Miracle-dz/UniFAR-FTUs huggingface dataset:
Reconstruction of engineered yeast factory for high yield production of ginsenosides Rg3 and Rd

Panax notoginseng is one of the most valuable traditional Chinese herbs. The main active ingredients, dammarane-type ginsenosides, show multiple pharmacological activities. Recently, the key UDP-dependent glycosyltransferases (UGTs) involved in the biosynthesis of common ginsenosides have been widely studied. However, only a few UGTs that catalyze ginsenoside formation have been reported. This study further investigated the new catalytic function of 10 characterized UGTs from the public database. PnUGT31(PnUGT94B2) and PnUGT53 (PnUGT71B8)exhibited promiscuous sugar-donor specificity of UDP-glucose and UDP-xylose, which could catalyze the glycosylation of C20-OH sites and elongation of the sugar chain at the C3 and/or C20 sites. We further analyzed the expression patterns in P. notoginseng and predicted the catalytic mechanisms of PnUGT31 and PnUGT53 using molecular docking simulations. Moreover, different gene modules were built to increase the yield of ginsenosides in engineered yeast. The metabolic flow of the proginsenediol (PPD) synthetic pathway was enhanced by LPPDS gene modules based on the engineered strain. The resulting yeast was constructed to produce 1.72 g/L PPD in a shaking flask, but cell growth was significantly inhibited. EGH and LKG gene modules were constructed to achieve high-level production of dammarane-type ginsenosides. The production of G-Rg3 controlled by LKG modules increased 3.84 times (254.07 mg/ L), whereas the G-Rd titer reached 56.68 mg/L after 96 h in shaking flask culture under the control of all modules, both of which yielded the highest values for known microbes.
The transportome of the endophyte Serendipita indica in free life and symbiosis with Arabidopsis and its expression in moderate salinity

Serendipita indica is an endophytic root symbiont fungus that enhances the growth of various plants under different stress conditions, including salinity. Here, the functional characterization of two fungal Na+/H+ antiporters, SiNHA1 and SiNHX1 has been carried out to study their putative role in saline tolerance. Although their gene expression does not respond specifically to saline conditions, they could contribute, together with the previously characterized Na+ efflux systems SiENA1 and SiENA5, to relieve Na+ from the S. indica cytosol under this stressed condition. In parallel, an in-silico study has been carried out to define its complete transportome. To further investigate the repertoire of transporters expressed in free-living cells of S. indica and during plant infection under saline conditions, a comprehensive RNA-seq approach was taken. Interestingly, SiENA5 was the only gene significantly induced under free-living conditions in response to moderate salinity at all the tested time points, revealing that it is one of the main salt-responsive genes of S. indica. In addition, the symbiosis with Arabidopsis thaliana also induced SiENA5 gene expression, but significant changes were only detected after long periods of infection, indicating that the association with the plant somehow buffers and protects the fungus against the external stress. Moreover, the significant and strongest induction of the homologous gene SiENA1 occurred during symbiosis, regardless the exposure to salinity. The obtained results suggest a novel and relevant role of these two proteins during the establishment and maintenance of fungus-plant interaction.
Recent advances on 3D-printed PCL-based composite scaffolds for bone tissue engineering

