Arabidopsis cryptochromes interact with SOG1 to promote the repair of DNA double-strand breaks.

Cryptochromes (CRYs) are blue light (BL) photoreceptors to regulate a variety of physiological processes including DNA double-strand break (DSB) repair. SUPPRESSOR OF GAMMA RADIATION 1 (SOG1) acts as the central transcription factor of DNA damage response (DDR) to induce the transcription of downstream genes, including DSB repair-related genes BRCA1 and RAD51. Whether CRYs regulate DSB repair by directly modulating SOG1 is unknown. Here, we demonstrate that CRYs physically interact with SOG1. Disruption of CRYs and SOG1 leads to increased sensitivity to DSBs and reduced DSB repair-related genes' expression under BL. Moreover, we found that CRY1 enhances SOG1's transcription activation of DSB repair-related gene BRCA1. These results suggest that the mechanism by which CRYs promote DSB repair involves positive regulation of SOG1's transcription of its target genes, which is likely mediated by CRYs-SOG1 interaction.

Emergence of aztreonam/avibactam and tigecycline-resistant Pseudomonas putida group Co-producing blaIMP-1, blaAFM-4 and blaOXA-1041 with a novel sequence type ST268 in Southwestern China.

OBJECTIVES: The emergence of carbapenem-resistant Pseudomonas putida (CRPP) has raised public awareness. This study investigated two strains from the Pseudomonas putida group that were resistant to carbapenem, tigecycline, and aztreonam-avibactam (ATM-AVI), with a focus on their microbial and genomic characteristics. METHODS: We assessed the antibiotic resistance profile using broth dilution, disk diffusion, and E-test methods. Efflux pump phenotype testing and real-time quantitative PCR were employed to evaluate efflux pump activity in tigecycline resistance, while polymerase chain reaction was utilized to detect common carbapenem genes. Additionally, whole-genome sequencing was performed to analyze genomic characteristics. The transferability of blaIMP-1 and blaAFM-4 was assessed through a conjugation experiment. Furthermore, growth kinetics and biofilm formation were examined using growth curves and crystal violet staining. RESULTS: Both strains demonstrated resistance to carbapenem, tigecycline, and ATM-AVI. Notably, NMP can restore sensitivity to tigecycline. Subsequent analysis revealed that they co-produced blaIMP-1, blaAFM-4, tmexCD-toprJ, and blaOXA-1041, belonging to a novel sequence type ST268. Although they were closely related on the phylogenetic tree, they exhibited different levels of virulence. Genetic environment analysis indicated variations compared to prior studies, particularly regarding the blaIMP-1 and blaAFM-4 genes, which showed limited horizontal transferability. Moreover, it was observed that temperature exerted a specific influence on their biological factors. CONCLUSION: We initially identified two P. putida ST268 strains co-producing blaIMP-1, blaAFM-4, blaOXA-1041, and tmexCD-toprJ. The resistance to tigecycline and ATM-AVI can be attributed to the presence of multiple drug resistance determinants. These findings underscore the significance of P. putida as a reservoir for novel antibiotic resistance genes. Therefore, it is imperative to develop alternative antibiotic therapies and establish effective monitoring of bacterial resistance.

Carbapenem-Resistant Enterobacter cloacae Complex in Southwest China: Molecular Characteristics and Risk Factors Caused by NDM Producers.

