Oxysulfonylation of Alkynes with Sodium Sulfinates to Access ß-Keto Sulfones Catalyzed by BF3·OEt2.

An efficient and operationally simple method for the synthesis of ß-keto sulfones through the BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed. With its facile and selective access to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and good yields. Notably, the reaction does not require metal catalysts or chemical reagents with pungent odors.

Theoretical elucidation of the structure, bonding, and reactivity of the CaMn4Ox clusters in the whole Kok cycle for water oxidation embedded in the oxygen evolving center of photosystem II. New molecular and quantum insights into the mechanism of the O-O bond formation.

This paper reviews our historical developments of broken-symmetry (BS) and beyond BS methods that are applicable for theoretical investigations of metalloenzymes such as OEC in PSII. The BS hybrid DFT (HDFT) calculations starting from high-resolution (HR) XRD structure in the most stable S1 state have been performed to elucidate structure and bonding of whole possible intermediates of the CaMn4Ox cluster (1) in the Si (i = 0 ~ 4) states of the Kok cycle. The large-scale HDFT/MM computations starting from HR XRD have been performed to elucidate biomolecular system structures which are crucial for examination of possible water inlet and proton release pathways for water oxidation in OEC of PSII. DLPNO CCSD(T0) computations have been performed for elucidation of scope and reliability of relative energies among the intermediates by HDFT. These computations combined with EXAFS, XRD, XFEL, and EPR experimental results have elucidated the structure, bonding, and reactivity of the key intermediates, which are indispensable for understanding and explanation of the mechanism of water oxidation in OEC of PSII. Interplay between theory and experiments have elucidated important roles of four degrees of freedom, spin, charge, orbital, and nuclear motion for understanding and explanation of the chemical reactivity of 1 embedded in protein matrix, indicating the participations of the Ca(H2O)n ion and tyrosine(Yz)-O radical as a one-electron acceptor for the O-O bond formation. The Ca-assisted Yz-coupled O-O bond formation mechanisms for water oxidation are consistent with recent XES and very recent time-resolved SFX XFEL and FTIR results.

Stable maternal proteins underlie distinct transcriptome, translatome, and proteome reprogramming during mouse oocyte-to-embryo transition.

BACKGROUND: The oocyte-to-embryo transition (OET) converts terminally differentiated gametes into a totipotent embryo and is critically controlled by maternal mRNAs and proteins, while the genome is silent until zygotic genome activation. How the transcriptome, translatome, and proteome are coordinated during this critical developmental window remains poorly understood. RESULTS: Utilizing a highly sensitive and quantitative mass spectrometry approach, we obtain high-quality proteome data spanning seven mouse stages, from full-grown oocyte (FGO) to blastocyst, using 100 oocytes/embryos at each stage. Integrative analyses reveal distinct proteome reprogramming compared to that of the transcriptome or translatome. FGO to 8-cell proteomes are dominated by FGO-stockpiled proteins, while the transcriptome and translatome are more dynamic. FGO-originated proteins frequently persist to blastocyst while corresponding transcripts are already downregulated or decayed. Improved concordance between protein and translation or transcription is observed for genes starting translation upon meiotic resumption, as well as those transcribed and translated only in embryos. Concordance between protein and transcription/translation is also observed for proteins with short half-lives. We built a kinetic model that predicts protein dynamics by incorporating both initial protein abundance in FGOs and translation kinetics across developmental stages. CONCLUSIONS: Through integrative analyses of datasets generated by ultrasensitive methods, our study reveals that the proteome shows distinct dynamics compared to the translatome and transcriptome during mouse OET. We propose that the remarkably stable oocyte-originated proteome may help save resources to accommodate the demanding needs of growing embryos. This study will advance our understanding of mammalian OET and the fundamental principles governing gene expression.

Start of life controlled by poly(A) tail-mediated remodeling.

Understanding a remarkable event at the start of life, the oocyte-to-embryo transition (OET), has remained elusive, especially in humans. Using newly developed techniques, Liu et al. showed that human maternal mRNAs undergo global poly(A) tail-mediated remodeling during OET, identified the enzymes involved, and demonstrated the essentiality of remodeling for embryo cleavage.

E40 glutenase detoxification capabilities of residual gluten immunogenic peptides in in vitro gastrointestinal digesta of food matrices made of soft and durum wheat.

