Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.

Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.

Ribosome excursions during mRNA translocation mediate broad branching of frameshift pathways.

Programmed ribosomal frameshifting produces alternative proteins from a single transcript. -1 frameshifting occurs on Escherichia coli's dnaX mRNA containing a slippery sequence AAAAAAG and peripheral mRNA structural barriers. Here, we reveal hidden aspects of the frameshifting process, including its exact location on the mRNA and its timing within the translation cycle. Mass spectrometry of translated products shows that ribosomes enter the -1 frame from not one specific codon but various codons along the slippery sequence and slip by not just -1 but also -4 or +2 nucleotides. Single-ribosome translation trajectories detect distinctive codon-scale fluctuations in ribosome-mRNA displacement across the slippery sequence, representing multiple ribosomal translocation attempts during frameshifting. Flanking mRNA structural barriers mechanically stimulate the ribosome to undergo back-and-forth translocation excursions, broadly exploring reading frames. Both experiments reveal aborted translation around mutant slippery sequences, indicating that subsequent fidelity checks on newly adopted codon position base pairings lead to either resumed translation or early termination.

All-perovskite tandem solar cells with 3D/3D bilayer perovskite heterojunction.

All-perovskite tandem solar cells promise higher power-conversion efficiency (PCE) than single-junction perovskite solar cells (PSCs) while maintaining a low fabrication cost1-3. However, their performance is still largely constrained by the subpar performance of mixed lead-tin (Pb-Sn) narrow-bandgap (NBG) perovskite subcells, mainly because of a high trap density on the perovskite film surface4-6. Although heterojunctions with intermixed 2D/3D perovskites could reduce surface recombination, this common strategy induces transport losses and thereby limits device fill factors (FFs)7-9. Here we develop an immiscible 3D/3D bilayer perovskite heterojunction (PHJ) with type II band structure at the Pb-Sn perovskite-electron-transport layer (ETL) interface to suppress the interfacial non-radiative recombination and facilitate charge extraction. The bilayer PHJ is formed by depositing a layer of lead-halide wide-bandgap (WBG) perovskite on top of the mixed Pb-Sn NBG perovskite through a hybrid evaporation-solution-processing method. This heterostructure allows us to increase the PCE of Pb-Sn PSCs having a 1.2-µm-thick absorber to 23.8%, together with a high open-circuit voltage (Voc) of 0.873 V and a high FF of 82.6%. We thereby demonstrate a record-high PCE of 28.5% (certified 28.0%) in all-perovskite tandem solar cells. The encapsulated tandem devices retain more than 90% of their initial performance after 600 h of continuous operation under simulated one-sun illumination.

Translation initiation site of mRNA is selected through dynamic interaction with the ribosome.

Initiation of protein synthesis from the correct start codon of messenger RNA (mRNA) is crucial to translation fidelity. In bacteria, the start codon is usually preceded by a 4- to 6-mer adenosine/guanosine-rich Shine­Dalgarno (SD) sequence. Both the SD sequence and the start codon comprise the core ribosome-binding site (RBS), to which the 30S ribosomal subunit binds to initiate translation. How the rather short and degenerate information inside the RBS can be correctly accommodated by the ribosome is not well understood. Here, we used single-molecule techniques to tackle this long-standing issue. We found that the 30S subunit initially binds to mRNA through the SD sequence, whereas the downstream RBS undergoes dynamic motions, especially when it forms structures. The mRNA is either dissociated or stabilized by initiation factors, such as initiation factor 3 (IF3). The initiator transfer RNA (tRNA) further helps the 30S subunit accommodate mRNA and unwind up to 3 base pairs of the RBS structure. Meanwhile, the formed complex of the 30S subunit with structured mRNA is not stable and tends to disassociate. IF3 promotes dissociation by dismissing the bound initiator tRNA. Thus, initiation factors may accelerate the dynamic assembly­disassembly process of 30S­mRNA complexes such that the correct RBS can be preferentially selected. Our study provides insights into how the bacterial ribosome identifies a typical translation initiation site from mRNA.

Mutational and biophysical analyses reveal a TFIIIC binding region in the TFIIF-related Rpc53 subunit of RNA polymerase III.