Purpose: The isolation rate of carbapenem-resistant Enterobacter cloacae complex (CREC) is continuously increasing. The aims of this study were to investigate the molecular characteristics and risk factors associated with CREC infections. Methods: Bacterial species were identified using the matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) (Bruker Daltonik GmbH, Bremen, Germany), and the hsp60 gene was utilized for further typing. Antimicrobial susceptibilities were assessed through the MicroScan WalkAway 96 Plus system (Siemens, Germany) and the microbroth dilution method. Antimicrobial resistance genes were screened through polymerase chain reaction (PCR), while the homologous relationship was assessed using multilocus sequence typing (MLST). Conjugation experiments were performed to verify whether the plasmid could be transferred. Additionally, logistic regression model was employed to analyze risk factors for CREC infections. Results: 32 strains of CREC bacteria were isolated during the study, yet only 20 were retained for preservation. While the isolates demonstrated resistance to the majority of antibiotics, they exhibited high sensitivity to polymyxin B and tigecycline. All isolates carried the blaNDM resistance gene, including 13 blaNDM-1 isolates and 7 blaNDM-5 isolates. MLST homology analysis revealed the presence of seven known ST types and one new ST type. Conjugation experiments confirmed that 13 isolates were capable of transferring the blaNDM resistance gene to Escherichia coli strain EC600. Single-factor analysis identified multiple primary risk factors for CREC infection, but multivariate analysis did not reveal independent risk factors. Conclusion: This study investigates the molecular characteristics and risk factors associated with CREC infections. The detection rate of CREC strains in our hospital is continuously rising and homology analysis suggested that strains might spread in our hospital, emphasizing the importance of implementing effective preventive measures to control the horizontal transmission of plasmid-mediated antimicrobial resistance genes.

ADA2b acts to positively regulate blue light-mediated photomorphogenesis in Arabidopsis.

Cryptochromes (CRYs) act as blue light photoreceptors to regulate various plant physiological processes including photomorphogenesis and repair of DNA double strand breaks (DSBs). ADA2b is a conserved transcription co-activator that is involved in multiple plant developmental processes. It is known that ADA2b interacts with CRYs to mediate blue light-promoted DSBs repair. Whether ADA2b may participate in CRYs-mediated photomorphogenesis is unknown. Here we show that ADA2b acts to inhibit hypocotyl elongation and hypocotyl cell elongation in blue light. We found that the SWIRM domain-containing C-terminus mediates the blue light-dependent interaction of ADA2b with CRYs in blue light. Moreover, ADA2b and CRYs act to co-regulate the expression of hypocotyl elongation-related genes in blue light. Based on previous studies and these results, we propose that ADA2b plays dual functions in blue light-mediated DNA damage repair and photomorphogenesis.

Artificial Neural Synapses Based on Microfluidic Memristors Prepared by Capillary Tubes and Ionic Liquid.

Neuromorphic simulation, i.e., the use of electronic devices to simulate the neural networks of the human brain, has attracted a lot of interest in the fields of data processing and memory. This work provides a new method for preparing a 1,3-dimethylimidazolium nitrate ([MMIm][NO3]:H2O) microfluidic memristor that is ultralow cost and technically uncomplicated. Such a fluidic device uses capillaries as memory tubes, which are structurally similar to interconnected neurons by simple solution treatment. When voltage is applied, the transmission of anions and cations in the tube corresponds to the release of neurotransmitters from the presynaptic membrane to the postsynaptic membrane. The change of synaptic weights (plasticity) also can be simulated by the gradual change of conductance of the fluid memristor. The learning process of microfluidic memristors is very obvious, and the habituation and recovery behaviors they exhibit are extremely similar to biological activities, representing its good use for simulating neural synapses.

Reprogramming and multi-lineage transdifferentiation attenuate the tumorigenicity of colorectal cancer cells.

Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduced tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiated into terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.

Cell Reprogramming Techniques: Contributions to Cancer Therapy.