Gluten degrading enzymes, which are commonly referred to as "glutenases," represent attractive candidates for the development of a pharmacological treatment of gluten related disorders, such as coeliac disease (CeD). Endoprotease-40 (E40), a novel glutenase secreted by the actinomycete Actinoallomurus A8 and recombinantly produced in S. lividans TK24, was shown to be active at pH 3 to 6 (optimum pH 5), resistant to pepsin and trypsin degradation, able to destroy immunotoxicity of both gliadin 33-mer peptide and whole proteins and to strongly reduce the response of specific T cells when added to gliadin in in vitro gastrointestinal digestion. This study aims to functionally assess the capabilities of Endoprotease-40 (E40) to detoxify residual gluten immunogenic peptides in gastrointestinal digesta of food matrices made of soft and durum wheat. The INFOGEST harmonized protocols were applied to the multicompartmental model of simulated human gastrointestinal digestion, for the quantitative assessment of residual gluten in liquid (beer) and solid (bread and pasta) foods, made of either soft or durum wheat. Proteomic and immunological techniques, and functional assays on intestinal T cell lines from celiac disease patients were used to identify gluten-derived immunogenic peptide sequences surviving in gastric and gastrointestinal digesta after the addition of E40 at increasing enzyme: wheat proteins ratios. During the gastric phase (2 h incubation time), the addition of E40 demonstrated an extensive (≥ 95%) dose-dependent detoxification of whole gluten in real food matrices. Overall, the residual gluten content was found at, or even below, the 20 ppm gluten-free threshold for soft and durum wheat-based food. Furthermore, unlike in untreated gastrointestinal digesta, none of the immunodominant α-gliadin peptides survived in E40-treated digesta. Traces of ω- and γ-gliadin derived immunogenic peptides were still detected in E40-treated digesta, but unable to stimulate celiac-intestinal T cells. In conclusion, E40 is a promising candidate for the oral enzymatic therapy of CeD, as a stand-alone enzyme being efficient along the complete gastrointestinal digestion of gluten.

Optical Dielectrophoretic (DEP) Manipulation of Oil-Immersed Aqueous Droplets on a Plasmonic-Enhanced Photoconductive Surface.

We present a plasmonic-enhanced dielectrophoretic (DEP) phenomenon to improve optical DEP performance of a floating electrode optoelectronic tweezers (FEOET) device, where aqueous droplets can be effectively manipulated on a light-patterned photoconductive surface immersed in an oil medium. To offer device simplicity and cost-effectiveness, recent studies have utilized a polymer-based photoconductive material such as titanium oxide phthalocyanine (TiOPc). However, the TiOPc has much poorer photoconductivity than that of semiconductors like amorphous silicon (a-Si), significantly limiting optical DEP applications. The study herein focuses on the FEOET device for which optical DEP performance can be greatly enhanced by utilizing plasmonic nanoparticles as light scattering elements to improve light absorption of the low-quality TiOPc. Numerical simulation studies of both plasmonic light scattering and electric field enhancement were conducted to verify wide-angle scattering light rays and an approximately twofold increase in electric field gradient with the presence of nanoparticles. Similarly, a spectrophotometric study conducted on the absorption spectrum of the TiOPc has shown light absorption improvement (nearly twofold) of the TiOPc layer. Additionally, droplet dynamics study experimentally demonstrated a light-actuated droplet speed of 1.90 mm/s, a more than 11-fold improvement due to plasmonic light scattering. This plasmonic-enhanced FEOET technology can considerably improve optical DEP capability even with poor-quality photoconductive materials, thus providing low-cost, easy-fabrication solutions for various droplet-based microfluidic applications.

An efficient approach for the synthesis of novel methyl sulfones in acetic acid medium and evaluation of antimicrobial activity.

A series of nine methyl sulphones ( 3a -3 i ) starting from the aldehydes ( 1a-1i ) were synthesized in two consecutive steps. In the first step, preparation of allyl alcohols ( 2a-2i ) from their corresponding aldehydes by the reaction of sodium borohydride in methanol at room temperature is reported. Finally, methyl sulphones are synthesized by condensing sodium methyl sulfinates with allyl alcohols in the presence of BF 3 .Et 2 O in acetic acid medium at room temperature for about 2-3 h. The reaction conditions are simple, yields are high (85%-95%), and the products were obtained with good purity. All the synthesized compounds were characterized by their 1 H, 13 C NMR, and mass spectral analysis. All the title compounds were screened for antimicrobial activity. Among the compounds tested, the compound 3f has inhibited both Gram positive and Gram negative bacteria effectively and compound 3i has shown potent antifungal activity. These promising components may help to develop more potent drugs in the near future for the treatment of bacterial and fungal infections.

The role of SCF ubiquitin-ligase complex at the beginning of life.

