Integrative single-cell chromatin and transcriptome analysis of human plasma cell differentiation.

ABSTRACT: Plasma cells (PCs) are highly specialized cells representing the end stage of B-cell differentiation. We have shown that PC differentiation can be reproduced in vitro using elaborate culture systems. The molecular changes occurring during PC differentiation are recapitulated in this in vitro differentiation model. However, a major challenge exists to decipher the spatiotemporal epigenetic and transcriptional programs that drive the early stages of PC differentiation. We combined single cell (sc) RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high throughput sequencing (scATAC-seq) to decipher the trajectories involved in PC differentiation. ScRNA-seq experiments revealed a strong heterogeneity of the preplasmablastic and plasmablastic stages. Among genes that were commonly identified using scATAC-seq and scRNA-seq, we identified several transcription factors with significant stage specific potential importance in PC differentiation. Interestingly, differentially accessible peaks characterizing the preplasmablastic stage were enriched in motifs of BATF3, FOS and BATF, belonging to activating protein 1 (AP-1) transcription factor family that may represent key transcriptional nodes involved in PC differentiation. Integration of transcriptomic and epigenetic data at the single cell level revealed that a population of preplasmablasts had already undergone epigenetic remodeling related to PC profile together with unfolded protein response activation and are committed to differentiate in PC. These results and the supporting data generated with our in vitro PC differentiation model provide a unique resource for the identification of molecular circuits that are crucial for early and mature PC maturation and biological functions. These data thus provide critical insights into epigenetic- and transcription-mediated reprogramming events that sustain PC differentiation.

Production of activated carbon from agave residues and its synergistic application in a hybrid adsorption-AOPs system for effective removal of sulfamethazine from aqueous solutions.

Tequila production in Mexico generates large quantities of agave bagasse (AB), a waste that could be used more efficiently. AB has a high cellulose, hemicellulose, and lignin content, which allows its use as a precursor for synthesizing carbonaceous materials. In the present work, the synthesis of activated carbon impregnated with Fe2+ (AG-Fe-II) and Fe3+ (AG-Fe-III) was carried out and evaluated in a hybrid adsorption-AOP (advanced oxidation process) methodology for sulfamethazine removal (SMT). The materials were characterized before and after the process to determine their morphological, textural, and physicochemical properties. Subsequently, the effect of the main operational variables (pH, initial SMT concentration, mass, and activator dosage) on the hybrid adsorption-degradation process was studied. The Fenton-like reaction was selected as the AOP for the degradation step, and potassium persulfate (K2S2O8) was used as an activating agent. The main iron crystallographic phases in AG-Fe-II were FeS, with a uniform distribution of iron particles over the material's surface. The main crystallographic phase for AG-Fe-III was Fe3O4. The hybrid process achieved 61% and 78% removal efficiency using AG-Fe-II and AG-Fe-III samples, respectively. The pH and initial SMT concentration were the most critical factors for removing SMT from an aqueous phase. Finally, the material was successfully tested in repeated adsorption-degradation cycles.

New trends in modelling of breakthrough curves to remove pollutants using adsorption on advanced monoliths geometries.

This work proposes a rigorous mathematical model capable of reproducing the adsorption process in dynamic regime on advanced monoliths geometries. For this, four bed geometries with axisymmetric distribution of channels and similar solid mass were proposed. In each geometry a different distribution of channels was suggested, maintaining constant the bed dimensions of 15 cm high and 5 cm radius. The mathematical modeling includes mass and momentum transfer phenomena, and it was solved with the COMSOL Multiphysics software using mass transfer parameters published in the literature. The overall performance of the column was evaluated in terms of breakthrough (CA/CA0 = 0.1) and saturation times (CA/CA0 = 0.9). The mass and velocity distributions obtained from the proposed model show good physical consistency with what is expected in real systems. In addition, the model proved to be easy to solve given the short convergence times required (2-4 h). Modifications were made to the bed geometry to achieve a better use of the adsorbent material which reached up to 80%. The proposed bed geometries allow obtaining different mixing distributions, in such a way that inside the bed a thinning of the boundary layer is caused, thus reducing diffusive effects at the adsorbent solid-fluid interface, given dissipation rates of about 323 × 10-11 m2/s3. The bed geometry composed of intersecting rings deployed the best performance in terms of usage of the material adsorbent, and acceptable hydrodynamical behavior inside the channels (maximum fluid velocity = 35.4 × 10-5 m/s and drop pressure = 0.19 Pa). Based on these results, it was found that it is possible to reduce diffusional effects and delimit the mass transfer zone inside the monoliths, thus increasing the efficiency of adsorbent fixed beds.