The reprogramming of terminally differentiated cells over the past few years has become important for induced pluripotent stem cells (iPSCs) in the field of regenerative medicine and disease drug modeling. At the same time, iPSCs have also played an important role in human cancer research. iPSCs derived from cancer patients can be used to simulate the early progression of cancer, for drug testing, and to study the molecular mechanism of cancer occurrence. In recent years, with the application of cellular immunotherapy in cancer therapy, patient-derived iPSC-induced immune cells (T, natural killer, and macrophage cells) solve the problem of immune rejection and have higher immunogenicity, which greatly improves the therapeutic efficiency of immune cell therapy. With the continuous progress of cancer differentiation therapy, iPSC technology can reprogram cancer cells to a more primitive pluripotent undifferentiated state, and successfully reverse cancer cells to a benign phenotype by changing the epigenetic inheritance of cancer cells. This article reviews the recent progress of cell reprogramming technology in human cancer research, focuses on the application of reprogramming technology in cancer immunotherapy and the problems solved, and summarizes the malignant phenotype changes of cancer cells in the process of reprogramming and subsequent differentiation.

Photoexcited cryptochromes interact with ADA2b and SMC5 to promote the repair of DNA double-strand breaks in Arabidopsis.

Cryptochromes (CRYs) act as blue-light photoreceptors that regulate development and circadian rhythms in plants and animals and as navigating magnetoreceptors in migratory birds. DNA double-strand breaks (DSBs) are the most serious type of DNA damage and threaten genome stability in all organisms. Although CRYs have been shown to respond to DNA damage, whether and how they participate in DSB repair is not well understood. Here we report that Arabidopsis CRYs promote the repair of DSBs through direct interactions with ADA2b and SMC5 in a blue-light-dependent manner to enhance their interaction. Mutations in CRYs and in ADA2b lead to similar enhanced DNA damage accumulation. In response to DNA damage, CRYs are localized at DSBs, and the recruitment of SMC5 to DSBs is dependent on CRYs. These results suggest that CRY-enhanced ADA2b-SMC5 interaction promotes ADA2b-mediated recruitment of SMC5 to DSBs, leading to DSB repair.

Arabidopsis lamin-like proteins CRWN1 and CRWN2 interact with SUPPRESSOR OF NPR1-1 INDUCIBLE 1 and RAD51D to prevent DNA damage.

Plants cope with various recurring stress conditions that often induce DNA damage, ultimately affecting plant genome integrity, growth, and productivity. The CROWDED NUCLEI (CRWN) family comprises lamin-like proteins with multiple functions, such as regulating gene expression, genome organization, and DNA damage repair in Arabidopsis (Arabidopsis thaliana). However, the mechanisms and consequences of CRWNs in DNA damage repair are largely unknown. Here, we reveal that CRWNs maintain genome stability by forming repairing nuclear bodies at DNA double-strand breaks. We demonstrate that CRWN1 and CRWN2 physically associate with the DNA damage repair proteins RAD51D and SUPPRESSOR OF NPR1-1 Inducible 1 (SNI1) and act in the same genetic pathway to mediate this process. Moreover, CRWN1 and CRWN2 partially localize at γ-H2AX foci upon DNA damage. Notably, CRWN1 and CRWN2 undergo liquid-liquid phase separation to form highly dynamic droplet-like structures with RAD51D and SNI1 to promote the DNA damage response (DDR). Collectively, our data shed light on the function of plant lamin-like proteins in the DDR and maintenance of genome stability.

PIFs interact with SWI2/SNF2-related 1 complex subunit 6 to regulate H2A.Z deposition and photomorphogenesis in Arabidopsis.

Light is an essential environmental signal perceived by a broad range of photoreceptors in plants. Among them, the red/far-red light receptor phytochromes function to promote photomorphogenesis, which is critical to the survival of seedlings after seeds germination. The basic-helix-loop-helix transcription factors phytochrome-interacting factors (PIFs) are the pivotal direct downstream components of phytochromes. H2A.Z is a highly conserved histone variant regulating gene transcription, and its incorporation into nucleosomes is catalyzed by SWI2/SNF2-related 1 complex, in which SWI2/SNF2-related 1 complex subunit 6 (SWC6) and actin-related protein 6 (ARP6) serve as core subunits. Here, we show that PIFs physically interact with SWC6 in vitro and in vivo, leading to the disassociation of HY5 from SWC6. SWC6 and ARP6 regulate hypocotyl elongation partly through PIFs in red light. PIFs and SWC6 coregulate the expression of auxin-responsive genes such as IAA6, IAA19, IAA20, and IAA29 and repress H2A.Z deposition at IAA6 and IAA19 in red light. Based on previous studies and our findings, we propose that PIFs inhibit photomorphogenesis, at least in part, through repression of H2A.Z deposition at auxin-responsive genes mediated by the interactions of PIFs with SWC6 and promotion of their expression in red light.

