Changes in the mRNAs encoding subtypes I, II and III sodium channel alpha subunits following kainate-induced seizures in rat brain.
Several lines of evidence underscore a possible role of voltage-gated Na+ channels (NaCH) in epilepsy. We compared the regional distribution of mRNAs coding for Na+ channel alpha subunit I, II and III in brains from control and kainate-treated rats using non-radioactive in situ hybridization with subtype-specific digoxigenin-labelled cRNA probes. Labelling intensity was evaluated by a densitometric analysis of digitized images. Heterogeneous distribution of the three Na+ channel mRNAs was demonstrated in brain from adult control rats, which confirmed previous studies. Subtype II mRNAs were shown to be abundant in cerebellum and hippocampus. Subtype I mRNAs were also detected in these areas. Subtype III mRNAs were absent in cerebellar cortex, but significantly expressed in neurons of the medulla oblongata and hippocampus. The three subtypes were differentially distributed in neocortical layers. Subtype II mRNAs were present in all of the layers, but mRNAs for subtypes I and III were concentrated in pyramidal cells of neocortex layers IV-V. During kainate-induced seizures, we observed an increase in Na+ channel II and III mRNA levels in hippocampus. In dentate gyrus, subtype III mRNAs increased 3 h after KA administration to a maximum at 6 h. At this latter time, a lower increase in NaCh III mRNAs was also recorded in areas CA1 and CA3. NaCh III overexpression in dentate gyrus persisted for at least 24 h. In the same area, NaCh II mRNAs were also increased with a peak 3 h after KA injection and a return to control levels by 24 h. No changes in NaCh I mRNAs were seen. The KA-induced up-regulation in NaCh mRNAs probably resulted in an increase in hippocampal neuronal excitability.


Development and validation of a nomogram for 30-day readmission after hip fracture surgery in geriatric patients.
30-day readmission after hip fracture surgery in the elderly is common and costly. A predictive tool to identify high-risk patients could significantly improve outcomes. This study aims to develop and validate a risk nomogram for 30-day readmission after hip fracture surgery in geriatric patients. We retrospectively analyzed 1,249 geriatric hip fracture patients (≥60 years) undergoing surgery at Dandong Central Hospital from October 2011 to October 2023. Using a 7:3 ratio, patients were randomly divided into training (n=877) and validation (n=372) sets. Independent risk factors for 30-day readmission were identified using LASSO regression and logistic regression in the training set. A nomogram was constructed using the identified predictors. Finally, the C-index, ROC curve, calibration curve, and decision curve analysis were used to validate the model in the training and validation sets respectively. The nomogram was developed based on the 8 predictors of age, prior stroke, chronic liver disease, treatment, uric acid (UA), total protein (TP), albumin (ALB), and pneumonia that were found to be independently associated with 30-day readmission. The nomogram showed good discrimination with a C-index of 0.88 in the training set and 0.84 in the validation set. Calibration curves exhibited good agreement between predicted and observed outcomes. Decision curve analysis demonstrated clinical utility. We developed and validated a nomogram incorporating eight clinical variables to accurately predict the individualized risk of 30-day readmission after hip fracture surgery in elderly patients. The model demonstrated favorable discrimination, calibration, and clinical utility. It can help to identify high-risk patients needing additional interventions to prevent avoidable hospital readmissions.


In-silico analysis on biofabricating vascular networks using kinetic Monte Carlo simulations.
We present a computational modeling approach to study the fusion of multicellular aggregate systems in a novel scaffold-less biofabrication process, known as 'bioprinting'. In this novel technology, live multicellular aggregates are used as fundamental building blocks to make tissues or organs (collectively known as the bio-constructs,) via the layer-by-layer deposition technique or other methods; the printed bio-constructs embedded in maturogens, consisting of nutrient-rich bio-compatible hydrogels, are then placed in bioreactors to undergo the cellular aggregate fusion process to form the desired functional bio-structures. Our approach reported here is an agent-based modeling method, which uses the kinetic Monte Carlo (KMC) algorithm to evolve the cellular system on a lattice. In this method, the cells and the hydrogel media, in which cells are embedded, are coarse-grained to material's points on a three-dimensional (3D) lattice, where the cell-cell and cell-medium interactions are quantified by adhesion and cohesion energies. In a multicellular aggregate system with a fixed number of cells and fixed amount of hydrogel media, where the effect of cell differentiation, proliferation and death are tactically neglected, the interaction energy is primarily dictated by the interfacial energy between cell and cell as well as between cell and medium particles on the lattice, respectively, based on the differential adhesion hypothesis. By using the transition state theory to track the time evolution of the multicellular system while minimizing the interfacial energy, KMC is shown to be an efficient time-dependent simulation tool to study the evolution of the multicellular aggregate system. In this study, numerical experiments are presented to simulate fusion and cell sorting during the biofabrication process of vascular networks, in which the bio-constructs are fabricated via engineering designs. The results predict the feasibility of fabricating the vascular structures via the bioprinting technology and demonstrate the morphological development process during cellular aggregate fusion in various engineering designed structures. The study also reveals that cell sorting will perhaps not significantly impact the final fabricated products, should the maturation process be well-controlled in bioprinting.


Intracellular and extracellular acid-base regulation in the tropical fresh-water teleost fish Synbranchus marmoratus in response to the transition from water breathing to air breathing.
In the tropical fresh water fish, Synbranchus marmoratus, transition from water breathing to air breathing, induced by reduction of oxygen partial pressure (PO2) in the environmental water below 16 mmHg, causes a considerable rise in the arterial partial pressure of carbon dioxide (PCO2), from 5.6 to 26 mmHg on the average (half time of the rise between 2 and 6.5 h). The associated fall in arterial plasma pH by about 0.6 units is not compensated by an increase in plasma bicarbonate concentration, whereas the intracellular pH of white skeletal muscle and heart muscle is kept almost constant by elevation of the intracellular bicarbonate concentration. The additional bicarbonate is generated by intracellular non-bicarbonate buffering, and by net transfer into the intracellular space of bicarbonate formed by buffering in blood. Only a relatively small quantity of bicarbonate is taken up from environmental water. This type of acid-base regulation, with almost complete intracellular pH compensation and only minor bicarbonate uptake (equivalent H+ release or OH- uptake) from water, is attributed to several factors. Probably the most important of these is the lack of continuous contact of the gills, which are the main site of ion transfer processes, with the environmental water during air breathing. Regardless of the mechanisms involved, this particular strategy of acid-base regulation provides a constant milieu for the intracellular structures and demonstrates the prevalence of intracellular over extracellular acid-base regulation.


Untreated Dyslipidemia in Lebanese Patients With Schizophrenia.
To investigate the prevalence of statin-untreated schizophrenic patients needing treatment according to the 2013 American College of Cardiology and the American Heart Association (ACC/AHA) guidelines and to compare the performance of these guidelines to the 2004 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) recommendations. A cross-sectional study was conducted using medical charts, patient inverventions, and various anthropometric measures between April 2016 and July 2016 at the Psychiatric Hospital of the Cross enrolled 329 patients with schizophrenia (DSM-5 criteria) to determine dyslipidemia and risk for atherosclerotic cardiovascular disease (ASCVD). Of the patients, 81.25% (130 patients of 160) who need a statin therapy according to the ACC/AHA guidelines would not need a therapy according to the NCEP ATP-III, while only 9.1% of the total population met the criteria for both guidelines concomitantly. A significant difference in favor of the ACC/AHA guideline was found between the 2 guidelines (P < .001). Among the 130 patients who need a statin treatment, 124 (95.4%) had ASCVD ≥ 7.5%, 13 patients (10%) had diabetes, 1 patient (0.8%) had clinical cardiovascular disease (CVD), and none had low-density lipoprotein > 190 mg/dL. Although our results showed the superiority of the 2013 ACC/AHA guidelines over the 2004 NCEP guidelines for detecting undiagnosed dyslipidemia, the absolute benefit or risk of a statin therapy according to these guideline recommendations remains unclear in this population of schizophrenic patients because the actual occurrence of CVD or statin-related adverse events was not investigated in this study. Further studies are needed to evaluate the reduction in CVD by a statin treatment according to both guidelines and thus compare the actual benefit of statin assignment in schizophrenic patients.


The extent to which psychometric tests differentiate subgroups of children with SLI.
This paper reports on the results of a large project involving 7-year-old children attending language units in England. A group of 242 children with specific language impairment (SLI) were assessed on a battery of psychometric tests. In addition, teacher interviews were carried out to ascertain teachers' opinions of the children's difficulties. Cluster analysis revealed six robust subgroups of children with language difficulties. The findings are discussed in the context of other approaches to the classification of language impairment in children with special reference to the work of Rapin and Allen (1987).


Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria.
Chronic inflammatory disease and acute infection are well known to inhibit gonadal steroidogenesis. Previous studies have demonstrated that immune activation in response to lipopolysaccharide (LPS) results in reductions in serum testosterone, and this is a direct effect on the Leydig cell. We hypothesize that during the early onset of LPS endotoxemia in vivo, testicular macrophages produce reactive oxygen species (ROS) leading to perturbation of Leydig cell mitochondria and an inhibition in steroidogenesis. To investigate the mechanism of LPS inhibition of Leydig cell steroidogenesis, alterations in mitochondria and markers of oxi-dative stress were assessed in vivo and in Leydig cell pri- mary culture. After a single injection of mice with LPS, serum testosterone was significantly decreased within 2 h. LPS injection of mice resulted in significant reductions in steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydogenase-Delta4-Delta5 isomerase (3beta-HSD) proteins. LPS significantly increased lipid peroxidation of Leydig cell membranes, indicating that LPS results in oxidative damage in vivo. Mitochondria in Leydig cells isolated from LPS-injected mice were disrupted and showed a marked reduction in the mitochondrial membrane potential (DeltaPsim). Similar to the effects of LPS, treatment of Leydig cells with hydrogen peroxide acutely inhibited steroidogenesis, reduced StAR and 3beta-HSD protein levels, and disrupted DeltaPsim. These results suggest that LPS acutely inhibits Leydig cell function by ROS-mediated disruption of Leydig cell mitochondria. Taken together, these results demonstrate the necessity of having respiring mitochondria with an intact DeltaPsim to facilitate StAR function and Leydig cell steroidogenesis. The acute effects of LPS demonstrate how sensitive Leydig cell mitochondrial steroidogenesis is to inflammation-induced oxidative stress.


