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Microglia, the largest population of brain immune cells, continuously interact with synapses to maintain brain homeostasis. In this study, we use conditional cell-specific gene targeting in mice with multi-omics approaches and demonstrate that the RhoGTPase Rac1 is an essential requirement for microglia to sense and interpret the brain microenvironment. This is crucial for microglia-synapse crosstalk that drives experience-dependent plasticity, a fundamental brain property impaired in several neuropsychiatric disorders. Phosphoproteomics profiling detects a large modulation of RhoGTPase signaling, predominantly of Rac1, in microglia of mice exposed to an environmental enrichment protocol known to induce experience-dependent brain plasticity and cognitive performance. Ablation of microglial Rac1 affects pathways involved in microglia-synapse communication, disrupts experience-dependent synaptic remodeling, and blocks the gains in learning, memory, and sociability induced by environmental enrichment. Our results reveal microglial Rac1 as a central regulator of pathways involved in the microglia-synapse crosstalk required for experience-dependent synaptic plasticity and cognitive performance. [Display omitted] • Microglial Rac1 is essential for experience-dependent brain plasticity • Rac1 modulates microglia-synapse interaction • Ablation of Rac1 in microglia hampers context-dependent learning, memory, and sociability • Increasing Rac1 signaling might improve cognitive performance in neurological disorders Socodato et al. show that Rac1 in microglia shapes microglia-synapse interactions, synaptic plasticity, and cognition driven by experience. Loss of Rac1 in microglia disrupts synaptic architecture and impairs experience-dependent learning, memory, and sociability. The work suggests that Rac1 could be a therapeutic target in neurological disorders associated with cognitive deficits. [ABSTRACT FROM AUTHOR]

The occurrence of pharmaceuticals in the environment is a topic of concern. Carbamazepine (CBZ) is a widespread antiepileptic drug and due to its physical-chemical characteristics minimal removal is achieved in conventional water treatments, and thus has been suggested as a molecular marker of wastewater contamination in surface water and groundwater. The present study reports the biotransformation of CBZ by the bacterial strain Labrys portucalensis F11. When supplied as a sole carbon source, a 95.4% biotransformation of 42.69 μM CBZ was achieved in 30 days. In co-metabolism with acetate, complete biotransformation was attained at a faster rate. Following a target approach, the detection and identification of 14 intermediary metabolites was achieved through UPLC-QTOF/MS/MS. Biotransformation of CBZ by the bacterial strain is mostly based on oxidation, loss of -CHNO group and ketone formation reactions; a biotransformation pathway with two routes is proposed. The toxicity of untreated and treated CBZ solutions was assessed using Vibrio Fischeri and Lepidium sativum acute toxicity tests and Toxi-Chromo Test. The presence of CBZ and/or its degradations products in solution resulted in moderate toxic effect on Vibrio Fischeri , whereas the other organisms were not affected. To the best of our knowledge this is the first report that proposes the metabolic degradation pathway of CBZ by a single bacterial strain. Unlabelled Image • Biotransformation of carbamazepine by L. portucalensis strain F11 was achieved. • The kinetics and pathway of carbamazepine degradation was proposed. • The supplementation with acetate resulted in increased biodegradation rates. • The chemical structure of fourteen degradation intermediates was proposed. • Carbamazepine biotransformation products revealed toxicity to V. fischeri. [ABSTRACT FROM AUTHOR]

An aerobic granular sludge-sequencing batch reactor (AGS-SBR) was fed for 28-days with a simulated wastewater containing a mixture of chiral pharmaceuticals (CPs) (alprenolol, bisoprolol, metoprolol, propranolol, venlafaxine, salbutamol, fluoxetine and norfluoxetine), each at 1.3 μg L −1 . AGS-SBR exhibited the highest removal efficiency for norfluoxetine, with preferential removal of the ( R )-enantiomer indicating that biological-mediated processes occurred. For all other CPs, removal was non-enantioselective, occurring through biosorption onto AGS. A gradual decline of CPs removal was observed, probably related to the decrease of AGS adsorption capacity. Moreover, chemical oxygen demand (COD) content in the bulk liquid after anaerobic feeding increased, and P-release dropped, probably because the polyphosphate-accumulating organism's activity was affected. Nitrification was also affected as indicated by the ammonium effluent concentration increase. Moreover, CPs exposure promoted AGS disintegration, with decreasing granule size. After stopping CPs feeding, the AGS started to recover its compact structure, and the system returned its normal performance concerning COD- and P-removal. N-removal seemed to be a more sensitive process, as while the ammonium levels were fully restored at the end of operation, nitrite reduction was only partially restored. Results provide useful information on AGS performance during the treatment of wastewater containing pharmaceuticals, a frequent scenario in WWTP. [ABSTRACT FROM AUTHOR]

