High titer production of gastrodin enabled by systematic refactoring of yeast genome and an antisense-transcriptional regulation toolkit.

Gastrodin, a phenolic glycoside, is a prominent component of Gastrodia elata, which is renowned for its sedative, hypnotic, anticonvulsant, and neuroprotective activities. Engineering heterologous production of plant natural products in microbial host represents a safe, cost-effective, and scalable alternative to plant extraction. Here, we present the construction of an engineered Yarrowia lipolytica yeast that achieves a high-titer production of gastrodin. We systematically refactored the yeast genome by enhancing the flux of the shikimate pathway and optimizing the glucosyl transfer system. We introduced more than five dozen of genetic modifications onto the yeast genome, including enzyme screening, alleviation of rate-limiting steps, promoter selection, genomic integration site optimization, downregulation of competing pathways, and elimination of gastrodin degradation. Meanwhile, we developed a Copper-induced Antisense-Transcriptional Regulation (CATR) tool. The developed CATR toolkit achieved dynamic repression and activation of violacein synthesis through the addition of copper in Y. lipolytica. This strategy was further used to dynamically regulate the pyruvate kinase node to effectively redirect glycolytic flux towards the shikimate pathway while maintaining cell growth at proper rate. Taken together, these efforts resulted in 9477.1 mg/L of gastrodin in shaking flaks and 13.4 g/L of gastrodin with a yield of 0.149 g/g glucose in a 5-L bioreactor, highlighting the potential for large-scale and sustainable production of gastrodin from microbial fermentation.

Polyethylene glycol with dual three-dimensional porous carbon nanotube/diamond: a high thermal conductivity of composite PCM.

Polyethylene glycol (PEG) is widely used as a phase change material (PCM) in thermal energy storage systems due to its high latent heat and chemical stability. However, practical application has been hindered by its low thermal conductivity and leakage issues. Therefore, developing shape-stable high thermal conductivity PCM is of great importance. In this study, new shape-stable composite PCM with high thermal conductivity and leak-prevention capabilities were designed. The porous carbon skeleton of diamond foam (DF) and dual-3D carbon nanotube-diamond foam (CDF) were prepared using the microwave plasma chemical vapor deposition method. The composite materials (DF/PEG and CDF/PEG) were produced by vacuum impregnation with PEG and skeletons. The results showed that CDF/PEG had the highest thermal conductivity, measuring 2.30 W·m-1·K-1, which is 707% higher than that of pure PEG. The employing of 3D networks of CNTs, which can improve the phonon mean free path in DF/PEG (1.79 W·m-1·K-1) while reducing phonon dispersion.The phonon vibration of dual-3D CDF plays an important role in heat transfer. PEG was physically absorbed and well-distributed in CDF, alleviating leakage of liquid PEG. The weight loss of CDF/PEG was only 25% at 70 °C for 120 s. Using CDF is an attractive and efficient strategy to increase the heat transfer of PEG and improve heat storage efficiency, alleviate the problem of poor shape-stability.

NCAPH regulates gastric cancer progression through DNA damage response.

Gastric cancer (GC) is one of the most common devastating and deadly malignancies of the gastrointestinal tract in the world. GLOBOCAN data analysis showed that GC accounted for approximately 1,033,000 new cases of cancer and 78,200 deaths in 2018. Nonstructural maintenance of chromosomes (non-SMC) condensin I complex subunit H (NCAPH) is a regulatory subunit that encodes the non-SMC condensin I complex. Previous studies have demonstrated that NCAPH is highly expressed in multiple cancers. This study aimed to explore the function and potential mechanism of NCAPH in GC. Our study showed that NCAPH expression was significantly upregulated in The Cancer Genome Atlas (TCGA) and Oncomine datasets. Quantitative real-time polymerase chain reaction and western blotting were used to detect NCAPH expression in GC and paracarcinoma tissues. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to examine cell proliferation. Cell scratch and Transwell invasion assays were performed to assess cell migration. In addition, western blotting was used to detect the expression of proteins related to the cell cycle, DNA damage repair, and epithelial-mesenchymal transition (EMT). Flow cytometry was applied for cell cycle and apoptosis detection. A xenograft model was employed to assess the effect of NCAPH in vivo. The results demonstrated that NCAPH expression was significantly increased in GC tissue samples and cell lines. Knockout of NCAPH notably inhibited cell proliferation, cell migration, cell invasion, cell cycle progression, and tumor growth in vitro and in vivo, and induced the G1-phase cell cycle arrest by regulating the DNA damage response. In addition, knockout of NCAPH promoted cell apoptosis and regulated the expression of EMT-related proteins. The results indicate that the knockout of NCAPH in GC cells inhibits proliferation and metastasis via the DNA damage response in vitro and in vivo. NCAPH plays an important role in GC and may be a potential therapeutic target for GC treatment.

