Transcriptional Regulation of De Novo Lipogenesis by SIX1 in Liver Cancer Cells.

De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (SIX1) is shown to directly increase the expression of DNL-related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 （HBO1/KAT7）, thus promoting lipogenesis. SIX1 expression is regulated by insulin/lncRNA DGUOK-AS1/microRNA-145-5p axis, which also modulates DNL-related gene expression as well as DNL. The DGUOK-AS1/microRNA-145-5p/SIX1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, SIX1 expression is positively correlated with DGUOK-AS1 and SCD1 expression and is negatively correlated with microRNA-145-5p expression. DGUOK-AS1 is a good predictor of prognosis. Thus, the DGUOK-AS1/microRNA-145-5p/SIX1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.

Changes of college students' psychological stress during the COVID-19 pandemic in China: A two-wave repeated survey.

COVID-19 has posed unprecedented challenges to the mental health of college students worldwide. We examined the trends in students' stress levels during and after China's first wave of COVID-19 outbreaks by analyzing their demographics, behavior, mental health status, career confidence, and Chinese Perceived Stress Scale (CPSS) scores. Our findings indicate an increase in students' stress levels since the COVID-19 onset, with more students experiencing higher stress levels after the first outbreak than during it (OR = 2.03, 95% CI 1.79, 2.30). Several factors were identified as being associated with higher CPSS scores, including higher class levels, residence in rural or town areas, low family income, and lack of familiarity with COVID-19, among others. Our study highlighted the urgency of developing and implementing effective strategies to cope with students' stress during and after a global pandemic.

Dynamic monitoring of TGW6 by selective autophagy during grain development in rice.

Crop yield must increase to achieve food security in the face of a growing population and environmental deterioration. Grain size is a prime breeding target for improving grain yield and quality in crop. Here, we report that autophagy emerges as an important regulatory pathway contributing to grain size and quality in rice. Mutations of rice Autophagy-related 9b (OsATG9b) or OsATG13a causes smaller grains and increase of chalkiness, whereas overexpression of either promotes grain size and quality. We also demonstrate that THOUSAND-GRAIN WEIGHT 6 (TGW6), a superior allele that regulates grain size and quality in the rice variety Kasalath, interacts with OsATG8 via the canonical Atg8-interacting motif (AIM), and then is recruited to the autophagosome for selective degradation. In consistent, alteration of either OsATG9b or OsATG13a expression results in reciprocal modulation of TGW6 abundance during grain growth. Genetic analyses confirmed that knockout of TGW6 in either osatg9b or osatg13a mutants can partially rescue their grain size defects, indicating that TGW6 is one of the substrates for autophagy to regulate grain development. We therefore propose a potential framework for autophagy in contributing to grain size and quality in crops.

Let-7b-5p inhibits breast cancer cell growth and metastasis via repression of hexokinase 2-mediated aerobic glycolysis.

Hexokinase 2 (HK2), a critical rate-limiting enzyme in the glycolytic pathway catalyzing hexose phosphorylation, is overexpressed in multiple human cancers and associated with poor clinicopathological features. Drugs targeting aerobic glycolysis regulators, including HK2, are in development. However, the physiological significance of HK2 inhibitors and mechanisms of HK2 inhibition in cancer cells remain largely unclear. Herein, we show that microRNA-let-7b-5p (let-7b-5p) represses HK2 expression by targeting its 3'-untranslated region. By suppressing HK2-mediated aerobic glycolysis, let-7b-5p restrains breast tumor growth and metastasis both in vitro and in vivo. In patients with breast cancer, let-7b-5p expression is significantly downregulated and is negatively correlated with HK2 expression. Our findings indicate that the let-7b-5p/HK2 axis plays a key role in aerobic glycolysis as well as breast tumor proliferation and metastasis, and targeting this axis is a potential therapeutic strategy for breast cancer.

Three-Dimensional Encoding Approach for Wearable Tactile Communication Devices.

In this work, we presented a novel encoding method for tactile communication. This approach was based on several tactile sensory characteristics of human skin at different body parts, such as the head and neck, where location coordinates in the three-dimensional (3D) space were clearly mapped in the brain cortex, and gentle stimulations of vibrational touching with varied strengths were received instantly and precisely. For certain applications, such as playing cards or navigating walk paths for blinded people, we demonstrated specifically designed code lists with different patterns of tactile points in varied temporal sequences. By optimizing these codes, we achieved excellent efficiency and accuracy in our test experiments. As this method matched well with the natural habits of tactile sensory, it was easy to learn in a short training period. The results of the present work have offered a silent, efficient and accurate communication solution for visually impaired people or other users.

