Growing Prospects of Dynamic Covalent Chemistry in Delivery Applications.
Delivery remains a major obstacle restricting the potential action of small molecular drugs as well as novel biologics which cannot readily enter cells without the help of a vector. A successful active delivery process involves three steps: (a) tagging the drug with a vector, (b) effective trafficking of this [drug-vector] conjugate through biological barriers, and finally (c) controlled drug release. While covalent bond formation and/or supramolecular association is involved in the making of the [drug-vector] conjugate, the final step requires precisely a controlled dissociation in order to trigger drug release. Therefore, in pursuit of smart, effective, and nontoxic delivery systems, it has become widely recognized that control over dynamic self-assembly could unleash the efficacy of artificial vectors. In this Account, I discuss our endeavors, and those of colleagues, in the recent implementation of Dynamic Covalent Chemistry (DCvC) in delivery applications. DCvC exploits reversible covalent reactions to generate covalent systems that can self-fabricate, adapt, respond, and fall apart in a controlled fashion. A privileged set of reversible covalent reactions has emerged in the community working on delivery applications and is based on condensation reactions (imine, acylhydrazone, oxime), and disulfide and boronate ester formations. The latest developments making this chemistry particularly attractive for such a DCvC approach are discussed. The rational justifying the potential of DCvC in delivery is based on the principle that using such reversible covalent reactions afford transient [drug-vector] conjugates which form spontaneously and chemoselectively, then adapt and self-correct their structure during self-assembly and trafficking thanks to the dynamic nature of the reversible covalent bonds, and finally respond to physicochemical stimuli such as pH and redox changes, thereby enabling controlled dissociation and concomitant drug release. For these reasons, DCvC has recently emerged as a leverage tool with growing prospects for advancing toward smarter delivery systems. The implementation of DCvC can follow three approaches that are discussed herein: (1) dynamic covalent bioconjugates, involving the transient covalent conjugation with a vector, (2) dynamic covalent vectors, involving the controlled dynamic and adaptive assembly and disassembly of vectors that complex drugs through supramolecular association, and (3) dynamic covalent targeting, involving the transient chemoselective formation of covalent bonds with the constituents of cell membranes. While DCvC has already attracted interest in material sciences, the recent results described in this Account showcase the vast potential of DCvC in biological sciences, and in particular in delivery applications where self-fabricated, adaptive, and responsive devices are of utmost importance.


Intensive care ethics in evolution.
The ethics of treating the seriously and critically ill have not been static throughout the ages. Twentieth century medicine has inherited from the nineteenth century a science which places an inappropriate weight on diagnosis over prognosis and management, combined with a seventeenth century duty to prolong life. However other earlier ethical traditions, both Hippocratic and Christian, respected both the limitations of medicine and emphasised the importance of prognosis. This paper outlines some of the historical precedents for the treatment of the critically ill, and also how the current paradigm limits clinical practice and causes ethical tensions. An understanding that other paradigms have been ethically acceptable in the past allows wider consideration and acceptance of alternatives for the future. However future alternatives will also have to address the role of technology, given its importance in this area of medicine.


Serum ferritin level as an early indicator of metabolic dysregulation in young obese adults - a cross-sectional study.
The aim of this study was to investigate the relationship between serum ferritin level and antioxidative status and metabolic dysregulation in young adult obese population. This cross-sectional study included 300 subjects of either sex, grouped as obese and non-obese subjects. The body mass index, total iron binding capacity, fasting blood glucose, superoxide dismutase activity, and levels of serum ferritin, iron, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, glutathione, and vitamin C were estimated. Analysis showed a significant alteration in all the parameters in obese adults. The correlation of ferritin level and body mass index showed a positive correlation (r = -0.81, p < 0.001, respectively) with levels of fasting blood glucose, superoxide dismutase, total cholesterol, low-density lipoprotein cholesterol, and triglyceride in obese individuals, whereas an insignificant correlation with vitamin C and glutathione level was observed in obese individuals. The significant positive correlation of ferritin level with the metabolic parameters and some antioxidative parameters in obese individuals signifies the development of metabolic disorders. Therefore, estimation of serum ferritin level will be an important early indicator for the risk of developing metabolic disorders in young adults.


