Chronic dietary exposure to a glyphosate-based herbicide results in total or partial reversibility of plasma oxidative stress, cecal microbiota abundance and short-chain fatty acid composition in broiler hens.
Glyphosate-based herbicides (GBHs) are massively used in agriculture. However, few studies have investigated the effects of glyphosate-based herbicides on avian species although they are largely exposed via their food. Here, we investigated the potential reversibility of the effects of chronic dietary exposure to glyphosate-based herbicides in broiler hens. For 42 days, we exposed 32-week-old hens to glyphosate-based herbicides via their food (47 mg/kg/day glyphosate equivalent, glyphosate-based herbicides, n = 75) corresponding to half glyphosate's no-observed-adverse-effect-level in birds. We compared their performance to that of 75 control animals (CT). Both groups (glyphosate-based herbicides and control animals) were then fed for 28 additional days without glyphosate-based herbicides exposure (Ex-glyphosate-based herbicides and Ex-control animals). Glyphosate-based herbicides temporarily increased the plasma glyphosate and AMPA (aminomethylphosphonic acid) concentrations. Glyphosate and aminomethylphosphonic acid mostly accumulated in the liver and to a lesser extent in the leg muscle and abdominal adipose tissue. Glyphosate-based herbicides also temporarily increased the gizzard weight and plasma oxidative stress monitored by TBARS (thiobarbituric acid reactive substances). Glyphosate-based herbicides temporarily decreased the cecal concentrations of propionate, isobutyrate and propionate but acetate and valerate were durably reduced. The cecal microbiome was also durably affected since glyphosate-based herbicides inhibited Barnesiella and favored Alloprevotella. Body weight, fattening, food intake and feeding behavior as well as plasma lipid and uric acid were unaffected by glyphosate-based herbicides. Taken together, our results show possible disturbances of the cecal microbiota associated with plasma oxidative stress and accumulation of glyphosate in metabolic tissues in response to dietary glyphosate-based herbicides exposure in broiler hens. Luckily, glyphosate-based herbicides at this concentration does not hamper growth and most of the effects on the phenotypes are reversible.


Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.
Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART). Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients. Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART. Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.


Electrochemically tuneable multi-colour electrochemiluminescence using a single emitter.
A single starting component electrochemiluminescence system from which red, green, blue or white emission can be obtained, depending on the applied potential or the mode of the ECL experiment, is described. The convoluted ECL spectral responses observed at different potentials are readily explained using a 3D-ECL technique, where the ECL spectral profile is continuously monitored as a function of potential during voltammetric scanning. The 3D plots obtained using this technique implicate cross-annihilation ECL reactions involving the complex itself and stable products resulting from its electrolysis. Combining this information with knowledge of the energetic requirements of the various reactions involved, suggests a mechanism involving traces of two emissive products, related to the loss of a methyl group from the triazole moiety. These products, while barely detectable electrochemically, are sufficiently emissive to influence and even dominate the ECL emission under some conditions.


Structural alterations of blood vessels in hypertensive rats.
Vascular changes in the mesenteric arteries were examined in three animals models for human essential hypertension. These models are: spontaneously hypertensive rats, which develop hypertension with age; Dahl model of genetic, salt-dependent hypertensive rats; and deoxycorticosterone-salt hypertensive rats. Morphometric measurements of the arterial wall components (e.g., endothelium, media) were carried out in the elastic arteries, muscular arteries, and arteriolar vessels from the mesenteric bed. The observed changes were correlated with the stages of hypertension development and the effect of antihypertension therapy, including sympathectomy. Specific emphasis was made to determine whether the changes observed were primary in nature, and related to the causes of hypertension, or they were secondary adaptive changes. A comparison of the three models showed that common changes in the intima, media, and adventitia were present in the three models. Alterations in the endothelium (e.g., enlargement of subendothelial space, necrotic changes), adventitia (collagen increase), and hypertrophy of the smooth muscle cells are secondary adaptive changes, because these changes occur subsequent to the development of hypertension, and antihypertensive therapy also prevent these changes from taking place. In contrast, hyperplasia of the smooth muscle cells is a primary change, because it occurs prior to the onset of hypertension. Functionally, alteration in the media is probably the most important change, because it can cause hyperreactivity of the arteries in response to stimulation. Damage to the endothelial cells may play a role in the maintenance of hypertension during the later phase. Alteration in adventitia is a passive change, which does not appear to have a major role in hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)


T lymphocytes: the "cellular" arm of acquired immunity in the peritoneum.
T cells are an important part of the acquired immune response and target specific antigen with their T cell receptor. The peritoneum is a special milieu within which T cells react. We describe briefly the anatomy important for T cell function. T cell biology including antigen presentation, T cell activation, and the different T cell subpopulations are reviewed. We also define innate and acquired immunity and describe the role of polymorphonuclear cells and peritoneal mesothelial cells in the regulation of leukocyte population recruitment during peritonitis. We focus particularly on peritoneal lymphocytes and compare them to the regular lymphocyte populations in the circulation. We illustrate the role of PMCs in antigen presentation and discuss the changes of CD4+ helper T cell subtypes (Th1 and Th2) during peritoneal dialysis. The role of CD8+ cytotoxic T lymphocytes and their possible destructive role for the peritoneal membrane modified by advanced glycation end products are discussed. Polymorphonuclear cells play an important role in the regulation of inflammation and immunity. We describe their possible role in supporting T cells and particularly for generating memory CD8+ T cells by secretion of interleukin-15, a potent T cell growth factor. Light is shed on gamma8T cells, a special T cell population that is able to recognize antigens without the restriction of antigen presentation. We end our review with a description of regulatory T cells. This cell population is extremely important in preventing autoimmunity and in the regulation of acquired immunity.


Double second toe transfer in congenital hand anomalies.
A series of 14 patients with congenital hand anomalies who received staged double second toe transfers to the same hand for restoration of function or form were reviewed retrospectively. There were three children with constriction ring syndrome, two with symbrachydactyly and nine with transverse absence (failure of formation). There were different indications, technical difficulties and results with the various anomalies. All transferred toes were mobile and sensate, and were reported to be of benefit in both function and appearance. However, secondary surgical procedures were required in all patients.


A Promiscuous CYP706A3 Reduces Terpene Volatile Emission from Arabidopsis Flowers, Affecting Florivores and the Floral Microbiome.
Flowers are essential but vulnerable plant organs, exposed to pollinators and florivores; however, flower chemical defenses are rarely investigated. We show here that two clustered terpene synthase and cytochrome P450 encoding genes (TPS11 and CYP706A3) on chromosome 5 of Arabidopsis (Arabidopsis thaliana) are tightly coexpressed in floral tissues, upon anthesis and during floral bud development. TPS11 was previously reported to generate a blend of sesquiterpenes. By heterologous coexpression of TPS11 and CYP706A3 in yeast (Saccharomyces cerevisiae) and Nicotiana benthamiana, we demonstrate that CYP706A3 is active on TPS11 products and also further oxidizes its own primary oxidation products. Analysis of headspace and soluble metabolites in cyp706a3 and 35S:CYP706A3 mutants indicate that CYP706A3-mediated metabolism largely suppresses sesquiterpene and most monoterpene emissions from opening flowers, and generates terpene oxides that are retained in floral tissues. In flower buds, the combined expression of TPS11 and CYP706A3 also suppresses volatile emissions and generates soluble sesquiterpene oxides. Florivory assays with the Brassicaceae specialist Plutella xylostella demonstrate that insect larvae avoid feeding on buds expressing CYP706A3 and accumulating terpene oxides. Composition of the floral microbiome appears also to be modulated by CYP706A3 expression. TPS11 and CYP706A3 simultaneously evolved within Brassicaceae and form the most versatile functional gene cluster described in higher plants so far.plantcell;31/12/2947/FX1F1fx1.


Osteochondroma of the OsCalcaneum- A Case Report.
Osteochondromas are common benign bone tumours. They usually occur in the patients who are below thirty years of age. They probably are developmental malformations rather than true neoplasms. They are believed to originate within the periosteum as small cartilaginous nodules. The foot is rarely a common site of presentation for these tumours. The calcaneum is one of the most unusual regions for the occurrence of osteochondromas 1. The osteochondromas which arise from the calcaneum, especially those which project onto the plantar surface, pose considerable problem to the ambulation. Malignant transformations are seen in less than 1% to 2% of the patients with solitary osteochondromas 2. We herewith present a case of osteochondroma which arose from the calcaneum, which was surgically excised to improve the patient's daily functioning. The patient was followed up for a period of one year. She is now able to walk comfortably.


Optoperforation of single, intact Arabidopsis cells for uptake of extracellular dye-conjugated dextran.
A plant science research goal is to manipulate single cells in an intact organism in order to study their interactions with neighboring cells. Based on a technique previously demonstrated in isolated plant cells, mammalian cells and cyanobacteria, Arabidopsis epidermal cells were optoperforated to allow for uptake of external cascade blue-labeled dextrans. Adverse organelle responses were determined to be minimal and dye retention was demonstrated for at least 72 hours. This technique overcomes the physical challenges presented by the plant cell wall and demonstrates the feasibility of in situ optoperforation.


