DeepSite: protein-binding site predictor using 3D-convolutional neural networks.

MOTIVATION: An important step in structure-based drug design consists in the prediction of druggable binding sites. Several algorithms for detecting binding cavities, those likely to bind to a small drug compound, have been developed over the years by clever exploitation of geometric, chemical and evolutionary features of the protein. RESULTS: Here we present a novel knowledge-based approach that uses state-of-the-art convolutional neural networks, where the algorithm is learned by examples. In total, 7622 proteins from the scPDB database of binding sites have been evaluated using both a distance and a volumetric overlap approach. Our machine-learning based method demonstrates superior performance to two other competitive algorithmic strategies. AVAILABILITY AND IMPLEMENTATION: DeepSite is freely available at www.playmolecule.org. Users can submit either a PDB ID or PDB file for pocket detection to our NVIDIA GPU-equipped servers through a WebGL graphical interface. CONTACT: gianni.defabritiis@upf.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Growth, structural, spectral, mechanical, thermal and dielectric characterization of phosphoric acid admixtured L-alanine (PLA) single crystals.

Phosphoric acid admixtured L-alanine (PLA) single crystals were grown successfully by solution method with slow evaporation technique at room temperature. Crystals of size 18 mm×12 mm×8 mm have been obtained in 28 days. The grown crystals were colorless and transparent. The solubility of the grown samples has been found out at various temperatures. The lattice parameters of the grown crystals were determined by X-ray diffraction technique. The reflection planes of the sample were confirmed by the powder X-ray diffraction study and diffraction peaks were indexed. Fourier transform infrared (FTIR) studies were used to confirm the presence of various functional groups in the crystals. UV-visible transmittance spectrum was recorded to study the optical transparency of grown crystal. The nonlinear optical (NLO) property of the grown crystal was confirmed by Kurtz-Perry powder technique and a study of its second harmonic generation efficiency in comparison with potassium dihydrogen phosphate (KDP) has been made. The mechanical strength of the crystal was estimated by Vickers hardness test. The grown crystals were subjected to thermo gravimetric and differential thermal analysis (TG/DTA). The dielectric behavior of the sample was also studied.

Neuropsychological and educational problems at school age associated with neonatal encephalopathy.

BACKGROUND: Adverse cognitive and educational outcomes are often ascribed to perinatal hypoxia without good evidence. OBJECTIVE: To investigate neurocognitive and behavioural outcomes after neonatal encephalopathy. METHODS: Sixty five children with neonatal encephalopathy, identified using the Trent Neonatal Survey database for 1992-1994, were followed up at the age of 7 years. They were examined at school, with a classmate for those in mainstream school, by a paediatrician and a psychologist. Neonatal encephalopathy was graded as moderate or severe using published definitions. FINDINGS: Fifteen children had major disability, all with cerebral palsy; eight were in special school with severe cognitive impairment (IQ<55). Disability was present in 6% of the moderate and 42% of the severe encephalopathy group. Of the 50 children without motor disability, cognitive scores were lowest in the severe group (mean IQ difference from peers -11.3 points (95% confidence interval (CI) -19.0 to -3.6) and with similar scores for the moderate group compared with classmates (mean difference -1.7 points (95% CI -7.3 to +3.9). Neuropsychological testing showed similar findings in all domains. In particular, memory and attention/executive functions were impaired in the severe group. Despite relatively small differences in performance of the moderate group, special educational needs were identified more often in both encephalopathy groups, associated with lower achievement on national curriculum attainment targets. INTERPRETATION: After neonatal encephalopathy, subtle cognitive impairments are found in the absence of neuromotor impairment. Subtle impairments are found more commonly after a more severe clinical course. Studies of brain protection strategies require long term follow up to study effects on cognitive outcome.

Action of histamine on eustachian tube function.

INTRODUCTION: The role of allergy in eustachian tube dysfunction is controversial. In this study, allergy was simulated by exposure to histamine, and eustachian tube function testing was performed in an experimental rat model. METHODS: Ventilatory function was assessed by measuring passive opening and closing pressures of the eustachian tube after challenge with either transtympanic or intranasal histamine. The mucociliary clearance time of the tubotympanum was assessed by observing dye transport from the middle ear to the nasopharynx after challenge with either transtympanic histamine or control solution. RESULTS: There was a statistically significant increase in passive opening and closing pressures with transtympanic histamine versus intranasal histamine. In addition, mucociliary clearance times of the tubotympanum after transtympanic histamine showed a statistically significant increase when compared with those after transtympanic control solution. CONCLUSIONS: Transtympanic histamine exposure causes eustachian tube dysfunction in the rat by increasing passive opening and closing pressures of the eustachian tube and impairing mucociliary clearance time.

Systemic reactivation of otitis media with effusion in a rat model.