Asymmetric interface excited chirality and its applications in reconfiguration.

In this paper, a chiral excitation method based on the asymmetric interface condition is proposed. The chiral characteristics of the metamaterials are affected by the difference in the environmental parameters of the front and rear surfaces. Thus, the device can achieve functional reconfiguration and two applications based on this mechanism are presented, one for sensing and the other for chiral switching. At the same time, a self-calibration measurement method that greatly simplifies the sensing system is proposed. These results have potential applications in the fields of chirality excitation, bio-sensing, and reconfigurable device.

Transcriptional Repression of Aerobic Glycolysis by OVOL2 in Breast Cancer.

Aerobic glycolysis (Warburg effect), a hallmark of cancer, plays a critical role in cancer cell growth and metastasis; however, direct inhibition of the Warburg effect remains largely unknown. Herein, the transcription factor OVO-like zinc finger 2 (OVOL2) is demonstrated to directly repress the expression of several glycolytic genes, blocking the Warburg effect and breast tumor growth and metastasis in vitro and in vivo. OVOL2 inhibits glycolysis by recruiting the nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3). The tumor suppressor p53, a key regulator of cancer metabolism, activates OVOL2 by binding to the oncoprotein mouse double minute 2 homolog (MDM2) and inhibiting MDM2-mediated ubiquitination and degradation of OVOL2. OVOL2 expression is negatively correlated with glycolytic gene expression and can be a good predictor of prognosis in patients with breast cancer. Therefore, targeting the p53/MDM2/OVOL2 axis provides a potential avenue for cancer treatment, especially breast cancer.

Typological characteristics of interlanguage: Across L2 modalities and proficiency levels.

In recent years, quantitative methods have been increasingly used in interlanguage studies, but these studies have mostly focused on the micro level with an emphasis on certain syntactic structures, rather than the macro where interlanguage is perceived as a whole. There remains a paucity of quantitative studies on interlanguage from the typological perspective. With the majority of the studies focused on the written interlanguage, there is also a lack of sufficient research on its spoken modality. Based on a syntactically annotated corpus and using the quantitative linguistic metric of dependency direction, we have investigated the typological changes in the Chinese interlanguage in both written and spoken modalities. The findings are as follows: (1) the typological features of interlanguage vary across modalities at both macro and micro levels; (2) dependency direction is proved to be an inappropriate indicator to measure the general typological characteristics of interlanguage development due to its failure to reflect the changes in the spoken modality; (3) both macro and micro perspectives taken into consideration, typological errors in the interlanguage is more likely to occur in the spoken modality than in the written one, in which learners may be restricted by greater time pressure and cognitive load in utterance. These factors may affect the distribution of dependency direction in the oral modality, and may be the reason why it is not appropriate to use dependency direction as a measure of changes in mediated language typological features in the oral modality. It is expected that our study will bring insight into second language research with more objective and holistic evidence.

The landscape of COVID-19 vaccination among healthcare workers at the first round of COVID-19 vaccination in China: willingness, acceptance and self-reported adverse effects.

The COVID-19 vaccines have been developed in a wide range of countries. This study aimed to examine factors that related to vaccination rates and willingness to be vaccinated against COVID-19 among Chinese healthcare workers (HCWs). From 3rd February to 18th February, 2021, an online cross-sectional survey was conducted among HCWs to investigate factors associated with the acceptance and willingness of COVID-19 vaccination. Sociodemographic characteristics and the acceptance of COVID-19 vaccination among Chinese HCWs were evaluated. A total of 2156 HCWs from 21 provinces in China responded to this survey (effective rate: 98.99%)), among whom 1433 (66.5%) were vaccinated with at least one dose. Higher vaccination rates were associated with older age, working as a clinician, having no personal religion, working in a fever clinic or higher hospital grade, and having received vaccine education, family history for influenza vaccination and strong familiarity with the vaccine. Willingness for vaccination was related to working in midwestern China, considerable knowledge of the vaccine, received vaccine education, and strong confidence in the vaccine. Results of this study can provide evidence for the government to improve vaccine coverage by addressing vaccine hesitancy in the COVID-19 pandemic and future public health emergencies.

Autophagy Dances with Phytohormones upon Multiple Stresses.

