Dynamic regulation and cofactor engineering of escherichia coli to enhance production of glycolate from corn stover hydrolysate.

Glycolic acid is widely employed in chemical cleaning, the production of polyglycolic acid-lactic acid, and polyglycolic acid. Currently, the bottleneck of glycolate biosynthesis lies on the imbalance of metabolic flux and the deficiency of NADPH. In this study, a dynamic regulation system was developed and optimized to enhance the metabolic flux from glucose to glycolate. Additionally, the knockout of transhydrogenase (sthA), along with the overexpression of pyridine nucleotide transhydrogenase (pntAB) and the implementation of the Entner-Doudoroff pathway, were performed to further increase the production of the NADPH, thereby increasing the titer of glycolate to 5.6 g/L. To produce glycolate from corn stover hydrolysate, carbon catabolite repression was alleviated and glucose utilization was accelerated. The final strain, E. coli Mgly10-245, is inducer-free, achieving a glycolate titer of 46.1 g/L using corn stover hydrolysate (77.1 % of theoretical yield). These findings will contribute to the advancement of industrial glycolate production.

Well-designed lamellar reduced graphene oxide-based foam for high-performance solar-driven water purification.

Although solar steam generation is promising for seawater desalination, it is less effective in purifying wastewater with both salt/heavy metal ions and organic contaminants. It is thus imperative to develop multifunctional integrated solar-driven water purification systems with high solar-thermal evaporation and photocatalytic degradation efficiencies. Herein, a lamellar reduced graphene oxide (L-RGO) foam with the vertical lamellar structure is fabricated by bidirectional-freezing, lyophilization, and slight chemical reduction for water purification. The unique vertical lamellar structure not only accelerates upward transport of water for facilitating water evaporation but also endows the L-RGO foam with superb high elasticity for tuning the interlayer distance and varying interactions between the oxygen-containing groups and water molecules to adjust water energy state. As a result, the L-RGO foam achieves a superb water evaporation rate of 2.40 kg m-2 h-1 along with an energy efficiency of 95.3 % under the compressive strain of 44.7 % under 1-sun irradiation. Equally importantly, the decoration of L-RGO foam with polypyrrole is capable of efficiently degrading organic pollutants while retaining high solar steam generation performances, exhibiting great potential in the comprehensive treatment of various water sources for relieving freshwater crisis.

Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma.

Mesothelioma is a cancer typically caused by asbestos. Mechanistically, asbestos carcinogenesis has been linked to the asbestos-induced release of HMGB1 from the nucleus to the cytoplasm, where HMGB1 promotes autophagy and cell survival, and to the extracellular space where HMGB1 promotes chronic inflammation and mesothelioma growth. Targeting HMGB1 inhibited asbestos carcinogenesis and the growth of mesothelioma. It is hoped that targeting HMGB1 will be a novel therapeutic strategy that benefits mesothelioma patients. Severe restrictions and/or a complete ban on the use of asbestos were introduced in the 80 and early 90s in the Western world. These measures have proven effective as the incidence of mesothelioma/per 100,000 persons is decreasing in these countries. However, the overall number of mesotheliomas in the Western world has not significantly decreased. There are several reasons for that which are discussed here: (1) the presence of asbestos in old constructions; (2) the development of rural areas containing asbestos or other carcinogenic mineral fibers in the terrain; (3) the discovery of an increasing fraction of mesotheliomas caused by germline genetic mutations of BAP1 and other tumor suppressor genes; (4) mesotheliomas caused by radiation therapy; (5) the overall increase in the population and of the fraction of older people who are much more susceptible to develop all types of cancers, including mesothelioma. In summary, the epidemiology of mesothelioma is changing, the ban on asbestos worked, there are opportunities to help mesothelioma patients especially those who develop in a background of germline mutations and there is the opportunity to prevent a mesothelioma epidemic in the developing world, where the use of asbestos is increasing exponentially. We hope that restrictive measures similar to those introduced in the Western world will soon be introduced in developing countries to prevent a mesothelioma epidemic.

HMGB1 released by mesothelial cells drives the development of asbestos-induced mesothelioma.