The TFIIF-like Rpc53/Rpc37 heterodimer of RNA polymerase (pol) III is involved in various stages of transcription. The C-terminal region of Rpc53 dimerizes with Rpc37 to anchor on the lobe domain of the pol III cleft. However, structural and functional features of the Rpc53 N-terminal region had not been characterized previously. Here, we conducted site-directed alanine replacement mutagenesis on the Rpc53 N-terminus, generating yeast strains that exhibited a cold-sensitive growth defect and severely compromised pol III transcriptional activity. Circular dichroism and NMR spectroscopy revealed a highly disordered 57-amino acid polypeptide in the Rpc53 N-terminus. This polypeptide is a versatile protein-binding module displaying nanomolar-level binding affinities for Rpc37 and the Tfc4 subunit of the transcription initiation factor TFIIIC. Accordingly, we denote this Rpc53 N-terminus polypeptide as the TFIIIC-binding region or CBR. Alanine replacements in the CBR significantly reduced its binding affinity for Tfc4, highlighting its functional importance to cell growth and transcription in vitro. Our study reveals the functional basis for Rpc53's CBR in assembly of the pol III transcription initiation complex.

Multiplex Aptamer-Based Fluorescence Assay Using Magnetism-Encoded Nanoparticles for Simultaneous Detection of Multiple Pathogenic Bacteria.

Multiplex assay has emerged as a robust and versatile method for the simultaneous detection of multiple analytes in a single test. However, challenges in terms of poor accuracy and complexity remained. In this work, we developed a multiplex aptamer-based fluorescence assay using magnetism-encoded nanoparticles for the simultaneous detection of multiple pathogenic bacteria. The encapsulation of different amounts of Fe3O4 nanoparticles in zeolitic imidazolate framework-90 (ZIF-90) leads to the formation of Fe3O4@ZIF-90 (FZ) composites with distinct magnetism strengths. By functionalizing a specific aptamer on the surface of the FZ composites, target bacteria can be specifically and precisely separated from a mixed sample in a sequential manner. This property allows for the simultaneous quantitative analysis of multiple target bacteria by using a single-color fluorescence label, thereby resulting in minimal spectral crosstalk interference and improved accuracy. The successful determination of multiple bacteria in contaminated milk samples demonstrates the applicability of this multiplex assay in complex biological matrices. Compared to conventional multiplex fluorescence assays, this approach offers distinct advantages of simplicity, efficiency, and implementation. We believe that this study can provide valuable insights into the development of the multiplex assay while introducing a new method for the simultaneous detection of multiple bacteria.

Nightly Sleep Predicts Next-Morning Expectations for Stress and Positive Experiences.

OBJECTIVE: Abundant research has linked nightly sleep as an antecedent of daily psychosocial experiences; however, less is known about sleep's influence on daily expectations of these experiences. Therefore, this research examined the day-to-day associations of sleep quality, duration, and efficiency with next-day expectations for stress(ors) and positive experiences, as well as whether these expectations were related to end-of-day reports of physical symptoms. METHODS: In Study 1, U.S. adults ( n = 354; ages 19 to 74) completed twice-daily diaries for 10 weekdays about sleep, expectations for encountering daily stressors and positive events, and physical symptoms. In Study 2, adults in Canada ( n = 246; ages 25 to 87) wore a sleep watch for 14 consecutive days and completed mobile surveys 5×/day about sleep, stressfulness and pleasantness expectations, and physical symptoms. RESULTS: Multilevel models indicated that self-reported sleep quality and duration, but not efficiency, were associated with lower next-day expectations for stressors (Study 1) and stressfulness (Study 2). Self-reported sleep quality (Study 1) and all sleep indices (Study 2) predicted greater next-day expectations for positive events and pleasantness, respectively. For actigraphy-assessed sleep (Study 2), only longer-than-usual actigraphic sleep duration was associated with lower stressfulness expectations, whereas both sleep duration and efficiency were positively linked with daily pleasantness expectations. Only pleasantness expectations (Study 2)-but not daily stressfulness and event expectations (Study 1)-predicted end-of-day physical symptoms. CONCLUSION: Findings suggest the importance of sleep on expectations of next-day stress and positive experiences, of which may have implications for daily physical health.

Long-term exposure to the mixture of phthalates induced male reproductive toxicity in rats and the alleviative effects of quercetin.