Efficient removal of triclosan from water through activated carbon adsorption and photodegradation processes.

This study investigated the application of adsorption with activated carbons (ACs) and photodegradation to reduce the concentration of triclosan (TCS) in aqueous solutions. Concerning adsorption, ACs (Darco, Norit, and F400) were characterised and batch experiments were performed to elucidate the effect of pH on equilibrium. The results showed that at pH = 7, the maximum adsorption capacity of TCS onto the ACs was 18.5 mg g-1 for Darco, 16.0 mg g-1 for Norit, and 15.5 mg g-1 for F400. The diffusional kinetic model allowed an adequate interpretation of the experimental data. The effective diffusivity varied and increased with the amount of TCS adsorbed, from 1.06 to 1.68 × 10-8 cm2 s-1. In the case of photodegradation, it was possible to ensure that the triclosan molecule was sensitive to UV light of 254 nm because the removal was over 80 % using UV light. The removal of TCS increased in the presence of sulfate radicals. It was possible to identify 2,4-dichlorophenol as one of the photolytic degradation products of triclosan, which does not represent an environmental hazard at low concentrations of triclosan in water. These results confirm that the use of AC Darco, Norit, and F400 and that photodegradation processes with UV light and persulfate radicals are effective in removing TCS from water, reaching concentration levels that do not constitute a risk to human health or environmental hazard. Both methods effectively eliminate pollutants with relatively easy techniques to implement.

Long chain capsaicin analogues synthetized by CALB-CLEAs show cytotoxicity on glioblastoma cell lines.

Glioblastoma is one of the most lethal tumors, displaying striking cellular heterogeneity and drug resistance. The prognosis of patients suffering from glioblastoma after 5 years is only 5%. In the present work, capsaicin analogues bearing modifications on the acyl chain with long-chain fatty acids showed promising anti-tumoral activity by its cytotoxicity on U-87 and U-138 glioblastoma multiforme cells. The capsaicin analogues were enzymatically synthetized with cross-linked enzyme aggregates of lipase B from Candida antarctica (CALB). The catalytic performance of recombinant CALB-CLEAs was compared to their immobilized form on a hydrophobic support. After 72 h of reaction, the synthesis of capsaicin analogues from linoleic acid, docosahexaenoic acid, and punicic acid achieved a maximum conversion of 69.7, 8.3 and 30.3% with CALB-CLEAs, respectively. Similar values were obtained with commercial CALB, with conversion yields of 58.3, 24.2 and 22% for capsaicin analogues from linoleic acid, DHA and punicic acid, respectively. Olvanil and dohevanil had a significant cytotoxic effect on both U-87 and U-138 glioblastoma cells. Irrespective of the immobilization form, CALB is an efficient biocatalyst for the synthesis of anti-tumoral capsaicin derivatives. KEY POINTS: • This is the first report concerning the enzymatic synthesis of capsaicin analogues from docosahexaenoic acid and punicic acid with CALB-CLEAs. • The viability U-87 and U-138 glioblastoma cells was significantly affected after incubation with olvanil and dohevanil. • Capsaicin analogues from fatty acids obtained by CALB-CLEAs are promising candidates for therapeutic use as cytotoxic agents in glioblastoma cancer cells.

