Design and application of genetically-encoded malonyl-CoA biosensors for metabolic engineering of microbial cell factories

Malonyl-CoA is the basic building block for synthesizing a range of important compounds including fatty acids, phenylpropanoids, flavonoids and non-ribosomal polyketides. Centering around malonyl-CoA, we summarized here the various metabolic engineering strategies employed recently to regulate and control malonyl-CoA metabolism and improve cellular productivity. Effective metabolic engineering of microorganisms requires the introduction of heterologous pathways and dynamically rerouting metabolic flux towards products of interest. Transcriptional factor-based biosensors translate an internal cellular signal to a transcriptional output and drive the expression of the designed genetic/biomolecular circuits to compensate the activity loss of the engineered biosystem. Recent development of genetically-encoded malonyl-CoA sensor has stood out as a classical example to dynamically reprogram cell metabolism for various biotechnological applications. Here, we reviewed the design principles of constructing a transcriptional factor-based malonyl-CoA sensor with superior detection limit, high sensitivity and broad dynamic range. We discussed various synthetic biology strategies to remove pathway bottleneck and how genetically-encoded metabolite sensor could be deployed to improve pathway efficiency. Particularly, we emphasized that integration of malonyl-CoA sensing capability with biocatalytic function would be critical to engineer efficient microbial cell factory. Biosensors have also advanced beyond its classical function of a sensor actuator for in situ monitoring of intracellular metabolite concentration. Applications of malonyl-CoA biosensors as a sensor-invertor for negative feedback regulation of metabolic flux, a metabolic switch for oscillatory balancing of malonyl-CoA sink pathway and source pathway and a screening tool for engineering more efficient biocatalyst are also presented in this review. We envision the genetically-encoded malonyl-CoA sensor will be an indispensable tool to optimize cell metabolism and cost-competitively manufacture malonyl-CoA-derived compounds

Solar photocatalytic degradation of polyethylene terephthalate nanoplastics: Evaluation of the applicability of the TiO2/MIL-100(Fe) composite material

For the first time, TiO2/MIL-100(Fe) photocatalysts supported on perlite mineral particles prepared by the solvothermal/microwave methods and post-annealing technique were tested in the degradation of polyethylene terephthalate nanoplastics (PET NPs). Powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, X-ray photoelectron spectroscopy, UV–vis diffuse reflectance spectroscopy, N2 physisorption, photoluminescence emission spectroscopy, photocurrent response, and electrochemical impedance spectroscopy were used to characterize the as-prepared materials. The response surface methodology approach was used to study the effects: pH of the NPs suspension and incorporated amount of MIL-100(Fe) on the TiO2/MIL-100(Fe) catalyst to optimize the photocatalytic degradation of the PET NPs under simulated solar light. The degradation of the PET NPs was evaluated by measuring turbidity and carbonyl index (FTIR) changes. The total organic carbon (TOC) in the solution during the degradation of the PET NPs was assessed to measure NPs oxidation into water-soluble degradation by-products. The active species involved in the photocatalytic degradation of PET NPs by the TiO2/MIL-100(Fe) composite was further examined based on trapping experiments. The use of 12.5 wt% TiO2/MIL-100(Fe) catalyst showed improved photocatalytic efficacy in the oxidation of PET NPs at pH 3 under simulated sunlight compared to bare TiO2. The increase in the carbonyl index (CI = 0.99), the reduction in the turbidity ratio (0.454), and the increase in the content of TOC released (3.00 mg/L) were possible with 12.5 wt% TiO2/MIL-100(Fe) material. In contrast, the PET NPs were slowly degraded by TiO2-based photocatalysis (CI = 0.96, turbidity ratio = 0.539, released TOC = 2.12 mg/L). The mesoporous TiO2/MIL-100(Fe) composites with high specific surface area, capacity to absorb visible light, and effective separation of photogenerated electron-hole charges clearly demonstrated the enhancement of the photocatalytic performance in the PET NPs degradation under simulated solar light

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: Results from the COVIDSER study

Objectives To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. Methods The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. Results A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients'' hospitalisation. Conclusions The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer

Altres ajuts: This work was co-finaced by the European Development Regional Fund, "A way to achieve Europe" ERDF; the Cellex Foundation; and "la Caixa" Banking Foundation (LCF/PR/PR15/ 11100003).Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion

Temporal distribution and genetic variants in influenza A(H1N1)pdm09 virus circulating in Mexico, seasons 2012 and 2013

