conditions (hot temperature, cold temperature, ethanol and osmotic stresses), tolerate gastric acid (pH 2.0, 3 h) and bile salts (0.3%), and adhere to Caco-2 cells. We also showed that E. faecium LZ86 is devoid of transferable antibiotic resistance and potential virulence factors. Together, here we report a B12-producing E. faecium strain LZ86 firstly, which has desirable probiotic properties and may serve as a good candidate for vitamin B12 fortification in food industry.

Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum.

There is a paucity of data on the effect of preterm birth on the immunological composition of breast milk throughout the different stages of lactation. We aimed to characterise the effects of preterm birth on the levels of immune factors in milk during the 1st month postpartum, to determine whether preterm milk is deficient in antimicrobial factors. Colostrum (days 2-5 postpartum), transitional milk (days 8-12) and mature milk (days 26-30) were collected from mothers of extremely preterm (<28 weeks of gestation, n 15), very preterm (28-<32 weeks of gestation, n 15), moderately preterm (32-<37 weeks of gestation, n 15) and term infants (37-41 weeks of gestation, n 15). Total protein, lactoferrin, secretory IgA, soluble CD14 receptor (sCD14), transforming growth factor-ß2 (TGF-ß2), α defensin 5 (HD5), ß defensins 1 (HBD1) and 2, IL-6, IL-10, IL-13, interferon-γ, TNF-α and lysozyme (LZ) were quantified in milk. We examined the effects of lactation stage, gestational age, volume of milk expressed, mode of delivery, parity and maternal infection on milk immune factor concentrations using repeated-measures regression analysis. The concentrations of all factors except LZ and HD5 decreased over the 1st month postpartum. Extremely preterm mothers had significantly higher concentrations of HBD1 and TGF-ß2 in colostrum than term mothers did. After controlling for other variables in regression analyses, preterm birth was associated with higher concentrations of HBD1, LZ and sCD14 in milk samples. In conclusion, preterm breast milk contains significantly higher concentrations of some immune proteins than term breast milk.

Using Lempel-Ziv Complexity to Assess ECG Signal Quality.

The poor quality of wireless electrocardiography (ECG) recordings can lead to misdiagnosis and waste of medical resources. This study presents an interpretation of Lempel-Ziv (LZ) complexity in terms of ECG quality assessment, and verifies its performance on real ECG signals. Firstly, LZ complexities for typical signals, namely high-frequency (HF) noise, low-frequency (LF) noise, power-line (PL) noise, impulse (IM) noise, clean artificial ECG signals, and ECG signals with various types of noise added (ECG plus HF, LF, PL, and IM noise, respectively) were analyzed. Then, the effects of noise, signal length, and signal-to-noise ratio (SNR) on the LZ complexity of ECG signals were analyzed. The simulation results show that LZ complexity for HF noise was obviously different from those for PL and LF noise. The LZ value can be used to determine the presence of HF noise. ECG plus HF noise had the highest LZ values. Other types of noise had low LZ values. Signal lengths of over 40 s had only a small effect on LZ values. The LZ values for ECG plus all types of noise increased monotonically with decreasing SNR except for LF and PL noise. For the test of real ECG signals plus three types of noise, namely muscle artefacts (MAs), baseline wander (BW), and electrode motion (EM) artefacts, LZ complexity varied obviously with increasing MA but not for BW and EM noise. This study demonstrates that LZ complexity is sensitive to noise level (especially for HF noise) and can thus be a valuable reference index for the assessment of ECG signal quality.

Identification of the C/EBPα C-terminal tail residues involved in the protein interaction with GABP and their potency in myeloid differentiation of K562 cells.