Neuroprotective Effects of Sodium Butyrate by Restoring Gut Microbiota and Inhibiting TLR4 Signaling in Mice with MPTP-Induced Parkinson's Disease.

Parkinson's disease (PD) is a prevalent type of neurodegenerative disease. There is mounting evidence that the gut microbiota is involved in the pathogenesis of PD. Sodium butyrate (NaB) can regulate gut microbiota and improve brain functioning in neurological disorders. Hence, we examined whether the neuroprotective function of NaB on PD was mediated by the modulation of gut microbial dysbiosis and revealed its possible mechanisms. Mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days to construct the PD model. NaB gavage was given 2 h after the daily MPTP injections for 21 days. NaB improved the motor functioning of PD mice, increased striatal neurotransmitter levels, and reduced the death of dopaminergic neurons. The 16S rRNA sequencing analysis revealed that NaB restored the gut microbial dysbiosis. NaB also attenuated the intestinal barrier's disruption and reduced serum, colon, and striatal pro-inflammatory cytokines, along with inhibiting the overactivation of glial cells, suggesting an inhibitory effect on inflammation from NaB throughout the gut-brain axis of the PD mice. Mechanistic studies revealed that NaB treatment suppressed the TLR4/MyD88/NF-kB pathway in the colon and striatum. In summary, NaB had a neuroprotective impact on the PD mice, likely linked to its regulation of gut microbiota to inhibit gut-brain axis inflammation.

eEF1A1 promotes colorectal cancer progression and predicts poor prognosis of patients.

Colorectal cancer (CRC) is a major leading cause of cancer mortality worldwide in which dysregulated protein synthesis plays an etiologic role. The eukaryotic elongation factor 1 A1 (eEF1A1) exerts significant effects on protein synthesis by contributing to peptide chain extension. Whereas its role in CRC remains to be investigated. In this study, we found that the mRNA and protein levels of eEF1A1 were significantly upregulated in CRC cell lines and tissues. Elevated expression of eEF1A1 was correlated with shorter overall survival in 94 CRC patients. The inhibition of proliferation and cell cycle block were observed in CRC cells after eEF1A1 downregulation. Mechanistically, weighted gene correlation network analysis and further Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that mitogen-activated protein kinases (MAPKs) signaling pathways were significantly enriched in high-eEF1A1 expression group, and the levels of phosphorylated p38/JNK/ERK MAPK were dramatically decreased after eEF1A1 downregulation. Overexpression of eEF1A1 in CRC correlated with a poor prognosis. Collectively, this study determined the oncogenic role of eEF1A1 in CRC proliferation and tumorigenesis. eEF1A1 might be a promising therapeutic target and prognostic biomarker in CRC.

tDCS-EEG for Predicting Outcome in Patients With Unresponsive Wakefulness Syndrome.