Asbestos is the main cause of malignant mesothelioma. Previous studies have linked asbestos-induced mesothelioma to the release of HMGB1 from the nucleus to the cytoplasm, and from the cytoplasm to the extracellular space. In the cytoplasm, HMGB1 induces autophagy impairing asbestos-induced cell death. Extracellularly, HMGB1 stimulates the secretion of TNFα. Jointly, these two cytokines kick-start a chronic inflammatory process that over time promotes mesothelioma development. Whether the main source of extracellular HMGB1 were the mesothelial cells, the inflammatory cells, or both was unsolved. This information is critical to identify the targets and design preventive/therapeutic strategies to interfere with asbestos-induced mesothelioma. To address this issue, we developed the conditional mesothelial HMGB1-knockout (Hmgb1ΔpMeso) and the conditional myelomonocytic-lineage HMGB1-knockout (Hmgb1ΔMylc) mouse models. We establish here that HMGB1 is mainly produced and released by the mesothelial cells during the early phases of inflammation following asbestos exposure. The release of HMGB1 from mesothelial cells leads to atypical mesothelial hyperplasia, and in some animals, this evolves over the years into mesothelioma. We found that Hmgb1ΔpMeso, whose mesothelial cells cannot produce HMGB1, show a greatly reduced inflammatory response to asbestos, and their mesothelial cells express and secrete significantly reduced levels of TNFα. Moreover, the tissue microenvironment in areas of asbestos deposits displays an increased fraction of M1-polarized macrophages compared to M2 macrophages. Supporting the biological significance of these findings, Hmgb1ΔpMeso mice showed a delayed and reduced incidence of mesothelioma and an increased mesothelioma-specific survival. Altogether, our study provides a biological explanation for HMGB1 as a driver of asbestos-induced mesothelioma.

A regionally adapted HRM-based technique to screen MMACHC carriers for methylmalonic acidemia with homocystinuria in Shandong Province, China.

Methylmalonic acidemia with homocystinuria (MMA-cblC) is an autosomal recessive genetic disorder of organic acid metabolism. Shandong, a northern province of China, has a significantly high incidence of about 1/4,000, suggesting a high carrying rate among the local population. The current study established a PCR technique involving high-resolution melting (HRM) to screen for carriers based on hotspot mutation analysis to further develop a preventive strategy to reduce the local incidence of this rare disease. Whole-exome sequencing of 22 families with MMA-cblC and a comprehensive literature review were used to identify MMACHC hotspot mutations in Shandong Province. Subsequently, a PCR-HRM assay based on the selected mutations was established and optimized for large-scale hotspot mutation screening. The accuracy and efficiency of the screening technique was validated using samples from 69 individuals with MMA-cblC and 1,000 healthy volunteers. Six hotspot mutations in the MMACHC gene (c.609G>A, c.658_660delAAG, c.80A>G, c.217C>T, c.567dupT and c.482G>A), which account for 74% of the alleles associated with MMA-cblC, were used to establish a screening technique. The established PCR-HRM assay detected 88 MMACHC mutation alleles in a validation study with 100% accuracy. In the general population in Shandong, the carrying rate of 6 MMACHC hotspot mutations was 3.4%. In conclusion, the 6 hotspots identified cover the majority of the MMACHC mutation spectrum, and the Shandong population has a particularly high carrying rate of MMACHC mutations. The PCR-HRM assay is highly accurate, cost-effective, and easy to use, making it an ideal choice for mass carrier screening.

BAP1 is a novel regulator of HIF-1α.

BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1ß forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

Parametric hologram optimization for enhanced underwater wireless optical communication.

The performance of the underwater optical communication (UWOC) systems was primarily limited by the low optical transmission efficiency due to the beam divergence and water interference. It has been proved in our previous works that holographic beam shaping can effectively increase the optical transmission efficiency and therefore the communication distances and speed. The conventional hologram optimisation method treated each pixel as an independent variable, leading to a large search space and a slow process. In this work, we proposed to use a small set of parameters to describe the beam shaping holograms that were able to limit the beam divergence and compensate for the wavefront distortion. This significantly reduced the number of variables to be optimised and enabled the optimisation to be more efficient and effective. In a proof-of-concept experiment based on the off-the-shelf components, the proposed method was able to generate the optimal hologram within 20 iterations while achieving a tenfold increase in the optical transmission efficiency for a 30 m link at 100 Mbps.

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy.

Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos.

Carriers of heterozygous germline BAP1 mutations (BAP1+/-) are affected by the "BAP1 cancer syndrome." Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1+/- cells secrete increased amounts of HMGB1, and that BAP1+/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

Design and Numerical Analysis of an Infrared Cassegrain Telescope Based on Reflective Metasurfaces.