ADOLESCENT MORBIDITY PATTERN IN A TERTIARY HEALTH FACILITY IN SOUTHERN NIGERIA.
Adolescents make up a large and growing percentage of the population in the world, especially in developing nations. They have peculiar health needs which are often neglected due to the paucity of data from our health institutions and non-implementation of adolescent health policies. The aim of the study was to determine the morbidity pattern among adolescents attending the Paediatric clinic of a tertiary health facility. This was a cross-sectional study of adolescents aged 10-17 years seen at the Paediatric clinics from first of July to 31st of December 2022. Consent was obtained from parents/caregivers and assent from the adolescents. The socio-demographic data obtained from them as well as the clinical details and diagnoses made by attending physicians were recorded in the study proforma. Data was analysed with IBM Statistical Package for the Social Sciences version 24. A total of 136 adolescents were enrolled in the study with a male:female ratio of 1:1.6. Most 90 (66.2%) were early adolescents, attended private secondary schools and belonged to the middle socioeconomic class. The commonest presenting complaints were body pains 24 (17.6%), convulsion 22 (16.2%) and cough 17 (12.5%). The three commonest diagnoses made were seizure disorder 25 (18.4%), respiratory tract infections 15(11%), and sickle cell disease (9.6%). Eleven (8.1%) were referred for surgical evaluation following surgical diagnoses such as appendicitis, inguino-scrotal hernia, ganglion and keloid. Only 3 (2.2%) were evaluated for school entry medical fitness. Forty-four (32.4%) of the adolescents were receiving treatment for various ailments in different Consultant Paediatric Clinics which included neurology 21 (15.4%), haematology 15 (11%), and infectious disease clinic (5.8%). The adolescents presented with mainly medical illnesses to the clinic comprising of infectious and non-infectious diseases. This highlights the need to have personnel and equipment to take care of them.


Continuous intravenous anaesthesia with sufentanil and midazolam in medetomidine premedicated New Zealand White rabbits.
Anaesthesia in rabbits is associated with a high mortality rate, compared to that in cats and dogs. Total intravenous anaesthesia (TIVA) with drugs that provide cardiovascular stability and are rapidly metabolised could be of benefit for use in rabbits. The aim was to evaluate cardiorespiratory effects of TIVA with sufentanil-midazolam in eight New Zealand White rabbits. Subcutaneous premedication with medetomidine (0.1 mg/kg BW) was followed by IV administration of a mixture of 2.5 μg/mL sufentanil and 0.45 mg/mL midazolam at a rate of 0.3 mL/kg BW/h for anaesthetic induction. Additionally, intravenous boluses of 0.1 mL of the mixture were administered every 20 s until the righting reflex was lost. Following endotracheal intubation, anaesthesia was maintained for 60 min with an infusion rate adjusted to supress the pedal withdrawal reflex. Air and oxygen (1:2) were delivered at 3 L/min. Physiological variables were recorded before induction and at predefined time points during and after anaesthesia. Righting and pedal withdrawal reflexes were lost within 3 and 5 min, respectively. Doses of sufentanil and midazolam were 0.48 μg/kg BW and 0.09 mg/kg BW for induction, and 0.72 μg/kg BW/h and 0.13 mg/kg BW/h for maintenance. Apnoea occurred in two rabbits. Induction of anaesthesia caused a significant increase in heart rate, cardiac output and arterial CO2 partial pressure and a decrease in mean arterial pressure, respiratory rate and pH. Mean time from stopping the infusion to endotracheal extubation was 5 min, and to return of the righting reflex 7 min. Anaesthesia was characterized by induction and recovery without excitation, with muscle relaxation, and absence of the pedal withdrawal reflex. TIVA with sufentanil-midazolam provided smooth induction and recovery of anaesthesia in rabbits but with marked hypotension and respiratory depression, requiring mechanical ventilation. Further evaluation is needed to establish if the protocol is useful for rabbits undergoing surgery.


Measuring quality of life in dysphonic patients: a systematic review of content development in patient-reported outcomes measures.
To review existing patient reported outcomes measures (PROMs) used in dysphonic populations to assess the procedures used in their development and the extent to which these meet current development standards for content generation and psychometric evaluation. The study is a systematic review. A systematic review of Medline, Cumulative Index to Nursing & Allied Health, and Health and Psychosocial Instruments databases was completed using voice, quality of life, and PROMs as keywords. We identified all patient or parent-reported questionnaires measuring quality of life associated with voice disorders from the review findings. Questionnaires were appraised for adherence to international guidelines for the development and evaluation of PROMs as outlined by the Scientific Advisory Committee of the Medical Outcome Trust. Nine PROMs fulfilled the inclusion criteria. The quality of these questionnaires was variable with regard to instrument development and none met all of the current, recommended criteria. Of the nine questionnaires, the Voice Symptom Scale underwent the most rigorous development process. Furthermore, many instruments have been augmented to allow for proxy administration, failing to address quality of life-related issues specific to the target population. Instrument development is often overlooked when attempting to quantify patient reported outcomes in dysphonic patients. Careful instrument development procedures are required to ensure that PROMs are valid, reliable, and responsive. Our review suggests that the deficits in psychometric properties of the current voice-related PROMs may be, at least in part, due to deficits in the development process. Furthermore, these data suggest the potential utility of a novel PROM adhering to rigorous international standards to better ensure that clinicians appreciate the variables most relevant to patients with voice disorders and address some of the psychometric shortcomings of the currently used questionnaires.


Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites.
A significant body of experimental structures of SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and the emergence of druggable binding pockets. Understanding the interplay of conformational dynamics changes induced by the Omicron variants and the identification of cryptic dynamic binding pockets in the S protein is of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study, we explore conformational landscapes and characterize the universe of binding pockets in multiple open and closed functional spike states of the BA.1 and BA.2 Omicron variants. By using a combination of atomistic simulations, a dynamics network analysis, and an allostery-guided network screening of binding pockets in the conformational ensembles of the BA.1 and BA.2 spike conformations, we identified all experimentally known allosteric sites and discovered significant variant-specific differences in the distribution of binding sites in the BA.1 and BA.2 trimers. This study provided a structural characterization of the predicted cryptic pockets and captured the experimentally known allosteric sites, revealing the critical role of conformational plasticity in modulating the distribution and cross-talk between functional binding sites. We found that mutational and dynamic changes in the BA.1 variant can induce the remodeling and stabilization of a known druggable pocket in the N-terminal domain, while this pocket is drastically altered and may no longer be available for ligand binding in the BA.2 variant. Our results predicted the experimentally known allosteric site in the receptor-binding domain that remains stable and ranks as the most favorable site in the conformational ensembles of the BA.2 variant but could become fragmented and less probable in BA.1 conformations. We also uncovered several cryptic pockets formed at the inter-domain and inter-protomer interface, including functional regions of the S2 subunit and stem helix region, which are consistent with the known role of pocket residues in modulating conformational transitions and antibody recognition. The results of this study are particularly significant for understanding the dynamic and network features of the universe of available binding pockets in spike proteins, as well as the effects of the Omicron-variant-specific modulation of preferential druggable pockets. The exploration of predicted druggable sites can present a new and previously underappreciated opportunity for therapeutic interventions for Omicron variants through the conformation-selective and variant-specific targeting of functional sites involved in allosteric changes.


Chitin nanocrystal-xyloglucan multilayer thin films.
For the first time, the adsorption of xyloglucan (XG) on chitin nanocrystals (ChiNC) surface was proved using quartz crystal microbalance with dissipation (QCM-D) and by successfully building up spin-coated assisted layer-by-layer (LbL) structures on solid substrates. Several parameters in the adsorption process, such as ChiNC concentrations (0.5-3.0 g L(-1)), number of layers, or the outmost layer material (ChiNC or XG), were investigated to better understand the fabrication process of multilayer films. The thickness of the homogeneous film increased linearly with the number of bilayers, with an average thickness per bilayer of 12.3 nm. Additionally surface morphology was studied by atomic force microscopy (AFM), which revealed an almost completely covered surface after the adsorption of ChiNC. The final structures were found to have semireflective properties capable of being tuned by adjusting the ChiNC dispersion parameters.


Self-assembly of porphyrin-grafted lipid into nanoparticles encapsulating doxorubicin for synergistic chemo-photodynamic therapy and fluorescence imaging.
The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.


Calcium ions promote formation of amyloid β-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer's disease.
Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca(2+) homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. We compared the aggregation pattern of Aβ(1-40) and that of Aβ(1-40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease. We found that in the presence of Ca(2+), Aβ(1-40) preferentially formed oligomers similar to those formed by Aβ(1-40)E22G with or without added Ca(2+), whereas in the absence of added Ca(2+) the Aβ(1-40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results of which were further supported by thioflavin T fluorescence experiments. In the samples without Ca(2+), Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1-40), that have been implicated in the pathogenesis of AD.


Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease.
Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1β, and tumor necrosis factor (TNF)-α. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1β and 21%-27% higher TNF-α compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low β-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-α and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.


The psmα locus regulates production of Staphylococcus aureus alpha-toxin during infection.
Staphylococcus aureus is a leading cause of human bacterial infection, causing a wide spectrum of disease ranging from skin and soft tissue infections to life-threatening pneumonia and sepsis. S. aureus toxins play an essential role in disease pathogenesis, contributing to both immunomodulation and host tissue injury. Prominent among these toxins are the membrane-active pore-forming cytolysin alpha-toxin (Hla) and the amphipathic α-helical phenol-soluble modulin (PSM) peptides. As deletion of either the hla or psm locus leads to a phenotypically similar virulence defect in skin and soft tissue infection, we sought to determine the relative contribution of each locus to disease pathogenesis. Here we show that production of Hla can be modulated by PSM expression. An S. aureus mutant lacking PSM expression exhibits a transcriptional delay in hla mRNA production and therefore fails to secrete normal levels of Hla at early phases of growth. This leads to attenuation of virulence in vitro and in murine skin and lung models of infection, correlating with reduced recovery of Hla from host tissues. Production of Hla and restoration of staphylococcal virulence can be achieved in the psm mutant by plasmid-driven overexpression of hla. Our study suggests the coordinated action of Hla and PSMs in host tissue during early pathogenesis, confirming a major role for Hla in epithelial injury during S. aureus infection. These findings highlight the possibility that therapeutics targeting PSM production may simultaneously prevent Hla-mediated tissue injury.


SP1-binding elements, within the common metaxin-thrombospondin 3 intergenic region, participate in the regulation of the metaxin gene.
Metaxin (Mtx) is an essential nuclear gene which is expressed ubiquitously in mice and encodes a mitochondrial protein. The gene is located upstream and is transcribed divergently from the thrombospondin 3 (Thbs3) gene; 1352 nucleotides separate the putative translation start sites. Although the Mtx and Thbs3 genes share a common intergenic region, transient transfection experiments in rat chondro-sarcoma cells and in NIH-3T3 fibroblasts demonstrated that the elements required for expression of the Mtx gene are situated within a short proximal promoter and have no major effect on the transcription of Thbs3. The metaxin --377 bp promoter contains four clustered GC boxes between nucleotides --146 and --58 and an inverted GT box between nucleotides --152 and --161, but does not contain TATA or CCAAT boxes. Like many genes regulated by a TATA-less promoter, the transcription start site of metaxin is heterogeneous. The major start site is only 13 bp upstream from the putative translation start site. Electrophoretic mobility shift, competition and supershift assays showed that the ubiquitous transcription factor, Sp1, and, to a lesser extent, the Sp1-related protein, Sp3, bind to four of these Sp1-binding motifs. Co-transfection of metaxin promoter-luciferase constructs and an Sp1 expression vector into Schneider Drosophila cells, which do not synthesize Sp1, demonstrated that the metaxin gene is activated by Sp1. Deletion of the four upstream Sp1-binding elements, on the other hand, demonstrated that these motifs are superfluous in context of the larger Mtx promoter. Thus, despite the potential for common regulatory mechanisms, the available evidence indicates that the Mtx minimal promoter does not significantly affect Thbs3 gene expression.


Altered NMDA receptor-evoked intracellular Ca2+ dynamics in magnocellular neurosecretory neurons of hypertensive rats.
NMDA receptor (NMDAR)-mediated Ca2+ signalling plays a critical role in modulating hypothalamic neurosecretory function. However, whether an altered NMDAR-evoked changes in Ca2+ (NMDAR-ΔCa2+ ) signalling in magnocellular neurosecretory cells (MNCs) may contribute to neurohumoral activation during disease states is unknown. We show that activation of NMDARs evoked similar inward currents in MNCs of sham and renovascular hypertensive (RVH) rats. Despite this, a prolonged and larger NMDAR-ΔCa2+ response was observed in the latter. The exacerbated NMDAR-ΔCa2+ responses in MNCs of RVH rats affected both somatic and dendritic compartments. Inhibition of the endoplasmic reticulum sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump prolonged NMDAR-ΔCa2+ responses in sham rats, but not in RVH rats. Our study supports an altered spatiotemporal dynamic of NMDAR-ΔCa2+ signalling in MNCs from RVH rats, partly due to blunted endoplasmic reticulum Ca2+ buffering capacity. A growing body of evidence supports an elevated NMDA receptor (NMDAR)-mediated glutamate excitatory function in the supraoptic nucleus and paraventricular nucleus of hypertensive rats that contributes to neurohumoral activation in this disease. However, the precise mechanisms underlying altered NMDAR signalling in hypertension remain to be elucidated. In this study, we performed simultaneous electrophysiology and fast confocal Ca2+ imaging to determine whether altered NMDAR-mediated changes in intracellular Ca2+ levels (NMDAR-ΔCa2+ ) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in renovascular hypertensive (RVH) rats. We found that despite evoking a similar excitatory inward current, activation of NMDARs resulted in a larger and prolonged ΔCa2+ in MNCs from RVH rats. Changes in NMDAR-ΔCa2+ dynamics were observed both in somatic and dendritic compartments. Inhibition of the sarcoendoplasmic reticulum calcium trasport ATPase (SERCA) pump activity with thapsigargin prolonged NMDAR-ΔCa2+ responses in MNCs of sham rats, but this effect was occluded in RVH rats, thus equalizing the magnitude and time course of the NMDA-ΔCa2+ responses between the two experimental groups. Taken together, our results support (1) an exacerbated NMDAR-ΔCa2+ response in somatodendritic compartments of MNCs of RVH rats, and (2) that a blunted ER Ca2+ buffering capacity contributes to the altered NMDAR-ΔCa2+ dynamics in this condition. Thus, altered spatiotemporal dynamics of the NMDAR-ΔCa2+ response stands as an underlying mechanism contributing to neurohumoral activation in neurogenic hypertension.


Use of natural zeolites as a landfill liner.
The purpose of this study is to investigate certain features of a novel material proposed to serve as an impervious liner in landfills. Various ratios of bentonites and zeolites (B/Z) compacted at optimum water content were tested to determine the strength parameters, permeability, pH, heavy metals and other properties. A B/Z ratio of 0.10 was found to be an ideal landfill liner material regarding its low hydraulic conductivity and high cation exchange capacity. The use of B/Z mixtures as an alternative to clay liners would provide potential to significantly reduce the thickness of base liner for landfills.


A meta-analytic review of theory of mind difficulties in behavioural-variant frontotemporal dementia.
Theory of mind (ToM) refers broadly to our understanding of others' complex emotions and mental states. Deficits in ToM are widely regarded as one of the key defining features of the behavioural variant of frontotemporal dementia (bvFTD), which is unsurprising given the key role that frontal and temporal neural systems are considered to play in mental state decoding. Here we report the first meta-analysis of this literature, providing a timely summary of the breadth, magnitude and specificity of ToM difficulties in this population. Across 15 datasets involving 800 participants (312 with bvFTD and for comparative purposes, 325 non-clinical controls and 163 participants with Alzheimer's disease), several key results emerged. Collapsed across all types of task, people with bvFTD performed more poorly than non-clinical controls, with the degree of ToM difficulty they experienced large in magnitude (r=-.60). These deficits were greater than those observed on control tasks matched to the ToM task in their general cognitive demands, but which can be solved without any mentalistic inference. BvFTD-related ToM difficulties were also significantly larger than the ToM difficulties seen in people with Alzheimer's disease. However, ToM difficulties in people with bvFTD were of a similar magnitude to the difficulties seen on measures of more basic social cue perception (emotion recognition). These data have important implications for understanding the types of ToM difficulties associated with bvFTD.


Enhanced viscoelasticity of human cystic fibrotic sputum correlates with increasing microheterogeneity in particle transport.
Current biochemical characterizations of cystic fibrosis (CF) sputum do not address the high degree of microheterogeneity in the rheological properties of the mucosal matrix and only provide bulk-average particle diffusion coefficients. The viscoelasticity of CF sputum greatly reduces the diffusion rates of colloidal particles, limiting the effectiveness of gene delivery to underlying lung cells. We determine diffusion coefficients of hundreds of individual amine-modified and carboxylated polystyrene particles (diameter 100-500 nm) embedded in human CF sputum with 5 nm and 33 ms of spatiotemporal resolution. High resolution multiple particle tracking is used to calculate the effective viscoelastic properties of CF sputum at the micron scale, which we relate to its macroscopic viscoelasticity. CF sputum microviscosity, as probed by 100- and 200-nm particles, is an order of magnitude lower than its macroviscosity, suggesting that nanoparticles dispersed in CF sputum are transported primarily through lower viscosity pores within a highly elastic matrix. Multiple particle tracking provides a non-destructive, highly sensitive method to quantify the high heterogeneity of the mucus pore network. The mean diffusion coefficient becomes dominated by relatively few but fast-moving particles as particle size is reduced from 500 to 100 nm. Neutrally charged particles with a diameter <200 nm undergo more rapid transport in CF sputum than charged particles. Treatment with recombinant human DNase (Pulmozyme) reduces macroviscoelastic properties of CF sputum by up to 50% and dramatically narrows the distribution of individual particle diffusion rates but surprisingly does not significantly alter the ensemble-average particle diffusion rate.