Genetic variability in Jatropha curcas L. from diallel crossing.
Physic nut (Jatropha curcas L.) presents high oilseed yield and low production cost. However, technical-scientific knowledge on this crop is still limited. This study aimed to evaluate and estimate the genetic variability of hybrids obtained from dialell crossing. Genetic variability was carried out using ISSR molecular markers. For genetic variability, nine primers were used, and six were selected with 80.7% polymorphism. Genetic similarity was obtained using the NTSYS pc. 2.1 software, and cluster analysis was obtained by the UPGMA method. Mean genetic similarity was 58.4% among hybrids; the most divergent pair was H1 and H10 and the most similar pair was H9 and H10. ISSR PCR markers provided a quick and highly informative system for DNA fingerprinting, and also allowed establishing genetic relationships of Jatropha hybrids.


[Education for future agricultural workers: role of schools and other public and private agencies].
The authors report their health education experience in the high schools of Pavia, emphasizing the responsibility of the public school in promoting a rational behaviour of the youth aimed at health maintenance, and illustrating the role recently played in this regard by a private institution (linked to the University of Pavia and several other Universities): the Salvatori Maugeri Foundation. Since the authors' experience also encompasses the prevention of work-related injuries and diseases, the article presents a didactic plan specifically aimed at the education of future agriculture workers. The program starts from the fundamental principle that considers risk not as something fatally ineluctable but as probabilty of damage, and then dwells on the consequent predictive meaning of a series of notions which allow interventions useful to minimize the various occupational risk factors (or "causes of damage"). The teaching program is composed by educational steps which gradually becomes more complete and specific according to the advancement of learning.


Substantia nigra gamma-aminobutyric acid receptors in Huntington's disease.
The specific binding of [3H]gamma-aminobutyric acid (GABA) to nigral GABA receptors has been studied in postmortem brains from controls and patients with Huntington's disease (HD). A specific increase in the number of high-affinity binding sites for [3H]GABA was observed in HD patients, analogous to changes observed in rat substantia nigra [3H]GABA binding after striatal kainic acid (KA) lesion. The results provide further support for the striatal KA lesion in the rat as an animal model of HD. The implications of the results for the proposed therapeutic potential of GABA agonists in HD are discussed.


Power, ethics, and corporate dentistry.
The North Carolina Dental Association recently sought to place clear statutory limits on the influence of corporate, nondental interests over dentists practices' decision-making. This report describes the two-year legislative battle with well-funded and politically connected parties that ultimately resulted in laws that protect patients' rights to be treated by a dentist free of outside commercial interests.


Cognitive reflection and antibiotic prescribing for acute respiratory infections.
Variation in clinical decision-making could be explained by clinicians' tendency to make 'snap-decisions' versus making more reflective decisions. One common clinical decision with unexplained variation is the prescription of antibiotics for acute respiratory infections (ARIs). We hypothesized that clinicians who tended toward greater cognitive reflection would be less likely to prescribe antibiotics for ARIs. The Cognitive Reflection Test (CRT) is a psychological test with three questions with intuitive but incorrect answers that respondents reach if they do not consider the question carefully. The CRT is scored from 0 to 3, representing the number of correct answers. A higher score indicates greater cognitive reflection. We administered the CRT to 187 clinicians in 50 primary care practices. From billing and electronic health record data, we calculated clinician-level antibiotic prescribing rates for ARIs in 3 categories: all ARIs, antibiotic-appropriate ARIs and non-antibiotic-appropriate ARIs. A total of 57 clinicians (31%) scored 0 points on the CRT; 38 (20%) scored 1; 51 (27%) scored 2; and 41 (22%) scored 3. We found a roughly U-shaped association between cognitive reflection and antibiotic prescribing. The antibiotic prescribing rate for CRT scores of 0, 1, 2 and 3 for all ARIs (n = 37080 visits) was 32%, 26%, 25% and 30% (P = 0.10); for antibiotic-appropriate ARIs (n = 11220 visits) was 60%, 55%, 54% and 58% (P = 0.63); and for non-antibiotic-appropriate ARIs (n = 25860 visits) was 21%, 17%, 13% and 18%, respectively (P = 0.03). In contrast to our hypothesis, there appears to be a 'sweet-spot' of cognitive reflection for antibiotic prescribing for non-antibiotic-appropriate ARIs. Differences in clinicians' cognitive reflection may be associated with other variations in care.


[Bordetella pertussis bacteriophage].
For the first time Bordetella pertussis bacteriophage was isolated, and its presence was confirmed by electron microscopy and by agar layer titration. The lysogenic strains were activated by their treatment with mitomycin C in a dose of 4.5 mg/ml. The phage system of the Bordetella genus, heretofore unknown, has been revealed: Bordetella pertussis phage lyzed all the tested strains of Bordetella parapertussis (25 strains) and could be passaged in these strains. The phage formed turbid and transparent negative colonies 0.1 mm and 0.15 mm in size. The phage titer (e. g., in strain No. 3865) was 1 X 10(10). The lysogenic variants of Bordetella pertussis, capable of spontaneous release of the phage, were obtained. These variants were characterized by changes in some of their phenotypical properties, e.g., the increased content of certain toxic substances and increased virulence.


On Building Online Visualization Maps for News Data Streams by Means of Mathematical Optimization.
In this article we develop a novel online framework to visualize news data over a time horizon. First, we perform a Natural Language Processing analysis, wherein the words are extracted, and their attributes, namely the importance and the relatedness, are calculated. Second, we present a Mathematical Optimization model for the visualization problem and a numerical optimization approach. The model represents the words using circles, the time-varying area of which displays the importance of the words in each time period. Word location in the visualization region is guided by three criteria, namely, the accurate representation of semantic relatedness, the spread of the words in the visualization region to improve the quality of the visualization, and the visual stability over the time horizon. Our approach is flexible, allowing the user to interact with the display, as well as incremental and scalable. We show results for three case studies using data from Danish news sources.


One-year follow-up in patients with brainstem infarction due to large-artery atherothrombosis.
Posterior circulation infarction accounts for approximately 25% of the ischemic strokes. A number of different conditions may be associated with the development of brainstem infarction. Prognosis and recurrence rate of brainstem infarction due to large-artery atherothrombosis is still controversial. A total of 826 patients with ischemic stroke were admitted to our clinic during a 15-month period. Patients with clinical and radiological evidence of brainstem infarction were comprehensively assessed with appropriate vascular imaging modalities and for cardiological causes. Subjects with an established diagnosis of large-artery atherothrombosis were followed up for 1 year in terms of prognosis and recurrence rates. Of the 101 patients with an established brainstem infarction, the diagnostic work-up indicated the presence of large-artery atherothrombosis as the causative factor in 53. A recurrent stroke was detected in the posterior circulation within the first 3 months in 5.8% and within 1 year in 9.8% of these individuals. The 1-year mortality rate was 11.7%. All patients with recurrent stroke had intracranial vascular narrowing at baseline. Our findings demonstrate a particularly high rate of recurrence and mortality at 1 year among patients who have a brainstem infarction due to intracranial arterial stenosis.


Fate of Foodborne Viruses in the "Farm to Fork" Chain of Fresh Produce.
Norovirus (NoV) and hepatitis A virus (HAV) are the most important foodborne viruses. Fresh produce has been identified as an important vehicle for their transmission. In order to supply a basis to identify possible prevention and control strategies, this review intends to demonstrate the fate of foodborne viruses in the farm to fork chain of fresh produce, which include the introduction routes (contamination sources), the viral survival abilities at different stages, and the reactions of foodborne viruses towards the treatments used in food processing of fresh produce. In general, the preharvest contamination comes mainly from soli fertilizer or irrigation water, while the harvest and postharvest contaminations come mainly from food handlers, which can be both symptomatic and asymptomatic. Foodborne viruses show high stabilities in all the stages of fresh produce production and processing. Low-temperature storage and other currently used preservation techniques, as well as washing by water have shown limited added value for reducing the virus load on fresh produce. Chemical sanitizers, although with limitations, are strongly recommended to be applied in the wash water in order to minimize cross-contamination. Alternatively, radiation strategies have shown promising inactivating effects on foodborne viruses. For high-pressure processing and thermal treatment, efforts have to be made on setting up treatment parameters to induce sufficient viral inactivation within a food matrix and to protect the sensory and nutritional qualities of fresh produce to the largest extent.


Narrow band imaging and white light endoscopy in the characterization of a polypectomy scar: A single-blind observational study.
To assess the incremental benefit of narrow band imaging (NBI) and white light endoscopy (WLE), randomizing the initial technique for the detection of residual neoplasia at the polypectomy scar after an endoscopic piecemeal mucosal resection (EPMR). We conducted an observational study in an academic center to assess the incremental benefit of NBI and WLE randomly applied 1:1 (NBI-WLE or WLE-NBI) in the follow-up of a post-EPMR scar by the same endoscopist. A total of 112 EPMR scars were included. The median baseline polyp size was 20 mm (interquartile range: 14-30). At first review, NBI and WLE showed good sensitivity (85.0% vs 78.9%), specificity (77.1% vs 84.2%) and overall accuracy (80.0% vs 82.5%). NBI after WLE (WLE-NBI group) improved accuracy, but this difference was not statistically significant [area under the curve (AUC): 86.8% vs 81.6%, P = 0.15]. WLE after NBI (NBI-WLE group) did not improve accuracy (AUC: 81.4% vs 81.1%, P = 0.9). Overall, recurrence was found in 39/112 (34.8%) lesions. Although no statistically significant differences were found between the two techniques at the first post-EPMR assessment, the use of NBI after WLE may improve residual neoplasia detection. Nevertheless, biopsy is still required in the first scar review.