Autophagy is an evolutionarily conserved process for turning over unwanted cellular components, thus promoting nutrient recycling and maintaining cellular homeostasis, which eventually enables plants to survive unfavorable growth conditions. In addition to plant growth and development, previous studies have demonstrated that autophagy is involved in the responses to various environmental challenges through interplaying with multiple phytohormones, including abscisic acid (ABA), jasmonic acid (JA), and salicylic acid (SA). In this review, we summarize the advances made in their synergistic interactions in response to multiple abiotic and biotic stresses; we also discuss the remaining issues and perspectives regarding their crosstalk.

Prognostic value of subclinical thyroid dysfunction in ischemic stroke patients treated with intravenous thrombolysis.

Data regarding the association between subclinical thyroid dysfunction and clinical outcomes in ischemic stroke patients with intravenous thrombolysis (IVT) are limited. We aimed to investigate the predictive value of subclinical thyroid dysfunction in END, functional outcome and mortality at 3 months among IVT patients. We prospectively recruited 563 IVT patients from 5 stroke centers in China. Thyroid function status was classified as subclinical hypothyroidism, subclinical hyperthyroidism (SHyper) and euthyroidism. The primary outcome was END, defined as ≥ 4 point in the NIHSS score within 24 h after IVT. Secondary outcomes included 3-month functional outcome and mortality. Of the 563 participants, END occurred in 14.7%, poor outcome in 50.8%, and mortality in 9.4%. SHyper was an independent predictor of END [odd ratio (OR), 4.35; 95% confidence interval [CI], 1.86-9.68, P = 0.003], 3-month poor outcome (OR, 3.24; 95% CI, 1.43-7.33, P = 0.005) and mortality [hazard ratio, 2.78; 95% CI, 1.55-5.36, P = 0.003]. Subgroup analysis showed that there was no significant relationship between SHyper and clinical outcomes in IVT patients with endovascular therapy. In summary, SHyper is associated with increased risk of END, and poor outcome and mortality at 3 months in IVT patients without endovascular therapy.

CRISPR/Cas9 systems have off-target activity with insertions or deletions between target DNA and guide RNA sequences.

CRISPR/Cas9 systems are a versatile tool for genome editing due to the highly efficient targeting of DNA sequences complementary to their RNA guide strands. However, it has been shown that RNA-guided Cas9 nuclease cleaves genomic DNA sequences containing mismatches to the guide strand. A better understanding of the CRISPR/Cas9 specificity is needed to minimize off-target cleavage in large mammalian genomes. Here we show that genomic sites could be cleaved by CRISPR/Cas9 systems when DNA sequences contain insertions ('DNA bulge') or deletions ('RNA bulge') compared to the RNA guide strand, and Cas9 nickases used for paired nicking can also tolerate bulges in one of the guide strands. Variants of single-guide RNAs (sgRNAs) for four endogenous loci were used as model systems, and their cleavage activities were quantified at different positions with 1- to 5-bp bulges. We further investigated 114 putative genomic off-target loci of 27 different sgRNAs and confirmed 15 off-target sites, each harboring a single-base bulge and one to three mismatches to the guide strand. Our results strongly indicate the need to perform comprehensive off-target analysis related to DNA and sgRNA bulges in addition to base mismatches, and suggest specific guidelines for reducing potential off-target cleavage.

Designing and testing the activities of TAL effector nucleases.

Transcription activator-like effector nucleases (TALENs) have rapidly developed into a powerful tool for genome editing. To avoid labor-intensive and time-consuming experimental screening for active TALENs, a scoring system can help select optimal target sites. Here we describe a procedure to design active TALENs using a scoring system named Scoring Algorithm for Predicted TALEN Activity (SAPTA) and a method to test the activity of individual and pairs of TALENs.

An online bioinformatics tool predicts zinc finger and TALE nuclease off-target cleavage.

Although engineered nucleases can efficiently cleave intracellular DNA at desired target sites, major concerns remain on potential 'off-target' cleavage that may occur throughout the genome. We developed an online tool: predicted report of genome-wide nuclease off-target sites (PROGNOS) that effectively identifies off-target sites. The initial bioinformatics algorithms in PROGNOS were validated by predicting 44 of 65 previously confirmed off-target sites, and by uncovering a new off-target site for the extensively studied zinc finger nucleases (ZFNs) targeting C-C chemokine receptor type 5. Using PROGNOS, we rapidly interrogated 128 potential off-target sites for newly designed transcription activator-like effector nucleases containing either Asn-Asn (NN) or Asn-Lys (NK) repeat variable di-residues (RVDs) and 3- and 4-finger ZFNs, and validated 13 bona fide off-target sites for these nucleases by DNA sequencing. The PROGNOS algorithms were further refined by incorporating additional features of nuclease-DNA interactions and the newly confirmed off-target sites into the training set, which increased the percentage of bona fide off-target sites found within the top PROGNOS rankings. By identifying potential off-target sites in silico, PROGNOS allows the selection of more specific target sites and aids the identification of bona fide off-target sites, significantly facilitating the design of engineered nucleases for genome editing applications.