The CCAAT/enhancer-binding protein α (C/EBPα) is the member of a family of related basic leucine zipper (bZIP) transcription factors and is critical for granulopoiesis. We previously demonstrated that C/EBPα interacts with the ETS domain of widely expressed GABPα, which leads to cooperative transcriptional activation of the myeloid-specific promoter for human FCAR encoding the Fc receptor for IgA (FcαR, CD89) in part by facilitating recruitment of C/EBPα to the promoter. The C/EBPα molecule contains transactivation domains (TADs) at its N-terminus and a DNA-binding and dimerization bZIP structure at its C-terminus. We demonstrate here that GABPα interacts with the last 18 residues of the C/EBPα C-terminus beyond the bZIP DNA-binding and dimerizing region. Deletion of this C-terminus resulted in loss of GABPα interaction but not affecting its DNA binding ability, indicating that it is not required for homodimer formation. Moreover, the C-terminus confers the ability to functionally synergize with GABP on a heterologous TAD when fused to the C-terminus of the VP16 TAD. We identified a three-amino acid stretch (amino acids 341-343) that is important for both functional and protein interactions with GABP. Ectopic expression in K562 cells of C/EBPα mutant incapable of interacting with GABPα does not induce expression of granulocytic differentiation markers including CD15, CD11b, GCSF-R and C/EBPε, and does not inhibit proliferation, whereas wild type does. These results demonstrate the functional importance of the C/EBPα C-terminus beyond the bZIP DNA-binding and dimerization region, which may mediate cooperative activation by C/EBPα and GABP of myeloid-specific genes involved in C/EBPα-dependent granulopoiesis.

p-Terphenyl O-ß-glucuronides, DNA topoisomerase inhibitors from Streptomyces sp. LZ35ΔgdmAI.

The analysis of genome sequence indicated that Streptomyces sp. LZ35 has the potential of producing many types of secondary metabolites, including p-terphenyls and geldanamycins. The fermentation of LZ35 in laboratory produces geldanamycins as the major components, which hampers the isolation of minor compounds. To clean the background of geldanamycins, the mutant strain LZ35ΔgdmAI of Streptomyces sp. LZ35 was constructed by disrupting the first PKS module of geldanamycin gene cluster (gdm). From this mutant, five novel p-terphenyls bearing glucuronic acid moiety, namely echosides A-E (1-5), were isolated with the aid of chromophore-guided fractionation. The structures of 1-5 were elucidated by the analysis of their HR-ESI-MS and NMR spectroscopic data. DNA relaxation assay indicated that compound 1 had evident inhibitory activity against topoisomerase I. Moreover, the inhibitory activity of compound 3 against topoisomerase IIα is approximately equal to VP16, indicating that p-terphenyl O-ß-glucuronides are promising leads for the development of novel inhibitors of topoisomerases.

Phosphate promotes uranium (VI) adsorption in Staphylococcus aureus LZ-01.

UNLABELLED: Staphylococcus aureus LZ-01 was isolated from the Yellow River upstream from Lanzhou which can resist and reduce chromium (VI) to chromium (III). In this study, strain LZ-01's uranium (VI) resistance and adsorption abilities were investigated. Our results showed that it can resist 2 mmol l(-1) U(VI) and adsorb 96% of 2 mmol l(-1) U(VI) after 6 h incubation. Transmission electron microscopy (TEM) images showed that precipitates were formed on the surface of the cells. Energy dispersive X-ray spectroscopy (EDX) analysis indicated that the precipitates contained uranium and phosphorus. The U(VI) adsorption rate of strain LZ-01 was promoted by 20 mmol l(-1) phosphate. It adsorbed 45% of 2·5 mmol l(-1) U(VI) in 30 min compared to 36% without phosphate (P < 0·05). Strain LZ-01 can resist heavy metals and survive in nuclear waste-contaminated environments. Strain LZ-01 might be a potential candidate for nuclear waste remediation with phosphate added. SIGNIFICANCE AND IMPACT OF THE STUDY: Staphylococcus aureus LZ-01 can resist 2 mmol l(-1) U(VI). It could adsorb more than 90% of the 2 mmol l(-1) U(VI) in 6 h. Uranium is precipitated with phosphorus on the surface of the cells. Phosphate promotes uranium adsorption in strain LZ-01, and its U(VI) adsorption capacity is related to its cell availability. These results indicate that the strain LZ-01 might be a potential candidate for remediation of nuclear waste when phosphate is added.