The 2012 and 2013 annual influenza epidemics in Mexico were characterized by presenting different seasonal patterns. In 2012 the A(H1N1)pdm09 virus caused a high incidence of influenza infections after a two-year period of low circulation; whereas the 2013 epidemic presented circulation of the A(H1N1)pdm09 virus throughout the year. We have characterized the molecular composition of the Hemagglutinin (HA) and Neuraminidase (NA) genes of the A(H1N1)pdm09 virus from both epidemic seasons, emphasizing the genetic characteristics of viruses isolated from Yucatan in Southern Mexico. The molecular analysis of viruses from the 2012 revealed that all viruses from Mexico were predominantly grouped in clade 7. Strikingly, the molecular characterization of viruses from 2013 revealed that viruses circulating in Yucatan were genetically different to viruses from other regions of Mexico. In fact, we identified the occurrence of two genetic variants containing relevant mutations at both the HA and NA surface antigens. There was a difference on the temporal circulation of each genetic variant, viruses containing the mutations HA-A141T / NA-N341S were detected in May, June and July; whereas viruses containing the mutations HA-S162I / NAL206S circulated in August and September. We discuss the significance of these novel genetic changes

First observations of oblique ionospheric sounding chirp signal in Mexico

The results of the first experiment of oblique ionospheric sounding (OIS) chirp signal reception in Mexico are reported. Maximal and Lowest Observed Frequencies variations were studied under the quiet Space Weather conditions. The diurnal ionospheric variations by OIS signal confirm the results based on GNSS data in the Mexican region. The best HF radio propagation conditions along the considered path are during morning and daytime hours. The multi-hop propagation is frequent. The interlayer propagation modes are present at nighttime

First joint observations of space weather events over Mexico

Abstract. The Mexican Space Weather Service (SCiESMEX in Spanish) and National Space Weather Laboratory (LANCE in Spanish) were organized in 2014 and in 2016, respectively, to provide space weather monitoring and alerts, as well as scientific research in Mexico. In this work, we presenttheresultsofthefirstjointobservationsoftwoevents (22 June and 29 September 2015) with our local network of instruments and their related products. This network includes the MEXART radio telescope (solar flare and radio burst), the Compact Astronomical Low-frequency, Low-cost Instrument for Spectroscopy in Transportable Observatories (CALLISTO)attheMEXARTstation(solarradioburst),the Mexico City Cosmic Ray Observatory (cosmic ray fluxes), GPS receiver networks (ionospheric disturbances), and the Teoloyucan Geomagnetic Observatory (geomagnetic field). The observations show that we detected significant space weather effects over the Mexican territory: geomagnetic and ionospheric disturbances (22 June 2015), variations in cosmicrayfluxes,andalsoradiocommunications’interferences (29September2015).Theeffectsoftheseperturbationswere registered,forthefirsttime,usingspaceweatherproductsby SCiESMEX:totalelectroncontent(TEC)maps,regionalgeomagneticindexKmex,radiospectrographsoflowfrequency, and cosmic ray fluxes. These results prove the importance of monitoring space weather phenomena in the region and the need to strengthening the instrumentation network

Martian Atmospheric Temperature and Density Profiles During the First Year of NOMAD/TGO Solar Occultation Measurements

We present vertical profiles of temperature and density from solar occultation (SO) observations by the “Nadir and Occultation for Mars Discovery” (NOMAD) spectrometer on board the Trace Gas Orbiter during its first operational year, which covered the second half of Mars Year 34. We used calibrated transmittance spectra in 380 scans, and apply an in-house pre-processing to clean data systematics. Temperature and CO2 profiles up to about 90 km, with consistent hydrostatic adjustment, are obtained, after adapting an Earth-tested retrieval scheme to Mars conditions. Both pre-processing and retrieval are discussed to illustrate their performance and robustness. Our results reveal the large impact of the MY34 Global Dust Storm (GDS), which warmed the atmosphere at all altitudes. The large GDS aerosols opacity limited the sounding of tropospheric layers. The retrieved temperatures agree well with global climate models (GCM) at tropospheric altitudes, but NOMAD mesospheric temperatures are wavier and globally colder by 10 K in the perihelion season, particularly during the GDS and its decay phase. We observe a warm layer around 80 km during the Southern Spring, especially in the Northern Hemisphere morning terminator, associated to large thermal tides, significantly stronger than in the GCM. Cold mesospheric pockets, close to CO2 condensation temperatures, are more frequently observed than in the GCM. NOMAD CO2 densities show oscillations upon a seasonal trend that track well the latitudinal variations expected. Results uncertainties and suggestions to improve future data re-analysis are briefly discussed

Search for heavy neutrinos mixing with tau neutrinos

We report on a search for heavy neutrinos (\nus) produced in the decay D_s\to \tau \nus at the SPS proton target followed by the decay \nudecay in the NOMAD detector. Both decays are expected to occur if \nus is a component of $\nu_{\tau}$.\ From the analysis of the data collected during the 1996-1998 runs with $4.1\times10^{19}$ protons on target, a single candidate event consistent with background expectations was found. This allows to derive an upper limit on the mixing strength between the heavy neutrino and the tau neutrino in the \nus mass range from 10 to 190 $\rm MeV$. Windows between the SN1987a and Big Bang Nucleosynthesis lower limits and our result are still open for future experimental searches. The results obtained are used to constrain an interpretation of the time anomaly observed in the KARMEN1 detector.\Comment: 20 pages, 7 figures, a few comments adde