Fluoxetine (FLX) is a chiral fluorinated pharmaceutical indicated mainly for the treatment of depression and is one of the most dispensed drugs in the world. There is clear evidence of environmental contamination with this drug and its active metabolite norfluoxetine (NFLX). In this study the enantioselective biodegradation of racemic FLX and of its enantiomers by Labrys portucalensis strain F11 was assessed. When 2 μM of racemic FLX was supplemented as sole carbon source, complete removal of both enantiomers, with stoichiometric liberation of fluoride, was achieved in 30 d. For racemic FLX concentration of 4 and 9 μM, partial degradation of the enantiomers was obtained. In the presence of acetate as an additional carbon source, at 4, 9 and 21 μM of racemic FLX and at 25 μM of racemic FLX, (S)-FLX or (R)-FLX, complete degradation of the two enantiomers occurred. At higher concentrations of 45 and 89 μM of racemic FLX, partial degradation was achieved. Preferential degradation of the (R)-enantiomer was observed in all experiments. To our knowledge, this is the first time that enantioselective biodegradation of FLX by a single bacterium is reported. [ABSTRACT FROM AUTHOR]

An aerobic granular sludge (AGS) sequencing batch reactor (SBR) adapted to salinity (12 g L−1 NaCl) was operated under alternating anaerobic-aerobic conditions for the treatment of synthetic saline wastewater containing endocrine-disrupting chemicals (EDCs), namely 17β–estradiol (E2), 17α–ethinylestradiol (EE2) and bisphenol-A (BPA). The SBR was intermittently fed with the EDCs at 2 mg L−1 of each compound. E2 was completely biodegraded, with 60–80% removal attained anaerobically and the remaining quickly consumed under aeration. EE2 was sorbed onto the granular sludge biomass in the anaerobic period, but it was desorbed in subsequent cycles even when the compound was not supplied to the reactor. BPA removal was poor but improved after bioaugmentation with an EDCs degrading bacteria. EDCs shock loads did not significantly affect the COD removal nor the activity of ammonium- and nitrite-oxidizing bacteria (AOB and NOB, respectively). In contrast, the activity of phosphate-accumulating organisms (PAOs) was affected, implying a decrease in P removal within the aerobic phase. AGS core microbiome grouped most bacteria belonging to the phylum Proteobacteria, followed by Bacteroidetes. The microbial profile showed that the introduction of the EDCs mixture increased the relative abundance of Chryseobacterium and Flavobacterium. AOB and NOB species were detected in the AGS biomass, with the latter showing lower relative abundance. Different PAOs, such as Rhodocyclus , Tetrasphaera and Gemmatimonas , were also part of the microbial community, but the addition of EDCs decreased significantly the relative abundance of Rhodocyclus. High microbial diversity was sustained over reactor operation, with the main bacterial groups responsible for nutrients and EDCs removal preserved in the AGS system. The results pointed to the maintenance of a core microbiome over reactor operation that may be related to the stability of the AGS process during EDCs loading. [Display omitted] • Degradation of endocrine-disrupting chemicals (E2, EE2 and BPA) by AGS was assessed. • High degradation was observed for E2, which mainly occurred anaerobically. • EE2 was not biodegraded, being adsorbed and desorbed during the successive cycles. • BPA biodegradation was enhanced upon bioaugmentation with a specialized strain. • Stable COD and NH 4 + removal despite EDCs shock loads, while P removal was impaired. [ABSTRACT FROM AUTHOR]

Abstract: Background: The details of the functional interaction between G proteins and the G protein coupled receptors (GPCRs) have long been subjected to extensive investigations with structural and functional assays and a large number of computational studies. Scope of review: The nature and sites of interaction in the G-protein/GPCR complexes, and the specificities of these interactions selecting coupling partners among the large number of families of GPCRs and G protein forms, are still poorly defined. Major conclusions: Many of the contact sites between the two proteins in specific complexes have been identified, but the three dimensional molecular architecture of a receptor-Gα interface is only known for one pair. Consequently, many fundamental questions regarding this macromolecular assembly and its mechanism remain unanswered. General significance: In the context of current structural data we review the structural details of the interfaces and recognition sites in complexes of sub-family A GPCRs with cognate G-proteins, with special emphasis on the consequences of activation on GPCR structure, the prevalence of preassembled GPCR/G-protein complexes, the key structural determinants for selective coupling and the possible involvement of GPCR oligomerization in this process. [Copyright &y& Elsevier]