Mucoepidermoid lung carcinoma in child.
Mucoepidermoid carcinoma (MEC) is a rare malignant tumor arising from the bronchial gland. A case of 6-year-old male child who presented with fever, hemoptysis and wheezing since 1month is reported. Chest X-ray showed features suggestive of foreign body with post-obstructive pneumonia and was treated for the same with medication without much improvement. Subsequently computerized tomography scan chest was carried out, which showed oval mass with speculated margin in right hilar region with distal segmental atelectasis. Bronchoscopy showed small growth with nodularity in the apical segmental bronchus of the right lower lobe with mucosal erosion and hence carried out broncho-alveolar lavage showed few atypical squamous cells. Patient underwent right lower lobectomy, which showed a grey white oval mass with solid and cystic areas in the right hilar region with extension in to the lung parenchyma. Histology of the tumor showed mixed solid and cystic areas with sheets of epidermoid cells and mucus-filled cysts of irregular size. Areas of solid growth were composed of squamoid and intermediate cells. Hence, the final diagnosis of mucoepidermoid carcinoma (MEC) intermediate grade of the lung was made. Early diagnosis can be accomplished if the clinician is alert to persistent pneumonia, coughing and tumor obstruction on image studies. MEC is a comparatively rare low-grade tumor, which reportedly carries a good prognosis with early surgical intervention.


Unruptured intracranial aneurysms and life insurance underwriting.
Unruptured intracranial aneurysms are common. Rupture is rare, but associated with considerable morbidity and mortality. Screening for unruptured intracranial aneurysms is indicated in certain patient populations, but many patients request screening outside of established guidelines. In addition, intracranial aneurysms may be discovered incidentally. The presence of an intracranial aneurysm has a negative effect for the patient seeking life insurance. This commentary provides a perspective on insurance underwriting in individuals with unruptured intracranial aneurysms and offers points for clinicians to consider when counseling patients seeking screening.


A 12-wk whole-grain wheat intervention protects against hepatic fat: the Graandioos study, a randomized trial in overweight subjects.
Whole-grain wheat (WGW) is described as nutritionally superior to refined wheat (RW) and thus advocated as the healthy choice, although evidence from intervention studies is often inconsistent. The liver, as the central organ in energy metabolism, might be an important target organ for WGW interventions. The aim of this study was to investigate the potential benefits of WGW consumption compared with RW consumption on liver health and associated parameters. We performed a double-blind, parallel trial in which 50 overweight 45- to 70-y-old men and postmenopausal women were randomly allocated to a 12-wk intervention with either WGW (98 g/d) or RW (98 g/d) products. Before and after the intervention we assessed intrahepatic triglycerides (IHTGs) and fat distribution by proton magnetic resonance spectroscopy/magnetic resonance imaging, fecal microbiota composition, adipose tissue gene expression, and several fasting plasma parameters, as well as postprandial plasma lipids after a mixed meal. Fasting plasma cholesterol, triglycerides, nonesterified fatty acids, and insulin were not affected by RW or WGW intervention. We observed a substantial increase of 49.1% in IHTGs in the RW when compared with the WGW group (P = 0.033). Baseline microbiota composition could not predict the increase in IHTGs after RW, but gut microbiota diversity decreased in the RW group when compared with the WGW group (P = 0.010). In the WGW group, we observed increased postprandial triglyceride levels compared with the RW group (P = 0.020). In addition, the WGW intervention resulted in a trend towards lower fasting levels of the liver acute-phase proteins serum amyloid A (P = 0.057) and C-reactive protein (P = 0.064) when compared to the RW intervention. A 12-wk RW intervention increases liver fat and might contribute to the development of nonalcoholic fatty liver disease, whereas a 12-wk 98-g/d WGW intervention prevents a substantial increase in liver fat. Our results show that incorporating feasible doses of WGW in the diet at the expense of RW maintains liver health. The study was registered at clinicaltrials.gov as NCT02385149.


Signatures of recent directional selection under different models of population expansion during colonization of new selective environments.
A major problem in population genetics is understanding how the genomic pattern of polymorphism is shaped by natural selection and the demographic history of populations. Complex population dynamics confounds patterns of variation and poses serious challenges for identifying genomic imprints of selection. We examine patterns of polymorphism using computer simulations and provide analytical predictions for hitchhiking effects under two models of adaptive niche expansion. The population split (PS) model assumes the separation of a founding population followed by directional selection in the new environment. Here, the new population undergoes a bottleneck and later expands in size. This model has been used in previous studies to account for demographic effects when testing for signatures of selection under colonization or domestication. The genotype-dependent colonization and introgression (GDCI) model is proposed in this study and assumes that a small number of migrants carrying adaptive genotype found a new population, which then grows logistically. The GDCI model also allows for constant migration between the parental and the new population. Both models predict reduction in variation and excess of high frequency of derived alleles relative to neutral expectations, with and without hitchhiking. Under comparable conditions, the GDCI model results in greater reduction in expected heterozygosity and more skew of the site frequency spectrum than the PS model. We also find that soft selective sweeps (fixation of multiple copies of a beneficial mutation) occurs less often in the GDCI model than in the PS model. This result demonstrates the importance of correctly modeling the ecological process in inferring adaptive evolution using DNA sequence polymorphism.


Fast inverse nonlinear Fourier transform.
This paper considers the non-Hermitian Zakharov-Shabat scattering problem which forms the basis for defining the SU(2)-nonlinear Fourier transform (NFT). The theoretical underpinnings of this generalization of the conventional Fourier transform is quite well established in the Ablowitz-Kaup-Newell-Segur formalism; however, efficient numerical algorithms that could be employed in practical applications are still unavailable. In this paper, we present two fast inverse NFT algorithms with O(KN+Nlog^{2}N) complexity and a convergence rate of O(N^{-2}), where N is the number of samples of the signal and K is the number of eigenvalues. These algorithms are realized using a new fast layer-peeling (LP) scheme [O(Nlog^{2}N)] together with a new fast Darboux transformation (FDT) algorithm [O(KN+Nlog^{2}N)] previously developed by V. Vaibhav [Phys. Rev. E 96, 063302 (2017)2470-004510.1103/PhysRevE.96.063302]. The proposed fast inverse NFT algorithm proceeds in two steps: The first step involves computing the radiative part of the potential using the fast LP scheme for which the input is synthesized under the assumption that the radiative potential is nonlinearly bandlimited, i.e., the continuous spectrum has a compact support. The second step involves addition of bound states using the FDT algorithm. Finally, the performance of these algorithms is demonstrated through exhaustive numerical tests.


Evolution of the Enterococcus faecalis sex pheromone system.
In this article we present data that form the basis of a model of the evolution of the unique Enterococcus faecalis sex pheromone system. The data indicate tht sex pheromone plasmid-encoded genes/functions, which are essential for this highly efficient plasmid collection system, are common among all sex pheromone plasmids; pAM373 seems to be only distantly related to all other pheromone plasmids. These genes appear to be restricted to sex pheromone plasmids (but see below for possible exceptions). However, the ability to produce sex pheromone-like peptides is not restricted to E. faecalis. We argue that the sex pheromone system of E. faecalis developed only once--but into at least 19 different variants--to form a system which is highly specific for this bacterium and is related to virulence.


Immunoreactivity for high-affinity choline transporter colocalises with VAChT in human enteric nervous system.
Cholinergic nerves are identified by labelling molecules in the ACh synthesis, release and destruction pathway. Recently, antibodies against another molecule in this pathway have been developed. Choline reuptake at the synapse occurs via the high-affinity choline transporter (CHT1). CHT1 immunoreactivity is present in cholinergic nerve fibres containing vesicular acetylcholine transporter (VAChT) in the human and rat central nervous system and rat enteric nervous system. We have examined whether CHT1 immunoreactivity is present in nerve fibres in human intestine and whether it is colocalised with markers of cholinergic, tachykinergic or nitrergic circuitry. Human ileum and colon were fixed, sectioned and processed for fluorescence immunohistochemistry with antibodies against CHT1, class III beta-tubulin (TUJ1), synaptophysin, common choline acetyl-transferase (cChAT), VAChT, nitric oxide synthase (NOS), substance P (SP) and vasoactive intestinal peptide (VIP). CHT1 immunoreactivity was present in many nerve fibres in the circular and longitudinal muscle, myenteric and submucosal ganglia, submucosa and mucosa in human colon and ileum and colocalised with immunoreactivity for TUJ1 and synaptophysin confirming its presence in nerve fibres. In nerve fibres in myenteric ganglia and muscle, CHT1 immunoreactivity colocalised with immunoreactivity for VAChT and cChAT. Some colocalisation occurred with SP immunoreactivity, but little with immunoreactivity for VIP or NOS. In the mucosa, CHT1 immunoreactivity colocalised with that for VIP and SP in nerve fibres and was also present in vascular nerve fibres in the submucosa and on epithelial cells on the luminal border of crypts. The colocalisation of CHT1 immunoreactivity with VAChT immunoreactivity in cholinergic enteric nerves in the human bowel thus suggests that CHT1 represents another marker of cholinergic nerves.