The Spectrum of Global Electron Content: A New Potential Indicator of Space Weather Activity.

The time evolution of the total number of free electrons in the Earth's ionosphere, i.e., the Global Electron Content (GEC), during more than two solar cycles is analyzed in this work. The GEC time series has been extracted from the Global Ionospheric Maps (GIMs) of Vertical Total Electron Content (VTEC) estimated by UPC-IonSAT with TOMION-v1 software from global GPS measurements since the end of 1996. A dual-layer voxel-based tomographic model solved with a forward Kalman scalar filter, from dual-frequency carrier GPS data only, provides the so-called UQRG GIM after VTEC kriging interpolation, with a resolution of 15 min in time, 5° in longitude and 2.5° in latitude. UQRG is one of the best behaving GIMs in the International GNSS Service (IGS).In this context, the potential application of the GEC spectrum evolution as a potential space weather index is discussed and demonstrated.

Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways.

BACKGROUND: Obesity is a negative chronic metabolic health condition that represents an additional risk for the development of multiple pathologies. Epidemiological studies have shown how maternal obesity or gestational diabetes mellitus during pregnancy constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring. Furthermore, epigenetic remodelling may help explain the molecular mechanisms that underlie these epidemiological findings. Thus, in this study we explored the DNA methylation landscape of children born to mothers with obesity and gestational diabetes during their first year of life. METHODS: We used Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 genome-wide CpG sites in blood samples from a paediatric longitudinal cohort consisting of 26 children born to mothers who suffered from obesity or obesity with gestational diabetes mellitus during pregnancy and 13 healthy controls (measurements taken at 0, 6 and 12 month; total N = 90). We carried out cross-sectional and longitudinal analyses to derive DNA methylation alterations associated with developmental and pathology-related epigenomics. RESULTS: We identified abundant DNA methylation changes during child development from birth to 6 months and, to a lesser extent, up to 12 months of age. Using cross-sectional analyses, we discovered DNA methylation biomarkers maintained across the first year of life that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes. Importantly, enrichment analyses suggested that these alterations constitute epigenetic signatures that affect genes and pathways involved in the metabolism of fatty acids, postnatal developmental processes and mitochondrial bioenergetics, such as CPT1B, SLC38A4, SLC35F3 and FN3K. Finally, we observed evidence of an interaction between developmental DNA methylation changes and maternal metabolic condition alterations. CONCLUSIONS: Our observations highlight the first six months of development as being the most crucial for epigenetic remodelling. Furthermore, our results support the existence of systemic intrauterine foetal programming linked to obesity and gestational diabetes that affects the childhood methylome beyond birth, which involves alterations related to metabolic pathways, and which may interact with ordinary postnatal development programmes.

Mechanistic evaluation in the removal of chlorpheniramine and ciprofloxacin on activated carbons.

Chlorpheniramine (CPM) and Ciprofloxacin (CIP) adsorption onto a granular (GAC) and pelletized activated carbon (PAC) analyzing the physicochemical mechanisms involved using the carbon's characterization were studied. Adsorption isotherm studies were performed at temperatures of 25 °C at pH values of 4, 7 and 9 and at 45 °C at a pH of 7. The characterization demonstrated that GAC has a predominantly acid character due to its predominantly negative surface charge and acidic site concentration alongside the characteristic bands detected in the X-ray Photoemission Spectroscopy (XPS) study. On the other hand, PAC presented a mostly basic character due to its positive surface charge and basic site concentrations. The adsorption isotherm studies demonstrated that the Freundlich isotherm better described the equilibrium data with an average deviation percentage of 7.45 and 6.74 for GAC and PAC. The temperature and desorption studies demonstrated that the adsorption process occurs through a chemisorption mechanism, and the pH study alongside the GAC and PAC characterization demonstrated that the mechanisms involved are a combination of electrostatic interactions and pi-pi interactions between the CPM and CIP molecules and the carbon's surface. These results demonstrate that the adsorption process of these pharmaceutical compounds is done through a combination of physical and chemical interactions.