Phthalates (PEs), such as di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) could cause reproductive and developmental toxicities, while human beings are increasingly exposed to them at low-doses. Phytochemical quercetin (Que) is a flavonoid that has estrogenic effect, anti-inflammatory and anti-oxidant effects. This study was conducted to assess the alleviative effect of Que. on male reproductive toxicity induced by the mixture of three commonly used PEs (MPEs) at low-dose in rats, and explore the underlying mechanism. Male rats were treated with MPEs (16 mg/kg/day) and/or Que. (50 mg/kg/d) for 91 days. The results showed that MPEs exposure caused male reproductive injuries, such as decreased serum sex hormones levels, abnormal testicular pathological structure, increased abnormal sperm rate and changed expressions of PIWIL1 and PIWIL2. Furthermore, MPEs also changed the expression of steroidogenic proteins in steroid hormone metabolism, including StAR, CYP11A1, CYP17A1, 17ß-HSD, CYP19A1. However, the alterations of these parameters were reversed by Que. MPEs caused male reproductive injuries in rats; Que. inhibited MPEs' male reproductive toxicity, which might relate to the improvement of testosterone biosynthesis.

Association between adult food insecurity and mortality among adults aged 20-79 years with diabetes: A population-based retrospective cohort study.

AIMS: There is limited research on the relationship between food insecurity and mortality among individuals with diabetes. This study aims to investigate the impact of food insecurity on all-cause and cause-specific mortality in adults with diabetes. RESEARCH DESIGN AND METHODS: This study included 5749 adults with diabetes from the National Health and Nutrition Examination Survey cycles 2003-2018 and followed up until 31 December 2019. Food insecurity was measured by the Food Security Survey Module. Cox proportional hazard models were employed to estimate hazard ratios (HRs) and 95% confidence intervals for both all-cause mortality and cause-specific mortality. RESULTS: The weighted prevalence of full food security, marginal food security, low food security, and very low food security was 70.8%, 11.0%, 10.4%, and 7.8%, respectively. Food insecurity demonstrated a significant correlation with diminished diet quality and reduced consumption of healthy foods. Over the course of 42,272.0 person-years of follow-up, we documented 1091 deaths, of which 370 were attributed to cardiovascular disease and 180 to cancer. After adjusting for multiple variables, food insecurity scores were significantly and linearly associated with increased all-cause mortality. Comparing to full food security, participants experiencing very low food security had a multivariate-adjusted HR of 1.48 (1.12, 1.95) for all-cause mortality (ptrend = 0.010). CONCLUSIONS: Food insecurity was associated with increased all-cause mortality and compromised diet quality, especially in individuals experiencing very low food security. Future strategies may necessitate the monitoring of and interventions for food insecurity among individuals with diabetes.

The dexd/H-box helicase DHX40 is a novel negative regulator during GCRV infection via targeting the host RLR helicases and viral nonstructural protein NS38.

RLR helicases RIG-I and MDA5, which are known as pattern recognition receptors to sense cytoplasmic viral RNAs and trigger antiviral immune responses, are DExD/H-box helicases. In teleost, whether and how non-RLR helicases regulate RLR helicases to affect viral infection remains unclear. Here, we report that the non-RLR helicase DHX40 from grass carp (namely gcDHX40) is a negative regulator of grass carp reovirus (GCRV) infection and RLR-mediated type I IFN production. GcDHX40 was a cytoplasmic protein. Ectopic expression of gcDHX40 facilitated GCRV replication and suppressed type I IFN production induced by GCRV infection and by those genes involved the RLR antiviral signaling pathway. Mechanistically, gcDHX40 promoted the generation of viral inclusion bodies (VIBs) by interacting with the NS38 protein of GCRV. Additionally, gcDHX40 interacted with RLR helicase, and impaired the formation of RLR-MAVS functional complexes. Taken together, our results indicate that gcDHX40 is a novel important proviral host factor involving in promoting the generation of GCRV VIBs and inhibiting the production of RLR-mediated type I IFNs.

Theoretical trends in the dynamics simulations of molecular machines across multiple scales.

Over the past few decades, molecular machines have been extensively studied, since they are composed of single molecules for functional materials capable of responding to external stimuli, enabling motion at scales ranging from the microscopic to the macroscopic level within molecular aggregates. This advancement holds the potential to efficiently transform external resources into mechanical movement, achieved through precise control of conformational changes in stimuli-responsive materials. However, the underlying mechanism that links microscopic and macroscopic motions remains unclear, demanding computational development associated with simulating the construction of molecular machines from single molecules. This bottleneck has impeded the design of more efficient functional materials. Advancements in theoretical simulations have successfully been developed in various computational models to unveil the operational mechanisms of stimulus-responsive molecular machines, which could help us reduce the costs in experimental trial-and-error procedures. It opens doors to the computer-aided design of innovative functional materials. In this perspective, we have reviewed theoretical approaches employed in simulating dynamic processes involving conformational changes in molecular machines, spanning different scales and environmental conditions. In addition, we have highlighted current challenges and anticipated future trends in the collective control of aggregates within molecular machines. Our goal is to provide a comprehensive overview of recent theoretical advancements in the field of molecular machines, offering valuable insights for the design of novel smart materials.