As the largest family of E3 ligases, the Skp1-cullin 1-F-box (SCF) E3 ligase complex is comprised of Cullins, Skp1 and F-box proteins. And the SCF E3 ubiquitin ligases play an important role in regulating critical cellular processes, which promote degradation of many cellular proteins, including signal transducers, cell cycle regulators, and transcription factors. We review the biological roles of the SCF ubiquitin-ligase complex in gametogenesis, oocyte-to-embryo transition, embryo development and the regulation for estrogen and progestin. We find that researches about the SCF ubiquitin-ligase complex at the beginning of life are not comprehensive, thus more in-depth researches will promote its eventual clinical application.

2-(4-Ethoxy phenyl)-4-phenyl quinoline organic phosphor for solution processed blue organic light-emitting diodes.

This paper reports the synthesis and characterization of 2-(4-ethoxyphenyl)-4-phenyl quinoline (OEt-DPQ) organic phosphor using an acid-catalyzed Friedlander reaction and the preparation of blended thin films by molecularly doping OEt-DPQ in poly(methyl methacrylate) (PMMA) at different wt%. The molecular structure of the synthesized phosphor was confirmed by Fourier transform infra-red (FTIR) spectroscopy and nuclear magnetic resonance spectra (NMR). Surface morphology and percent composition of the elements were assessed by scanning electron microscopy (SEM) and energy dispersive analysis of X-rays (EDAX). The thermal stability and melting point of OEt-DPQ and thin films were probed by thermo-gravimetric analysis (TGA)/differential thermal analysis (DTA) and were found to be 80°C and 113.6°C, respectively. UV-visible optical absorption spectra of OEt-DPQ in the solid state and blended films produced absorption bands in the range 260-340 nm, while photoluminescence (PL) spectra of OEt-DPQ in the solid state and blended thin films demonstrated blue emission that was registered at 432 nm when excited at 363-369 nm. However, solvated OEt-DPQ in chloroform, tetrahydrofuran or dichloromethane showed a blue shift of 31-43 nm. Optical absorption and emission parameters such as molar extinction coefficient (ε), energy gap (Eg ), transmittance (T), reflectance (R), refractive index (n), oscillator energy (E0 ) and oscillator strength (f), quantum yield (φf ), oscillator energy (E0 ), dispersion energy (Ed ), Commission Internationale de l'Éclairage (CIE) co-ordinates and energy yield fluorescence (EF ) were calculated to assess the phosphor's suitability as a blue emissive material for opto-electronic applications such as organic light-emitting diodes (OLEDs), flexible displays and solid-state lighting technology.

Effects of 17-DMAG on diffuse large B-cell lymphoma cell apoptosis.

17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) is a water soluble, semisynthetic derivative of endotoxin that has anticancer effects. The aim of the present study was to determine whether 17-DMAG enhances the apoptosis of lymphoma cells in diffuse large B-cell lymphoma. Apoptosis was induced in SU-DHL-4 diffuse large B-cell lymphoma cells treated with 17-DMAG, as evaluated by MTT assay and flow cytometry analysis. Apoptosis-associated protein levels were assessed using western blotting, and the results indicated that B-cell lymphoma 2 (Bcl-2)-associated protein X (Bax) was upregulated, whereas heat shock protein family A member 5 (HSPA5) and Bcl-2 were downregulated. Additionally, staining with 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide revealed that treatment with 17-DMAG decreased mitochondrial membrane potential in SU-DHL-4 diffuse large B-cell lymphoma cells. These results suggested that 17-DMAG is able to inhibit proliferation in diffuse large B-cell lymphoma cells in a concentration-dependent manner. The underlying mechanism may be that 17-DMAG induces oxidative stress, which inhibits the expression of HSPA5 and Bcl-2 and promotes the expression of Bax, leading to the apoptosis of SU-DHL-4 cells. Taken together, these results indicated that 17-DMAG may be an effective novel agent for the treatment of diffuse large B-cell lymphoma.

Synthesis and Fungicidal Activity of 1-(Carbamoylmethyl)-2-aryl-3,1-benzoxazines.

A series of new 1-(carbamoylmethyl)-2-aryl-3,1-benzoxazines were prepared in moderate to good yields by BF3·OEt2-catalyzed reactions of aromatic aldehydes with 2-(N-substituted carbamoylmethylamino)benzyl alcohols. The structures of the target compounds were confirmed by IR, ¹H-NMR, 13C-NMR, and elemental analyses. The fungicidal activities of the target compounds against plant fungi were preliminarily evaluated, and some of them exhibited good activity.

A Single-Flask Synthesis of α-Alkylidene and α-Benzylidene Lactones from Ethoxyacetylene, Epoxides/Oxetanes, and Carbonyl Compounds.