OBJECTIVE: This study addresses the interaction of bacterial antigens, specifically peptidoglycan-polysaccharide (PG-PS) and lipopolysaccharide (LPS), in the induction and reactivation of mucoid middle ear effusions. METHODS: Twenty-seven rats underwent eustachian tube obstruction before inoculation of the middle ear bulla with PG-PS. Three weeks later, after resolution of all middle ear effusions, 6 rats were randomly selected and euthanized as the first control group (control I). The remaining 21 animals were randomly assigned to 3 groups that received intravenous injections of Krebs Ringer (control II), PG-PS, and LPS, respectively. These rats were euthanized 2 days after intravenous injection. Middle ear mucin production and histologic changes were measured in all animals. RESULTS: The mean concentrations of mucin were 0.94 +/- 0.52 mg/mL, 0.41 +/- 0.87 mg/mL, 16.33 +/- 3.67 mg/mL, and 1.15 +/- 0.41 mg/mL in the control I, control II, PG-PS, and LPS groups, respectively. Thus the mean concentration of mucin in the middle ear lavage samples was significantly greater in rats that were injected intravenously with PG-PS than in rats in other groups (P < 0.05). Histologic analyses demonstrated a greater degree of goblet cell hyperplasia in the PG-PS group than in other groups. CONCLUSIONS: This is the first animal model of recurring otitis media with effusion in which a systemic injection of PG-PS was used to reactivate a middle ear effusion in rats previously primed with a transtympanic injection of PG-PS. This study suggests that after otitis media with effusion has resolved, it may be reactivated by the presence of bacterial antigens and/or cytokines in the systemic circulation.

The role of nitric oxide in the neural control of nasal fluid production.

The production of nasal fluids serves an important role in the protection of the upper respiratory system, but can also be a troublesome symptom of rhinitis. The chief sources of nasal fluids are serous and mucous glandular secretion, epithelial goblet cell exocytosis, and exudation from submucosal blood vessels. This study was designed to investigate the role of nitric oxide in neurogenically mediated nasal vascular exudation and mucus secretion. A rat model of the naso-nasal reflex was developed in which one nasal cavity was challenged with histamine while albumin and mucin production were measured in the continuously perfused contralateral side. Histamine challenge was associated with a significant rise in contralateral albumin and mucin content. Perfusion with a nitric oxide synthase inhibitor (L-NAME) in the nasal cavity contralateral to nasal challenge was found to block albumin leakage, but not mucin secretion, on that side. The inhibition of vascular exudation was overcome by the addition of L-arginine, the natural substrate of nitric oxide synthase, to the perfusate. Treatment of the ipsilateral nasal of the ipsilateral nasal cavity with L-NAME did not significantly after the contralateral response. A high correlation was observed between albumin and mucin concentration in the perfusate. These findings indicate that NO is a mediator of the effector arm of the naso-nasal reflex that increases vascular permeability, but is not involved in the sensory nerve afferent pathway or in reflex mucin release. Further elucidation of the role of NO in nasal physiology may lead to novel pharmacotherapeutic approaches to the treatment of allergic and non-allergic rhinitis.

Nitric oxide is a mediator of neurogenic vascular exudation in the nose.

Rhinorrhea is a troublesome symptom of rhinitis seen commonly by otolaryngologists. The sources of nasal fluid production are glandular secretions and exudation from submucosal blood vessels. This study was designed to investigate the role of nitric oxide in neurogenically mediated vascular exudation in the nose. A rat model of the nasonasal reflex was developed in which one nasal cavity was challenged with histamine while albumin exudation was measured on the contralateral side. Histamine challenge was associated with a significant rise in albumin leakage, indicating an increase in vascular permeability. Perfusion with a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester (L-NAME)) in the nasal cavity contralateral to nasal challenge was found to block albumin exudation on that side. This inhibition was overcome by the addition of L-arginine, the natural substrate of nitric oxide synthase, to the perfusate. Treatment of the ipsilateral nasal cavity with L-NAME did not significantly decrease the contralateral response. These findings indicate that NO is an important mediator of the effector arm of the nasonasal reflex that increases vascular permeability but is not involved in the sensory nerve afferent pathway. Further elucidation of the role of NO in nasal physiology may lead to novel pharmacotherapeutic approaches to the treatment of allergic and nonallergic rhinorrhea.

Nitric oxide mediates mucin secretion in endotoxin-induced otitis media with effusion.