A Pediatric Case Report of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis With Pericardial Effusion and Multiple Coronary Artery Aneurysms.

Pediatric coronary artery aneurysms (CAAs) are mainly detected in Kawasaki disease and in chronic active Epstein-Barr virus (EBV) infection sometimes, and cardiac complications are rare in viral-associated hemophagocytic lymphohistiocytosis (HLH) patients. Here, we report a pediatric case of EBV-associated HLH with pericardial effusion and multiple CAAs, whereas the patient did not fulfill the diagnostic criteria of Kawasaki disease or chronic active EBV. The case indicates that CAAs may occur in EBV-HLH. Specifically, in a patient with a long-term fever and a high EBV DNA copy number, the detection of cardiac complications may help signal the possible occurrence of HLH, and CAAs may affect the prognosis for high risk of cardiac events.

Rotor UAV's Micro-Doppler Signal Detection and Parameter Estimation Based on FRFT-FSST.

The micro-Doppler signal generated by the rotors of an Unmanned Aerial Vehicle (UAV) contains the structural features and motion information of the target, which can be used for detection and classification of the target, however, the standard STFT has the problems such as the lower time-frequency resolution and larger error in rotor parameter estimation, an FRFT (Fractional Fourier Transform)-FSST (STFT based synchrosqueezing)-based method for micro-Doppler signal detection and parameter estimation is proposed in this paper. Firstly, the FRFT is used in the proposed method to eliminate the influence of the velocity and acceleration of the target on the time-frequency features of the echo signal from the rotors. Secondly, the higher time-frequency resolution of FSST is used to extract the time-frequency features of micro-Doppler signals. Moreover, the specific solution methodologies for the selection of window length in STFT and the estimation of rotor parameters are given in the proposed method. Finally, the effectiveness and accuracy of the proposed method for target detection and rotor parameter estimation are verified through simulation and measured data.

A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report.

BACKGROUND: Neuronal ceroid lipofuscinosis (NCLs) are lysosomal storage disorders characterized by seizures, motor impairment, and loss of vision. Ceroid lipofuscinosis (CLN) gene mutations are the cause, but NCL cases arising from CLN6 mutations have not been described in China to date. The CLN6 protein, which plays a role in lysosomal function, is an endoplasmic reticulum (ER) membrane protein with seven transmembrane (TM) domains. It has a cytosolic-facing amino terminal domain and a luminal-facing carboxyl terminal domain, with six loops between the TM domains. CASE PRESENTATION: Here we report a case involving a Chinese boy whose suspected diagnosis was a hereditary leukoencephalopathy, based on brain MRI imaging and epilepsy symptoms, language articulation disorders, ataxia, and unstable gait. The electroencephalogram showed epileptic discharges, and the brain MRI scan showed high signal intensity adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images, along with cerebellar atrophy. Using next-generation sequencing for the genes in a panel for hereditary leukoencephalopathies, we detected a homozygous missense point mutation c.892G > A(p.Glu298Lys) in CLN6, and the variant was interpreted as pathogenic on in silico analysis. Absence of this mutation was confirmed in 259 controls. Late infantile NCL and secondary epilepsy were diagnosed, and oral sodium valproate was prescribed. The epilepsy was not well controlled, however, and the other signs had not improved at the 6-month follow-up. We also analyzed the loci of 31 CLN6 missense mutations, including those previously reported and the current one. We found that 22.6% (7/31) of the mutations are in the cytoplasmic domains, about 32.2% (10/31) are in the TM domains, and about 45.2% (14/31) are in the luminal domains. These mutations were mostly located in the TM3-TM4 loop (6/31), TM1-TM2 loop (4/31), and C-terminus (4/31), with none found in the TM4-TM5 loop, TM5-TM6 loop, or TM7. CONCLUSIONS: We report the first case in China of NCL caused by a CLN6 mutation, expanding the genotype options for NCLs. In practice, NCLs generally are not the initial suspected diagnosis for such cases. Use of a gene sequencing panel for investigating unexplained seizures or leukoencephalopathies can help confirm the diagnosis.

A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.

BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4). CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4. CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.

Bilateral abducens nerve palsy in an infant case of fulminant acute disseminated encephalomyelitis: a case report.

