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Abstract Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder associated with alterations in structural and functional coupling in gray matter. However, despite the detectability and modulation of brain signals in white matter, the structure-function coupling in white matter in autism remains less explored. Methods In this study, we investigated structural-functional coupling in white matter (WM) regions, by integrating diffusion tensor data that contain fiber orientation information from WM tracts, with functional connectivity tensor data that reflect local functional anisotropy information. Using functional and diffusion magnetic resonance images, we analyzed a cohort of 89 ASD and 63 typically developing (TD) individuals from the Autism Brain Imaging Data Exchange II (ABIDE-II). Subsequently, the associations between structural-functional coupling in WM regions and ASD severity symptoms assessed by Autism Diagnostic Observation Schedule-2 were examined via supervised machine learning in an independent test cohort of 29 ASD individuals. Furthermore, we also compared the performance of multi-model features (i.e. structural-functional coupling) with single-model features (i.e. functional or structural models alone). Results In the discovery cohort (ABIDE-II), individuals with ASD exhibited widespread reductions in structural-functional coupling in WM regions compared to TD individuals, particularly in commissural tracts (e.g. corpus callosum), association tracts (sagittal stratum), and projection tracts (e.g. internal capsule). Notably, supervised machine learning analysis in the independent test cohort revealed a significant correlation between these alterations in structural-functional coupling and ASD severity scores. Furthermore, compared to single-model features, the integration of multi-model features (i.e., structural-functional coupling) performed best in predicting ASD severity scores. Conclusion This work provides novel evidence for atypical structural-functional coupling in ASD in white matter regions, further refining our understanding of the critical role of WM networks in the pathophysiology of ASD.

Abstract Over the last decade, a number of clinical trials have reported effects of chronic treatment with intranasal oxytocin on autistic symptoms but with inconsistent findings. Autism is a heterogeneous disorder and one factor which may influence treatment outcome is whether a subtype of individuals is more sensitive to oxytocin. In a recent cross-over trial on 41 young autistic children we reported that 44% showed a reliable improvement in clinical symptoms (Autism Diagnostic Observation Schedule, ADOS-2) after a placebo-controlled, 6-week intranasal oxytocin intervention where treatment was given every other day followed by a period of positive social interaction. In the current re-assessment of the data, we used an unsupervised data-driven cluster analysis approach to identify autism subtypes using 23 different demographic, social subtype, endocrine, eye-tracking and clinical symptom measures taken before treatment and this revealed an optimum of two different subtypes. We then assessed the proportion of identified responders to oxytocin and found that while 61.5% of one subtype included responders only 13.3% of the other did so. During the placebo phase there was no difference between the two subtypes for the small proportion of responders (19.2% vs 6.7%). This oxytocin-sensitive subtype also showed overall significant post-treatment clinical and eye-tracking measure changes. The oxytocin-sensitive subtype was primarily characterized at baseline by lower initial clinical severity (ADOS-2) and greater interest in the eye-region of emotional faces. These features alone were nearly as efficient in identifying the two subtypes as all 23 baseline measures and this easy-to-conduct approach may help rapidly and objectively screen for oxytocin responders. Future clinical trials using oxytocin interventions may therefore achieve greater success by focusing on children with this specific autism subtype and help develop individualized oxytocin intervention.

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces, the global regulation based on epigenetic modification is not well explored. N4-methylcytosine (m4C), an abundant epigenetic marker in Actinomycetes’ genome, but its regulatory mechanism remains unclear. In this study, we identify a m4C methyltransferase (SroLm3) in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism. Notably, three BGCs in ΔsroLm3 strain exhibited decreased expression compared to wild type. In-frame deletion of sroLm3 in S.roseosporus L30 further revealed its role in enhancing daptomycin production. In summary, we characterized a m4C methyltransferase, revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment, and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation. Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.

ABSTRACT DNA methylation is a defense that microorganisms use against extreme environmental stress, and improving resistance against environmental stress is essential for industrial actinomycetes. However, research on strain optimization utilizing DNA methylation for breakthroughs is rare. Based on DNA methylome analysis and KEGG pathway assignment in Streptomyces roseosporus, we discovered an environmental stress resistance regulator, TagR. A series of in vivo and in vitro experiments identified TagR as a negative regulator, and it is the first reported regulator of the wall teichoic acid (WTA) ABC transport system. Further study showed that TagR had a positive self-regulatory loop and m4C methylation in the promoter improved its expression. The ΔtagR mutant exhibited better hyperosmotic resistance and higher decanoic acid tolerance than the wild type, which led to a 100% increase in the yield of daptomycin. Moreover, enhancing the expression of the WTA transporter resulted in better osmotic stress resistance in Streptomyces lividans TK24, indicating the potential for wide application of the TagR-WTA transporter regulatory pathway. This research confirmed the feasibility and effectiveness of mining regulators of environmental stress resistance based on the DNA methylome, characterized the mechanism of TagR, and improved the resistance and daptomycin yield of strains. Furthermore, this research provides a new perspective on the optimization of industrial actinomycetes. IMPORTANCE This study established a novel strategy for screening regulators of environmental stress resistance based on the DNA methylome and discovered a new regulator, TagR. The TagR-WTA transporter regulatory pathway improved the resistance and antibiotic yield of strains and has the potential for wide application. Our research provides a new perspective on the optimization and reconstruction of industrial actinomycetes.