The mechanisms that regulate mucin release in chronic otitis media with effusion, a leading cause of hearing loss in children, remain largely unknown. We developed an animal model using Sprague-Dawley rats to determine the factors responsible for mucin production in chronic otitis media with effusion. N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of nitric oxide synthase, was used to investigate the role of nitric oxide in mucin secretion by the middle ear epithelium. All rats underwent eustachian tube obstruction. In the first set of rats, the middle ear was then injected transtympanically with 35 microl of either 300 mOsm Krebs-Ringer bicarbonate buffer (control group) or 1 mg/ml lipopolysaccharide in Krebs-Ringer (experimental group 1). In a second set of rats, the middle ear space was injected with lipopolysaccharide and then infused at a continuous rate for 7 days with either Krebs-Ringer (experimental group 2) or 1 mmol/L L-NAME in Krebs-Ringer (experimental group 3) through an osmotic infusion pump. After 7 days the volume of effusion and the quantity of mucin collected were significantly greater in lipopolysaccharide-exposed ears than in controls. In addition, antimucin immunostaining demonstrated mucous cell hyperplasia in response to lipopolysaccharide. The lipopolysaccharide-induced production of mucin and mucous cell hyperplasia was inhibited in ears treated with lipopolysaccharide and L-NAME. These results suggest that nitric oxide is a mediator in the pathway of mucin secretion in chronic otitis media with effusion.

The role of glucocorticoids in endotoxin-mediated otitis media with effusion.

OBJECTIVE: To understand the actions of glucocorticoids on the development and progression of endotoxin-mediated otitis media with effusion. METHODS AND DESIGN: The middle ears of 20 Sprague-Dawley rats were exposed to 35 microL of either 300-mOsm Krebs-Ringer solution (control; n = 5) or lipopolysaccharide, 1 mg/mL, dissolved in Krebs-Ringer solution (n = 15). Among the group that received lipopolysaccharide, 10 rats were randomly selected to receive dexamethasone (1 mg/kg intramuscularly), either 2 hours (n = 5) or 24 hours (n = 5) before the introduction of lipopolysaccharide. Middle ear fluid was sampled after 2, 4, and 6 hours of exposure. OUTCOME MEASURES: Middle ear fluid volume and albumin content were determined as measures of vascular extravasation. Histological sections of the middle ear mucosa were used to quantify the degree of leukocyte exudation. Data were analyzed by 1- or 2-way analysis of variance with the significance level set at P < .05. RESULTS: Lipopolysaccharide exposure caused a significant increase in the mean +/- SEM middle ear fluid volume from 29.9 +/- 0.99 to 45.8 +/- 1.4 microL between the 2- and 6-hour samplings. Lipopolysaccharide exposure caused a significant increase in the albumin content of middle ear fluid from 70.1 +/- 19.2 to 271.0 +/- 93.1 micrograms between the 2- and 6-hour samplings. Both increases were significant compared with controls. Lipopolysaccharide also caused a significant increase in leukocytes localized to the middle ear mucosa. Pretreatment of animals with dexamethasone for either 2 or 24 hours inhibited the lipopolysaccharide-induced changes. There were no differences between 2- and 24-hour pretreatment with dexamethasone. CONCLUSIONS: Dexamethasone inhibits the development of endotoxin-induced otitis media with effusion.

Evidence against dormancy in the bacterial fish pathogen Aeromonas salmonicida subsp. salmonicida.

Results indicate that A. salmonicida does not enter an unculturable dormant state. The resuscitation of dormant cells by nutrient broth described by previous workers appears to be due to the presence of small numbers of viable, culturable cells too few to be detected by the sampling protocol employed.

Long-term care of patients with multiple sclerosis: a neurologist's perspective.

Multiple sclerosis is a chronic disease with varying degrees of disability and progression. Because there is no known specific therapy, for best care, patients are individualized, with attempts to deal with each patient and each complication separately, thoughtfully, and with psychological support when required. Efforts are directed toward helping the patient adjust to the realities of the disease and to specific disabilities. Ways and means of gaining patient confidence are discussed--and emphasis is placed on the known pathologic processes involved and how information, personalized professional attention, and support might function to aid the body's defense mechanisms for containment of the disease process. Several clinical cases were summarized (at the symposium) to illustrate the favorable and unfavorable effects of personality and emotional characteristics over a long term of care.

Methodology for analyzing clinical neurological data: ACTH in multiple sclerosis.

From 1965 to 1968 a multicenter (USA) clinical trial was conducted to compare ACTH with placebo for the treatment of multiple sclerosis patients in a stage of acute exacerbation. Of seven evaluation systems which were used, one was a quantitative neurological examination. In this report, the quantitative neurological data have been re-evaluated using a transformation of the data which express patient scores in terms of a percentage of age- and sex-matched normal function followed by a reduction of the data into composite neurological functions vs time. The results support the positive findings of previous reports. In addition, the methodology helps to simplify the therapists' task of interpreting results by enabling him to determine how near normal function the patient came following the treatment trial.

Some thoughts on the nature of mind. A holistic concept of nervous system function.

Some practical neurological ideas concerning the nature of mind are presented to assist clinicians in appreciating the fact that brain physiology first creates and then serves the mind--the highest of the hierarchical functions of the nervous system. The qualities of the mind are shaped and modulated by life experience and many disturbed responses can be tempered by a knowledgeable approach. To gain a holistic concept of the functioning nervous system one must recognize and accept that all manifestations of behavior, including those termed psychological, are the product of physiological processes.