Problems of rheumatoid arthritis and ankylosing spondylitis patients in their labor and life environments.
The results of a sociomedical study performed in a representative group 715 patients of productive age comparising 545 cases of rheumatoid arthritis (RA) and 170 cases of ankylosing spondylitis (AS), are presented in this paper. The set was constituted by means of a stratified selection from 6 districts in Slovakia. Data about the patients were obtained by medical examination accompanied by a sociological survey carried out in the form of a semi-standardized interview. Among the 545 RA patients women prevailed (80.4%), while in the AS group it was men (83.5%). In so far as the age was concerned, most of the RA patients were in their 5th and 6th decades while the AS patients were 10 years younger. 2/3 of the patients with RA had but a primary grade education, a significantly higher level of education could be found among the AS patients. When taking into account the degree of advancement of the disease there was a marked preponderance of medium grade stages among the RA cases (71.3% of the cases were of grades II and III), while among the AS 2/3 of the cases were of grades IV and V. Notwithstanding the more advanced stages of the disease the AS patients were more efficient functionally: 61.2% of them remained in their original employment (while the RA patients only in 45.5% of the cases) and 2.9% of them were entirely dependent upon help of others in self-care (among the RA patients it was in 9.5%). 36.4% of the RA patients and 51.1% of the AS patients whose disease was active were exposed to the effect of the weather in their work. A full invalid rent had to be given to 46.8% of the productive age RA patients and only to 28.8% of those suffering from AS. There was a direct relationship between the patients' labour activity and their eventual relegation to an invalid rent reception state and the degree of their education. In environmental conditions of life the narrow space of the apartment influenced negatively the activity of the rheumatoid process. Understanding and a favourable atmosphere in the family had a positive influence upon the course of the disease and this, not only from the subjective viewpoint but also upon the degree of functional efficiency of the patients, their activity and the dynamics of the inflammatory rheumatoid process (P less than 0.001). A feeling of loneliness was reported by 51.5% of the RA patients even in the productive age and in 35.2% of the AS cases.(ABSTRACT TRUNCATED AT 400 WORDS)


Prediction of seizure outcome in childhood epilepsies in countries with limited resources: a prospective study.
To identify predictors of seizure control in newly presenting children with epilepsy in countries with limited resources. Three hundred and ninety children (273 males, 117 females) aged 2 months to 15 years with newly diagnosed epilepsy were enrolled prospectively at first visit to the multidisciplinary clinic at the children's hospital in Dhaka, Bangladesh. Data about seizures, motor disability, psychomotor development, and electroencephalography were obtained. Regular monitoring of antiepileptic drug treatment was continued at least for one year. Associations between seizure control and potential predictors were determined by multivariate analysis. Three hundred and ninety children were enrolled in 6 months, of whom over 60% were from low-income families, 60% had onset at under 1 year, 74% had more than one seizure per week, 69% a single-seizure type, and 38% a history of delayed onset of breathing at birth. Cognitive deficits (IQ<70; 58%) and/or motor (significant limitation of daily living activities; 47%) deficits were common. After 1 year of regular treatment, seizure control was good (seizure freedom) in 53%, and poor (at least one seizure in the last 3mo of follow-up) in 47%. The predictors of poor seizure control were an IQ<70, associated motor disability, multiple seizure types, and a history of cognitive regression (1.9 times more likely to have poor seizure control). Seizure control can be predicted using three clinical factors (motor disability, cognitive impairment, and multiple seizure types) at the first clinic visit. Such predictors assist the development of referral plans and management guidelines for childhood epilepsies in resource-poor countries.


Plasmacytoma of the nasolacrimal duct simulating dacryocystitis: an uncommon presentation for extramedullary relapse of multiple myeloma.
The most common site for localized forms of plasma cell neoplasms (extramedullary plasmacytoma; EMP) is the upper respiratory tract, including the oropharynx, nasal cavities, sinuses and larynx. A 50-year-old woman with a history of myeloma in complete remission after autologous stem cell transplantation complained of two weeks of epiphora of the left eye with subsequent diplopia, bloody nasal discharge and progressive swelling around the nasolacrimal sac. A solitary mass in the left sinonasal area, extending to the nasolacrimal duct (NLD) was detected on MRI, whose histopathological examination was consistent with plasmacytoma. Further clinical investigation ruled out multiple myeloma (MM). The patient underwent debulking surgery and adjuvant chemotherapy followed by local radiotherapy in an attempt to achieve complete response. Despite being a rare entity, EMP of the NLD should be considered in the differential diagnosis of epiphora and dacryocystitis. To our knowledge, this is the first case of a plasmacytoma of the NLD presenting as isolated extramedullary relapse of MM. The follow-up in EMPs should include appropriate imaging studies, a systemic workup to rule out MM.