Abstract Background Majority of neuroblastoma patients develop metastatic disease at diagnosis and their prognosis is poor with current therapeutic approach. Major challenges are how to tackle the mechanisms responsible for tumorigenesis and metastasis. Human mesenchymal stem cells (hMSCs) may be actively involved in the constitution of cancer microenvironment. Methods An orthotopic neuroblastoma murine model was utilized to mimic the clinical scenario. Human neuroblastoma cell line SK-N-LP was transfected with luciferase gene, which were inoculated with/without hMSCs into the adrenal area of SCID-beige mice. The growth and metastasis of neuroblastoma was observed by using Xenogen IVIS 100 in vivo imaging and evaluating gross tumors ex vivo. The homing of hMSCs towards tumor was analyzed by tracing fluorescence signal tagged on hMSCs using CRI Maestro™ imaging system. Results hMSCs mixed with neuroblastoma cells significantly accelerated tumor growth and apparently enhanced metastasis of neuroblastoma in vivo. hMSCs could be recruited by primary tumor and also become part of the tumor microenvironment in the metastatic lesion. The metastatic potential was consistently reduced in lung and tumor when hMSCs were pre-treated with stromal cell derived factor-1 (SDF-1) blocker, AMD3100, suggesting that the SDF-1/CXCR4 axis was one of the prime movers in the metastatic process. Conclusions hMSCs accelerated and facilitated tumor formation, growth and metastasis. Furthermore, the homing propensity of hMSCs towards both primary tumor and metastatic loci can also provide new therapeutic insights in utilizing bio-engineered hMSCs as vehicles for targeted anti-cancer therapy.

Daptomycin is a cyclic lipopeptide antibiotic with a significant antibacterial action against antibiotic-resistant Gram-positive bacteria. Despite numerous attempts to enhance daptomycin yield throughout the years, the production remains unsatisfactory. This study reports the application of multilevel metabolic engineering strategies in Streptomyces roseosporus to reconstruct high-quality daptomycin overproducing strain L2797-VHb, including precursor engineering (i.e., refactoring kynurenine pathway), regulatory pathway reconstruction (i.e., knocking out negative regulatory genes arpA and phaR), byproduct engineering (i.e., removing pigment), multicopy biosynthetic gene cluster (BGC), and fermentation process engineering (i.e., enhancing O2 supply). The daptomycin titer of L2797-VHb arrived at 113 mg/l with 565% higher comparing the starting strain L2790 (17 mg/l) in shake flasks and was further increased to 786 mg/l in 15 L fermenter. This multilevel metabolic engineering method not only effectively increases daptomycin production, but can also be applied to enhance antibiotic production in other industrial strains.

Arf6 is a member of ADP‐ribosylation factor (Arf) family, which is widely implicated in the regulation of multiple physiological processes including endocytic recycling, cytoskeletal organization, and membrane trafficking during mitosis. In this study, we investigated the potential relationship between Arf6 and aging‐related oocyte quality, and its roles on organelle rearrangement and cytoskeleton dynamics in porcine oocytes. Arf6 expressed in porcine oocytes throughout meiotic maturation, and it decreased in aged oocytes. Disruption of Arf6 led to the failure of cumulus expansion and polar body extrusion. Further analysis indicated that Arf6 modulated ac‐tubulin for meiotic spindle organization and microtubule stability. Besides, Arf6 regulated cofilin phosphorylation and fascin for actin assembly, which further affected spindle migration, indicating the roles of Arf6 on cytoskeleton dynamics. Moreover, the lack of Arf6 activity caused the dysfunction of Golgi and ER for protein synthesis and signal transduction. Mitochondrial dysfunction was also observed in Arf6‐deficient porcine oocytes, which was supported by the increased ROS level and abnormal membrane potential. In conclusion, our results reported that insufficient Arf6 was related to aging‐induced oocyte quality decline through spindle organization, actin assembly, and organelle rearrangement in porcine oocytes. [ABSTRACT FROM AUTHOR]