BACKGROUND: Sixth (abducens) nerve palsy (ANP) is far less frequent in children and has not been reported as a sign of acute disseminated encephalomyelitis (ADEM). We present an infant case of ADEM with bilateral abducens nerve palsy (BANP). CASE PRESENTATION: We report one case of BANP in a 15-month-old boy of fulminant ADEM. The patient underwent physical examinations and brain MRI scan three times during about six months follow-up. The patient had BANP and developmental regression when he regained consciousness from a coma, and the signs had persisted for 6-months. CONCLUSIONS: BANP can be a symptom of ADEM.

[Research advances in candidate genes for autism spectrum disorder].

Autism spectrum disorder (ASD) is a kind of neurodevelopmental multigenic disorder. More than one hundred of candidate genes for ASD have been reported. The candidate gene research for ASD involves in chromosome loci and screening of candidate genes and epigenetic abnormalities for candidate genes. The reported genes encode neural adhesion molecules, ion channels, scaffold proteins, protein kinases, receptor protein and carrier protein, signaling modulate molecules and circadian relevant proteins. The research of mutation screening and expression regulation of candidate genes can help to elucidate genetic mechanisms for ASD, and may provide new approaches for the diagnosis and treatment of this disorder. This article reviews the research advance in candidate genes for ASD.

Clinical picture of combination therapy (metronidazole sustained release film with minocycine hydrochloride) in periodontitis.

This paper aimed to study the effect of metronidazole sustained-release film combined with minocycline hydrochloride on treating periodontitis. 138 patients with chronic periodontitis were collected and randomly divided into control group and observation group (each of 69 cases). Patients in control group were treated by using minocycline hydrochloride, while those in observation group were treated using metronidazole sustained-release film with minocycline hydrochloride, and each group with 4 weeks of treatment. Then we observed the periodontal mend matters, therapeutic effect, adverse reaction and relapse situation of patients in two groups. Results showed that compared with the prior treatment, the gingival index, dental plaque index, odontoseisis index and pocket depth of patients in two groups was significantly reduced. Moreover, the reduction range in observation group was significantly larger and the curative effect was superior to that in control group. Therefore, metronidazole sustained-release film combined minocycline hydrochloride can evidently improve patients' periodontal status, enhance drug therapeutic effect. It has less adverse reaction and low relapse rate, thus is worthy of clinical promotion.

Increased neural responses to unfairness in a loss context.

Unfairness plays an important role in economic decision making. This fMRI study sought to investigate how the loss and the gain contexts could modulate behavioral and brain responses to unfairness by focusing on participants' rejection behaviors during an Ultimatum Game paradigm. Participants were scanned while they were playing the Ultimatum Game as responders in both loss and gain contexts, i.e. receiving ¥50 as gains and paying for ¥50 as losses. At the behavioral level, lower fairness ratings and higher rejection rates were revealed for unfair losses than unfair gains. At the neural level, left dorsolateral prefrontal cortex, bilateral anterior insula, anterior cingulate cortex/anterior middle cingulate cortex and bilateral dorsal striatum were associated with rejection (vs. acceptance) in the loss context, but not in the gain context. Together, our data indicated that participants may experience more unfairness in UG and stronger desire to sanction social norm violations in the loss context than in the gain context, inducing more fairness-related neutral activities when rejecting (vs. accepting) unfair losses than unfair gains. These findings shed light on the significance of context (i.e. loss or gain) in fairness-related social decision-making processes.

The neural correlates of incidental self-processing induced by handwritten negative words.

Behavioral studies revealed that people were less likely to endorse negative information as self-descriptive. Neuroimaging studies have tapped on the neural mechanism underlying intentional self-processing of negative information using self-reflection tasks. Given that human self-processing occurring in our daily life is more likely to be captured by tasks involving incidental self-processing (automatic associations between the self- and external stimuli), rather than tasks involving intentional self-processing, it could be presumed that the relationship between self- and negative emotion might be better reflected during incidental self-processing. The present functional magnetic resonance imaging study aimed to explore incidental self-processing of negative information. To induce participants' incidental self-processing, we adopted negative and neutral words written by themselves or others as materials. They were scanned during judging whether the handwritten words were negative or neutral (additional non-self-task). Results revealed that incidental self-processing of negative information relied on the activation of left anterior insula, whereas medial prefrontal cortex activity was associated with incidental self-processing of neutral information.

Exposure to violence reduces empathetic responses to other's pain.

Past researches showed that empathy for pain not only triggers a resonance mechanism between other and self, but also is modulated by contextual factors. Using functional magnetic resonance imaging, the present study demonstrated that short-term media violence exposure reduced both pain ratings and also the activation of anterior insula and anterior mid-cingulate cortex to other's pain. Thus, violence exposure modulated empathic responses to other's pain based on a physiological desensitization.