Cancer drug addiction is relayed by an ERK2-dependent phenotype switch.
Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumours on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we must first define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of the serine/threonine-protein kinase BRAF, in order to functionally mine their genome for 'addiction genes'. Here we describe a signalling pathway comprising ERK2 kinase and JUNB and FRA1 transcription factors, disruption of which allowed addicted tumour cells to survive on treatment discontinuation. This occurred in both cultured cells and mice and was irrespective of the acquired drug resistance mechanism. In melanoma and lung cancer cells, death induced by drug withdrawal was preceded by a specific ERK2-dependent phenotype switch, alongside transcriptional reprogramming reminiscent of the epithelial-mesenchymal transition. In melanoma cells, this reprogramming caused the shutdown of microphthalmia-associated transcription factor (MITF), a lineage survival oncoprotein; restoring this protein reversed phenotype switching and prevented the lethality associated with drug addiction. In patients with melanoma that had progressed during treatment with a BRAF inhibitor, treatment cessation was followed by increased expression of the receptor tyrosine kinase AXL, which is associated with the phenotype switch. Drug discontinuation synergized with the melanoma chemotherapeutic agent dacarbazine by further suppressing MITF and its prosurvival target, B-cell lymphoma 2 (BCL-2), and by inducing DNA damage in cancer cells. Our results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.


Charged pair current networks in bioenergetics.
The operation of bioenergetic systems is postulated to be based on charged pair networks. The basic elements of the networks are pairs of opposite charges accompanied by conformational changes of the protein medium. The elementary events are the separation and recombination of charged pairs and partner exchange between two such pairs. The last event makes the construction of networks possible and provides for the flexibility of coupling modes in mitochondria. Bioenergetic systems appear to use electricity in a hitherto unsuspected way. The networks are constructed entirely on electrostatic principles. The possibility of generalization to include mechanical elements is discussed.


Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution.
Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague-Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.


[Changes in phosphorus-calcium metabolism in experimental renal insufficiency and after administration of dihydrotachysterol and thyrocalcitonin].
Development of experimental chronic renal insufficiency in rats was accompanied by an increase in concentration of residual nitrogen and phosphorus in blood and also by a decrease in intestinal absorption of Ca2+, however, no hypocalcemia was observed and the alkaline phosphatase activity was unaltered in blood serum. At the same time the renal insufficiency caused in some animals metastatic calcification of aorta and kidney, which was manifested by increased calcium concentration in these tissues. Administration of dihydrotachysterol increased the active transport of Ca2+ in rat intestine at the later steps of the impairment and led to development of moderate hypercalcemia and particularly to an increase in the degree of calcinosis of aorta and kidney. Administration of thyrocalcitonine did not prevent the hypercalcemia and calcinosis of internal tissues.


[Dynamics of the hormone profile and cardiovascular changes in toxic goiter as affected by lithium carbonate].
Clinical and physiological data, characterizing a total endocrinological status, thyroid hormone secretion and the cardiovascular functional state, were determined in 68 patients with diffuse toxic goiter of different severity. Lithium carbonate tablets (0.3 g) were indicated orally in a dose of 0.9 to 1.2 g daily during 3--4 months. Good results were obtained in 48.5% of the patients, moderate ones in 41.2% and in 10.3% of cases the drug was ineffective. Over a period of lithium carbonate treatment the thyroid iodine-containing and hormone-forming functions improved, renin plasmatic activity and cortisol level lowered, hyperactivity of the insular apparatus diminished. Hemocirculatory signs returned to normal and hyperdynamic ones decreased. Lithium carbonate is particularly effective in mild and moderate thyrotoxicoses, as well as during a preparing patients for the radical treatment, i.e. strumectomy.


Regulation of salt tolerance in fission yeast by a protein-phosphatase-Z-like Ser/Thr protein phosphatase.
In the yeast Saccharomyces cerevisiae, Na+ efflux is mediated by the Ena1 ATPase, and the expression of the ENA1 gene is regulated by the Ppz1 and Ppz2 Ser/Thr protein phosphatases. On the contrary, in the fission yeast Schizosaccharomyces pombe, effective output of Na+ is attributed to the H+/Na+ antiporter encoded by the sod2 gene. We have isolated a S. pombe gene (pzh1) that encodes a 515-amino-acid protein that is 78% identical, from residue 193 to the COOH terminus, to the PPZ1 and PPZ2 gene products. Bacterially expressed Pzh1p shows enzymatic characteristics virtually identical to those of recombinant Ppz1p. When expressed in high-copy number from the PPZ1 promoter, the pzh1 ORF rescues the caffeine-induced lytic defect and slightly decreases the high salt tolerance of S. cerevisiae ppz1delta mutants. Disruption of pzh1 yields viable S. pombe cells and has virtually no effect on tolerance to caffeine or osmotic stress, but it renders the cells highly tolerant to Na+ and Li+, and hypersensitive to K+. Although lack of pzh1 results in a 2-3-fold increase in sod2 mRNA, the pzh1 mutation significantly increases salt tolerance in the absence of the sod2 gene, suggesting that the phosphatase also regulates a Sod2-independent mechanism. Therefore, the finding of a PPZ-like protein phosphatase involved in the regulation of salt tolerance in fission yeast reveals unexpected aspects of cation homeostasis in this organism.


Tumor length in prostate cancer.
To evaluate the impact of tumor length and fraction of positive biopsy cores on overall survival, I used the data for 526 patients with prostate cancer. Median follow-up in patients not observed until death was more than 6 years. In a Cox model analysis that included age, serum prostate-specific antigen (PSA) level, grade, and fraction of positive cores, tumor length was the most closely associated with overall survival time (P=6 x 10(-5)); however, the impact of tumor length was mostly for a subset of men with tumors measuring more than 20 mm. Patient age, serum PSA level, Gleason score, fraction of cores with tumor, and tumor length were all significantly codependent variables. For routine cases of prostate cancer, measuring tumor length in the needle cores may be unnecessary. Tumor length may assist studies of long-term outcomes or treatment trials in prostate cancer by reducing baseline variance better than other prognostic variables. For the few patients with unusually large amounts of tumor in biopsy specimens, tumor length may provide a concise indicator for the likelihood of an adverse outcome, especially when the values of other prognostic variables appear by themselves to be less ominous.


Fragile X protein FMRP is required for homeostatic plasticity and regulation of synaptic strength by retinoic acid.
Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis of AMPA-type glutamate receptors (AMPARs) in dendrites and promotes synaptic insertion of newly synthesized AMPARs. Here, we show that fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knock-out neurons, RA-dependent dendritic translation of GluR1-type AMPA receptors is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity that is dependent on both RA signaling and local protein synthesis. Postsynaptic expression of wild-type or mutant FMRP(I304N) in knock-out neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Expression of FMRP lacking the RGG box RNA-binding domain had no effect on AMPAR levels. Importantly, postsynaptic expression of wild-type FMRP, but not FMRP(I304N) or FMRPΔRGG, restored synaptic scaling when expressed in knock-out neurons. Together, these findings identify an unanticipated role for FMRP in regulating homeostatic synaptic plasticity downstream of RA. Our results raise the possibility that at least some of the symptoms of fragile X syndrome reflect impaired homeostatic plasticity and impaired RA signaling.


Cultural legacies, fire ecology, and environmental change in the Stone Country of Arnhem Land and Kakadu National Park, Australia.
We use the fire ecology and biogeographical patterns of Callitris intratropica, a fire-sensitive conifer, and the Asian water buffalo (Bubalus bubalis), an introduced mega-herbivore, to examine the hypothesis that the continuation of Aboriginal burning and cultural integration of buffalo contribute to greater savanna heterogeneity and diversity in central Arnhem Land (CAL) than Kakadu National Park (KNP). The 'Stone Country' of the Arnhem Plateau, extending from KNP to CAL, is a globally renowned social-ecological system, managed for millennia by Bininj-Kunwok Aboriginal clans. Regional species declines have been attributed to the cessation of patchy burning by Aborigines. Whereas the KNP Stone Country is a modern wilderness, managed through prescribed burning and buffalo eradication, CAL remains a stronghold for Aboriginal management where buffalo have been culturally integrated. We surveyed the plant community and the presence of buffalo tracks among intact and fire-damaged C. intratropica groves and the savanna matrix in KNP and CAL. Aerial surveys of C. intratropica grove condition were used to examine the composition of savanna vegetation across the Stone Country. The plant community in intact C. intratropica groves had higher stem counts of shrubs and small trees and higher proportions of fire-sensitive plant species than degraded groves and the savanna matrix. A higher proportion of intact C. intratropica groves in CAL therefore indicated greater gamma diversity and habitat heterogeneity than the KNP Stone Country. Interactions among buffalo, fire, and C. intratropica suggested that buffalo also contributed to these patterns. Our results suggest linkages between ecological and cultural integrity at broad spatial scales across a complex landscape. Buffalo may provide a tool for mitigating destructive fires; however, their interactions require further study. Sustainability in the Stone Country depends upon adaptive management that rehabilitates the coupling of indigenous culture, disturbance, and natural resources.


Does comorbid chronic pain affect posttraumatic stress disorder diagnosis and treatment? Outcomes of posttraumatic stress disorder screening in Department of Veterans Affairs primary care.
Because posttraumatic stress disorder (PTSD) is both prevalent and underrecognized, routine primary care-based screening for PTSD has been implemented across the Veterans Health Administration. PTSD is frequently complicated by the presence of comorbid chronic pain, and patients with both conditions have increased symptom severity and poorer prognosis. Our objective was to determine whether the presence of pain affects diagnosis and treatment of PTSD among Department of Veterans Affairs (VA) patients who have a positive PTSD screening test. This retrospective cohort study used clinical and administrative data from six Midwestern VA medical centers. We identified 4,244 VA primary care patients with a positive PTSD screen and compared outcomes for those with and without a coexisting pain diagnosis. Outcomes were three clinically appropriate responses to positive PTSD screening: (1) mental health visit, (2) PTSD diagnosis, and (3) new selective serotonin reuptake inhibitor (SSRI) prescription. We found that patients with coexisting pain had a lower rate of mental health visits than those without pain (hazard ratio: 0.889, 95% confidence interval: 0.821-0.962). There were no significant differences in the rate of PTSD diagnosis or new SSRI prescription between patients with and without coexisting pain.