Abstract Background Although leukemic blast cells of Pro-B cell acute lymphoblastic leukemia (ALL) are arrested at the same stage of B cell differentiation, the immature B cell subtype is still biologically heterogeneous and is associated with diverse outcomes. This study aimed to explore the clinical-biological characteristics of pediatric pro-B ALL and factors associated with outcomes. Methods This study enrolled 121 pediatric patients aged 6 months to 14 years with newly diagnosed CD19+CD10− pro-B cell acute lymphoblastic leukemia (pro-B ALL) treated at Beijing Children’s Hospital from March 2003 to October 2018. Genetic abnormalities, immunophenotypic markers, minimal residual disease (MRD) at early treatment stage and long-term outcomes of children treated on two consecutive protocols were analyzed. Results KMT2A rearrangements were the most frequent abnormalities (incidence rate 33.06%), and were associated with lower frequency of CD13, CD33, CD22 and CD34 expression and higher frequency of CD7 and NG2 expression. Higher frequency of CD15 and CD133 expression was found in KMT2A-AFF1 + patients, exclusively. Presence of CD15 and absence of CD34 at diagnosis correlated with the high burden of MRD at the early stage of treatment. Outcomes were more favorable in patients older than 1 year, with absence of CD20 expression and KMT2A rearrangements, and with MRD lower than 1% at the end of induction and 0.1% before consolidation. Increased intensity of chemotherapy based on MRD analysis did not improve outcomes significantly (5-year EFS 73.9 ± 6.5% for BCH-2003 and 76.1 ± 5.3% for CCLG-2008, P = 0.975). Independent adverse prognostic factors were MRD ≥ 0.1% before consolidation and presence of KMT2A gene rearrangements (odds ratios [ORs] 9.424 [95% confidence interval (CI) 3.210, 27.662; P

One of the most robust effects of intranasal oxytocin treatment is its enhancement of emotional empathy responses across cultures to individuals displaying emotions in realistic contexts in the Multifaceted Empathy Task (MET). However, it is not established if this effect of oxytocin on emotional empathy is due to altered visual attention toward different components of the stimulus pictures or an enhanced empathic response. In the current randomized placebo-controlled within-subject experiment on 40 healthy male individuals, we both attempted a further replication of emotional empathy enhancement by intranasal oxytocin (24 IU) and used eye-tracking measures to determine if this was associated by altered visual attention toward different components of the picture stimuli (background context, human face, and body posture). Results replicated previous findings of enhanced emotional empathy in response to both negative and positive stimuli and that this was associated with an increased proportion of time viewing the faces of humans in the pictures and a corresponding decrease in that toward the rest of the body and/or background context. Overall, our findings suggest that enhanced emotional empathy following oxytocin administration is due to increased attention to the faces of others displaying emotions and away from other contextual and social cues.Clinical Trial Registration:www.ClinicalTrials.gov Oxytocin Modulates Eye Gaze Behavior During Social Processing; registration ID: NCT03293511; URL: https://clinicaltrials.gov/ct2/show/NCT03293511.

The continuous wave mud pulse transmission holds great promise for the future of downhole data communication. However, significant noise interference during the transmission process poses a formidable challenge for decoding. In particular, effectively eliminating random noise with a substantial amplitude that overlaps with the pulse signal spectrum has long been a complex issue. To address this, an enhanced integration algorithm that merges variational mode decomposition (VMD) and compressed sensing (CS) to suppress high-intensity random noise is proposed in this paper. In response to the inadequacy of manually preset parameters in VMD, which often leads to suboptimal decomposition outcomes, the gray wolf optimization algorithm is designed to obtain the optimal penalty factor and decomposition mode number in VMD. Subsequently, the optimized parameter combination decomposes the signal into a series of intrinsic modes. The mode exhibiting a stronger correlation with the original signal is retained to enhance signal sparsity, thereby fulfilling the prerequisite for compressed sensing. The signal is then observed and reconstructed using the compressed sensing method to yield the final signal. The proposed algorithm has been compared with VMD, CS, and CEEMD; the results demonstrate that the method can enhance the signal–noise ratio by up to ∼20.55 dB. Furthermore, it yields higher correlation coefficients and smaller mean square errors. Moreover, the experimental results using real field data show that the useful pulse waveforms can be recognized effectively, assisting surface workers in acquiring precise downhole information, enhancing drilling efficiency, and significantly reducing the risk of engineering accidents. [ABSTRACT FROM AUTHOR]

Oocyte maturation defect can lead to maternal reproduction disorder. NAMPT is a rate‐limiting enzyme in mammalian NAD+ biosynthesis pathway, which can regulate a variety of cellular metabolic processes including glucose metabolism and DNA damage repair. However, the function of NAMPT in porcine oocytes remains unknown. In this study, we showed that NAMPT involved into multiple cellular events during oocyte maturation. NAMPT expressed during all stages of porcine oocyte meiosis, and inhibition of NAMPT activity caused the cumulus expansion and polar body extrusion defects. Mitochondrial dysfunction was observed in NAMPT‐deficient porcine oocytes, which showed decreased membrane potential, ATP and mitochondrial DNA content, increased oxidative stress level and apoptosis. We also found that NAMPT was essential for spindle organization and chromosome arrangement based on Ac‐tubulin. Moreover, lack of NAMPT activity caused the increase of lipid droplet and affected the imbalance of lipogenesis and lipolysis. In conclusion, our study indicated that lack of NAMPT activity affected porcine oocyte maturation through its effects on mitochondria function, spindle assembly and lipid metabolism. [ABSTRACT FROM AUTHOR]