Objectives: We aimed to assess the role of transcranial direct current stimulation (tDCS) combined with electroencephalogram (EEG) for predicting prognosis in UWS cases. Methods: This was a historical control study that enrolled 85 patients with UWS. The subjects were assigned to the control (without tDCS) and tDCS groups. Conventional treatments were implemented in both the control and tDCS groups, along with 40 multi-target tDCS sessions only in the tDCS group. Coma Recovery Scale-Revised (CRS-R) was applied at admission. The non-linear EEG index was evaluated after treatment. The modified Glasgow Outcome Scale (mGOS) was applied 12 months after disease onset. Results: The mGOS improvement rate in the tDCS group (37.1%) was higher than the control value (22.0%). Linear regression analysis revealed that the local and remote cortical networks under unaffected pain stimulation conditions and the remote cortical network under affected pain stimulation conditions were the main relevant factors for mGOS improvement. Furthermore, the difference in prefrontal-parietal cortical network was used to examine the sensitivity of prognostic assessment in UWS patients. The results showed that prognostic sensitivity could be increased from 54.5% (control group) to 84.6% (tDCS group). Conclusions: This study proposes a tDCS-EEG protocol for predicting the prognosis of UWS. With multi-target tDCS combined with EEG, the sensitivity of prognostic assessment in patients with UWS was improved. The recovery might be related to improved prefrontal-parietal cortical networks of the unaffected hemisphere.

Shoe Bending Stiffness Influence on Lower Extremity Energetics in Consecutive Jump Take-Off.

Objective: This study examined the influence of shoe bending stiffness on lower extremity energetics in the take-off phase of consecutive jump. Methods: Fifteen basketball and volleyball players wearing control shoes and stiff shoes performed consecutive jumps. Joint angle, angular velocity, moments, power, jump height, take-off velocity, take-off time, and peak vertical ground reaction force data were simultaneously captured by motion capture system and force platform. Paired t-tests were performed on data for the two shoe conditions that fit the normal distribution assumptions, otherwise Wilcoxon signed-rank tests. Results: There are significant differences (P < 0.05) in take-off velocity and take-off time between stiff and control shoe conditions; the stiff shoes had faster take-off velocity and shorter take-off time than control shoes. There was no significant difference between two conditions in jump height (P = 0.512) and peak vertical ground reaction force (P = 0.589). The stiff shoes had significantly lower MTP dorsiflexion angle and greater joint work than the control shoes (P < 0.05). The MTP range of motion and maximum angular velocity in stiff shoe condition were significantly lower than those in control shoe condition (P < 0.01). However, there are no significant differences between two conditions in kinetics and kinematics of the ankle, knee, and hip joint. Conclusions: The findings suggest that wearing stiff shoes can reduce the effect of participation of the MTP joint at work and optimize the energy structure of lower-limb movement during consecutive jumps.

Phytochromes A and B Mediate Light Stabilization of BIN2 to Regulate Brassinosteroid Signaling and Photomorphogenesis in Arabidopsis.

Phytochromes A and B (phyA and phyB) are the far-red and red lights photoreceptors mediating many light responses in Arabidopsis thaliana. Brassinosteroid (BR) is a pivotal phytohormone regulating a variety of plant developmental processes including photomorphogenesis. It is known that phyB interacts with BES1 to inhibit its DNA-binding activity and repress BR signaling. Here, we show that far-red and red lights modulate BR signaling through phyA and phyB regulation of the stability of BIN2, a glycogen synthase kinase 3 (GSK3)-like kinase that phosphorylates BES1/BZR1 to inhibit BR signaling. The BIN2 gain-of-function mutant bin2-1 displays an enhanced photomorphogenic phenotype in both far-red and red lights. phyA-enhanced accumulation of BIN2 promotes the phosphorylation of BES1 in far-red light. BIN2 acts genetically downstream from PHYA to regulate photomorphogenesis under far-red light. Both phyA and phyB interact directly with BIN2, which may promote the interaction of BIN2 with BES1 and induce the phosphorylation of BES1. Our results suggest that far-red and red lights inhibit BR signaling through phyA and phyB stabilization of BIN2 and promotion of BES1 phosphorylation, which defines a new layer of the regulatory mechanism that allows plants to coordinate light and BR signaling pathways to optimize photomorphogenesis.

Interfacial DNA Framework-Enhanced Background-to-Signal Transition for Ultrasensitive and Specific Micro-RNA Detection.

