MicroRNAs control mRNA fate by compartmentalization based on 3 ' UTR length in male germ cells

Post-transcriptional regulation of gene expression can be achieved through the control of mRNA stability, cytoplasmic compartmentalization, 3' UTR length and translational efficacy. Spermiogenesis, a process through which haploid male germ cells differentiate into spermatozoa, represents an ideal model for studying post-transcriptional regulation in vivo because it involves a large number of transcripts that are physically sequestered in ribonucleoprotein particles (RNPs) and thus subjected to delayed translation. To explore how small RNAs regulate mRNA fate, we conducted RNA-Seq analyses to determine not only the levels of both mRNAs and small noncoding RNAs, but also their cytoplasmic compartmentalization during spermiogenesis. Result: Among all small noncoding RNAs studied, miRNAs displayed the most dynamic changes in both abundance and subcytoplasmic localization. mRNAs with shorter 3' UTRs became increasingly enriched in RNPs from pachytene spermatocytes to round spermatids, and the enrichment of shorter 3' UTR mRNAs in RNPs coincided with newly synthesized miRNAs that target these mRNAs at sites closer to the stop codon. In contrast, the translocation of longer 3' UTR mRNAs from RNPs to polysomes correlated with the production of new miRNAs that target these mRNAs at sites distal to the stop codon. Conclusions: miRNAs appear to control cytoplasmic compartmentalization of mRNAs based on 3' UTR length. Our data suggest that transcripts with longer 3' UTRs tend to contain distal miRNA binding sites and are thus targeted to polysomes for translation followed by degradation. In contrast, those with shorter 3' UTRs only possess proximal miRNA binding sites, which, therefore, are targeted into RNPs for enrichment and delayed translation

Multifunctional antimicrobial biometallohydrogels based on amino acid coordinated self-assembly

There is a real need for new antibiotics against self‐evolving bacteria. One option is to use biofriendly broad‐spectrum and mechanically tunable antimicrobial hydrogels that can combat multidrug‐resistant microbes. Whilst appealing, there are currently limited options. Herein, broad‐spectrum antimicrobial biometallohydrogels based on the self‐assembly and local mineralization of Ag+‐coordinated Fmoc‐amino acids are reported. Such biometallohydrogels have the advantages of localized delivery and sustained release, reduced drug dosage and toxicity yet improved bioavailability, prolonged drug effect, and tunable mechanical strength. Furthermore, they can directly interact with the cell walls and membrane, resulting in the detachment of the plasma membrane and leakage of the cytoplasm. This leads to cell death, triggering a significant antibacterial effect against both Gram‐negative (Escherichia coli) and Gram‐positive (Staphylococcus aureus) bacteria in cells and mice. This study paves the way for developing a multifunctional integration platform based on simple biomolecules coordinated self‐assembly toward a broad range of biomedical applications

Microfluidic mass production of stabilized and stealthy liquid metal nanoparticles

Functional nanoparticles comprised of liquid metals, such as eutectic gallium indium (EGaIn) and Galinstan, present exciting opportunities in the fields of flexible electronics, sensors, catalysts, and drug delivery systems. Methods used currently for producing liquid metal nanoparticles have significant disadvantages as they rely on both bulky and expensive high-power sonication probe systems, and also generally require the use of small molecules bearing thiol groups to stabilize the nanoparticles. Herein, we describe an innovative microfluidics-enabled platform as an inexpensive, easily accessible method for the on-chip mass production of EGaIn nanoparticles with tunable size distributions in an aqueous medium. We also report a novel nanoparticle-stabilization approach using brushed polyethylene glycol chains with trithiocarbonate end-groups negating the requirements for thiol additives whilst imparting a ‘stealth’ surface layer. Furthermore, we demonstrate a surface modification of the nanoparticles using galvanic replacement, and conjugation with antibodies. We envision that the demonstrated microfluidic technique can be used as an economic and versatile platform for the rapid production of liquid metal-based nanoparticles for a range of biomedical applications.