SAPTA: a new design tool for improving TALE nuclease activity.

Transcription activator-like effector nucleases (TALENs) have become a powerful tool for genome editing due to the simple code linking the amino acid sequences of their DNA-binding domains to TALEN nucleotide targets. While the initial TALEN-design guidelines are very useful, user-friendly tools defining optimal TALEN designs for robust genome editing need to be developed. Here we evaluated existing guidelines and developed new design guidelines for TALENs based on 205 TALENs tested, and established the scoring algorithm for predicting TALEN activity (SAPTA) as a new online design tool. For any input gene of interest, SAPTA gives a ranked list of potential TALEN target sites, facilitating the selection of optimal TALEN pairs based on predicted activity. SAPTA-based TALEN designs increased the average intracellular TALEN monomer activity by >3-fold, and resulted in an average endogenous gene-modification frequency of 39% for TALENs containing the repeat variable di-residue NK that favors specificity rather than activity. It is expected that SAPTA will become a useful and flexible tool for designing highly active TALENs for genome-editing applications. SAPTA can be accessed via the website at http://baolab.bme.gatech.edu/Research/BioinformaticTools/TAL_targeter.html.

Nanomedicine: tiny particles and machines give huge gains.

Nanomedicine is an emerging field that integrates nanotechnology, biomolecular engineering, life sciences and medicine; it is expected to produce major breakthroughs in medical diagnostics and therapeutics. Nano-scale structures and devices are compatible in size with proteins and nucleic acids in living cells. Therefore, the design, characterization and application of nano-scale probes, carriers and machines may provide unprecedented opportunities for achieving a better control of biological processes, and drastic improvements in disease detection, therapy, and prevention. Recent advances in nanomedicine include the development of nanoparticle (NP)-based probes for molecular imaging, nano-carriers for drug/gene delivery, multifunctional NPs for theranostics, and molecular machines for biological and medical studies. This article provides an overview of the nanomedicine field, with an emphasis on NPs for imaging and therapy, as well as engineered nucleases for genome editing. The challenges in translating nanomedicine approaches to clinical applications are discussed.

Synthesis and biological evaluation of 2-(3-fluoro-4-nitro phenoxy)-n-phenylacetamide derivatives as novel potential affordable antitubercular agents.

A novel series of 2-(3-fluoro-4-nitrophenoxy)-N-phenylacetamide compounds were designed, synthesized and in vitro assessed for their antitubercular activities by a microdilution method. All the novel derivatives exerted potent or moderate active against M. tuberculosis H37Rv, with MIC values ranging from 4 to 64 µg/mL. The most potent derivative 3m showed an identical MIC value of 4 µg/mL for both M. tuberculosis H37Rv and rifampin-resistant M. tuberculosis 261. It demonstrated no inhibitory effects against six different tumor cell lines by a MTT assay and had a good safety profile in a vero cell line, providing a good lead for subsequent optimization in search of novel affordable antitubercular agents.

Syntheses and cell-based phenotypic screen of novel 7-amino pyrido[2,3-d]pyrimidine-6-carbonitrile derivatives as potential antiproliferative agents.

A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC(50) value of 12.5 mM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC(50) value of 6.9 mM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.

Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents.

A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H(37)Rv by a microdilution method, with MIC values ranging from 4 to 64µg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R(2) group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4µg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.

[Studies on chemical components of essential oil of crude semen sinapis and roasted semen sinapis].

OBJECTIVE: To study the chemical components of the essential oil of the Semen Sinapis with the different processing methods. METHOD: The essential oils of the crude Semen Sinapis and the roasted Semen Sinapis were extracted by steam distillation. The chemical components were analyzed by means of GC-MS-DS. The relative content of each component was calculated by area normalization. RESULT: The main chemical components of the essential oil of the crude Semen Sinapis and the roasted Semen Sinapis were similar. The main chemical components were allyl isothiocyanate and 4-isothio-cyanato-1-butene. The chemical components of the essential oil of the crude Semen Sinapis were more than that of the roasted Semen Sinapis. CONCLUSION: The effect of different processing methods on the chemical components of the essential oil of Semen Sinapis was significant. Certain chemical components such as isothiocyanato-containing substances, were found in the crude Semen Sinapis.