Reflective imaging systems such as Cassegrain-type telescopes are widely utilized in astronomical observations. However, curved mirrors in traditional Cassegrain telescopes unavoidably make the imaging system bulky and costly. Recent developments in the field of metasurfaces provide an alternative way to construct optical systems, possessing the potential to make the whole system flat, compact and lightweight. In this work, we propose a design for a miniaturized Cassegrain telescope by replacing the curved primary and secondary mirrors with flat and ultrathin metasurfaces. The meta-atoms, consisting of SiO2 stripes on an Al film, provide high reflectance (>95%) and a complete phase coverage of 0~2π at the operational wavelength of 4 µm. The optical functionality of the metasurface Cassegrain telescope built with these meta-atoms was confirmed and studied with numerical simulations. Moreover, fabrication errors were mimicked by introducing random width errors to each meta-atom; their influence on the optical performance of the metasurface device was studied numerically. The concept of the metasurface Cassegrain telescope operating in the infrared wavelength range can be extended to terahertz (THz), microwave and even radio frequencies for real-world applications, where metasurfaces with a large aperture size are more easily obtained.

Adaptive beam shaping for enhanced underwater wireless optical communication.

In this paper, we proposed and experimentally verified a diffraction-based optical beam shaping technique for underwater optical communication (UWOC) applications. The proposed method aimed to address the key issue in UWOC links, i.e., the high propagation loss experienced by the launched optical beam. It enabled a significantly higher portion of the launched signal to be collected by the receiver. The optimal transmission distance could also be fine-tuned by the software configuration. In a proof-of-concept demonstration based on the off-the-shelf components, 100 Mbps transmission was achieved over 15-meter distance and a significant enhancement in the transmission quality was observed. There is a huge scope for further improvement in the transmission distance and data rate when the proposed technique was used with purpose-built optical components and advanced coding schemes.

Combination of Plasma-Based Metabolomics and Machine Learning Algorithm Provides a Novel Diagnostic Strategy for Malignant Mesothelioma.

BACKGROUND: Malignant mesothelioma (MM) is an aggressive and incurable carcinoma that is primarily caused by asbestos exposure. However, the current diagnostic tool for MM is still under-developed. Therefore, the aim of this study is to explore the diagnostic significance of a strategy that combined plasma-based metabolomics with machine learning algorithms for MM. METHODS: Plasma samples collected from 25 MM patients and 32 healthy controls (HCs) were randomly divided into train set and test set, after which analyzation was performed by liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were screened out from the samples of the train set. Subsequently, metabolite-based diagnostic models, including receiver operating characteristic (ROC) curves and Random Forest model (RF), were established, and their prediction accuracies were calculated for the test set samples. RESULTS: Twenty differential plasma metabolites were annotated in the train set; 10 of these metabolites were validated in the test set. The seven most prevalent diagnostic metabolites were taurocholic acid), 0.7142 (uracil), 0.7142 (biliverdin), 0.8571 (histidine), 0.5000 (tauroursodeoxycholic acid), 0.8571 (pyrroline hydroxycarboxylic acid), and 0.7857 (phenylalanine). Furthermore, RF based on 20 annotated metabolites showed a prediction accuracy of 0.9286, and its optimized version achieved 1.0000 in the test set. Moreover, the comparison between the samples of peritoneal MM (n = 8) and pleural MM (n = 17) illustrated a significant increase in levels of taurocholic acid and tauroursodeoxycholic acid, as well as an evident decrease in biliverdin. CONCLUSIONS: Our results revealed the potential diagnostic value of plasma-based metabolomics combined with machine learning for MM. Further research with large sample size is worthy conducting. Moreover, our data demonstrated dysregulated metabolism pathways in MM, which aids in better understanding of molecular mechanisms related to the initiation and development of MM.

The role of the intestinal microbiota in the pathogenesis of host depression and mechanism of TPs relieving depression.

Depression is a prevalent neuropsychiatric disease with a high recurrence rate, affecting over 350 million people worldwide. Intestinal flora disorders and gut-brain-axis (GBA) dysfunction may cause mental disorders. Alterations in the intestinal flora composition could increase the permeability of the gut barrier, activate systemic inflammation and immune responses, regulate the release and efficacy of monoamine neurotransmitters, alter the activity and function of the hypothalamic-pituitary-adrenal (HPA) axis, and modify the abundance of the brain-derived neurotrophic factor (BDNF); all of these showed a close correlation with the occurrence of depression. In addition, the disturbance of the intestinal flora is related to circadian rhythm disorders, which aggravate the symptoms of depression. Tea polyphenols (TPs) have been found to have antidepressant effects. Therefore, the close reciprocity between the intestinal flora and circadian rhythm provides a new opportunity for TPs to regulate depression relying on the intestinal flora. In this review, we discussed the relationship between intestinal flora dysbiosis and the pathogenesis of depression and the mechanism of TPs relieving depression via the GBA.

Phase flicker minimisation for crosstalk suppression in optical switches based on digital liquid crystal on silicon devices.