Pathological Tau From Alzheimer’s Brain Induces Site-Specific Hyperphosphorylation and SDS- and Reducing Agent-Resistant Aggregation of Tau in vivo

Neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau are a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Hyperphosphorylation of tau is responsible for its loss of normal physiological function, gain of toxicity and its aggregation to form NFTs. Injection of misfolded tau seeds into mouse brain induces tau aggregation, but the nature of tau phosphorylation in pathologic tau seeded pathology is unclear. In the present study, we injected hyperphosphorylated and oligomeric tau isolated from AD brain (AD P-tau) into hippocampus of human tau transgenic mice and found that in addition to tau aggregation/pathology, tau was hyperphosphorylated at Ser202/Thr205, Thr212, Ser214, Thr217, Ser262, and Ser422 in AD P-tau injected hippocampus and at Ser422 in the contralateral hippocampus and in the ipsilateral cortex. AD P-tau-induced AD-like high molecular weight aggregation of tau that was SDS- and reducing agent-resistant and site-specifically hyperphosphorylated in the ipsilateral hippocampus. There were no detectable alterations in levels of tau phosphatases or tau kinases in AD P-tau-injected brains. Furthermore, we found that hyperphosphorylated tau was easier to be captured by AD P-tau and that aggregated tau was more difficult to be dephosphorylated than the non-aggregated tau by protein phosphatase 2A (PP2A). Based on these findings, we speculate that AD P-tau seeds hyperphosphorylated tau to form aggregates, which resist to the dephosphorylation by PP2A, resulting in hyperphosphorylation and pathology of tau

The functional and structural alterations of the striatum in chronic spontaneous urticaria

The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSU patients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient’s clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch

Association Between the Methylation Statuses at CpG Sites in the Promoter Region of the SLCO1B3, RNA Expression and Color Change in Blue Eggshells in Lushi Chickens

The formation mechanism underlying the blue eggshell characteristic has been discovered in birds, and SLCO1B3 is the key gene that regulates the blue eggshell color. Insertion of an endogenous retrovirus, EAV-HP, in the SLCO1B3 5′ flanking region promotes SLCO1B3 expression in the chicken shell gland, and this expression causes bile salts to enter the shell gland, where biliverdin is secreted into the eggshell, forming a blue shell. However, at different laying stages of the same group of chickens, the color of the eggshell can vary widely, and the molecular mechanism underlying the eggshell color change remains unknown. Therefore, to reveal the molecular mechanism of the blue eggshell color variations, we analyzed the change in the eggshell color during the laying period. The results indicated that the eggshell color in Lushi chickens can be divided into three stages: 20–25 weeks for dark blue, 26–45 weeks for medium blue, and 46–60 weeks for light blue. We further investigated the expression and methylation levels of the SLCO1B3 gene at eight different weeks, finding that the relative expression of SLCO1B3 was significantly higher at 25 and 30 weeks than at other laying weeks. Furthermore, the overall methylation rate of the SLCO1B3 gene in Lushi chickens increased gradually with increasing weeks of egg production, as shown by bisulfite sequencing PCR. Pearson correlation analysis showed that methylation of the promoter region of SLCO1B3 was significantly negatively correlated with both SLCO1B3 expression in the shell gland tissue and eggshell color. In addition, we predicted that CpG5 and CpG8 may be key sites for regulating SLCO1B3 gene transcription. Our findings show that as the level of methylation increases, methylation of the CpG5 and CpG8 sites hinders the binding of transcription factors to the promoter, reducing SLCO1B3 expression during the late period and resulting in a lighter eggshell color

The chemical profiling of Salvia plebeia during different growth periods and the biosynthesis of its main flavonoids ingredients

Salvia plebeia (Lamiaceae) is a valuable medicinal plant widely distributed across Asia and Oceania. However, the composition and accumulation patterns of its active ingredients in different organs during the growth and their biosynthetic mechanism remain unknown. Therefore, we conducted metabolite profiling, transcriptomic analysis, and biological functional verification to explore the distribution, accumulation, and biosynthesis mechanisms of flavonoids in S. plebeia. We identified 70 metabolites including 46 flavonoids, 16 phenolic acids, seven terpenoids, and one organic acid, of which 21 were previously unreported in S. plebeia. Combining metabolomic-transcriptomic analysis and biological functional verification, we identified the key genes involved in biosynthesis of its main active ingredients, hispidulin and homoplantaginin, including SpPAL, SpC4H, Sp4CL2, Sp4CL5, SpCHS1, SpCHI, SpFNS, SpF6H1, SpF6OMT1, SpF6OMT2, SpUGT1, SpUGT2, and SpUGT3. Using the identified genes, we reconstructed the hispidulin and homoplantaginin biosynthesis pathways in Escherichia coli, and obtained a yield of 5.33 and 3.86 mg/L for hispidulin and homoplantaginin, respectively. Our findings provide valuable insights into the changes in chemical components in different organs of S. plebeia during different growth and harvest stages and establishes a foundation for identifying and synthesizing its active components