TGF-beta and vitamin D3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83+ dendritic cells.
We previously demonstrated that agents known to signal infection or inflammation can rapidly and directly drive differentiation of human CD14+ monocytes into CD83+ dendritic cells (DCs) when introduced to cells under serum-free conditions. In this study, we evaluated the effects of TGF-beta and vitamin D3 (VitD3) on the proportion and function of monocytes that adopt DC characteristics. TGF-beta significantly decreased the proportion of cells that rapidly adopted stable DC characteristics in response to LPS, but had little or no effect on calcium ionophore-induced differentiation. In contrast, VitD3 showed no such pathway specificity and dramatically suppressed differentiation of monocytes into DCs in response to these agents. Both TGF-beta and VitD3 altered cytokine and chemokine production in LPS-treated monocytes, inhibited IL-12 and IL-10 secretion, and decreased the functional capacity of DCs. Despite the similar effects of TGF-beta and VitD3, there are significant differences in the signaling pathways used by these agents, as evidenced by their distinct effects on LPS- and calcium ionophore-induced DC differentiation, on LPS-induced secretion of IL-10, and on two members of the NF-kappaB family of transcription factors, RelB and cRel. These studies identify TGF-beta and VitD3 as potent regulatory factors that use distinct pathways to suppress both the differentiation of DCs as well as their capacity to secrete the Th1-polarizing cytokine IL-12. Because these agents are present in serum and negatively affect DC differentiation at physiological concentrations, our findings are likely to have significance regarding the in vivo role of TGF-beta and VitD3 in determining the type of immune responses.


Detection of bluetongue virus in Culicoides spp. in southern Yunnan Province, China.
Culicoides (Diptera: Ceratopogonidae) are vectors for many arboviruses. At least 20 species are considered as vectors or potential vectors of bluetongue virus (BTV) which cause bluetongue disease in ruminants. A BTV prevalence of 30-50% among cattle and goats in tropical southern Yunnan Province, China, prompted an investigation of the potential BTV vectors in this area. Culicoides were collected by light trapping at three sites in the tropical region of Yunnan Province. Species were identified based on morphology and DNA sequences of cytochrome c oxidase subunit 1 (cox1). PCR and quantitative PCR following reverse transcription were used to test for the presence of BTV RNA in these specimens. Phylogenetic analysis was used to analyze the cox1 sequences of Culicoides specimens infected with BTV. Approximately 67,000 specimens of Culicoides were collected, of which 748 were tested for the presence of BTV. Five specimens, including two of Culicoides jacobsoni, one of C. tainanus and two of C. imicola, were identified as infected with BTV. No specimens of C. (subgenus Trithecoides) or C. oxystoma tested were positive for BTV infection. To our knowledge this is the first report of C. jacobsoni as a potential BTV vector and the fourth report of an association between C. tainanus and BTV, as well as the first direct evidence of an association between BTV and C. imicola in Asia. A fourth potential cryptic species within C. tainanus was identified in this study. Further analysis is required to confirm the importance of C. jacobsoni and C. tainanus in BTV epidemiology in Asia.


The bHLH proteins BEE and BIM positively modulate the shade avoidance syndrome in Arabidopsis seedlings.
The shade avoidance syndrome (SAS) refers to a set of plant responses initiated after perception by the phytochromes of light with a reduced red to far-red ratio, indicative of vegetation proximity or shade. These responses, including elongation growth, anticipate eventual shading from potential competitor vegetation by overgrowing neighboring plants or flowering to ensure production of viable seeds for the next generation. In Arabidopsis thaliana seedlings, the SAS includes dramatic changes in gene expression, such as induction of PHYTOCHROME RAPIDLY REGULATED 1 (PAR1), encoding an atypical basic helix-loop-helix (bHLH) protein that acts as a transcriptional co-factor to repress hypocotyl elongation. Indeed, PAR1 has been proposed to act fundamentally as a dominant negative antagonist of conventional bHLH transcription factors by forming heterodimers with them to prevent their binding to DNA or other transcription factors. Here we report the identification of PAR1-interacting factors, including the brassinosteroid signaling components BR-ENHANCED EXPRESSION (BEE) and BES1-INTERACTING MYC-LIKE (BIM), and characterize their role as networked positive regulators of SAS hypocotyl responses. We provide genetic evidence that these bHLH transcriptional regulators not only control plant growth and development under shade and non-shade conditions, but are also redundant in the control of plant viability. Our results suggest that SAS responses are initiated as a consequence of a new balance of transcriptional regulators within the pre-existing bHLH network triggered by plant proximity, eventually causing hypocotyls to elongate.


[Adenomatous degeneration in a prepuberal patient with generalized juvenile polyposis and angiomas of the oral mucosa].
The authors present a 12 year old patient affected by a juvenile polyposis syndrome. They describe the clinic and the complementary tests carried out, especially the findings of the digestive fibroendoscopy which allowed multiple polyps in the duodenum, colon and rectum to be shown, confirmed by an anatomopathological study. Two years afterwards, a total colectomy and ileoproctostomy was carried out. In the operative piece included numerous hamartomatous polyps with adenomatous isolated foci. A subsequent endoscopic exploration showed numerous polyps in anus and rectal stump. The adenomatous transformation and recidivation of her polyposis require close vigilance and a follow-up of this female patient in view of the possibility of the precocious development of a colorectal carcinoma.


Optimal design of loudspeaker arrays for robust cross-talk cancellation using the Taguchi method and the genetic algorithm.
An optimal design technique of loudspeaker arrays for cross-talk cancellation with application in three-dimensional audio is presented. An array focusing scheme is presented on the basis of the inverse propagation that relates the transducers to a set of chosen control points. Tikhonov regularization is employed in designing the inverse cancellation filters. An extensive analysis is conducted to explore the cancellation performance and robustness issues. To best compromise the performance and robustness of the cross-talk cancellation system, optimal configurations are obtained with the aid of the Taguchi method and the genetic algorithm (GA). The proposed systems are further justified by physical as well as subjective experiments. The results reveal that large number of loudspeakers, closely spaced configuration, and optimal control point design all contribute to the robustness of cross-talk cancellation systems (CCS) against head misalignment.


Serological evidence of Coxiella burnetii, Leptospira interrogans Hardjo, Neospora caninum and bovine pestivirus infections in a dairy cattle herd from the United Arab Emirates.
The serostatus of five abortigenic agents and the association between abortion history and Coxiella burnetii seropositivity were assessed in 350 dairy cattle from Al Ain, UAE. The bovine sera were ELISA-screened for C. burnetii, Leptospira Hardjo, Neospora caninum, and Brucella abortus antibodies, plus bovine pestivirus (BVDV) antigen. The serology data were collated and the level of significance between the proportions of C. burnetii-seropositive cattle with and without abortion history assessed by the Z test of two proportions. Of the 350 cattle, 41.4%, 1.7%, 1.4%, 0.3%, and 0.0% were seropositive to the above pathogens, respectively. Besides, 61.9%, 2.9%, 1.0%, 0.0%, and 0.0% of the 105 cattle with history of abortion and 32.7%, 1.2%, 1.6%, 0.0% and 0.0% of the 245 seropositive cattle with no history of abortion were also seropositive for the above pathogens respectively. Moreover, the proportion of C. burnetii-seropositive cattle with history of abortion were significantly higher than the C. burnetii-seropositive ones without abortion history (p-value < 0.01). Apparent C. burnetii infections were relatively higher than the other four pathogens suggesting this bacterium contributed to abortion in the herd. Additional research on the public and bovine health implications of C. burnetii and Leptospira in the UAE are urgently needed.


Comparative Experimental Investigation of Biodegradable Antimicrobial Polymer-Based Composite Produced by 3D Printing Technology Enriched with Metallic Particles.
Due to the prevailing existence of the COVID-19 pandemic, novel and practical strategies to combat pathogens are on the rise worldwide. It is estimated that, globally, around 10% of hospital patients will acquire at least one healthcare-associated infection. One of the novel strategies that has been developed is incorporating metallic particles into polymeric materials that neutralize infectious agents. Considering the broad-spectrum antimicrobial potency of some materials, the incorporation of metallic particles into the intended hybrid composite material could inherently add significant value to the final product. Therefore, this research aimed to investigate an antimicrobial polymeric PLA-based composite material enhanced with different microparticles (copper, aluminum, stainless steel, and bronze) for the antimicrobial properties of the hybrid composite. The prepared composite material samples produced with fused filament fabrication (FFF) 3D printing technology were tested for different time intervals to establish their antimicrobial activities. The results presented here depict that the sample prepared with 90% copper and 10% PLA showed the best antibacterial activity (99.5%) after just 20 min against different types of bacteria as compared to the other samples. The metallic-enriched PLA-based antibacterial sheets were remarkably effective against Staphylococcus aureus and Escherichia coli; therefore, they can be a good candidate for future biomedical, food packaging, tissue engineering, prosthetic material, textile industry, and other science and technology applications. Thus, antimicrobial sheets made from PLA mixed with metallic particles offer sustainable solutions for a wide range of applications where touching surfaces is a big concern.