The phase flicker in digital liquid crystal on silicon (LCOS) device introduces temporal phase noise to the phase pattern displayed on the device. Such temporal phase noise could elevate the power of unwanted diffraction orders and ultimately cause crosstalk in optical switches based on the LCOS technology. Building on our previous work, this paper demonstrated an automated phase flicker optimisation process by using the genetic algorithm. The method developed in this work further shortened the optimisation process by 10x. It was also demonstrated that the optimised digital driving waveform set was able to reduce the crosstalk level in the optical switches by at least 3 dB.

Vitamin D receptor upregulates lncRNA TOPORS-AS1 which inhibits the Wnt/ß-catenin pathway and associates with favorable prognosis of ovarian cancer.

Long non-coding RNAs (lncRNAs) have important biological functions, but their involvement in ovarian cancer remains elusive. We analyzed high-throughput data to identify lncRNAs associated with ovarian cancer outcomes. Our search led to the discovery of lncRNA TOPORS Antisense RNA 1 (TOPORS-AS1). Patients with high TOPORS-AS1 expression had favorable overall survival compared to low expression. This association was replicated in our study and confirmed by meta-analysis. In vitro experiments demonstrated that overexpressing TOPORS-AS1 in ovarian cancer cells suppressed cell proliferation and inhibited aggressive cell behaviors, including migration, invasion, and colony formation. Analysis of tumor cell transcriptomes indicated TOPORS-AS1's influence on the Wnt/ß-catenin signaling. Additional experiments revealed that TOPORS-AS1 increased the phosphorylation of ß-catenin and suppressed the expression of CTNNB1, disrupting the Wnt/ß-catenin pathway. Our experiments further discovered that vitamin D receptor (VDR) upregulated TOPORS-AS1 expression and that inhibition of ß-catenin by TOPORS-AS1 required a RNA binding protein, hnRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1). Taken together, these findings suggest that TOPORS-AS1 may behave like a tumor suppressor in ovarian cancer through interrupting the Wnt/ß-catenin signaling and that VDR upregulates the expression of TOPORS-AS1. Assessing TOPORS-AS1 expression in ovarian cancer may help predict disease prognosis and develop treatment strategy.

Asbestos-induced chronic inflammation in malignant pleural mesothelioma and related therapeutic approaches-a narrative review.

OBJECTIVE: The aim of this review is addressing the mechanisms of asbestos carcinogenesis, including chronic inflammation and autophagy-mediated cell survival, and propose potential innovative therapeutic targets to prevent mesothelioma development or improve drug efficacy by reducing inflammation and autophagy. BACKGROUND: Diffuse malignant pleural mesothelioma is an aggressive cancer predominantly related to chronic inflammation caused by asbestos exposure. Millions of individuals have been exposed to asbestos or to other carcinogenic mineral fibers occupationally or environmentally, resulting in an increased risk of developing mesothelioma. Overall patient survival rates are notably low (about 8-14 months from the time of diagnosis) and mesothelioma is resistant to existing therapies. Additionally, individuals carrying inactivating germline mutations in the BRCA-associated protein 1 (BAP1) gene and other genes are predisposed to developing cancers, prevalently mesothelioma. Their risk of developing mesothelioma further increases upon exposure to asbestos. Recent studies have revealed the mechanisms and the role of inflammation in asbestos carcinogenesis. Biomarkers for asbestos exposure and malignant mesothelioma have also been identified. These findings are leading to the development of novel therapeutic approaches to prevent or delay the growth of mesothelioma. METHODS: Review of full length manuscripts published in English from January 1980 to February 2021 gathered from PubMed.gov from the National Center of Biotechnology Information and the National Library of Medicine were used to inform this review. CONCLUSION: Key regulators of chronic inflammation mediate asbestos-driven mesothelial cell transformation and survival through autophagic pathways. Recent studies have elucidated some of the key mechanisms involved in asbestos-induced chronic inflammation, which are largely driven by extracellular high mobility group box 1 (HMGB1). Upon asbestos exposure, mesothelial cells release HMGB1 from the nucleus to the cytoplasm and extracellular space, where HMGB1 initiates an inflammatory response. HMGB1 translocation and release also activates autophagy and other pro-survival mechanisms, which promotes mesothelioma development. HMGB1 is currently being investigated as a biomarker to detect asbestos exposure and to detect mesothelioma development in its early stage when therapy is more effective. In parallel, several approaches inhibiting HMGB1 activities have been studied and have shown promising results. Moreover, additional cytokines, such as IL-1ß and TNF-α are being targeted to interfere with the inflammatory process that drives mesothelioma growth. Developing early detection methods and novel therapeutic strategies is crucial to prolong overall survival of patients with mesothelioma. Novel therapies targeting regulators of asbestos-induced inflammation to reduce mesothelioma growth may lead to clinical advancements to benefit patients with mesothelioma.