Nonlinear Robust Control by a Modulating-Function-Based Backstepping Super-Twisting Controller for a Quadruple Tank System.

In this paper, a robust nonlinear approach for control of liquid levels in a quadruple tank system (QTS) is developed based on the design of an integrator backstepping super-twisting controller, which implements a multivariable sliding surface, where the error trajectories converge to the origin at any operating point of the system. Since the backstepping algorithm is dependent on the derivatives of the state variables, and it is sensitive to measurement noise, integral transformations of the backstepping virtual controls are performed via the modulating functions technique, rendering the algorithm derivative-free and immune to noise. The simulations based on the dynamics of the QTS located at the Advanced Control Systems Laboratory of the Pontificia Universidad Católica del Perú (PUCP) showed a good performance of the designed controller and therefore the robustness of the proposed approach.

Pyrolysis Kinetics of Byrsonima crassifolia Stone as Agro-Industrial Waste through Isoconversional Models.

This study is aimed at the analysis of the pyrolysis kinetics of Nanche stone BSC (Byrsonima crassifolia) as an agro-industrial waste using non-isothermal thermogravimetric experiments by determination of triplet kinetics; apparent activation energy, pre-exponential factor, and reaction model, as well as thermodynamic parameters to gather the required fundamental information for the design, construction, and operation of a pilot-scale reactor for the pyrolysis this lignocellulosic residue. Results indicate a biomass of low moisture and ash content and a high volatile matter content (≥70%), making BCS a potential candidate for obtaining various bioenergy products. Average apparent activation energies obtained from different methods (KAS, FWO and SK) were consistent in value (~123.8 kJ/mol). The pre-exponential factor from the Kissinger method ranged from 105 to 1014 min-1 for the highest pyrolytic activity stage, indicating a high-temperature reactive system. The thermodynamic parameters revealed a small difference between EA and ∆H (5.2 kJ/mol), which favors the pyrolysis reaction and indicates the feasibility of the energetic process. According to the analysis of the reaction models (master plot method), the pyrolytic degradation was dominated by a decreasing reaction order as a function of the degree of conversion. Moreover, BCS has a relatively high calorific value (14.9 MJ/kg) and a relatively low average apparent activation energy (122.7 kJ/mol) from the Starink method, which makes this biomass very suitable to be exploited for value-added energy production.

Speech naturalness detection and language representation in the dog brain.

Family dogs are exposed to a continuous flow of human speech throughout their lives. However, the extent of their abilities in speech perception is unknown. Here, we used functional magnetic resonance imaging (fMRI) to test speech detection and language representation in the dog brain. Dogs (n = 18) listened to natural speech and scrambled speech in a familiar and an unfamiliar language. Speech scrambling distorts auditory regularities specific to speech and to a given language, but keeps spectral voice cues intact. We hypothesized that if dogs can extract auditory regularities of speech, and of a familiar language, then there will be distinct patterns of brain activity for natural speech vs. scrambled speech, and also for familiar vs. unfamiliar language. Using multivoxel pattern analysis (MVPA) we found that bilateral auditory cortical regions represented natural speech and scrambled speech differently; with a better classifier performance in longer-headed dogs in a right auditory region. This neural capacity for speech detection was not based on preferential processing for speech but rather on sensitivity to sound naturalness. Furthermore, in case of natural speech, distinct activity patterns were found for the two languages in the secondary auditory cortex and in the precruciate gyrus; with a greater difference in responses to the familiar and unfamiliar languages in older dogs, indicating a role for the amount of language exposure. No regions represented differently the scrambled versions of the two languages, suggesting that the activity difference between languages in natural speech reflected sensitivity to language-specific regularities rather than to spectral voice cues. These findings suggest that separate cortical regions support speech naturalness detection and language representation in the dog brain.

Conservation of Aging and Cancer Epigenetic Signatures across Human and Mouse.

Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and nontumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally, we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point toward the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits.

Enhanced Detection of Viral RNA Species Using FokI-Assisted Digestion of DNA Duplexes and DNA/RNA Hybrids.

The accurate detection of nucleic acids from certain biological pathogens is critical for the diagnosis of human diseases. However, amplified detection of RNA molecules from a complex sample by direct detection of RNA/DNA hybrids remains a challenge. Here, we show that type IIS endonuclease FokI is able to digest DNA duplexes and DNA/RNA hybrids when assisted by a dumbbell-like fluorescent sensing oligonucleotide. As proof of concept, we designed a battery of sensing oligonucleotides against specific regions of the SARS-CoV-2 genome and interrogated the role of FokI relaxation as a potential nicking enzyme for fluorescence signal amplification. FokI-assisted digestion of SARS-CoV-2 probes increases the detection signal of ssDNA and RNA molecules and decreases the limit of detection more than 3.5-fold as compared to conventional molecular beacon approaches. This cleavage reaction is highly specific to its target molecules, and no detection of other highly related B-coronaviruses was observed in the presence of complex RNA mixtures. In addition, the FokI-assisted reaction has a high multiplexing potential, as the combined detection of different viral RNAs, including different SARS-CoV-2 variants, was achieved in the presence of multiple combinations of fluorophores and sensing oligonucleotides. When combined with isothermal rolling circle amplification technologies, FokI-assisted digestion reduced the detection time of SARS-CoV-2 in COVID-19-positive human samples with adequate sensitivity and specificity compared to conventional reverse transcription polymerase chain reaction approaches, highlighting the potential of FokI-assisted signal amplification as a valuable sensing mechanism for the detection of human pathogens.

Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera.

Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.

Application of Orange Peel Waste as Adsorbent for Methylene Blue and Cd2+ Simultaneous Remediation.

Pollution by dyes and heavy metals is one of the main concerns at the environmental level due to their toxicity and inefficient elimination by traditional water treatment. Orange peel (OP) without any treatment was applied to effectively eliminate methylene blue (MB) and cadmium ions (Cd2+) in mono- and multicomponent systems. Although the single adsorption processes for MB and Cd2+ have been investigated, the effects and mechanisms of interactions among multicomponent systems are still unclear. Batch experiments showed that in monocomponent systems, the maximum adsorption capacities were 0.7824 mmol g-1 for MB and 0.2884 mmol g-1 for Cd2+, while in multicomponent systems (Cd2+ and MB), both contaminants competed for the adsorption sites on OP. Particularly, a synergic effect was observed since the adsorption capacity of Cd2+ increased compared to the monocomponent system. Results of desorption and adsorbent reuse confirmed that the adsorbent presents good regeneration performance. The low cost of this material and its capacity for the individual or simultaneous removal of Cd2+ and MB in aqueous solutions makes it a potential adsorbent for polluted water treatment processes.

Comparative Brain Imaging Reveals Analogous and Divergent Patterns of Species and Face Sensitivity in Humans and Dogs.