A chronology of global air quality.
Air pollution has been recognized as a threat to human health since the time of Hippocrates, ca 400 BC. Successive written accounts of air pollution occur in different countries through the following two millennia until measurements, from the eighteenth century onwards, show the growing scale of poor air quality in urban centres and close to industry, and the chemical characteristics of the gases and particulate matter. The industrial revolution accelerated both the magnitude of emissions of the primary pollutants and the geographical spread of contributing countries as highly polluted cities became the defining issue, culminating with the great smog of London in 1952. Europe and North America dominated emissions and suffered the majority of adverse effects until the latter decades of the twentieth century, by which time the transboundary issues of acid rain, forest decline and ground-level ozone became the main environmental and political air quality issues. As controls on emissions of sulfur and nitrogen oxides (SO2 and NOx) began to take effect in Europe and North America, emissions in East and South Asia grew strongly and dominated global emissions by the early years of the twenty-first century. The effects of air quality on human health had also returned to the top of the priorities by 2000 as new epidemiological evidence emerged. By this time, extensive networks of surface measurements and satellite remote sensing provided global measurements of both primary and secondary pollutants. Global emissions of SO2 and NOx peaked, respectively, in ca 1990 and 2018 and have since declined to 2020 as a result of widespread emission controls. By contrast, with a lack of actions to abate ammonia, global emissions have continued to grow. This article is part of a discussion meeting issue 'Air quality, past present and future'.


IL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosis.
Based on studies by our group and others, we hypothesized that IL-7 may possess antifibrotic activities in an IFN-gamma-dependent and independent manner. Here, we have evaluated the antifibrotic therapeutic potential of IL-7 in both in vitro and in vivo pulmonary fibrosis models. IL-7 inhibited both TGF-beta production and signaling in fibroblasts and required an intact JAK1/STAT1 signal transduction pathway. IL-7-mediated inhibition of TGF-beta signaling was found to be associated with an increase in Smad7, a major inhibitory regulator in the SMAD family. In the presence of IL-7, Smad7 dominant negative fibroblasts restored TGF-beta-induced collagen synthesis, indicating that an IL-7-mediated increase in Smad7 suppressed TGF-beta signaling. Consistent with these in vitro findings, recombinant IL-7 decreased bleomycin-induced pulmonary fibrosis in vivo, independent of IFN-gamma. The antifibrotic activities of IL-7 merit further basic and clinical investigation for the treatment of pulmonary fibrosis.


Prevalence and public health significance of aluminum residues in milk and some dairy products.
Sixty random samples of bulk farm milk, market milk, locally manufactured processed cheese, and milk powder were collected to be analyzed for aluminum (Al) concentration using graphite furnace atomic absorption spectrometry (GFAAS). The results were compared with provisional acceptable permissible limits (PAPLs). The maximum estimated dietary intake (MEDI) of Al for the examined samples was calculated. In addition, an experimental study was conducted to determine the possible leaching of Al from cookware in milk during boiling. The obtained results showed that Al concentration in examined bulk farm milk samples was found to be negligible. In contrast, market milk revealed higher concentration, 65.0% of the examined samples were above the PAPLs. The results revealed significant difference of Al concentration among them. The Al levels in processed cheese wrapped in Al foil were significantly higher than those found in samples packed in glass containers with a significant difference of Al concentration between them. Also, 20% of the examined milk powder samples exceeded the PAPLs (0.01 to 0.4 mg/kg). The MEDI for Al in bulk farm milk, control market milk, market milk boiled in Al cookware, market milk boiled in stainless-steel cookware, processed cheese wrapped in Al foil, processed cheese packed in glass containers, and milk powder were calculated as 3.0%, 61.0%, 63.0%, 61.0%, 428.0%, 220.0%, and 166.0% from "PTDI," respectively. The results of the experimental study showed no marked significant differences of Al concentration between market milk (control group) and those boiled in Al cookware, as well as to those boiled in stainless-steel cookware. The results of the present study indicate that Al level in milk kept in Al containers and dairy products packed in Al foil is beyond the permissible limits, suggesting health hazard. Therefore, all milk cans should be constructed of stainless steel, prevent the entrance of tap water into milk, and the processed cheese should be packed in glass containers and not wrapped in Al foil. Leaching of Al increased to a significant percent more during storage than during boiling, so milk should be kept in stainless steel or glass containers in the refrigerator.


Navigating the seas of caregiving. Allies & ideas for success.
Formal and informal caregivers share an awesome responsibility in caregiving. If they are going to be effective, caregivers must take care of themselves, communicate with each other, and understand the elements of caring. Home care professionals who recognize the interdependence among formal and informal caregivers and their patients can create a supportive caregiving team.


Information sources, donation knowledge, and attitudes toward transplant recipients in Australia.
Knowledge is linked consistently with organ donation attitudes, willingness, and consent. Negative information about donation and the recipients of donation can affect public opinion and donation willingness. However, it is unclear which information sources are most important in forming knowledge, particularly in Australia where little prior research exists. To identify information sources that may inform Australians' organ donation knowledge and attitudes toward transplant recipients. 1487 Australian residents aged 18 years or older who completed an online survey. Self-reported knowledge, information sources, and attitudes toward transplant recipients. Participants felt fairly well informed about organ donation, particularly if they registered donation wishes, were female, and were older. More than half reported their driver's license, television news, and discussion with family/friends as donation information sources. However, information sources contributing to knowledge were personal experience, online, hospital, government campaign, discussion with family/friends, Medicare, doctor's surgery, and the newspaper. Differences based on registration status, sex, and age, were found. Discussion with family/friends and movies or television shows, as well as not having seen information in a newspaper or doctor's surgery, contributed to positive attitudes toward recipients, although the variance explained was small. People felt more informed by personal, medical, and government information sources than by mass media. Family discussion was not only a common information source but also contributed significantly and positively to both donation knowledge and attitudes toward recipients. Further exploration of information sources contributing to donation knowledge and community attitudes toward transplant recipients among young men is needed.


Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression.
Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3β (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.


Launching a self-assessment process for systems integration: framework and findings.
The National Chronic Care Consortium developed the SASI tool to help health-care networks plan, implement, and measure chronic care integration across their full continuums of care. An integrated network for chronic care can be applied to any care population, and the SASI tool can assist in integration efforts in a variety of circumstances.


Visualization of viral clearance in the living animal.
The early events in viral dissemination via the bloodstream were identified by monitoring the fate of 123I-radiolabeled reovirus after it was injected intravenously in rats. Continuous scintillation camera imaging showed that reovirus serotypes 1 and 3 were cleared from the circulation in less than 10 minutes by specific and distinct target organs. Reovirus serotype 1 accumulated predominantly in the lungs and the liver, whereas serotype 3 accumulated in the liver and the spleen with very little virus uptake by the lungs. Incubation of reovirus serotype 1 with a monoclonal antibody directed against the viral hemagglutinin before injection totally inhibited the clearance of the virus by the lungs. Similar results were obtained when viruses biolabeled with 35S were used. These results demonstrate that viruses can be rapidly transported through the bloodstream to specific target organs and that the localization of the viruses depends on the interaction between specific viral surface components and the target organ.


[Activity of carbohydrate metabolism enzymes in Streptomyces imbricatus, producing imbricin in controlled antibiotic biosynthesis].
Changes in the fermentative activity of Streptomyces imbricatus under the conditions of stimulated biosynthesis of imbricin with addition of a crude endoregulator to the medium were studied. The activity of the two main enzymes of the glycolysis, i. e. phosphofructokinase and fructose-1,6-diphosphate aldolase (aldolase) was determined and the functioning of the pentozophosphate pathway was estimated by the activity of glucose-6-phosphate dehydrogenase and NADP-specific glutamate dehydrogenase. Under the conditions of the endoregulation the increase of the imbricin production was observed when the level of the glucose catabolism either by the glycolytic pathway or by the pentozophosphate pathway was comparatively high, thus providing the antibiotic biosynthesis with the required precursors and reducing equivalents.