Renaturation and purification of human tissue factor pathway inhibitor expressed in recombinant E. coli.
Tissue factor pathway inhibitor is an inhibitor of the extrinsic coagulation pathway. Evaluation of the pharmacological effects of tissue factor pathway inhibitor in animal models has been limited by the high cost and low availability of mammalian tissue culture produced protein. In order to circumvent this obstacle, a 277-amino-acid nonglycosylated tissue factor pathway inhibitor variant possessing an N-terminal alanine was expressed in recombinant E. coli using the tac promoter expression system. High-level expression in recombinant E. coli resulted in the accumulation of ala-tissue factor pathway inhibitor in inclusion bodies. Active protein was produced by solubilization of the inclusion bodies in 8 M urea, purification of the full-length molecule by cation exchange chromatography, and renaturation in 6 M urea. Fractionation of crude refold mixtures using cation exchange chromatography yielded a purified nonglycosylated tissue factor pathway inhibitor possessing in vitro prothrombin time activity comparable to inhibitor purified from mammalian cell lines.


Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase.
Phytochemicals such as soy isoflavone genistein have been reported to possess therapeutic effects for obesity, diabetes, and cardiovascular diseases. In the present study, the molecular basis of selective phytochemicals with emphasis on their ability to control intracellular signaling cascades of AMP-activated kinase (AMPK) responsible for the inhibition of adipogenesis was investigated. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, emerges as a possible target molecule of anti-obesity. Hypothalamic AMPK was found to integrate nutritional and hormonal signals modulating feeding behavior and energy expenditure. We have investigated the effects of genistein, EGCG, and capsaicin on adipocyte differentiation in relation to AMPK activation in 3T3-L1 cells. Genistein (20-200muM) significantly inhibited the process of adipocyte differentiation and led to apoptosis of mature adipocytes. Genistein, EGCG, and capsaicin stimulated the intracellular ROS release, which activated AMPK rapidly. We suggest that AMPK is a novel and critical component of both inhibition of adipocyte differentiation and apoptosis of mature adipocytes by genistein or EGCG or capsaicin further implying AMPK as a prime target of obesity control.


Cholesteryl Ester Transfer Protein Inhibitors - Future Soon to be REVEALed.
Reduction of the remaining residual cardiovascular risk is a clinical unmet need currently being addressed through a combination of further reduction of plasma concentrations of low-density lipoproteins (LDLs) and increasing plasma concentrations of high-density lipoproteins (HDLs). This brief review sets out the so-called HDL hypothesis and summarises the clinical results of the family of drugs, which function to raise plasma HDL concentration through inhibition of cholesteryl ester transfer proteins (CEPT).


Stable 1T-MoSe2 and Carbon Nanotube Hybridized Flexible Film: Binder-Free and High-Performance Li-Ion Anode.
Two-dimensional stable metallic 1T-MoSe2 with expanded interlayer spacing of 10.0 Å in situ grown on SWCNTs film is fabricated via a one-step solvothermal method. Combined with X-ray absorption near-edge structures, our characterization reveals that such 1T-MoSe2 and single-walled carbon nanotubes (abbreviated as 1T-MoSe2/SWCNTs) hybridized structure can provide strong electrical and chemical coupling between 1T-MoSe2 nanosheets and SWCNT film in a form of C-O-Mo bonding, which significantly benefits a high-efficiency electron/ion transport pathway and structural stability, thus directly enabling high-performance lithium storage properties. In particular, as a flexible and binder-free Li-ion anode, the 1T-MoSe2/SWCNTs electrode exhibits excellent rate capacity, which delivers a capacity of 630 mAh/g at 3000 mA/g. Meanwhile, the strong C-O-Mo bonding of 1T-MoSe2/SWCNTs accommodates volume alteration during the repeated charge/discharge process, which gives rise to 89% capacity retention and a capacity of 971 mAh/g at 300 mA/g after 100 cycles. This synthetic route of a multifunctional MoSe2/SWCNTs hybrid might be extended to fabricate other 2D layer-based flexible and light electrodes for various applications such as electronics, optics, and catalysts.