Population ageing and various diseases have increased the demand for bone grafts in recent decades. Bone tissue engineering (BTE) using a three-dimensional (3D) scaffold helps to create a suitable microenvironment for cell proliferation and regeneration of damaged tissues or organs. The 3D printing technique is a beneficial tool in BTE scaffold fabrication with appropriate features such as spatial control of microarchitecture and scaffold composition, high efficiency, and high precision. Various biomaterials could be used in BTE applications. PCL, as a thermoplastic and linear aliphatic polyester, is one of the most widely used polymers in bone scaffold fabrication. High biocompatibility, low cost, easy processing, non-carcinogenicity, low immunogenicity, and a slow degradation rate make this semi-crystalline polymer suitable for use in load-bearing bones. Combining PCL with other biomaterials, drugs, growth factors, and cells has improved its properties and helped heal bone lesions. The integration of PCL composites with the new 3D printing method has made it a promising approach for the effective treatment of bone injuries. The purpose of this review is give a comprehensive overview of the role of printed PCL composite scaffolds in bone repair and the path ahead to enter the clinic. This study will investigate the types of 3D printing methods for making PCL composites and the optimal compounds for making PCL composites to accelerate bone healing. Graphical Abstract
Diffusible signal factor primes plant immunity against Xanthomonas campestris pv. campestris (Xcc) via JA signaling in Arabidopsis and Brassica oleracea

Background Many Gram-negative bacteria use quorum sensing (QS) signal molecules to monitor their local population density and to coordinate their collective behaviors. The diffusible signal factor (DSF) family represents an intriguing type of QS signal to mediate intraspecies and interspecies communication. Recently, accumulating evidence demonstrates the role of DSF in mediating inter-kingdom communication between DSF-producing bacteria and plants. However, the regulatory mechanism of DSF during the Xanthomonas-plant interactions remain unclear. Methods Plants were pretreated with different concentration of DSF and subsequent inoculated with pathogen Xanthomonas campestris pv. campestris (Xcc). Pathogenicity, phynotypic analysis, transcriptome combined with metabolome analysis, genetic analysis and gene expression analysis were used to evaluate the priming effects of DSF on plant disease resistance. Results We found that the low concentration of DSF could prime plant immunity against Xcc in both Brassica oleracea and Arabidopsis thaliana. Pretreatment with DSF and subsequent pathogen invasion triggered an augmented burst of ROS by DCFH-DA and DAB staining. CAT application could attenuate the level of ROS induced by DSF. The expression of RBOHD and RBOHF were up-regulated and the activities of antioxidases POD increased after DSF treatment followed by Xcc inoculation. Transcriptome combined with metabolome analysis showed that plant hormone jasmonic acid (JA) signaling involved in DSF-primed resistance to Xcc in Arabidopsis. The expression of JA synthesis genes (AOC2, AOS, LOX2, OPR3 and JAR1), transportor gene (JAT1), regulator genes (JAZ1 and MYC2) and responsive genes (VSP2, PDF1.2 and Thi2.1) were up-regulated significantly by DSF upon Xcc challenge. The primed effects were not observed in JA relevant mutant coi1-1 and jar1-1. Conclusion These results indicated that DSF-primed resistance against Xcc was dependent on the JA pathway. Our findings advanced the understanding of QS signal-mediated communication and provide a new strategy for the control of black rot in Brassica oleracea.
The good and the bad of T cell cross-reactivity: challenges and opportunities for novel therapeutics in autoimmunity and cancer

T cells are main actors of the immune system with an essential role in protection against pathogens and cancer. The molecular key event involved in this absolutely central task is the interaction of membrane-bound specific T cell receptors with peptide-MHC complexes which initiates T cell priming, activation and recall, and thus controls a range of downstream functions. While textbooks teach us that the repertoire of mature T cells is highly diverse, it is clear that this diversity cannot possibly cover all potential foreign peptides that might be encountered during life. TCR cross-reactivity, i.e. the ability of a single TCR to recognise different peptides, offers the best solution to this biological challenge. Reports have shown that indeed, TCR cross-reactivity is surprisingly high. Hence, the T cell dilemma is the following: be as specific as possible to target foreign danger and spare self, while being able to react to a large spectrum of body-threatening situations. This has major consequences for both autoimmune diseases and cancer, and significant implications for the development of T cell-based therapies. In this review, we will present essential experimental evidence of T cell cross-reactivity, implications for two opposite immune conditions, i.e. autoimmunity vs cancer, and how this can be differently exploited for immunotherapy approaches. Finally, we will discuss the tools available for predicting cross-reactivity and how improvements in this field might boost translational approaches.
The impact of the European Association of Endoscopic Surgery research grant scheme—a mixed qualitative quantitative methodology study protocol