Implicit learning of mappings between forms and metaphorical meanings.

Previous research has shown that people can implicitly acquire mappings between word forms and literal meanings (Williams, 2004, 2005). We argue, from the metaphor-representation and embodiment perspectives, that people can unconsciously establish mappings between word forms and not only literal but also metaphorical meanings. Using Williams' (2005) paradigm, we found that transfer of form-meaning connections from a concrete domain (space) to an abstract domain (power) was achieved in a metaphor-consistent way without awareness. Our results support the view that unconscious knowledge can be flexibly deployed in an abstract way not previously explored in the implicit learning literature.

The nature of the memory buffer in implicit learning: learning Chinese tonal symmetries.

Previous research has established that people can implicitly learn chunks, which (in terms of formal language theory) do not require a memory buffer to process. The present study explores the implicit learning of nonlocal dependencies generated by higher than finite-state grammars, specifically, Chinese tonal retrogrades (i.e. centre embeddings generated from a context-free grammar) and inversions (i.e. cross-serial dependencies generated from a mildly context-sensitive grammar), which do require buffers (for example, last in-first out and first in-first out, respectively). People were asked to listen to and memorize artificial poetry instantiating one of the two grammars; after this training phase, people were informed of the existence of rules and asked to classify new poems, while providing attributions of the basis of their judgments. People acquired unconscious structural knowledge of both tonal retrogrades and inversions. Moreover, inversions were implicitly learnt more easily than retrogrades constraining the nature of the memory buffer in computational models of implicit learning.

Unconsciously learning task-irrelevant perceptual sequences.

We demonstrated unconscious learning of task-irrelevant perceptual regularities in a Serial Reaction Time (SRT) task in both visual and auditory domains. Participants were required to respond to different letters ('F' or 'J', experiment 1) or syllables ('can' or 'you', experiment 2) which occurred in random order. Unbeknownst to participants, the color (red, green, blue or yellow) of the two letters or the tone (1-4) of the syllables varied according to certain rules. Reaction times indicated that people indeed learnt both the color and tonal regularities indicating that task-irrelevant sequence structure can be learned perceptually. In a subsequent prediction test of knowledge of the color or tonal cues using subjective measures, we showed that people could acquire task irrelevant knowledge unconsciously.

The Impact of New Urbanization Construction on Sustainable Economic Growth of Resource-Based Cities.

New urbanization construction is important for promoting sustainable economic growth in resource-based cities and can help resource-based cities achieve a sustainable development model with efficient resource allocation and green and low-carbon industrial transformation. Based on the background of the comprehensive pilot policy of new urbanization, we examined whether new urbanization construction promoted the economic growth of resource-based cities using 2011-2017 data on prefecture-level cities and the difference-in-differences (DID) method. It was found that new urbanization construction significantly promoted the growth in GDP per capita of resource-based cities, with a coefficient estimate of 0.1330, and this result passed a robustness test. The mechanism test indicated that new urbanization construction promoted the economic growth of resource-based cities by improving the efficiency of resource allocation and promoting industrial structure upgrading, with interaction term coefficient estimates of 0.1465 and 0.2929, respectively. Heterogeneity analysis showed that the policy effect of new urbanization construction was stronger in resource-rich cities than in resource-poor cities, significant in energy-based resource-based cities but not in metal-based and other resource-based cities, and significant in resource-based cities in the eastern and western regions of China but not in the central region. This study provides government departments implementing new urbanization policies with the results of a policy performance assessment of new urbanization construction for resource-based cities and feasible policy recommendations for the sustainable transformation of resource-based cities.

Engineering Yarrowia lipolytica for the biosynthesis of geraniol.

Geraniol is a monoterpene with wide applications in the food, cosmetics, and pharmaceutical industries. Microbial production has largely used model organisms lacking favorable properties for monoterpene production. In this work, we produced geraniol in metabolically engineered Yarrowia lipolytica. First, two plant-derived geraniol synthases (GES) from Catharanthus roseus (Cr) and Valeriana officinalis (Vo) were tested based on previous reports of activity. Both wild type and truncated mutants of GES (without signal peptide targeting chloroplast) were examined by co-expressing with MVA pathway enzymes tHMG1 and IDI1. Truncated CrGES (tCrGES) produced the most geraniol and thus was used for further experimentation. The initial strain was obtained by overexpression of the truncated HMG1, IDI and tCrGES. The acetyl-CoA precursor pool was enhanced by overexpressing mevalonate pathway genes such as ERG10, HMGS or MVK, PMK. The final strain overexpressing 3 copies of tCrGES and single copies of ERG10, HMGS, tHMG1, IDI produced approximately 1 g/L in shake-flask fermentation. This is the first demonstration of geraniol production in Yarrowia lipolytica and the highest de novo titer reported to date in yeast.