[Tinnitus and its radiological diagnosis and therapy].
Tinnitus is a familiar symptom in diseases of the central nervous system. Its aetiology being of a varied nature, the type of tinnitus is a pointer to the pathoanatomic findings that are responsible for the disease. The causes of tinnitus are often found in the borderline areas between various neighbouring disciplines, such as otology, neurology and neurosurgery, whereas the final identification of the real causes is mainly within the scope of radiological diagnosis, in which computed tomography and superselective angiography play an essential role. In addition to arteriovenous fistulas near the petrous bone and glomus tumours, which are well known, there are a few other aetiologies of pulse-synchronous tinnitus that are being discussed in this paper. In recent years there has been substantial therapeutical progress owing to the introduction of new techniques and the development of improved materials for embolisation in interventional neuroradiology. Their application is discussed in connection with various patient groups.


A near-fatal case of intussusception and ischaemic perforation of stomach in first-trimester pregnancy: eight years after laparoscopic Roux-en-Y gastric bypass.
The increasing demand and popularity of bariatric surgery are not only due to the ever-increasing obesity epidemic but to tackle obesity-related comorbidities like diabetes and hypertension. However, bariatric surgery is not free of complications. One rare complication is intussusception, jejuno-jejunal intussusception being the most common. Intussusception has been defined both in pregnant and in non-pregnant women as well as men. We describe the case of a 40-year-old woman in the first trimester of pregnancy came to the hospital with worsening abdominal pain, was found to have intussusception of small bowel involving the jejunum, along with ischaemic perforation and necrosis of the fundus of the stomach. Postsurgery, the patient had a complete recovery and eventually, she successfully delivered an intact, viable fetus.


Nucleophilic catalysis with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) for the esterification of carboxylic acids with dimethyl carbonate.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is an effective nucleophilic catalyst for carboxylic acid esterification with dimethyl carbonate (DMC). The reaction pathway of this new class of nucleophilic catalysis has been studied. A plausible, multistep mechanism is proposed, which involves an initial N-acylation of DBU with DMC to form a carbamate intermediate. Subsequent O-alkylation of the carboxylate with this intermediate generates the corresponding methyl ester in excellent yield. In the absence of DBU or in the presence of other bases, such as ammonium hydroxide or N-methylmorpholine, the same reaction affords no desired product. This method is particularly valuable for the synthesis of methyl esters that contain acid-sensitive functionality.


Recent advances in point-of-care testing of COVID-19.
Advances in microfluidic device miniaturization and system integration contribute to the development of portable, handheld, and smartphone-compatible devices. These advancements in diagnostics have the potential to revolutionize the approach to detect and respond to future pandemics. Accordingly, herein, recent advances in point-of-care testing (POCT) of coronavirus disease 2019 (COVID-19) using various microdevices, including lateral flow assay strips, vertical flow assay strips, microfluidic channels, and paper-based microfluidic devices, are reviewed. However, visual determination of the diagnostic results using only microdevices leads to many false-negative results due to the limited detection sensitivities of these devices. Several POCT systems comprising microdevices integrated with portable optical readers have been developed to address this issue. Since the outbreak of COVID-19, effective POCT strategies for COVID-19 based on optical detection methods have been established. They can be categorized into fluorescence, surface-enhanced Raman scattering, surface plasmon resonance spectroscopy, and wearable sensing. We introduced next-generation pandemic sensing methods incorporating artificial intelligence that can be used to meet global health needs in the future. Additionally, we have discussed appropriate responses of various testing devices to emerging infectious diseases and prospective preventive measures for the post-pandemic era. We believe that this review will be helpful for preparing for future infectious disease outbreaks.


A mariner transposon vector adapted for mutagenesis in oral streptococci.
This article describes the construction and characterization of a mariner-based transposon vector designed for use in oral streptococci, but with a potential use in other Gram-positive bacteria. The new transposon vector, termed pMN100, contains the temperature-sensitive origin of replication repATs-pWV01, a selectable kanamycin resistance gene, a Himar1 transposase gene regulated by a xylose-inducible promoter, and an erythromycin resistance gene flanked by himar inverted repeats. The pMN100 plasmid was transformed into Streptococcus mutans UA159 and transposon mutagenesis was performed via a protocol established to perform high numbers of separate transpositions despite a low frequency of transposition. The distribution of transposon inserts in 30 randomly picked mutants suggested that mariner transposon mutagenesis is unbiased in S. mutans. A generated transposon mutant library containing 5000 mutants was used in a screen to identify genes involved in the production of sucrose-dependent extracellular matrix components. Mutants with transposon inserts in genes encoding glycosyltransferases and the competence-related secretory locus were predominantly found in this screen.


A map of neurofilament light chain species in brain and cerebrospinal fluid and alterations in Alzheimer's disease.
Neurofilament light is a well-established marker of both acute and chronic neuronal damage and is increased in multiple neurodegenerative diseases. However, the protein is not well characterized in brain tissue or body fluids, and it is unknown what neurofilament light species are detected by commercial assays and whether additional species exist. We developed an immunoprecipitation-mass spectrometry assay using custom antibodies targeting various neurofilament light domains, including antibodies targeting Coil 1A/1B of the rod domain (HJ30.13), Coil 2B of the rod domain (HJ30.4) and the tail region (HJ30.11). We utilized our assay to characterize neurofilament light in brain tissue and CSF of individuals with Alzheimer's disease dementia and healthy controls. We then validated a quantitative version of our assay and measured neurofilament light concentrations using both our quantitative immunoprecipitation-mass spectrometry assay and the commercially available immunoassay from Uman diagnostics in individuals with and without Alzheimer's disease dementia. Our validation cohort included CSF samples from 30 symptomatic amyloid-positive participants, 16 asymptomatic amyloid-positive participants, 10 symptomatic amyloid-negative participants and 25 amyloid-negative controls. We identified at least three major neurofilament light species in CSF, including N-terminal and C-terminal truncations, and a C-terminal fragment containing the tail domain. No full-length neurofilament light was identified in CSF. This contrasts with brain tissue, which contained mostly full-length neurofilament and a C-terminal tail domain fragment. We observed an increase in neurofilament light concentrations in individuals with Alzheimer's disease compared with healthy controls, with larger differences for some neurofilament light species than for others. The largest differences were observed for neurofilament light fragments including NfL165 (in Coil 1B), NfL324 (in Coil 2B) and NfL530 (in the C-terminal tail domain). The Uman immunoassay correlated most with NfL324. This study provides a comprehensive evaluation of neurofilament light in brain and CSF and enables future investigations of neurofilament light biology and utility as a biomarker.


Roseibium aquae sp. nov., isolated from a saline lake.
A Gram-staining-negative bacterium, strain DSG-S4-2(T), was isolated from Dasugan Lake, a saline lake (salinity 3.1%, w/v) in Qaidam basin, Qinghai, China and its taxonomic position was determined by using a polyphasic approach. Cells of strain DSG-S4-2(T) were non-spore-forming rods, 0.5-0.8 µm wide and 1.2-3.8 µm long and motile by means of a single polar flagellum. Strain DSG-S4-2(T) was strictly heterotrophic and aerobic, catalase-positive and oxidase-negative. PufLM and coxL genes were present, bacteriochlorophyll a (BChl a) and a carotenoid pigment were produced. Growth was observed in the presence of 0-8.0% (w/v) NaCl (optimum, 1.0-2.0%), at 20-40 °C (optimum, 35 °C) and pH 6.5-10.5 (optimum, pH 7.5-8.0). Strain DSG-S4-2(T) contained Q-10 as the sole respiratory quinone. The polar lipids contained two aminolipids, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, sulphoquinovosyldiacylglyceride, phosphatidylcholine and some unknown phospholipids, like the other members of the genus Roseibium. The predominant fatty acid (>70%) was summed feature 8 (C(18 : 1)ω7c and/or C(18 : 1)ω6c). The DNA G+C content was 61.4 mol% (determined from melting temperature). Phylogenetic trees (neighbour-joining, maximum-likelihood and maximum-parsimony) based on 16S rRNA gene sequences showed that strain DSG-S4-2(T) was associated with the members of the genus Roseibium, with highest 16S rRNA gene sequence similarity to Roseibium denhamense OCh 254(T) (96.3%) and Roseibium hamelinense OCh 368(T) (96.3%). Based on the data presented above, it is concluded that strain DSG-S4-2(T) represents a novel species of the genus Roseibium, for which the name Roseibium aquae sp. nov. is proposed. The type strain is DSG-S4-2(T) ( = CGMCC 1.12426(T) = JCM 19310(T)).


[Effect of early nutritional intervention in the a outcome of patients at risk clinical nutrition].
Hospital malnutrition is a multi-causal process and high prevalence. Nutritional intervention at an early stage improves prognosis of affected patients. To compare the effect of early nutritional intervention with a routine care on clinical outcome in patients with detected nutritional risk screening tool NRS Nutritional Risk Screening 2002, entering an institution of complex health. A quasi-experimental study. Was assessed in the first 48 hours of admission to 891 patients, of whom 247 were at nutritional risk, 116 were the routine care group and 54 the intervention group. We evaluated complications, hospital stay, weight loss, change in body mass index and protein-calorie adequacy. Patients undergoing caloric intake had higher (1617 ± 444.5 vs 1366 ± 467.1 kcal, p = 0.002) and protein (1.2 ± 0.2 vs 0.9 ± 0.3 g, p = 0.000), average weight gain of 0.7% vs a loss of 2.3% (p = 0.000), a proportion of moderate complications 8.2% vs 25.2% (p = 0.012) and decreased time hospital stay of 2.2 days (p = 0.138) compared with routine care group. Early nutritional intervention in patients at nutritional risk decreased the proportion of moderate complications, improved the adequacy of energy, protein and nutritional evolution in terms of weight gain and change in BMI. The length of stay did not differ significantly.