Highlights: [•] Imaging of NOS in vivo with 99mTc(I) probes would allow earlier diagnosis of diseases. [•] Re(I) non-radioactive surrogates display different degrees of iNOS inhibition. [•] A computational study combining molecular docking, MD simulations and FEP calculations was performed to establish a structure activity relationship. [•] Interactions responsible for iNOS-recognizing ability of the complexes were identified. [•] Electrostatic interactions between the Re(CO)3 core and R260/R382 are a key issue. [Copyright &y& Elsevier]

Globally with over 10 million deaths per year, cancer is the most transversal disease across countries, cultures, and ethnicities, affecting both developed and developing regions. Tumorigenesis is dynamically altered by distinct events and can be lethal when untreated. Despite the innovative therapeutics available, multidrug resistance (MDR) to chemotherapy remains the major hindrance to the success of cancer therapy. The multiple mechanisms by which cancer cells evade cell death are diverse, indicating that MDR involves complex interconnected biological networks. Molecular profiling is currently able to stratify cancer into its distinct subtypes and help identify the best therapeutics, leading to "translational systems medicine". Highly specialized methodologies are generating a large amount of " omics " data – including epigenetics, genomics, transcriptomics, proteomics, metabolomics, as well as pharmacogenomics. Many of the resulting databases store data in non-standard formats, which need to be converted, interpreted, and merged into readable formats. The latest development of artificial intelligence (AI) methodologies and tools, coupled with advancements in large-scale data management and powerful graphic processing computing units, potentiate the integration of these large data sources into relevant biological networks, which will enhance our understanding of cancer MDR. In this review, we revisit common MDR mechanisms and compile a list of the most relevant "omics " public databases. We highlight examples of AI methods that are now decisively contributing to clear advances in cancer research, such as identification of new drugs from large databases and prediction of relevant drug, target, and system properties. An overview of several freely available "ready-to-use" algorithms is also provided. The described molecular scale AI algorithms and tools will undoubtedly guide important improvements in efficiency and efficacy of traditional methods of cancer diagnostics and treatment. [ABSTRACT FROM AUTHOR]

Abstract: Due to the widespread use of chlorobenzene (CB), environmental contamination with this compound is a major concern. A previously isolated bacterium named Labrys portucalensis (strain F11), that is able to use fluorobenzene (FB) as sole carbon and energy source, was tested for its capability to degrade CB. Strain F11 was able to partially degrade CB only when F11 cells were previously grown in FB. Biodegradation of 0.5 mM of CB was achieved at a rate of 7.95 ± 0.39 μmol l−1 day−1 with concomitant stoichiometric release of 50% of the chloride, while degradation of 1 mM of this compound resulted in 85% degradation at a rate of 16.9 ± 0.81 μmol l−1 day−1 and with a 15% chloride release on the basis of the amount of compound biodegraded. Total CB biodegradation and dechlorination was only achieved when FB was also supplied to F11 cultures, suggesting cometabolic transformation. Total degradation of 0.5 mM of CB and 0.5 mM of FB occurred simultaneously at degradation rates of 105 ± 6.07 μmol l−1 day−1 and 126 ± 16.2 μmol l−1 day−1 respectively, with stoichiometric halogen release. Growth yield was lower when both substrates were present, suggesting synergistic inhibition. To our knowledge, this is the first time that co-metabolic biodegradation of CB in the presence of the fluorinated analogue is reported. [Copyright &y& Elsevier]

Highlights: [•] Enantioseparation of fluoxetine and norfluoxetine on a Chirobiotic V. [•] Enantioselective HPLC-FD method for quantification of fluoxetine and norfluoxetine. [•] FLX was degraded in wastewater effluent samples. [ABSTRACT FROM AUTHOR]

Background Membrane proteins (MPs) play diverse and important functions in living organisms. They constitute 20% to 30% of the known bacterial, archaean and eukaryotic organisms' genomes. In humans, their importance is emphasized as they represent 50% of all known drug targets. Nevertheless, experimental determination of their three-dimensional (3D) structure has proven to be both time consuming and rather expensive, which has led to the development of computational algorithms to complement the available experimental methods and provide valuable insights. Scope of review This review highlights the importance of membrane proteins and how computational methods are capable of overcoming challenges associated with their experimental characterization. It covers various MP structural aspects, such as lipid interactions, allostery, and structure prediction, based on methods such as Molecular Dynamics (MD) and Machine-Learning (ML). Major conclusions Recent developments in algorithms, tools and hybrid approaches, together with the increase in both computational resources and the amount of available data have resulted in increasingly powerful and trustworthy approaches to model MPs. General significance Even though MPs are elementary and important in nature, the determination of their 3D structure has proven to be a challenging endeavor. Computational methods provide a reliable alternative to experimental methods. In this review, we focus on computational techniques to determine the 3D structure of MP and characterize their binding interfaces. We also summarize the most relevant databases and software programs available for the study of MPs. [ABSTRACT FROM AUTHOR]