Background The European Association of Endoscopic Surgery (EAES) is a surgical society who promotes the development and expansion of minimally invasive surgery to surgeons and surgical trainees. It does so through its activities in education, training, and research. The EAES research committee aims to promote the highest quality clinical research in endoscopic and minimally invasive surgery. They have provided grant funding since 2009 in education, surgery, and basic science. Despite the success and longevity of the scheme, the academic and non-academic impact of the research funding scheme has not been evaluated. Aims The primary aim of this project is to assess the short, long term academic and real world impact of the EAES funding scheme. The secondary aims are to identify barriers and facilitators for achieving good impact. Methods This will be a mixed qualitative and quantitative study. Semi-structured interviews will be performed with previous grant recipients. The questions for the interviews will be selected after a consensus is achieved amongst the members of the steering committee of this project. The responses will be transcribed and thematic analysis will be applied. The results of the thematic analysis will be used to populate a questionnaire which will be disseminated to grant recipients. This study is kindly funded by the EAES. Discussion The first question this project is expected to answer is whether the EAES research funding scheme had a significant positive impact on research output, career progression but also non-academic output such as change in clinical guidelines, healthcare quality and cost-effectiveness improvement. This project however is also expected to identify facilitators and barriers to successful completion of projects and to achieving high impact. This will inform EAES and the rest of the surgical and academic communities as to how clinicians would like to be supported when conducting research. There should also be a positive and decisive change towards removing factors that hinder the timely and successful completion of projects.
Paxbp1 is indispensable for the survival of CD4 and CD8 double-positive thymocytes

The lifespan of double-positive (DP) thymocytes is critical for intrathymic development and shaping the peripheral T cell repertoire. However, the molecular mechanisms that control DP thymocyte survival remain poorly understood. Paxbp1 is a conserved nuclear protein that has been reported to play important roles in cell growth and development. Its high expression in T cells suggests a possible role in T cell development. Here, we observed that deletion of Paxbp1 resulted in thymic atrophy in mice lacking Paxbp1 in the early stages of T cell development. Conditional loss of Paxbp1 resulted in fewer CD4+CD8+ DP T cells, CD4 and CD8 single positive (SP) T cells in the thymus, and fewer T cells in the periphery. Meanwhile, Paxbp1 deficiency had limited effects on the CD4-CD8- double negative (DN) or immature single-positive (ISP) cell populations. Instead, we observed a significant increase in the susceptibility of Paxbp1-deficient DP thymocytes to apoptosis. Consistent with this, RNA-Seq analysis revealed a significant enrichment of the apoptotic pathway within differentially expressed genes in Paxbp1-deficient DP cells compared to control DP cells. Together, our results suggest a new function for Paxbp1, which is an important mediator of DP thymocyte survival and critical for proper thymic development.
Genomic landscape and expression profile of consensus molecular subtype four of colorectal cancer

Background Compared to other subtypes, the CMS4 subtype is associated with lacking of effective treatments and poorer survival rates. Methods A total of 24 patients with CRC were included in this study. DNA and RNA sequencing were performed to acquire somatic mutations and gene expression, respectively. MATH was used to quantify intratumoral heterogeneity. PPI and survival analyses were performed to identify hub DEGs. Reactome and KEGG analyses were performed to analyze the pathways of mutated or DEGs. Single-sample gene set enrichment analysis and Xcell were used to categorize the infiltration of immune cells. Results The CMS4 patients had a poorer PFS than CMS2/3. CTNNB1 and CCNE1 were common mutated genes in the CMS4 subtype, which were enriched in Wnt and cell cycle signaling pathways, respectively. The MATH score of CMS4 subtype was lower. SLC17A6 was a hub DEG. M2 macrophages were more infiltrated in the tumor microenvironment of CMS4 subtype. The CMS4 subtype tended to have an immunosuppressive microenvironment. Conclusion This study suggested new perspectives for exploring therapeutic strategies for the CMS4 subtype CRC.
Assessing uncertainty in genomic offset forecasts from landscape genomic models (and implications for restoration and assisted migration)