What we have learned about cachexia in gastrointestinal cancer.
It is appreciated widely by clinicians that significant malnutrition accompanies malignant processes in approximately 50% of patients and eventually leads to severe wasting which accounts for approximately 30% of cancer-related deaths overall, 30-50% of deaths in patients with gastrointestinal tract cancers, and up to 80% of deaths in patients with advanced pancreatic cancer. The body wasting known as cancer cachexia is a complex syndrome characterized by progressive tissue depletion and decreased nutrient intake that is manifested clinically as inexplicable, recalcitrant anorexia and inexorable host weight loss. Decreased nutritional intake, increased metabolic expenditure and dysfunctional metabolic processes, including hormonal and cytokine-related abnormalities, all appear to play roles in the development of cancer cachexia. Although this condition of advanced protein-calorie malnutrition, sometimes described as the cancer anorexia-cachexia syndrome, is not entirely understood, it appears to be multifactorial, is a major cause of morbidity and mortality in cancer patients, and ultimately leads to death. Therapeutic interventions have met with little success, and, regardless of tremendous efforts throughout the decades, the exact nature of the mediators responsible for cancer cachexia remain elusive. The pathogenesis of cancer cachexia appears to be related to proinflammatory cytokines, alterations in the neuroendocrine axis and tumor-derived catabolic factors. Despite trials of conventional and/or aggressive nutritional support by a myriad of feeding techniques, patients with cancer cachexia have failed to gain consistent significant benefits in terms of weight gain, functional ability, quality of life or survival. Additionally, attempts to ameliorate the abnormal clinical and metabolic features of cancer cachexia with a variety of pharmacologic agents have met with only limited success. Either until cancer of the gastrointestinal tract can be cured or until it is possible to identify the exact causes and mechanisms of the cancer cachexia syndrome, the most realistic and practical options currently are directed toward minimizing adverse gastrointestinal side effects or complications of the malignant process and/or therapy, as well as increasing appetite, food intake and nutrient utilization in an effort to enhance quality of life and improve survival.


Molecular mechanisms and pathophysiology of necrotic cell death.
Necrotic cell death has long been considered an accidental and uncontrolled mode of cell death. But recently it has become clear that necrosis is a molecularly regulated event that is associated with pathologies such as ischemia-reperfusion (IR) injury, neurodegeneration and pathogen infection. The serine/threonine kinase receptor-interacting protein 1 (RIP1) plays a crucial role during the initiation of necrosis induced by ligand-receptor interactions. On the other hand, ATP depletion is an initiating factor in ischemia-induced necrotic cell death. Common players in necrotic cell death irrespective of the stimulus are calcium and reactive oxygen species (ROS). During necrosis, elevated cytosolic calcium levels typically lead to mitochondrial calcium overload, bioenergetics effects, and activation of proteases and phospholipases. ROS initiates damage to lipids, proteins and DNA and consequently results in mitochondrial dysfunction, ion balance deregulation and loss of membrane integrity. Membrane destabilization during necrosis is also mediated by other factors, such as acid-sphingomyelinase (ASM), phospholipase A(2) (PLA(2)) and calpains. Furthermore, necrotic cells release immunomodulatory factors that lead to recognition and engulfment by phagocytes and the subsequent immunological response. The knowledge of the molecular mechanisms involved in necrosis has contributed to our under-standing of necrosis-associated pathologies. In this review we will focus on the intracellular and intercellular signaling events in necrosis induced by different stimuli, such as oxidative stress, cytokines and pathogen-associated molecular patterns (PAMPs), which can be linked to several pathologies such as stroke, cardiac failure, neurodegenerative diseases, and infections.


Virtual screening of GPCRs: an in silico chemogenomics approach.
The G-protein coupled receptor (GPCR) superfamily is currently the largest class of therapeutic targets. In silico prediction of interactions between GPCRs and small molecules in the transmembrane ligand-binding site is therefore a crucial step in the drug discovery process, which remains a daunting task due to the difficulty to characterize the 3D structure of most GPCRs, and to the limited amount of known ligands for some members of the superfamily. Chemogenomics, which attempts to characterize interactions between all members of a target class and all small molecules simultaneously, has recently been proposed as an interesting alternative to traditional docking or ligand-based virtual screening strategies. We show that interaction prediction in the chemogenomics framework outperforms state-of-the-art individual ligand-based methods in accuracy both for receptor with known ligands and without known ligands. This is done with no knowledge of the receptor 3D structure. In particular we are able to predict ligands of orphan GPCRs with an estimated accuracy of 78.1%. We propose new methods for in silico chemogenomics and validate them on the virtual screening of GPCRs. The methods represent an extension of a recently proposed machine learning strategy, based on support vector machines (SVM), which provides a flexible framework to incorporate various information sources on the biological space of targets and on the chemical space of small molecules. We investigate the use of 2D and 3D descriptors for small molecules, and test a variety of descriptors for GPCRs. We show that incorporating information about the known hierarchical classification of the target family and about key residues in their inferred binding pockets significantly improves the prediction accuracy of our model.


Breast cancer mortality trends in Peruvian women.
Breast cancer (BC) is the most common malignancy in Latin American women, but with a wide variability with respect to their mortality. This study aims to estimate the mortality rates from BC in Peruvian women and to assess mortality trends over 15 years. We calculated BC age-standardized mortality rate (ASMR) per 100,000 women-years using the world standard SEGI population. We estimated joinpoint regression models for BC in Peru and its geographical areas. The spatial analysis was performed using the Moran's I statistic. In a 15-year period, Peru had a mortality rate of 9.97 per 100,000 women-years. The coastal region had the highest mortality rate (12.15 per 100,000 women-years), followed by the highlands region (4.71 per 100,000 women-years). In 2003, the highest ASMR for BC were in the provinces of Lima, Arequipa, and La Libertad (above 8.0 per 100,000 women-years), whereas in 2017, the highest ASMR were in Tumbes, Callao, and Moquegua (above 13.0 per women-years). The mortality trend for BC has been declining in the coastal region since 2005 (APC = - 1.35, p < 0.05), whereas the highlands region experienced an upward trend throughout the study period (APC = 4.26, p < 0.05). The rainforest region had a stable trend. Spatial analysis showed a Local Indicator of Spatial Association of 0.26 (p < 0.05). We found regional differences in the mortality trends over 15 years. Although the coastal region experienced a downward trend, the highlands had an upward mortality trend in the entire study period. It is necessary to implement tailored public health interventions to reduce BC mortality in Peru.


Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives.
Follicular dendritic cells (FDC) are found in the follicles of virtually all secondary lymphoid tissues. In health, these cells trap and retain antigens (Ag) in the form of immune complexes and preserve them for months in their native conformation. FDC thus serve as a long-term repository of extracellular Ag important for induction and maintenance of memory responses. In retroviral infection, FDC trap and retain large numbers of retroviral particles with profound effects on FDC. FDC-trapped retrovirus induces follicular hyperplasia, and conventional Ag trapped prior to infection are lost and new Ag cannot be trapped. Concomitantly, antibody-forming cells (AFC) specific for Ag lost from FDC decrease followed by loss of specific serum antibody (Ab). Eventually, FDC die and follicular lysis occurs. From the pathogen perspective, binding to FDC is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Furthermore, FDC permit HIV to infect surrounding cells even in the presence of a vast excess of neutralizing Ab. Preliminary data suggest that FDC maintain virus infectivity-even when the virus cannot replicate. Thus retrovirus infection monopolizes FDC networks, thereby transforming the FDC Ag repository into a highly infectious retroviral reservoir.


Delphinidin inhibits epidermal growth factor-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma cells.
Epithelial-to-mesenchymal transition (EMT), important cellular process in metastasis of primary tumors, is characterized by loss of their cell polarity, disruption of cell-cell adhesion, and gain certain properties of mesenchymal phenotype that enable migration and invasion. Delphinidin is a member of anthocyanidin belong to flavonoid groups, known as having pharmacological and physiological effects including anti-tumorigenic, antioxidative, anti-inflammatory, and antiangiogenic effects. However, the effects of delphinidin on EMT is rarely investigated. Epidermal growth factor (EGF) is known as a crucial inducer of EMT in various cancer including hepatocellular carcinoma (HCC). To determine whether delphinidin inhibits EGF-induced EMT in HCC cells, antiproliferative effect of delphinidin on Huh7 and PLC/PRF/5 cells were measured by Cell Counting Kit-8 assay. As a result, delphinidin inhibited cell proliferation in a dose-dependent manner. Based on the result of proliferation, to measure the effects of delphinidin on EGF-induced EMT, we designated a proper concentration of delphinidin, which is not affected to cell proliferation. We found that delphinidin inhibits morphological changes from epithelial to mesenchymal phenotype by EGF. Moreover, delphinidin increased the messenger RNA and protein expression of E-cadherin and decreased those of Vimentin and Snail in EGF-induced HCC cells. Also, delphinidin prevented motility and invasiveness of EGF-induced HCC cells through suppressing activation of matrix metalloproteinase 2, EGF receptor (EGFR), AKT, and extracellular signal-regulated kinase (ERK). Taken together, our findings demonstrate that delphinidin inhibits EGF-induced EMT by inhibiting EGFR/AKT/ERK signaling pathway in HCC cells.


Identification of 2-piperidone as a biomarker of CYP2E1 activity through metabolomic phenotyping.
Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometry-based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity.