Low temperature treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3•OEt2, followed by addition of aldehydes or ketones and warming to room temperature, affords structurally diverse five- and six-membered α-alkylidene and α-benzylidene lactones (5) in good to excellent yields. This one-pot process, in which three new carbon-carbon bonds and a ring are formed, affords substituted α,ß-unsaturated lactones of predominantly Z-configuration. The reaction likely occurs via alkyne-carbonyl metathesis of a hydroxy-ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization.

Flavonoid derivative exerts an antidiabetic effect via AMPK activation in diet-induced obesity mice.

In our previous study, a derivative of tiliroside, 3-O-[(E)-4-(4-ethoxyphenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-OEt) significantly enhanced glucose consumption in insulin resistant HepG2 cells. This article deals with the antihyperglycemic and antihyperlipidemic effects of Fla-OEt in diet-induced obesity (DIO) mice. Daily administration of Fla-OEt significantly decreased oral glucose tolerance test, intraperitoneal insulin tolerance test and serum lipids. Hyperinsulinemic-euglycemic clamp and the ratio of high-density-lipoprotein/low-density-lipoprotein with Fla-OEt treatment were increased comparing with high-fat diet (HFD) group, so lipid metabolism was improved. Histopathology examination showed that the Fla-OEt restored the damage of adipose tissues and liver in DIO mice. Moreover, compared with HFD group, Fla-OEt treatment significantly increased the phosphorylation of AMPK and ACC in adiposity tissues, liver, and muscles. The mechanism of its action might be the activation of AMPK pathway. It appears that Fla-OEt is worth further study for development as a lead compound for a potential antidiabetic agent.

Mechanistic investigation of capability of enzymatically synthesized polycysteine to cross-link proteins.

BACKGROUND: Previously, we had reported that α-chymotrypsin-catalyzed polymerization of l-cysteine ethyl ester in a frozen buffer provided poly-l-cysteine (PLCys) in good yield, of which degree of polymerization had been determined to be 6-11. Almost all of SH groups in PLCys were in free forms. Such a multi-thiol peptide may cross-link proteins through thiol/disulfide (SH/SS) exchange reactions, considering the knowledge that other synthetic multi-thiol additives changes properties of protein materials. METHODS: This study explored the capability of PLCys to cross-link proteins using lysozyme as a model protein which has four disulfide bonds but no free SH group. The protein was incubated with PLCys at neutral pH and at below 70 °C to avoid PLCys-independent, ß-elimination-mediated cross-linkings. Protein polymerization was analyzed by SDS-PAGE and SEC. PLCys peptides involved in the protein polymer, which were released by reduction with dithiothreitol, were analyzed by RP-HPLC. CONCLUSIONS: Addition of urea and thermal treatment at 60 °C caused PLCys-induced lysozyme polymerization. Compared with free cysteine, a higher level of PLCys was required for the polymerization probably due to its low water solubility. RP-HPLC analyses suggested that PLCys played a role in the protein polymerization as a cross-linker. GENERAL SIGNIFICANCE: Enzymatically synthesized PLCys shows promise as a peptidic cross-linker for the production of protein polymers with novel physiochemical properties and functionalities.

The Maternal-to-Zygotic Transition in C. elegans.

In Caenorhabditis elegans, the first zygotic transcription can be detected in the 4-cell stage C. elegans embryo, a little over 2h after fertilization. However, early development until the onset of gastrulation at approximately the 28-cell stage takes place normally even in the absence of zygotic transcription. Therefore, posttranslational and posttranscriptional regulation of the maternal proteins and mRNAs, respectively, that are loaded into the developing oocytes is sufficient to direct development prior to gastrulation. Protein phosphorylation is extensively used throughout the C. elegans maternal-to-zygotic transition (MZT): (1) for maternal protein activation, (2) for coordination of the meiotic and mitotic cell cycle, (3) to mark specific proteins for degradation, and/or (4) to switch the biochemical activity of specific proteins. Maternally loaded mRNAs are regulated primarily by a set of maternal RNA-binding proteins (RBPs), each of which binds to sometimes overlapping target sequences within the mRNA 3'UTRs and either promotes or inhibits translation. Most maternal transcripts are uniformly distributed throughout the embryo but specific transcripts are translated only in certain blastomeres. This control is achieved by the asymmetric distribution of the maternal RBPs, such that the blastomere-specific constellation of RBPs present, and their relative levels, determines the translational readout for their target transcripts. In certain well-studied cases, such as the specification of the sole endodermal precursor in the 8-cell embryo, the maternal transcripts and proteins along with their directly targeted zygotic genes have been identified.

Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4·OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities.

A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4·OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity.

Prediction of protein structure classes using hybrid space of multi-profile Bayes and bi-gram probability feature spaces.

Proteins are the executants of biological functions in living organisms. Comprehension of protein structure is a challenging problem in the era of proteomics, computational biology, and bioinformatics because of its pivotal role in protein folding patterns. Owing to the large exploration of protein sequences in protein databanks and intricacy of protein structures, experimental and theoretical methods are insufficient for prediction of protein structure classes. Therefore, it is highly desirable to develop an accurate, reliable, and high throughput computational model to predict protein structure classes correctly from polygenetic sequences. In this regard, we propose a promising model employing hybrid descriptor space in conjunction with optimized evidence-theoretic K-nearest neighbor algorithm. Hybrid space is the composition of two descriptor spaces including Multi-profile Bayes and bi-gram probability. In order to enhance the generalization power of the classifier, we have selected high discriminative descriptors from the hybrid space using particle swarm optimization, a well-known evolutionary feature selection technique. Performance evaluation of the proposed model is performed using the jackknife test on three low similarity benchmark datasets including 25PDB, 1189, and 640. The success rates of the proposed model are 87.0%, 86.6%, and 88.4%, respectively on the three benchmark datasets. The comparative analysis exhibits that our proposed model has yielded promising results compared to the existing methods in the literature. In addition, our proposed prediction system might be helpful in future research particularly in cases where the major focus of research is on low similarity datasets.

Oxidative stress potentially enhances FcεRI-mediated leukotriene C4 release dependent on the late-phase increase of intracellular glutathione in mast cells.

Cysteinyl leukotrienes (cysLTs), which include leukotriene C4 (LTC4), are the predominant class of LTs synthesized by mast cells. CysLTs can induce many of the abnormalities seen in asthma. LTC4 is generated by the conjugation of LTA4 with reduced glutathione (GSH) by LTC4 synthase. During screening of the effects of prostanoids on high-affinity IgE receptor (FcεRI)-mediated LTC4 release from mast cells, we realized that some prostanoids, including ONO-AE1-259-01 and ONO-AE-248, inhibited LTC4 release, which was associated with a decrease in the amount of intracellular total GSH. We ascertained that l-buthionine-S,R-sulfoximine (BSO), a selective inhibitor of glutamate-cysteine ligase, inhibited LTC4 release. In addition, cell-permeable GSH, the glutathione reduced form ethyl ester (GSH-OEt), enhanced LTC4 release in accordance with the change in intracellular total GSH. Depletion of intracellular total GSH induced by ONO-AE-248 or BSO enhanced FcεRI-mediated LTB4 release in contrast to LTC4. Oxidative stress contributes to many pathological conditions including asthma. GSH is a major soluble antioxidant and a cofactor for several detoxifying enzymes including GSH peroxidase. Exposure of mast cells to hydrogen peroxide (H2O2) or diamide to mimic oxidative stress unexpectedly increased rather than decreased the intracellular reduced GSH content as well as total GSH in the late phase (i.e., 24 or 48 h after exposure), which was accompanied by an increase in LTC4 release. In conclusion, FcεRI-mediated LTC4 release from mast cells is mainly regulated by the amount of intracellular GSH. In some cases, oxidative stress may induce a late-phase increase in intracellular GSH, resulting in enhanced LTC4 release from mast cells.

Predicting protein subchloroplast locations with both single and multiple sites via three different modes of Chou's pseudo amino acid compositions.

Owing to the fact that location information can indicate important functionalities of proteins, developing computational tools to predict protein subcellular localization is one of the most efficient and meaningful tasks with no doubt. The existence methods dealing with prediction of protein subchloroplast locations can only handle the case of single location site. Therefore, it is meaningful and challenging to make effort in how to deal with the proteins with multiple subchloroplast location sites instead of just excluding them. To solve this problem, new systems for predicting protein subchloroplast localization with single or multiple sites are developed and discussed in the paper. Three different editions of KNN algorithms and four different types of feature extraction were adopted to construct the prediction systems. This is the first effort to predict the proteins with multiple subchloroplast locations. The overall jackknife success rates achieved by the best combination (features+classifier) on three dataset with different levels of homology were 89.08%, 81.29% and 71.11%. The performance of the prediction models indicate that the proposed methods might be applied as a useful and efficient assistant tool for the prediction of sub-subcellular localizations.

Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory.

The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 µmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1ß, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1ß and TNF-α levels. Concomitantly, MMA increased levels of IL-1ß, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.