Ultrafast hydrogen production in boron/oxygen-codoped graphitic carbon nitride revealed by nonadiabatic dynamics simulations.

Graphitic carbon nitride (g-C3N4 or GCN) shows promise in photocatalytic water splitting, despite facing the challenge of rapid electron-hole recombination. In this study, we investigated the influence of boron/oxygen codoping on the photocatalytic performance of GCN systems for hydrogen generation. First-principles calculations and nonadiabatic molecular dynamics (NAMD) simulations were employed to reveal that the recombination time of photogenerated carriers could be increased by 16% to 64% in the codoped systems compared to the pristine GCN. The time-dependent density functional theory (TDDFT) scheme was utilized to select energy windows and initiate dynamics in cluster models of B/O co-doped heptazine with water molecules. Notably, we observed efficient direct photodissociation of hydrogen atoms from water molecules within 60 fs and proton hops within the hydrogen-bonded network within 80 fs in the co-doped system, diverging from the previously proposed mechanism for pristine heptazine in NAMD simulations. This discovery underscores the significant role of faster proton-coupled electron transfer (PCET) reactions and rapid radiationless relaxation in achieving high photocatalytic efficiency in water splitting. Our work enhances the understanding of the internal mechanism of highly efficient photocatalysts for water splitting and provides a new design strategy for doped GCN.

Enhanced OER catalytic activity of single metal atoms supported by the pentagonal NiN2 monolayer: insight from density functional theory calculations.

Two-dimensional material-supported single metal atom catalysts have been extensively studied and proved effective in electrocatalytic reactions in recent years. In this work, we systematically investigate the OER catalytic properties of single metal atoms supported by the NiN2 monolayer. Several typical transition metals with high single atom catalytic activity, such as Fe, Co, Ru, Rh, Pd, Ir, and Pt, were selected as catalytic active sites. The energy calculations show that transition metal atoms (Fe, Co, Ru, Rh, Pd, Ir, and Pt) are easily embedded in the NiN2 monolayer with Ni vacancies due to the negative binding energy. The calculated OER overpotentials of Fe, Co, Ru, Rh, Pd, Ir and Pt embedded NiN2 monolayers are 0.92 V, 0.47 V, 1.13 V, 0.66 V, 1.25 V, 0.28 V, and 0.94 V, respectively. Compared to the 0.57 V OER overpotential of typical OER noble metal catalysts IrO2, Co@NiN2 and Ir@NiN2 exhibit high OER catalytic activity due to lower overpotential, especially for Ir@NiN2. The high catalytic activity of the Ir embedded NiN2 monolayer can be explained well by the d-band center model. It is found that the adsorption strength of the embedded TM atoms with intermediates follows a linear relationship with their d-band centers. Besides, the overpotential of the Ir embedded NiN2 monolayer can be further reduced to 0.24 V under -2% biaxial strain. Such findings are expected to be employed in more two-dimensional material-supported single metal atom catalyzed reactions.

How spin state and oxidation number of transition metal atoms determine molecular adsorption: a first-principles case study for NH3.

Understanding how the electronic state of transition metal atoms can influence molecular adsorption on a substrate is of great importance for many applications. Choosing NH3 as a model molecule, its adsorption behavior on defected SnS2 monolayers is investigated. The number of valence electrons n is controlled by decorating the monolayer with different transition metal atoms, ranging from Sc to Zn. Density-Functional Theory based calculations show that the adsorption energy of NH3 molecules oscillates with n and shows a clear odd-even pattern. There is also a mirror symmetry of the adsorption energies for large and low electron numbers. This unique behavior is mainly governed by the oxidation state of the TM ions. We trace back the observed trends of the adsorption energy to the orbital symmetries and ligand effects which affect the interaction between the 3σ orbitals (NH3) and the 3d orbitals of the transition metals. This result unravels the role which the spin state of TM ions plays in different crystal fields for the adsorption behavior of molecules. This new understanding of the role of the electronic structure on molecular adsorption can be useful for the design of high efficiency nanodevices in areas such as sensing and photocatalysis.