Ocular toxoplasmosis in immunocompetent adults: current cost-effectiveness of four treatment regimens in Colombia.
Ocular toxoplasmosis is an infection caused by Toxoplasma gondii. In South America, the clinical course of ocular toxoplasmosis is more severe than in Europe and North America because virulent strains of the parasite are present. Ocular toxoplasmosis is the leading cause of posterior uveitis and retinochoroiditis in Colombia, requiring timely and appropriate treatment. However, there is no standardized therapy protocol based on economic studies for the country. To compare the cost-effectiveness of four first-line treatment regimens for active ocular toxoplasmosis in immunocompetent adults in Colombia, using the number of averted therapeutic failures as the outcome. We performed an economic and cost-effectiveness analysis to compare four first-line treatment regimens for ocular toxoplasmosis from the perspective of a third-party payer (Colombian General System of Social Security in Health). A decision analysis tree was used over a 24-week time horizon, considering only direct costs. Additionally, we performed a discrete sensitivity analysis and a probabilistic sensitivity analysis with 10,000 iterations in the Monte Carlo simulation. For the base case, trimethoprim/sulfamethoxazole showed 86% effectiveness at a cost of <57 United States Dollars, resulting in the most cost-effective first-line alternative. When performing the probabilistic sensitivity analysis and maintaining the willingness to pay 466.00 United States Dollars, the trimethoprim/sulfamethoxazole regimen remained the most cost-effective alternative. Ocular toxoplasmosis is a public health issue in Latin America. Despite severe visual consequences for affected patients, there are no standardized treatment guidelines in countries such as Colombia. Our evidence supports the use of trimethoprim/sulfamethoxazole as first-line treatment in Colombia because of its availability and optimal cost-effectiveness performance; it reduces recurrences and complications, while averting therapeutic failure. Furthermore, our evidence can be generalized to other Latin American countries with similar frequencies and severities of Toxoplasma gondii ocular infection and health systems similar to the Colombian system.


Clinical Reasoning: A 24-Year-Old Pregnant Woman With Headache and Behavioral Change Progressing to Coma.
The broad differential diagnosis associated with progressive subacute encephalopathy can be intimidating, especially in a young, pregnant woman. In this case, a 24-year-old woman at 21 weeks of gestation presented with persistent, drug-resistant fronto-parietal headache, with subsequent progressive development of psychomotor lentification and inappropriate behavior. Physical examination was normal, as were routine laboratory parameters and CT findings, and these symptoms were initially interpreted in the context of chronic depression. Later, the patient developed generalized dystonia and fever, with rapid clinical deterioration, depression of consciousness and, eventually, progression to coma. This case emphasizes the complexity and challenges involved in the diagnostic approach to a patient with progressive subacute encephalopathy framed by worsening CNS symptoms. It highlights the clinical considerations and complementary investigation of various etiologies, in a step-by-step approach, ultimately leading to the final diagnosis. Early recognition and appropriate treatment of these conditions can lead to more favorable outcomes, particularly in gestating patients, where prompt intervention is crucial, and where critical decisions may have to be made regarding pregnancy and the safety of treatment options.


Low-Temperature Phase Transitions of the Ionic Liquid 1-Ethyl-3-methylimidazolium Dicyanamide.
Several calorimetric measurements have shown that 1-ethyl-3-methylimidazolium dicyanamide, [C2C1im][N(CN)2], is a glass-forming liquid, even though it is a low-viscous liquid at room temperature. Here, we found slow crystallization during cooling of [C2C1im][N(CN)2] along Raman spectroscopy measurements. The low-frequency range of the Raman spectrum shows that the same crystalline phase is obtained at 210 K either by cooling or by reheating the glass (cold-crystallization). Another crystalline phase is formed at ca. 260 K just prior the melting at 270 K. X-ray diffraction and calorimetric measurements confirm that there are two crystalline phases of [C2C1im][N(CN)2]. The Raman spectra indicate that polymorphism is related to [C2C1im]+ with the ethyl chain on the plane of the imidazolium ring (the low-temperature crystal) or nonplanar (the high-temperature crystal). The structural reason for the glass-forming ability of [C2C1im][N(CN)2], despite the relatively simple molecular structures of the ions, was pursued by quantum chemistry calculations and molecular dynamics (MD) simulations. Density functional theory calculations were performed for ionic pairs in order to draw free-energy surfaces of the anion around the cation. The MD simulations using a polarizable model provided maps of occurrence of anions around cations. Both the quantum and classical calculations suggest that the delocalization of preferred positions of the anion around the cation, which adopts different conformations of the ethyl chain, is on the origin of the crystallization being hampered during cooling and the resulting glass-forming ability of [C2C1im][N(CN)2].


Flight performance in the altricial zebra finch: Developmental effects and reproductive consequences.
The environmental conditions animals experience during development can have sustained effects on morphology, physiology, and behavior. Exposure to elevated levels of stress hormones (glucocorticoids, GCs) during development is one such condition that can have long-term effects on animal phenotype. Many of the phenotypic effects of GC exposure during development (developmental stress) appear negative. However, there is increasing evidence that developmental stress can induce adaptive phenotypic changes. This hypothesis can be tested by examining the effect of developmental stress on fitness-related traits. In birds, flight performance is an ideal metric to assess the fitness consequences of developmental stress. As fledglings, mastering takeoff is crucial to avoid bodily damage and escape predation. As adults, takeoff can contribute to mating and foraging success as well as escape and, thus, can affect both reproductive success and survival. We examined the effects of developmental stress on flight performance across life-history stages in zebra finches (Taeniopygia guttata). Specifically, we examined the effects of oral administration of corticosterone (CORT, the dominant avian glucocorticoid) during development on ground-reaction forces and velocity during takeoff. Additionally, we tested for associations between flight performance and reproductive success in adult male zebra finches. Developmental stress had no effect on flight performance at all ages. In contrast, brood size (an unmanipulated variable) had sustained, negative effects on takeoff performance across life-history stages with birds from small broods performing better than birds from large broods. Flight performance at 100 days posthatching predicted future reproductive success in males; the best fliers had significantly higher reproductive success. Our results demonstrate that some environmental factors experienced during development (e.g. clutch size) have stronger, more sustained effects than others (e.g. GC exposure). Additionally, our data provide the first link between flight performance and a direct measure of reproductive success.


[Comparative radiobiology of the genetic loci of eukaryotes as the basis for a general theory of mutation].
One of the fundamental problems of modern molecular cellular radiobiology is to reveal general and peculiar processes of the formation of gene mutations and chromosome aberrations in each stage of their formation in the irradiated genome of the higher eukaryotes. The solution of the problems depends on the development of research within the framework of comparative radiobiology of genetic loci of the higher eukaryotes that makes it possible to study quantitative regularities in the formation of gene (point) mutations and chromosome aberrations in one object and in the same experiment.


In situ thermally cross-linked polyacrylonitrile as binder for high-performance silicon as lithium ion battery anode.
Electrode integrity and electric contact between particles and between particle and current collector are critical for electrochemical performance, especially for that of electrode materials with large volume change during cycling and with poor electric conductivity. We report on the in situ thermally cross-linked polyacrylonitrile (PAN) as a binder for silicon-based anodes of lithium-ion batteries. The electrode delivers excellent cycle life and rate capability with a reversible capacity of about 1450 mA h g(-1) even after 100 cycles. The improved electrochemical performance of such silicon electrodes is attributed to heat-treatment-induced cross-linking and the formation of conjugated PAN. These findings open new avenues to explore other polymers for both anode and cathode electrodes of rechargeable batteries.


Molecular biology in ophthalmology. A review of principles and recent advances.
Molecular biology is a young scientific discipline that has already had a profound impact on biomedical science, including basic and clinical eye research. In the coming years, molecular advances will increasingly influence aspects of diagnosis, prognosis, and therapy in clinical ophthalmology. Our current understanding of ocular pathophysiology and classification of eye disease will be advanced and challenged by new discoveries in molecular biology. A knowledge of genotype can clarify apparent phenotype. At the present time, diagnostic tests in ophthalmology for both acquired and inherited diseases are being revolutionized by molecular technology. The molecular genetics of ocular disease is currently the subject of intense investigation using techniques of gene mapping and isolation. Rapid progress in understanding the molecular basis of eye diseases will advance the treatment of these conditions, including the potential for gene therapy.


Headache as an initial manifestation of systemic disease.
While headache frequently arises from local dysfunction, there are many systemic diseases in which headache may be the initial or sole manifestation of the underlying process. These include infectious disease, vascular disease, drug or heavy metal intoxication, metabolic abnormalities, migraine, cluster headache, headache associated with ENT disease and cranial neuralgias (these disease entities are described in detail in the International Headache Society Classification). The work up of a patient with headache must include a consideration of these entities.