Comparative whole genome analysis reveals re-emergence of human Wa-like and DS-1-like G3 rotaviruses after Rotarix vaccine introduction in Malawi.
G3 rotaviruses rank among the most common rotavirus strains worldwide in humans and animals. However, despite a robust long-term rotavirus surveillance system from 1997 at Queen Elizabeth Central Hospital in Blantyre, Malawi, these strains were only detected from 1997 to 1999 and then disappeared and re-emerged in 2017, 5 years after the introduction of the Rotarix rotavirus vaccine. Here, we analysed representative twenty-seven whole genome sequences (G3P[4], n = 20; G3P[6], n = 1; and G3P[8], n = 6) randomly selected each month between November 2017 and August 2019 to understand how G3 strains re-emerged in Malawi. We found four genotype constellations that were associated with the emergent G3 strains and co-circulated in Malawi post-Rotarix vaccine introduction: G3P[4] and G3P[6] strains with the DS-1-like genetic backbone genes (G3-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2 and G3-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2), G3P[8] strains with the Wa-like genetic backbone genes (G3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1), and reassortant G3P[4] strains consisting of the DS-1-like genetic backbone genes and a Wa-like NSP2 (N1) gene (G3-P[4]-I2-R2-C2-M2-A2-N1-T2-E2-H2). Time-resolved phylogenetic trees demonstrated that the most recent common ancestor for each ribonucleic acid (RNA) segment of the emergent G3 strains was between 1996 and 2012, possibly through introductions from outside the country due to the limited genetic similarity with G3 strains which circulated before their disappearance in the late 1990s. Further genomic analysis revealed that the reassortant DS-1-like G3P[4] strains acquired a Wa-like NSP2 genome segment (N1 genotype) through intergenogroup reassortment; an artiodactyl-like VP3 through intergenogroup interspecies reassortment; and VP6, NSP1, and NSP4 segments through intragenogroup reassortment likely before importation into Malawi. Additionally, the emergent G3 strains contain amino acid substitutions within the antigenic regions of the VP4 proteins which could potentially impact the binding of rotavirus vaccine-induced antibodies. Altogether, our findings show that multiple strains with either Wa-like or DS-1-like genotype constellations have driven the re-emergence of G3 strains. The findings also highlight the role of human mobility and genome reassortment events in the cross-border dissemination and evolution of rotavirus strains in Malawi necessitating the need for long-term genomic surveillance of rotavirus in high disease-burden settings to inform disease prevention and control.


Transcriptome-Wide Comparison of Stress Granules and P-Bodies Reveals that Translation Plays a Major Role in RNA Partitioning.
The eukaryotic cytosol contains multiple RNP granules, including P-bodies and stress granules. Three different methods have been used to describe the transcriptome of stress granules or P-bodies, but how these methods compare and how RNA partitioning occurs between P-bodies and stress granules have not been addressed. Here, we compare the analysis of the stress granule transcriptome based on differential centrifugation with and without subsequent stress granule immunopurification. We find that while differential centrifugation alone gives a first approximation of the stress granule transcriptome, this methodology contains nonspecific transcripts that play a confounding role in the interpretation of results. We also immunopurify and compare the RNAs in stress granules and P-bodies under arsenite stress and compare those results to those for the P-body transcriptome described under nonstress conditions. We find that the P-body transcriptome is dominated by poorly translated mRNAs under nonstress conditions, but during arsenite stress, when translation is globally repressed, the P-body transcriptome is very similar to the stress granule transcriptome. This suggests that translation is a dominant factor in targeting mRNAs into both P-bodies and stress granules, and during stress, when most mRNAs are untranslated, the composition of P-bodies reflects this broader translation repression.


Thoracolumbar spinal abnormalities in Stickler syndrome.
Retrospective review of clinical and radiographic records of patients with Stickler syndrome. To describe thoracolumbar spinal abnormalities and their correlation with age and back pain among patients with Stickler syndrome. Stickler syndrome (hereditary arthro-ophthalmopathy) is an autosomal dominant connective tissue disorder characterized by skeletal, ocular, oral-facial, cardiac, and auditory manifestations. Prevalence is approximately 1 in 10,000 (similar to that of Marfan syndrome). No one has investigated spinal abnormalities in a large series of patients. A single-center evaluation of 53 patients from 24 families with Stickler syndrome (age range, 1-70 years) in a multidisciplinary genetics clinic. Thoracolumbar radiographs were analyzed for spinal abnormalities and correlation with age and back pain. Thirty-four percent of patients had scoliosis, 74% endplate abnormalities, 64% Schmorl's nodes, 43% platyspondylia, and 43% Scheuermann-like kyphosis. Sixty-seven percent of patients and 85% of adults reported chronic back pain. Endplate abnormalities and Schmorl's nodes were associated with adult age; endplate abnormalities, Schmorl's nodes, and adult age were associated with back pain. Only one adult patient was free of spinal abnormalities. Spinal abnormalities are nearly uniformly observed in Stickler syndrome, progress with age, and are associated with back pain. Although common, scoliosis is generally self-limited (only one patient needed surgical treatment). Correct diagnosis of this syndrome facilitates early identification and management of other potentially severe systemic manifestations and genetic counseling for affected families. Moreover, recognition of Stickler syndrome allows accurate prognosis for skeletal abnormalities and anticipation of potential surgical complications.


Radiolabeled ligands for imaging the muscarinic-cholinergic receptors of the heart and brain.
Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development of the new iodinated IQNP ligand based on IQNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the "partial" subtype selective IQNP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.


Emergent properties in optically bound matter.
Sub-micron particles have been observed to spontaneously form regular two-dimensional structures in counterpropagating evanescent laser fields. We show that collective properties of large numbers of optically-trapped particles can be qualitatively different to the properties of small numbers. This is demonstrated both with a computer model and with experimental results. As the number of particles in the structure is increased, optical binding forces can be sufficiently large to overcome the optical landscape imposed by the interference fringes of the laser beams and impose a different, competing structure.


Neuropathologic correlates for diffusion tensor imaging in postinfectious encephalopathy.
Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children.


Ligand-Induced Conformational Changes near the Active Site Regulating Enzyme Activity of Momorcharins from Seeds of Bitter Gourd.
It is reasonable to consider that Type I-ribosomal inactivation proteins (RIP) retain some specific affinity to harmful pathogens to complete the role as a bio-defense relating protein. In the present studies, it was shown that two Type I-RIPs, α- and β-momorcharins, maintained the abilities to bind with N-acetylglucosamine (NAG) to change the conformation around the active sites and to regulate their N-glycosidase activities. By the binding of NAG, the freedom of internal motion of Trp192 in α-momorcharin was increased 1.5 times near the active site and, on the other hand, the corresponding motion of Trp190 was limited 50% in β-momorcharin. The results in the fluorescence resonance excitation energy transfer experiments demonstrated that Trp-190 of β-momorcharin was kept away from Tyr-70 but Trp192 contrarily approached closer to the nearest neighboring Tyr residue consisting of the active center of α-momorcharin by the binding with NAG. These conformational changes near the active site close correlated with promotion and/or suppression of the N-glucosidase activities of β- and α-momorcharins.


Foreign body ingestion: rare cause of cervical abscess.
Foreign body ingestion is a frequent emergency occurrence. Serious complications, although rare, include pharyngooesophageal perforation, aorto-oesophageal fistula and deep neck infection. A retrospective review was performed of all cases of foreign body ingestion requiring hospitalization between 1989 and 2011, in a tertiary Hospital. Cases complicated by deep cervical abscess were selected and their clinical presentation, results of diagnostic exams, therapeutics and clinical evolution are presented. Among a total of 1679 cases, 319 were related to pediatric patients and 1360 to adults. Two cases were reported (0.12%): an adult, 41 years-old, with parapharyngeal abscess subsequent to fishbone ingestion, and a child, 13 months-old, with retropharyngeal abscess consequent to chicken bone ingestion. Complications appeared three and four days after foreign body removal, respectively. In both situations cervical computerized tomography scan with contrast and surgical drainage were accomplished; the child was also submitted to rigid esophagoscopy for residual foreign body removal and closure of the associated pharyngeal laceration. Deep cervical abscesses are an uncommon but possible complication of foreign body ingestion and constitute a diagnostic challenge, particularly in children. Previous oesophageal manipulation by flexible endoscopy may be considered a risk factor for such complication. Imagiological studies proved to be crucial for diagnosis and therapeutic planning. Although a rare complication, given a recent history of foreign body ingestion/removal and the presence of compatible symptoms, cervical abscesses should be taken into account, highlighting their potential morbimortality in the absence of an appropriate therapeutic approach.


A 2-screw fixation technique for subtalar joint fusion: a retrospective case series introducing a novel 2-screw fixation construct with operative pearls.
A variety of fixation methods are used in fusion of the subtalar joint (STJ) including 1 screw and 2 screw constructs. The rate of union is generally high for STJ fusion, regardless of the fixation method, provided the joint surfaces have been properly prepared and compressed and the patient avoids premature stress on the fusion site. Certain populations are known to have an increased risk of nonunion or delayed union including diabetics, smokers, and those undergoing revision of failed fusion. In this high-risk patient population, we propose that our novel 2-screw construct might have advantages over traditional fixation constructs without identified disadvantages. The technique is simple enough to be used in all primary and revision STJ fusion procedures, and this has become our practice. In the present study, 15 feet in 15 consecutive patients who underwent STJ fusion using a novel 2-screw fixation construct were retrospectively reviewed to assess the fusion outcome and complications. Specifically, we offer a novel 2-screw construct that offers the stability of the traditional parallel 2-screw construct while maintaining a maximum raw bone surface area at the posterior facet achieved by single-screw fixation. A retrospective review of radiographs taken 10 weeks postoperatively indentified a 100% fusion rate (15 of 15). All patients in our series achieved fusion, including several high-risk cases, and no significant complications were identified.