Investigation of the Inhibitory Effects of Illicium verum Essential Oil Nanoemulsion on Fusarium proliferatum via Combined Transcriptomics and Metabolomics Analysis.

Fusarium proliferatum is the main pathogen that causes Panax notoginseng root rot. The shortcomings of strong volatility and poor water solubility of Illicium verum essential oil (EO) limit its utilization. In this study, we prepared traditional emulsion (BDT) and nanoemulsion (Bneo) of I. verum EO by ultrasonic method with Tween-80 and absolute ethanol as solvents. The chemical components of EO, BDT, and Bneo were identified by gas chromatography-mass spectrometry (GC-MS) and the antifungal activity and mechanism were compared. The results show that Bneo has good stability and its particle size is 34.86 nm. The contents of (-) -anethole and estragole in Bneo were significantly higher than those in BDT. The antifungal activity against F. proliferatum was 5.8-fold higher than BDT. In the presence of I. verum EO, the occurrence of P. notoginseng root rot was significantly reduced. By combining transcriptome and metabolomics analysis, I. verum EO was found to be involved in the mutual transformation of pentose and glucuronic acid, galactose metabolism, streptomycin biosynthesis, carbon metabolism, and other metabolic pathways of F. proliferatum, and it interfered with the normal growth of F. proliferatum to exert antifungal effects. This study provide a theoretical basis for expanding the practical application of Bneo.

Ultrasound-based radiomics-clinical nomogram for noninvasive prediction of residual cancer burden grading in breast cancer.

PURPOSE: To assess the predictive value of an ultrasound-based radiomics-clinical nomogram for grading residual cancer burden (RCB) in breast cancer patients. METHODS: This retrospective study of breast cancer patients who underwent neoadjuvant therapy (NAC) and ultrasound scanning between November 2020 and July 2023. First, a radiomics model was established based on ultrasound images. Subsequently, multivariate LR (logistic regression) analysis incorporating both radiomic scores and clinical factors was performed to construct a nomogram. Finally, Receiver operating characteristics (ROC) curve analysis and decision curve analysis (DCA) were employed to evaluate and validate the diagnostic accuracy and effectiveness of the nomogram. RESULTS: A total of 1122 patients were included in this study. Among them, 427 patients exhibited a favorable response to NAC chemotherapy, while 695 patients demonstrated a poor response to NAC therapy. The radiomics model achieved an AUC value of 0.84 in the training cohort and 0.83 in the validation cohort. The ultrasound-based radiomics-clinical nomogram achieved an AUC value of 0.90 in the training cohort and 0.91 in the validation cohort. CONCLUSIONS: Ultrasound-based radiomics-clinical nomogram can accurately predict the effectiveness of NAC therapy by predicting RCB grading in breast cancer patients.

The Effect of S-Allyl L-Cysteine on Retinal Ischemia: The Contributions of MCP-1 and PKM2 in the Underlying Medicinal Properties.

Retinal ischemia plays a vital role in vision-threatening retinal ischemic disorders, such as diabetic retinopathy, age-related macular degeneration, glaucoma, etc. The aim of this study was to investigate the effects of S-allyl L-cysteine (SAC) and its associated therapeutic mechanism. Oxidative stress was induced by administration of 500 µM H2O2 for 24 h; SAC demonstrated a dose-dependent neuroprotective effect with significant cell viability effects at 100 µM, and it concurrently downregulated angiogenesis factor PKM2 and inflammatory biomarker MCP-1. In a Wistar rat model of high intraocular pressure (HIOP)-induced retinal ischemia and reperfusion (I/R), post-administration of 100 µM SAC counteracted the ischemic-associated reduction of ERG b-wave amplitude and fluorogold-labeled RGC reduction. This study supports that SAC could protect against retinal ischemia through its anti-oxidative, anti-angiogenic, anti-inflammatory, and neuroprotective properties.

[Mechanism of total glucosides of White Paeony Capsules in ameliorating acute lung injury based on NLRP3 inflammasome].