San Wu Huangqin Decoction, a Chinese Herbal Formula, Inhibits Influenza a/PR/8/34 (H1N1) Virus Infection In Vitro and In Vivo.
The San Wu Huangqin Decoction (SWHD), a traditional Chinese medicine formula, is used to treat colds caused by exposure to wind-pathogen, hyperpyrexia, infectious diseases and cancer; moreover, it is used for detoxification. The individual herbs of SWHD, such as Sophora flavescens and Scutellaria baicalensis, exhibit a wide spectrum of antiviral, anti-inflammatory, antibacterial, anticancer and other properties. The Chinese compound formula of SWHD is composed of S. flavescens, S. baicalensis and Rehmannia glutinosa. However, the effect of SWHD on the influenza virus (IFV) and its mechanism remain unknown. The aim of this study was to evaluate, for the first time, whether SWHD could be used to treat influenza. Results showed that SWHD could effectively inhibit influenza A/PR/8/34 (H1N1) virus at different stages of viral replication (confirmed through antiviral effect assay, penetration assay, attachment assay and internalization assay) in vitro. It could reduce the infection of the virus in a dose- and time-dependent manner, as confirmed by observing the cell cytopathic effect and calculating the cell viability (p < 0.05). SWHD demonstrated better antiviral activity than oseltamivir in the evaluation of antiviral prophylaxis on influenza (p < 0.05). The antiviral activity of SWHD may be related to its regulation ability on the immune system. Western blot, real-time polymerase chain reaction and indirect immunofluorescence assay showed that the expression of the four target viral proteins of the IFV (namely, haemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP) and matrix-2 (M2)) reduced significantly (p < 0.05). Moreover, SWHD (23.40 and 11.70 g/kg) significantly alleviated the clinical signs, reduced the mortality and increased the survival time of infected mice (p < 0.05). The lung index, virus titres, pathological changes in lung tissues and the expression of key proteins of the IFV in mice also decreased (p < 0.05). In conclusion, SWHD possessed anti-influenza activity. This work provided a new view of complementary therapy and drug discovery for clinical treatment.


Evaluation of red chicory extract as a natural antioxidant by pure lipid oxidation and yeast oxidative stress response as model systems.
The search for renewable and abundant sources of antioxidants has recently focused on agricultural byproducts, especially promising due to their natural origins and low costs. In particular, plant raw materials are sources of important compounds such as dietary fiber, carotenoids, tocopherols, and polyphenolics, which are mostly discarded during harvesting and processing. Among these vegetal crops, red chicory is attractive because of the large quantity of its byproducts (residues as leaves and stems); moreover, there is no information on its role as a food and feed ingredient. In this study, red chicory leaf residue was evaluated as a natural substitute for synthetic antioxidants for the food and feed industry. After lyophilization, a red chicory extract (RC) was characterized for its phenolic profile and its oxidative stability as compared to BHT. RC was shown to reduce lipid peroxidation of different oils in the Rancimat test. In addition, the antioxidant property of RC was studied in a model system by evaluating the Saccharomyces cerevisiae response to oxidative stress by means of gene expression. In this analysis, the RC extract, added to the yeast culture prior to oxidative stress induction, exhibited a pleiotropic protective effect on stress responsive genes.


Oncohistone Mutations Occur at Functional Sites of Regulatory ADP-Ribosylation.
Recent studies have identified cancer-associated mutations in histone genes that lead to the expression of mutant versions of core histones called oncohistones. Many oncohistone mutations occur at Asp and Glu residues, two amino acids known to be ADP-ribosylated (ADPRylated) by PARP1. We screened 25 Glu or Asp oncohistone mutants for their effects on cell growth in breast and ovarian cancer cells. Ectopic expression of six mutants of three different core histones (H2B, H3, and H4) altered cell growth in at least two different cell lines. Two of these sites, H2B-D51 and H4-D68, were indeed sites of ADPRylation in wild-type (unmutated) histones, and mutation of these sites inhibited ADPRylation. Mutation of H2B-D51 dramatically altered chromatin accessibility at enhancers and promoters, as well as gene expression outcomes, whereas mutation of H4-D68 did not. Additional biochemical, cellular, proteomic, and genomic analyses demonstrated that ADPRylation of H2B-D51 inhibits p300-mediated acetylation of H2B at many Lys residues. In breast cancer cell xenografts in mice, H2B-D51A promoted tumor growth, but did not confer resistance to the cytotoxic effects of PARP inhibition. Collectively, these results demonstrate that functional Asp and Glu ADPRylation sites on histones are mutated in cancers, allowing cancer cells to escape the growth-regulating effects of post-translational modifications via distinct mechanisms. This study identifies cancer-driving mutations in histones as sites of PARP1-mediated ADP-ribosylation in breast and ovarian cancers, providing a molecular pathway by which cancers may subvert the growth-regulating effects of PARP1.


Non-invasive electric current stimulation for restoration of vision after unilateral occipital stroke.
Occipital stroke often leads to visual field loss, for which no effective treatment exists. Little is known about the potential of non-invasive electric current stimulation to ameliorate visual functions in patients suffering from unilateral occipital stroke. One reason is the traditional thinking that visual field loss after brain lesions is permanent. Since evidence is available documenting vision restoration by means of vision training or non-invasive electric current stimulation future studies should also consider investigating recovery processes after visual cortical strokes. Here, protocols of repetitive transorbital alternating current stimulation (rtACS) and transcranial direct current stimulation (tDCS) are presented and the European consortium for restoration of vision (REVIS) is introduced. Within the consortium different stimulation approaches will be applied to patients with unilateral occipital strokes resulting in homonymous hemianopic visual field defects. The aim of the study is to evaluate effects of current stimulation of the brain on vision parameters, vision-related quality of life, and physiological parameters that allow concluding about the mechanisms of vision restoration. These include EEG-spectra and coherence measures, and visual evoked potentials. The design of stimulation protocols involves an appropriate sham-stimulation condition and sufficient follow-up periods to test whether the effects are stable. This is the first application of non-invasive current stimulation for vision rehabilitation in stroke-related visual field deficits. Positive results of the trials could have far-reaching implications for clinical practice. The ability of non-invasive electrical current brain stimulation to modulate the activity of neuronal networks may have implications for stroke rehabilitation also in the visual domain.


Trisomy 21 Down syndrome. II. Structural chromosome rearrangements in the parents.
In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased ascertainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of etiologic significance.


Accuracy and reliability of landmark-based, surface-based and voxel-based 3D cone-beam computed tomography superimposition methods.
To evaluate and compare the accuracy and reliability of 3 different methods of three-dimensional cone-beam computed tomography scans (3D CBCTs) superimpositions: landmark-based, surface-based and voxel-based. Pre- and post-orthodontic treatment CBCTs (T1 and T2) of 20 subjects with a mean age of 11 years were obtained. Seven points on the zygomatic arch and supraorbital region were selected to perform landmark-based superimposition. Surface-based and voxel-based superimpositions were performed using the anterior cranial base as a reference. Each superimposition method of T1 and T2 scans was repeated twice to assess the reliability. Accuracy of each technique was tested by superimposing duplicated sets of T1 scans. A total of 11 landmarks on the anterior cranial base, maxilla and mandible were located, and deviations of these landmarks on superimposed data were quantified to assess reliability and accuracy of all superimpositions. There were no significant differences from zero when duplicated sets of T1 scans were superimposed using surface-based and voxel-based methods. Statistical significant differences were detected in several parameters when evaluating the accuracy of the landmark superimposition. Superimposition of T1 and T2 scans for testing the reliability revealed intraclass correlation coefficients greater than 0.90 for all measurements except for ACP-x and PNS-y of landmark-based method as well as ANS-x of voxel-based method. Surface-based and voxel-based superimposition methods using the anterior cranial base as a reference structure were accurate and reliable in detecting changes in landmark positions when superimposing. Landmark-based superimposition method was reliable but less accurate than the other methods.


Higher Blood-brain barrier permeability in patients with major depressive disorder identified by DCE-MRI imaging.
Studies from animal models and clinical trials of blood and cerebrospinal fluid have proposed that blood-brain barrier (BBB) dysfunction in depression (MDD). But there are no In vivo proves focused on BBB dysfunction in MDD patients. The present study aimed to identify whether there was abnormal BBB permeability, as well as the association with clinical status in MDD patients using dynamic contrast-enhanced magnetic resonance (DCE-MRI) imaging. Patients with MDD and healthy adults were recruited and underwent DCE-MRI and structural MRI scans. The mean volume transfer constant (Ktrans) values were calculated for a quantitative assessment of BBB leakage. For each subject, the mean Ktrans values were calculated for the whole gray matter, white matter, and 90 brain regions of the anatomical automatic labeling template (AAL). The differences in Ktrans values between patients and controls and between treated and untreated patients were compared. 23 MDD patients (12 males and 11 females, mean age 28.09 years) and 18 healthy controls (HC, 8 males and 10 females, mean age 30.67 years) were recruited in the study. We found that the Ktrans values in the olfactory, caudate, and thalamus were higher in MDD patients compared to healthy controls (p<0.05). The Ktrans values in the orbital lobe, anterior cingulate gyrus, putamen, and thalamus in treated patients were lower than the patients never treated. There were positive correlations between HAMD total score with Ktrans values in whole brain WM, hippocampus and thalamus. The total HAMA score was positively correlated with the Ktrans of hippocampus. These findings supported a link between blood-brain barrier leakage and depression and symptom severity. The results also suggested a role for non-invasive DCE-MRI in detecting blood-brain barrier dysfunction in depression patients.