Structural analysis of Arabidopsis thaliana chromosome 5. III. Sequence features of the regions of 1,191,918 bp covered by seventeen physically assigned P1 clones.
A total of 17 P1 and TAC clones each containing a marker(s) specifically mapped on chromosome 5 were isolated from P1 and TAC libraries of the Arabidopsis thaliana Columbia genome, and their nucleotide sequences were determined according to the shot gun-based strategy and precisely located on the physical map of chromosome 5. The total length of the clones sequenced in this study was 1,191,918 bp. As we have previously reported the sequence of 2,662,078 bp by analysis of 33 P1 clones, the total length of the sequences of chromosome 5 determined so far is now 3,853,996 bp. The sequences determined in this study were subjected to similarity search against protein and EST databases and analysis with computer programs for gene modeling, and a total of 310 potential protein-coding genes and/or gene segments with known or predicted functions were identified. The positions of exons which do not show apparent similarity to known genes were also predicted by computer-aided analysis. An average density of the assigned genes and/or gene segments was 1 gene/3,845 bp. Introns were identified in 78% of the potential protein genes, and the average number per gene and the average length of the introns were 3.7 and 185 bp, respectively. The numbers of the Arabidopsis ESTs matched to each of the predicted genes have been counted to monitor the transcription level. The sequence data and gene information are available on the World Wide Web database KAOS (Kazusa Arabidopsis data Opening Site) at http://www.kazusa.or.jp/arabi/.


Predictors of Bacteremia in Children Hospitalized With Community-Acquired Pneumonia.
The yield of blood cultures in children hospitalized with community-acquired pneumonia (CAP) is low. Characteristics of children at increased risk of bacteremia remain largely unknown. We conducted a secondary analysis of a retrospective cohort study of children aged 3 months to 18 years hospitalized with CAP in 6 children's hospitals from 2007 to 2011. We excluded children with complex chronic conditions and children without blood cultures performed at admission. Clinical, laboratory, microbiologic, and radiologic data were assessed to identify predictors of bacteremia. Among 7509 children hospitalized with CAP, 2568 (34.2%) had blood cultures performed on the first day of hospitalization. The median age was 3 years. Sixty-five children with blood cultures performed had bacteremia (2.5%), and 11 children (0.4%) had bacteremia with a penicillin-nonsusceptible pathogen. The prevalence of bacteremia was increased in children with a white blood cell count >20 × 103 cells per µL (5.4%; 95% confidence interval 3.5%-8.1%) and in children with definite radiographic pneumonia (3.3%; 95% confidence interval 2.4%-4.4%); however, the prevalence of penicillin-nonsusceptible bacteremia was below 1% even in the presence of individual predictors. Among children hospitalized outside of the ICU, the prevalence of contaminated blood cultures exceeded the prevalence of penicillin-nonsusceptible bacteremia. Although the prevalence of bacteremia is marginally higher among children with leukocytosis or radiographic pneumonia, the rates remain low, and penicillin-nonsusceptible bacteremia is rare even in the presence of these predictors. Blood cultures should not be obtained in children hospitalized with CAP in a non-ICU setting.


Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs.
Second-generation antipsychotics have been thought to cause fewer extrapyramidal side-effects (EPS) than first-generation antipsychotics, but recent pragmatic trials have indicated equivalence. To determine whether second-generation antipsychotics had better outcomes in terms of EPS than first-generation drugs. We conducted an intention-to-treat, secondary analysis of data from an earlier randomised controlled trial (n = 227). A clinically significant difference was defined as double or half the symptoms in groups prescribed first- v. second-generation antipsychotics, represented by odds ratios greater than 2.0 (indicating advantage for first-generation drugs) or less than 0.5 (indicating advantage for the newer drugs). We also examined EPS in terms of symptoms emergent at 12 weeks and 52 weeks, and symptoms that had resolved at these time points. At baseline those randomised to the first-generation antipsychotic group (n = 118) had similar EPS to the second-generation group (n = 109). Indications of resolved Parkinsonism (OR = 0.5) and akathisia (OR = 0.4) and increased tardive dyskinesia (OR = 2.2) in the second-generation drug group at 12 weeks were not statistically significant and the effects were not present by 52 weeks. Patients in the second-generation group were dramatically (30-fold) less likely to be prescribed adjunctive anticholinergic medication, despite equivalence in terms of EPS. The expected improvement in EPS profiles for participants randomised to second-generation drugs was not found; the prognosis over 1 year of those in the first-generation arm was no worse in these terms. The place of careful prescription of first-generation drugs in contemporary practice remains to be defined, potentially improving clinical effectiveness and avoiding life-shortening metabolic disturbances in some patients currently treated with the narrow range of second-generation antipsychotics used in routine practice. This has educational implications because a generation of psychiatrists now has little or no experience with first-generation antipsychotic prescription.


Untrained young men have dysfunctional HDL compared with strength-trained men irrespective of body weight status.
We examined the impact of strength fitness and body weight on the redox properties of high-density lipoprotein (HDL) and associations with indices of vascular and metabolic health. Ninety young men were categorized into three groups: 1) overweight untrained (OU; n = 30; BMI 30.7 ± 2.1 kg/m(2)); 2) overweight trained [OT; n = 30; BMI 29.0 ± 1.9; ≥4 d/wk resistance training (RT)]; and 3) lean trained (LT; n = 30; BMI 23.7 ± 1.4; ≥4 d/wk RT). Using a novel assay on the basis of the HDL-mediated rate of oxidation of dihydrorhodamine (DOR), we determined the functional (redox) properties of HDL and examined correlations between DOR and indices of vascular and metabolic health in the cohort. DOR was significantly lower in both trained groups compared with the untrained group (LT, 1.04 ± 0.49; OT, 1.39 ± 0.57; OU, 1.80 ± 0.74; LT vs. OU P < 0.00001; OT vs. OU P = 0.02), however, DOR in the OT group was not significantly different from that of the LT group. DOR was negatively associated with HDL-cholesterol (R = -0.64), relative strength (R = -0.42), sex hormone-binding globulin (R = -0.42), and testosterone (R = -0.35) (all P ≤ 0.001); whereas DOR was positively associated with triglycerides (R = 0.39, P = 0.002), oxidized low-density lipoprotein (R = 0.32), body mass index (R = 0.43), total mass (R = 0.35), total fat mass (R = 0.42), waist circumference (R = 0.45), and trunk fat mass (R = 0.42) (all P ≤ 0.001). Chronic RT is associated with improved HDL redox activity. This may contribute to the beneficial effects of RT on reducing cardiovascular disease risk, irrespective of body weight status.


On the specificity of antibiotics targeting the large ribosomal subunit.
The peptidyltransferase center of the large ribosomal subunit is responsible for catalyzing peptide bonds. This active site is the target of a variety of diverse antibiotics, many of which are used clinically. The past decade has seen a plethora of structures of antibiotics in complex with the large ribosomal subunit, providing unprecedented insight into the mechanism of action of these inhibitors. Ten distinct antibiotics (chloramphenicol, clindamycin, linezolid, tiamulin, sparsomycin, and five macrolides) have been crystallized in complex with four distinct ribosomal species, three bacterial, and one archaeal. This review aims to compare these structures in order to provide insight into the conserved and species-specific modes of interaction for particular members of each class of antibiotics. Coupled with the wealth of biochemical data, a picture is emerging defining the specific functional states of the ribosome that antibiotics preferentially target. Such mechanistic insight into antibiotic inhibition will be important for the development of the next generation of antimicrobial agents.


AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells.
To test the hypothesis that AURKA amplification contributes to pancreatic tumorigenesis by increasing centrosome abnormality and chromosome instability, the current study explored the associations between AURKA amplification, chromosome instability, centrosome abnormality, and the expression of several important proteins that are involved in cell proliferation (Ki-67), cell cycle regulation (p53, p16), and apoptosis (survivin) in 12 human pancreatic carcinoma cell lines. Using fluorescence in situ hybridization (FISH), we observed that 5 of the 12 cell lines had an AURKA amplification index (AI) (percentage of cells with more than three signals) >60%. Both the AURKA AI and the average number of signals per cell (ANSPC) were significantly associated with the copy number of chromosome 9 but not chromosome 17. The AURKA ANSPC was positively associated with the percentage of cells with the centrosome abnormality. Furthermore, centrosome abnormality was significantly associated with the frequency of cells with abnormal nuclei and abnormal mitotic figures, but no direct association was detected between the frequency of centrosome abnormalities and chromosome instabilities. The AURKA AI was also associated with a lower expression of Ki-67, a higher expression of survivin, and the lack of expression of p16. These associations support our hypothesis that AURKA amplification contributes to pancreatic carcinogenesis by increasing chromosome instability and centrosome abnormality.