This study deciphered the ameliorating effect and molecular mechanism of the total glucosides of White Paeony Capsules(TGP) in the treatment of mice model with acute lung injury(ALI) via NOD-like receptor thermal protein domain associated protein 3(NLRP3) signaling pathway of the inflammasome. The study established an inflammasome activation model of primed bone marrow-derived macrophages(BMDMs), and its molecular mechanism was investigated by Western blot(WB), immunofluorescence staining, enzyme-linked immunosorbent assay(ELISA), and flow cytometry. C57BL/6J mice were randomly divided into a blank control group, a TGP group, a model group(LPS group), LPS+low-and high-dose TGP groups, LPS+MCC950 group, and LPS+MCC950+TGP group, with eight mice per group. The ALI model was induced in mice. Finally, bronchoalveolar lavage fluid(BALF) and lung tissue were collected. Lung index and lung weight wet-to-dry ratio were determined for each group of mice. The pathological changes in lung tissue were observed through hematoxylin-eosin(HE) staining. The number of neutrophils in the BALF of each group was detected using flow cytometry. The levels of interleukin(IL)-1ß, IL-6, and tumor necrosis factor(TNF)-α in the BALF were determined by ELISA. The expressions of IL-1ß, IL-18, IL-6, and TNF-α in the lung tissue were determined by real-time quantitative PCR(RT-qPCR). This study demonstrated that TGP dramatically blocked the activation of the NLRP3 inflammasome by inhibiting the production of upstream mitochondrial reactive oxygen species(mtROS) and the subsequent oligomerization of apoptosis-associated specks(ASC). Additionally, in the ALI mice model, compared with the blank control group, the model group showed alveolar structure rupture, thic-kening of alveolar septa, and dramatically increased lung index, lung weight wet-to-dry ratio in lung tissue, neutrophil count, and inflammatory factor levels. Compared with the model group, the pathological morphology of lung tissue was significantly ameliorated in the TGP and MCC950 groups, and the lung index and lung weight wet-to-dry ratio were significantly reduced. Neutrophil counts were reduced, and levels of inflammatory factors were significantly downregulated. Notably, compared with the MCC950 group, there was no significant difference in effect in the MCC950+TGP group. Collectively, the study reveals that TGP may ameliorate ALI in mice by inhibiting the activation of NLRP3 inflammasome, providing a safe and effective drug candidate for the prevention or treatment of ALI/ARDS.

Global fitness landscapes of the Shine-Dalgarno sequence.

Shine-Dalgarno sequences (SD) in prokaryotic mRNA facilitate protein translation by pairing with rRNA in ribosomes. Although conventionally defined as AG-rich motifs, recent genomic surveys reveal great sequence diversity, questioning how SD functions. Here, we determined the molecular fitness (i.e., translation efficiency) of 49 synthetic 9-nt SD genotypes in three distinct mRNA contexts in Escherichia coli We uncovered generic principles governing the SD fitness landscapes: (1) Guanine contents, rather than canonical SD motifs, best predict the fitness of both synthetic and endogenous SD; (2) the genotype-fitness correlation of SD promotes its evolvability by steadily supplying beneficial mutations across fitness landscapes; and (3) the frequency and magnitude of deleterious mutations increase with background fitness, and adjacent nucleotides in SD show stronger epistasis. Epistasis results from disruption of the continuous base pairing between SD and rRNA. This "chain-breaking" epistasis creates sinkholes in SD fitness landscapes and may profoundly impact the evolution and function of prokaryotic translation initiation and other RNA-mediated processes. Collectively, our work yields functional insights into the SD sequence variation in prokaryotic genomes, identifies a simple design principle to guide bioengineering and bioinformatic analysis of SD, and illuminates the fundamentals of fitness landscapes and molecular evolution.

BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis†.

Recurrent pregnancy loss (RPL) is a common pathological problem during pregnancy, and its clinical etiology is complex and unclear. Dysfunction of trophoblasts may cause a series of pregnancy complications, including preeclampsia, fetal growth restriction, and RPL. Recently, lncRNAs have been found to be closely related to the occurrence and regulation of pregnancy-related diseases, but few studies have focused on their role in RPL. In this study, we identified a novel lncRNA BBOX1-AS1 that was significantly upregulated in villous tissues and serum of RPL patients. Functionally, BBOX1-AS1 inhibited proliferation, migration, invasion, tube formation and promoted apoptosis of trophoblast cells. Mechanistically, overexpression of BBOX1-AS1 activated the p38 and JNK MAPK signaling pathways by upregulating GADD45A expression. Further studies indicated that BBOX1-AS1 could increase the stability of GADD45A mRNA by binding hnRNPK and ultimately cause abnormal trophoblast function. Collectively, our study highlights that the BBOX1-AS1/hnRNPK/GADD45A axis plays an important role in trophoblast-induced RPL and that BBOX1-AS1 may serve as a potential target for the diagnosis of RPL.