Interfacial DNA self-assembly is fundamental to solid nucleic acid biosensors, whereas how to improve the signal-to-noise ratio has always been a challenge, especially in the charge-based electrochemical DNA sensors because of the large noise from the negatively charged DNA capture probes. Here, we report a DNA framework-reversed signal-gain strategy through background-to-signal transition for ultrasensitive and highly specific electrical detection of microRNAs (miRNAs) in blood. By using a model of enzyme-catalyzed deposition of conductive molecules (polyaniline) targeting to DNA, we observed the highest signal contribution per unit area by the highly charged three-dimensional (3D) tetrahedral DNA framework probe, relative to the modest of two-dimensional (2D) polyA probe and the lowest of one-dimensional (1D) single-stranded (ss)DNA probe, suggesting the positive correlation of background DNA charge with signal enhancement. Using such an effective signal-transition design, the DNA framework-based electrochemical sensor achieves ultrasensitive miRNAs detection with sensitivity up to 0.29 fM (at least 10-fold higher than that with 1D ssDNA or 2D polyA probes) and high specificity with single-base resolution. More importantly, this high-performance sensor allows for a generalized sandwich detection of tumor-associated miRNAs in the complex matrices (multiple cell lysates and blood serum) and further distinguishes the tumor patients (e.g., breast, lung, and liver cancer) from the normal individuals. These advantages signify the promise of this miRNA sensor as a versatile tool in precision diagnosis.

Corrigendum: Phytochromes A and B mediate light stabilization of BIN2 to regulate brassinosteroid signaling and photomorphogenesis in Arabidopsis.

[This corrects the article DOI: 10.3389/fpls.2022.865019.].

Arabidopsis cryptochrome 1 undergoes COP1 and LRBs-dependent degradation in response to high blue light.

Arabidopsis cryptochrome 1 (CRY1) is an important blue light photoreceptor that promotes photomorphogenesis under blue light. The blue light photoreceptors CRY2 and phototropin 1, and the red/far-red light photoreceptors phytochromes B and A undergo degradation in response to blue and red light, respectively. This study investigated whether and how CRY1 might undergo degradation in response to high-intensity blue light (HBL). We demonstrated that CRY1 is ubiquitinated and degraded through the 26S proteasome pathway in response to HBL. We found that the E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) is involved in mediating HBL-induced ubiquitination and degradation of CRY1. We also found that the E3 ubiquitin ligases LRBs physically interact with CRY1 and are also involved in mediating CRY1 ubiquitination and degradation in response to HBL. We further demonstrated that blue-light inhibitor of cryptochromes 1 interacts with CRY1 in a blue-light-dependent manner to inhibit CRY1 dimerization/oligomerization, leading to the repression of HBL-induced degradation of CRY1. Our findings indicate that the regulation of CRY1 stability in HBL is coordinated by COP1 and LRBs, which provides a mechanism by which CRY1 attenuates its own signaling and optimizes photomorphogenesis under HBL.

The Multiple Roles of Periostin in Non-Neoplastic Disease.

Periostin, identified as a matricellular protein and an ECM protein, plays a central role in non-neoplastic diseases. Periostin and its variants have been considered to be normally involved in the progression of most non-neoplastic diseases, including brain injury, ocular diseases, chronic rhinosinusitis, allergic rhinitis, dental diseases, atopic dermatitis, scleroderma, eosinophilic esophagitis, asthma, cardiovascular diseases, lung diseases, liver diseases, chronic kidney diseases, inflammatory bowel disease, and osteoarthrosis. Periostin interacts with protein receptors and transduces signals primarily through the PI3K/Akt and FAK two channels as well as other pathways to elicit tissue remodeling, fibrosis, inflammation, wound healing, repair, angiogenesis, tissue regeneration, bone formation, barrier, and vascular calcification. This review comprehensively integrates the multiple roles of periostin and its variants in non-neoplastic diseases, proposes the utility of periostin as a biological biomarker, and provides potential drug-developing strategies for targeting periostin.