Introduction Ecological genomic models are increasingly used to guide climate-conscious restoration and conservation practices in the light of accelerating environmental change. Genomic offsets that quantify the disruption of existing genotype–environment associations under environmental change are a promising model-based tool to inform such measures. With recent advances, potential applications of genomic offset predictions include but are not restricted to: (1) assessing in situ climate risks, (2) mapping future habitat suitability while accounting for local adaptations, or (3) selecting donor populations and recipient areas that maximize genomic diversity and minimize maladaptation to future environments in assisted migration planning. As for any model-based approach, it is crucial to understand how arbitrary decisions made during the modeling process affect predictions and induce uncertainty. Methods Here, we present a sensitivity analysis of how various modeling components influence forecasts of genomic offset-based metrics, using red spruce (Picea rubens), a cool-temperate tree species endemic to eastern North America, as a case study. We assess the effects of genomic marker set, climatic predictor set, climate change scenario, and “not-to-exceed” offset threshold and evaluate how uncertainty in predictions varies across space. Results Climate change scenario induced by far the largest uncertainty to our forecasts; however, the choice of predictor set was also important in regions of the Southern and Central Appalachians that are of high relevance for conservation and restoration efforts. While much effort is often expended in identifying candidate loci, we found that genomic marker set was of minor importance. The choice of a maximum offset threshold to limit transfers between potential donor and recipient locations in assisted migration programs has mostly affected the magnitude rather than geographic variation in our predictions. Discussion Overall, our model forecasts suggest high climate change risks across the entire distributional range of red spruce and strongly underscore the potential for assisted migration to help ameliorate these risks. In that regard, populations in the Southern and Central Appalachians as well as along the US and Canadian east coast seem the best candidates for both in situ conservation and relocation.
Sex differences in the renin-angiotensin-aldosterone system and its roles in hypertension, cardiovascular, and kidney diseases

Cardiovascular disease is a pathology that exhibits well-researched biological sex differences, making it possible for physicians to tailor preventative and therapeutic approaches for various diseases. Hypertension, which is defined as blood pressure greater than 130/80 mmHg, is the primary risk factor for developing coronary artery disease, stroke, and renal failure. Approximately 48% of American men and 43% of American women suffer from hypertension. Epidemiological data suggests that during reproductive years, women have much lower rates of hypertension than men. However, this protective effect disappears after the onset of menopause. Treatment-resistant hypertension affects approximately 10.3 million US adults and is unable to be controlled even after implementing ≥3 antihypertensives with complementary mechanisms. This indicates that other mechanisms responsible for modulating blood pressure are still unclear. Understanding the differences in genetic and hormonal mechanisms that lead to hypertension would allow for sex-specific treatment and an opportunity to improve patient outcomes. Therefore, this invited review will review and discuss recent advances in studying the sex-specific physiological mechanisms that affect the renin-angiotensin system and contribute to blood pressure control. It will also discuss research on sex differences in hypertension management, treatment, and outcomes.
Silicon modulator based on interleaved capacitors in subwavelength grating waveguides

Modulators based on free-carrier plasma dispersion effect has attracted a lot of attention in the recent years. Particularly, a lot of effort is dedicated nowadays into optimizing carrier accumulation silicon modulators. In this work a novel structure of carrier accumulation modulator is proposed and analyzed. The structure is based on interleaved capacitors in a periodic segmented waveguide such as SubWavelength Gratings (SWG) waveguides. This new structure overcomes the major limitation of carrier accumulation structures, which is the limited overlap of the optical mode with the region where the carrier accumulation takes place. The analysis of this novel structure is presented in detail from the optical and the electrical point of view. Furthermore, the procedure to analyze and extract the modulator performance is also presented. Values of modulation efficiency and loss below 0.5Vcm and 5 dB respectively were obtained for the proposed modulator.
Ion beam divergence characteristics of three-grid accelerator systems