The effect of perioperative immunonutrition on patients undergoing esophagectomy: a systematic review and updated meta-analysis.

Introduction: Background: immunonutrition has been introduced and proposed to have positive modulating effects on inflammatory and immune responses in surgical patients. This meta-analysis aimed to assess whether perioperative enteral immunonutrition (EIN) can reduce postoperative complications or reduce inflammatory responses in esophageal cancer (EC) patients undergoing esophagectomy. Methods: PubMed, Embase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of EIN before and/or after surgery in EC patients undergoing esophagectomy were identified. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Results: ten RCTs involving 1,052 patients were included in the meta-analysis, including 573 patients in the EIN group and 479 patients in the enteral nutrition (EN) group. Overall, no significant difference was observed between the two groups in the incidence of postoperative pneumonia, surgical site infection, intra-abdominal abscess, septicemia, and urinary tract infection. No significant incidence of postoperative anastomotic leakage, acute respiratory distress syndrome (ARDS), and in-hospital mortality was found. Conclusions: perioperative enteral immunonutrition did not reduce the incidence of infectious complications and anastomotic leakage in EC patients undergoing esophagectomy, nor did it reduce postoperative CRP and IL-6, but did not increase in-hospital mortality.

Introducción: Antecedentes: se ha introducido y propuesto la inmunonutrición para regular activamente la inflamación y la respuesta inmune en pacientes quirúrgicos. El presente metaanálisis fue diseñado para evaluar si la inmunonutrición enteral perioperatoria (EIN, por sus siglas en inglés) puede reducir las complicaciones postoperatorias o la inflamación en pacientes con cáncer de esófago (CE) sometidos a esofagectomía. Métodos: se realizó una búsqueda sistemática en las bases de datos de PubMed, Embase, Web of Science, EBSCO y Cochrane Library. Se evaluó el efecto de la EIN preoperatoria y/o postoperatoria en un ensayo aleatorizado controlado (RCT) en pacientes con cáncer de esófago sometidos a esofagectomía. Dos investigadores buscaron independientemente artículos, extrajeron datos y evaluaron la calidad de los artículos incluidos. Resultados: el metanálisis incluyó diez ensayos controlados aleatorios en los que participaron 1.052 pacientes, de los cuales 573 fueron incluidos en el grupo EIN y 479, en el grupo de nutrición enteral (NE). En general, no hubo diferencia significativa en la incidencia de neumonía postoperatoria, infección del sitio quirúrgico, absceso intraperitoneal, sepsis e infección del tracto urinario entre los dos grupos. No hubo diferencia significativa en la incidencia de fístula anastomótica postoperatoria, síndrome de distrés respiratorio agudo (SDRA) y mortalidad hospitalaria. Conclusión: la inmunonutrición enteral perioperatoria no puede reducir la incidencia de complicaciones infecciosas postoperatorias y fístulas anastomóticas, ni la PCR postoperatoria ni la IL-6. Pero no aumentó la mortalidad hospitalaria.

Hippocampal activity is associated with self-descriptiveness effect in memory, whereas self-reference effect in memory depends on medial prefrontal activity.

The self has long been regarded as a unique cognitive structure by virtue of its superior mnemonic abilities. Two separate effects result from this self memory facilitation: self-reference effect and self-descriptiveness effect in memory. Self-reference effect denotes that information processed with reference to the self is better remembered than information processed with reference to others, whereas self-descriptiveness effect indicates that items judged to be self-relevant is remembered better than items judged not to be relevant to self during self-reference task. Although there is a compelling connection between self-reference effect in memory and self mentalization processes indexed by the medial prefrontal activity, the underlying mechanisms of the self-descriptiveness effect in memory have remained underspecified. In the present fMRI study, we used a subsequent memory paradigm to examine the neural correlates of self-descriptiveness and self-reference effect in memory. Participants encoded personality traits while performing self-reference and other-reference task (judged the descriptiveness of the traits to themselves or a famous person "Bruce Lee"), and then were given a test of recognition memory outside the scanner. It is revealed that the hippocampal activity corresponded with self-descriptiveness effect in memory, but the activity of the medial prefrontal cortex and perirhinal cortex related to self-reference effect in memory. These findings suggested that the memory boost for self-relevant items relies on the enhanced relational binding mechanisms employed during self-relevant items.