Coupled dynamics of iron, manganese, and phosphorus in brackish coastal sediments populated by cable bacteria.
Coastal waters worldwide suffer from increased eutrophication and seasonal bottom water hypoxia. Here, we assess the dynamics of iron (Fe), manganese (Mn), and phosphorus (P) in sediments of the eutrophic, brackish Gulf of Finland populated by cable bacteria. At sites where bottom waters are oxic in spring, surface enrichments of Fe and Mn oxides and high abundances of cable bacteria were observed in sediments upon sampling in early summer. At one site, Fe and P were enriched in a thin layer (~ 3 mm) just below the sediment-water interface. X-ray absorption near edge structure and micro X-ray fluorescence analyses indicate that two-thirds of the P in this layer was associated with poorly crystalline Fe oxides, with an additional contribution of Mn(II) phosphates. The Fe enriched layer was directly overlain by a Mn oxide-rich surface layer (~ 2 mm). The Fe oxide layer was likely of diagenetic origin, formed through dissolution of Fe monosulfides and carbonates, potentially induced by cable bacteria in the preceding months when bottom waters were oxic. Most of the Mn oxides were likely deposited from the water column as part of a cycle of repeated deposition and remobilization. Further research is required to confirm whether cable bacteria activity in spring indeed promotes the formation of distinct layers enriched in Fe, Mn, and P minerals in Gulf of Finland sediments. The temporal variations in biogeochemical cycling in this seasonally hypoxic coastal system, potentially controlled by cable bacteria activity, have little impact on permanent sedimentary Fe, Mn, and P burial.


Homogeneous Differential Magnetic Assay.
Assays are widely used for detection of various targets, including pathogens, drugs, and toxins. Homogeneous assays are promising for the realization of point-of-care diagnostics as they do not require separation, immobilization, or washing steps. For low concentrations of target molecules, the speed and sensitivity of homogeneous assays have hitherto been limited by slow binding kinetics, time-consuming amplification steps, and the presence of a high background signal. Here, we present a homogeneous differential magnetic assay that utilizes a differential magnetic readout that eliminates previous limitations of homogeneous assays. The assay uses a gradiometer sensor configuration combined with precise microfluidic sample handling. This enables simultaneous differential measurement of a positive test sample containing a synthesized Vibrio cholerae target and a negative control sample, which reduces the background signal and increases the readout speed. Very low concentrations of targets down to femtomolar levels are thus detectable without any additional amplification of the number of targets. Our homogeneous differential magnetic assay method opens new possibilities for rapid and highly sensitive diagnostics at the point of care.


Chemical genomics strategy for the discovery of new anticancer agents.
Chemical genomics represents a cooperation of biology and chemistry to identify and intervene the biological targets. Small molecules with diverse structural characteristics should be used to validate the target through interfering with the biological processes. Because of the limitation of existing chemical libraries, the diversity can be exploited using both the molecular design techniques; structure-based design and ligand-based design. These methods can guide the selection of small molecules with optimal binding properties to desired biological targets. Studies of potential molecular targets for novel anticancer drug discovery including in silico screening, QSAR, and de novo design demonstrated the importance of chemical genomics strategy to find the chemical probes and drug lead compounds.


Formulation for transfollicular drug administration: some recent advances.
The percutaneous administration of drug products is of current therapeutic interest, mainly with regard to reduction of hepatic metabolism and systemic toxicity, and delivery to specific sites. Hair follicles and sebaceous glands can be privileged pathways for some molecules or formulations, which enter faster into these shunts than they do through the stratum corneum. The aim of this paper is to outline some examples of recent formulation methodologies that allow administration of a drug product through the follicular pathway (1) when the common, localized diseases of the pilosebaceous unit could benefit from specific delivery; and (2) to shunt the stratum corneum barrier.


Image coding based on a fractal theory of iterated contractive image transformations.
The author proposes an independent and novel approach to image coding, based on a fractal theory of iterated transformations. The main characteristics of this approach are that (i) it relies on the assumption that image redundancy can be efficiently exploited through self-transformability on a block-wise basis, and (ii) it approximates an original image by a fractal image. The author refers to the approach as fractal block coding. The coding-decoding system is based on the construction, for an original image to encode, of a specific image transformation-a fractal code-which, when iterated on any initial image, produces a sequence of images that converges to a fractal approximation of the original. It is shown how to design such a system for the coding of monochrome digital images at rates in the range of 0.5-1.0 b/pixel. The fractal block coder has performance comparable to state-of-the-art vector quantizers.


Effects of Body Mass Index on the Lipid Profile and Biomarkers of Inflammation and a Fibrinolytic and Prothrombotic State.
Both an overweight status and obesity are associated with high cardiovascular morbidity and mortality. The aim of this study was to examine the effects of obesity on different underlying mechanisms, i.e. inflammation, fibrinolysis and a prothrombotic state, in a young high-risk population in the Mediterranean area. The study population included 237 subjects (median age: 44 years). We recorded the presence of cardiovascular risk factors and premature ischaemic heart disease and performed weight stratification using the body mass index (BMI) according to the established World Health Organization (WHO) criteria. We also measured the serum/plasma lipid, fibrinogen, D-dimer, von Willebrand factor, tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) and high-sensitivity C-reactive protein (CRP-hs) levels in samples of peripheral blood. The subjects with premature ischaemic heart disease and hypertension had higher BMI values (p<0.01), and the subjects with an increased weight showed an unadjusted detrimental lipid profile, with a proinflammatory, prothrombotic state and abnormal fibrinolytic parameters. According to a multivariate analysis, the HDL-cholesterol (r(2)=0.176; p<0.001), t-PA antigen (r(2)=0.235; p<0.001), PAI-1 antigen (r(2)=0.164; p<0.001) and CRP-hs (r(2)=0.096; p=0.019) levels were significantly related to the weight stratification. A high BMI is a common finding in young populations at high risk of cardiovascular disease. In the current study, the patients with an increased BMI demonstrated an unhealthy lipid profile, as well as a proinflammatory and prothrombotic state and abnormal fibrinolytic parameters.


Predictive tests for Meniere's disease.
The prognostic value of electrocochleography and of the glycerol dehydration test in Meniere's disease is well recognized. Abnormal electrocochleographic waveforms carry a poorer prognosis. After adequate dehydration, significant threshold changes for better or worse predict the likely course of events following endolymphatic sac surgery. Meniere's disease frequently becomes bilateral. Vestibular aqueduct tomography in patients with Meniere's disease gives very different results, in both ears, compared with those in control patients. The acetazolamide cochlear hydration test can help detect latent hydrops. Plasma osmolality studies are an essential part of all these tests. Otoadmittance investigations show significantly higher baseline values in fluctuant endolymphatic hydrops compared with nonfluctuant Meniere's disease or control subjects. When the hearing improves after dehydration there is a paradoxical increased resistance to the flow of sound energy through the inner ear. Reduced hearing after glycerol is associated with an increase in maximum conductance or a decreased cochlear resistance. Otoadmittance studies on the "normal" ear of patients with "unilateral" Meniere's disease show similar abnormalities and changes. A study of serum levels of immune complexes and complement in patients with Meniere's disease shows elevated levels compared with controls. As yet the significance of this finding is unclear, though it may be related to disease activity.


Elastic modulus and collagen organization of the rabbit cornea: epithelium to endothelium.
The rabbit is commonly used to evaluate new corneal prosthetics and study corneal wound healing. Knowledge of the stiffness of the rabbit cornea would better inform the design and fabrication of keratoprosthetics and substrates with relevant mechanical properties for in vitro investigations of corneal cellular behavior. This study determined the elastic modulus of the rabbit corneal epithelium, anterior basement membrane (ABM), anterior and posterior stroma, Descemet's membrane (DM) and endothelium using atomic force microscopy (AFM). In addition, three-dimensional collagen fiber organization of the rabbit cornea was determined using nonlinear optical high-resolution macroscopy. The elastic modulus as determined by AFM for each corneal layer was: epithelium, 0.57 ± 0.29 kPa (mean ± SD); ABM, 4.5 ± 1.2 kPa, anterior stroma, 1.1 ± 0.6 kPa; posterior stroma, 0.38 ± 0.22 kPa; DM, 11.7 ± 7.4 kPa; and endothelium, 4.1 ± 1.7 kPa. The biophysical properties, including the elastic modulus, are unique for each layer of the rabbit cornea and are dramatically softer in comparison to the corresponding regions of the human cornea. Collagen fiber organization is also dramatically different between the two species, with markedly less intertwining observed in the rabbit vs. human cornea. Given that the substratum stiffness considerably alters the corneal cell behavior, keratoprosthetics that incorporate mechanical properties simulating the native human cornea may not elicit optimal cellular performance in rabbit corneas that have dramatically different elastic moduli. These data should allow for the design of substrates that better mimic the biomechanical properties of the corneal cellular environment.


Aging, cognitive load, dementia and hearing loss.
Sensorineural systems play a crucial role in the diagnosis, treatment and management of several neurological disorders. The function of the eye and ear represents a unique window for testing various conditions in cognitive decline or dementia. Touch and smell have also been found to be strongly involved in neurodegenerative conditions, and their decline has been significantly associated with the progression of the disease; hence, the idea that restoring sensory function in cognitively impaired adults might enable a significant improvement in their cognitive status, reducing the worldwide incidence and prevalence of dementia. Not all sensorineural 'windows' can benefit equally from the same procedures; however, hearing and vision can certainly gain the most from dependable therapeutic and other diagnostic options. The ear, including the vestibular system, deserves an honored place among the sensory organs in this context due mainly to the sophisticated electrical devices available that have amply demonstrated their effectiveness in treating hearing loss. Restoring an individual's hearing can reduce the cognitive 'load', i.e. the neural activity needed to understand/recognize the spoken word - an activity that becomes more demanding if the brain is obliged to recruit different neural populations to achieve the same performance, as happens in older adults with sensory impairments. The sensory interfaces may also facilitate the early diagnosis of conditions characterized by a lengthy preclinical phase, as well as enabling noninvasive, follow-up procedures to assess the outcome of rehabilitation measures and distinguish physiological brain aging from neurodegenerative disorders. The present study is a brief literature review on the issues and prospects relating to the unique relationship between hearing and cognitive decline, with a general introduction to the main topics before focusing on rehabilitation training with hearing aids and cochlear implants to combat cognitive decline.