A comprehensive experimental investigation of the geometrical and operating conditions which affect most strongly the ion beam divergence of three-grid accelerator systems is presented. Three-grid accelerator systems are shown to offer significant improvements in ion beam focusing over two-grid accelerator systems. These improvements are greatest for low net-to-total accelerating voltage ratios and small screen-to-accelerator grid separation ratios (i.e., high perveance grid sets). Ion beam focusing gains are negligible at a net-to-total accelerating voltage ratio near unity. Low decelerator grid impingement currents and low ion beam divergence angles require that the decelerator hole diameter be about 25% larger than the accelerator hole diameter, and also that the decelerator grid be spaced as close as is practically possible to the accelerator grid. The graphical results contained herein provide guidelines for the design of three-grid ion accelerator systems.
Conference on ‘ Impact of nutrition science to human health: past perspectives and future directions ’

Vitamin D is crucial for musculoskeletal health, with evidence suggesting non-skeletal bene ﬁ ts. Cutaneous vitamin D synthesis is limited in Ireland due to its northern latitude (52 – 55°N) and the population is dependent on dietary sources, yet intakes are inadequate. No study to-date has comprehensively examined vitamin D intakes and status in Ireland (Northern Ireland and the Republic). We aimed to review the evidence since 2010 and summarise the results in subgroups of the Irish population. We found that in the largest studies prevalence of de ﬁ ciency [25-hydroxyvitamin D (25(OH)D) < 30 n M /l] was 15 – 17 % in pregnancy, 15 – 23 % in children and 13 % in adults. Approximately half the population had 25(OH)D < 50 n M /l. There were only four small studies in an ethnic population with the largest in Southeast Asians ﬁ nding that 67 % were de ﬁ cient. All studies found higher rates of de ﬁ ciency and levels <50 n M /l in winter v. summer. Vitamin D intake was lowest in children (mean 2 ⋅ 3 – 4 ⋅ 2 μ g/d) and pregnant women (mean 1 ⋅ 9 – 5 ⋅ 1 μ g/d) and highest in older adults (6 ⋅ 9 μ g/d), with over 90 % of the population not meeting the recommended daily allowance. This review indicates that low vitamin D status and dietary vitamin D intake are widespread with children, adolescents, younger adults, pregnant women and ethnic minorities most at-risk. However, data are sparse in at-risk groups including the Travelling community, non-Europeans and institutionalised adults. Given the signi ﬁ cant prevalence of de ﬁ ciency, public health policies to promote better awareness of recommended vitamin D intakes and explore the options of food forti ﬁ cation are needed to address this issue.
A Study on EWMA charts with runs rules—the Markov chain approach

ABSTRACT Runs rules are usually used with Shewhart-type charts to enhance the charts' sensitivities toward small and moderate shifts. Abbas et al. in 2011 took it a step further by proposing two runs rules schemes, applied to the exponentially weighted moving average (EWMA) chart and evaluated their average run length (ARL) performances using simulation. They showed that the proposed schemes are superior to the classical EWMA chart and other schemes being investigated. Besides pointing out some erroneous ARL and standard deviation of the run length (SDRL) computations in Abbas et al., this paper presents a Markov chain approach for computing the ARL, percentiles of the run length (RL) distribution and SDRL, for the two runs rules schemes of Abbas et al. Using Markov chain, we also propose two combined runs rules EWMA schemes to quicken the two schemes of Abbas et al. in responding to large shifts. The runs rules (basic and combined rules) EWMA schemes will be compared with some existing control charting methods, where the former charts are shown to prevail.