Conspecific-preference in social perception is evident for multiple sensory modalities and in many species. There is also a dedicated neural network for face processing in primates. However, the evolutionary origin and the relative role of neural species sensitivity and face sensitivity in visuo-social processing are largely unknown. In this comparative study, species sensitivity and face sensitivity to identical visual stimuli (videos of human and dog faces and occiputs) were examined using functional magnetic resonance imaging in dogs (n = 20; 45% female) and humans (n = 30; 50% female). In dogs, the bilateral mid suprasylvian gyrus showed conspecific-preference, no regions exhibited face-preference, and the majority of the visually-responsive cortex showed greater conspecific-preference than face-preference. In humans, conspecific-preferring regions (the right amygdala/hippocampus and the posterior superior temporal sulcus) also showed face-preference, and much of the visually-responsive cortex showed greater face-preference than conspecific-preference. Multivariate pattern analyses (MVPAs) identified species-sensitive regions in both species, but face-sensitive regions only in humans. Across-species representational similarity analyses (RSAs) revealed stronger correspondence between dog and human response patterns for distinguishing conspecific from heterospecific faces than other contrasts. Results unveil functional analogies in dog and human visuo-social processing of conspecificity but suggest that cortical specialization for face perception may not be ubiquitous across mammals.SIGNIFICANCE STATEMENT To explore the evolutionary origins of human face-preference and its relationship to conspecific-preference, we conducted the first comparative and noninvasive visual neuroimaging study of a non-primate and a primate species, dogs and humans. Conspecific-preferring brain regions were observed in both species, but face-preferring brain regions were observed only in humans. In dogs, an overwhelming majority of visually-responsive cortex exhibited greater conspecific-preference than face-preference, whereas in humans, much of the visually-responsive cortex showed greater face-preference than conspecific-preference. Together, these findings unveil functional analogies and differences in the organizing principles of visuo-social processing across two phylogenetically distant mammal species.

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Ibuprofen degradation and energy generation in a microbial fuel cell using a bioanode fabricated from devil fish bone char.

Ibuprofen degradation and energy generation in a single-chamber Microbial Fuel Cell (MFC) were evaluated using a bioanode fabricated from devil fish bone char (BCA) synthesized by calcination in air atmosphere. Its performance was compared with conventional carbon felt (CF). Bone char textural properties were determined by nitrogen adsorption. Before and after, the bacterial colonization on the materials was analyzed by environmental scanning electron microscopy. Energy generation was evaluated by electrochemical techniques as open-circuit potential, linear sweep voltammetry, and electrochemical impedance spectroscopy. Ibuprofen degradation was analyzed by High-Performance Liquid Chromatography-Ultraviolet, and the chemical oxygen demand (COD) removal was measured. Results showed a specific area of 136 m2/g for BCA, having enough space to immobilize microorganisms. The micrographs confirmed the biofilm formation on the electrode materials. Over the 14 days, MFC with BCA reached a maximum power density of 4.26 mW/m2, 175% higher than CF, and an electron transfer resistance 2.1 times lower than it. This coincides with the COD removal and ibuprofen degradation efficiencies, which were 43.6% and 34% for BCA and 31.8% and 27% for CF. Hence, these findings confirmed that BCA in MFC could provide an alternative electrode material for ibuprofen degradation and energy generation.

Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis.

Loss of 5-hydroxymethylcytosine (5hmC) has been associated with mutations of the ten-eleven translocation (TET) enzymes in several types of cancer. However, tumors with wild-type TET genes can also display low 5hmC levels, suggesting that other mechanisms involved in gene regulation might be implicated in the decline of this epigenetic mark. Here we show that DNA hypermethylation and loss of DNA hydroxymethylation, as well as a marked reduction of activating histone marks in the TET3 gene, impair TET3 expression and lead to a genome-wide reduction in 5hmC levels in glioma samples and cancer cell lines. Epigenetic drugs increased expression of TET3 in glioblastoma cells and ectopic overexpression of TET3 impaired in vitro cell growth and markedly reduced tumor formation in immunodeficient mice models. TET3 overexpression partially restored the genome-wide patterns of 5hmC characteristic of control brain samples in glioblastoma cell lines, while elevated TET3 mRNA levels were correlated with better prognosis in glioma samples. Our results suggest that epigenetic repression of TET3 might promote glioblastoma tumorigenesis through the genome-wide alteration of 5hmC.

Loss of 5hmC identifies a new type of aberrant DNA hypermethylation in glioma.

Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5-methylcytosine (5mC) in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island shores. The DNA regions containing these CpG sites were enriched in H3K4me2 and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. As this 5mC gain is inversely correlated with loss of 5hmC and has not been identified with classical sodium bisulfite-based technologies, we conclude that our data identifies a novel 5hmC-dependent type of aberrant DNA hypermethylation in glioma.