Cardiometabolic risk and disease in Indigenous Australians: the heart of the heart study.
This study assessed the burden and determinants of cardiovascular and metabolic risk in a community sample of high risk Indigenous Australians. Indigenous Australians are over-represented in the most disadvantaged strata of Australian society. The role of psychosocial and socioeconomic factors in patterning cardiometabolic disease in this population is unclear. The Heart of the Heart Study was a cross sectional study of 436 Aboriginal adults from remote, urban and peri-urban communities around Alice Springs (Northern Territory, Australia). Participants underwent detailed assessments of socio-demographic, psychosocial, cardiovascular and metabolic status. Individuals with depression were twice as likely to have cardiovascular disease (OR 2.03; 1.07-3.88; p<0.05). Chronic kidney disease (39.7%, 37.2% and 18.2%) and diabetes (28.4%, 34.0% and 19.2%) were more common in peri-urban and remote compared to urban communities. Cardiovascular disease did not vary across locations (p=0.069), but coronary artery disease did (p=0.035 for trend). Unemployed individuals were more likely to have cardiovascular disease (OR 2.32; 1.33-4.06; p<0.001). Socioeconomic gradients in coronary artery disease, all cardiovascular disease and diabetes, as measured by income, operated differentially across locations (p for location/socioeconomic status interactions 0.002; 0.01 and 0.04 respectively). Participants had high rates of pre-existing cardiovascular disease, diabetes and chronic kidney disease. Cardiovascular risk in these communities was associated with psychosocial factors and socioeconomic indicators. However, gradients operated differentially across location. These data provide a strong foundation for better understanding key drivers of increased levels of cardiovascular and other common forms of non-communicable disease in Indigenous people.


Angiojet catheter-based thrombectomy in a neonate with postoperative pulmonary embolism.
A 2-day-old male with pulmonary atresia and an intact ventricular septum underwent central aortopulmonary shunt placement and right ventricular outflow tract reconstruction. Postoperatively, the patient had difficulty weaning from mechanical ventilation and was found to have a large thrombus occluding the entire right lower pulmonary artery. The patient underwent successful percutaneous catheter-based thrombectomy in the early postoperative period with the Possis AngioJet catheter. The patient had immediate improvement in gas exchange and was able to be weaned from the ventilator shortly thereafter. This represents the first published use of mechanical thrombectomy in a postoperative neonate.


A new model for the body size-metabolism relationship.
The allometric 3/4 power relation, initially used for describing the relation between mammalian basal metabolic rate and body size, is often used as a general model for organismal design. The use of allometric regression as a model has important limitations: it is not mechanistic, it combines all physiological variables into one correlate of body size, and it combines data from several physiological states. In reassessing the use of allometric equations, we first describe problems with their use in studies of organismal design and then use a formulation for distributed net heat production and temperature distribution within the body to derive an alternative equation for the relation between basal metabolism and body size. Tests of the heat flow equation against data reported in the literature indicate that it is an accurate estimator of basal metabolism under thermoneutral conditions and suggest that the allometric equation is a special case of this mechanistic and more general model. We propose that our method is more meaningful and widely applicable for thermoneutral conditions than is a purely allometric approach.


[Vascular prostheses and renal transplantation].
To evaluate the complications, the morbidity and mortality of renal transplantation in patients with a vascular prosthesis inserted either prior to or at the same time as renal transplantation. Between January 2001 and January 2006, six renal transplantations were performed in patients with arterial vascular prostheses or requiring concomitant insertion of a vascular prosthesis during renal transplantation. The mean age was 58 years [range: 47-69 years]. In each case, we evaluated operative difficulties, complications and postoperative course (morbidity, mortality) and the renal functional result. The mean operating time was 230 minutes [range: 130-380 minutes] with a mean blood loss of 390 ml [175-750 ml]. Three patients required another surgical operation for femoral thrombosis, iliofemoral thrombosis and compressive haematoma. The median length of hospital stay was 21 days [range: 9-78 days]. Graft function was restored immediately in all six patients, and one case of graft loss was observed. The morbidity was higher than that usually observed after renal transplantation. With a mean follow-up of 26 months, the vascular and renal results are satisfactory. Renal transplantation in patients with a history of vascular prosthesis or requiring replacement of the vascular prosthesis at the same time as renal transplantation can be performed with satisfactory results but with an increased morbidity. The vascular treatment must be part of a multidisciplinary strategy in the context of transplantation.


Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency.
This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.


Re-enculturation: culturally congruent interventions for Mäori with alcohol- and drug-use-associated problems in New Zealand.
Generally, the relationship between culture and substance use has been explored in two ways. Firstly, high rates of substance use and related problems amongst indigenous and migrant populations generated interest in genetics and cultural susceptibility. Acculturation-strain type theories suggested the stress of culture-change increased the risk of substance use and related harm. Secondly, there has been an increasing emphasis on taking account of the diversity of social, psychological, and cultural factors in the assessment and treatment of alcohol- and drug-use-associated problems. Utilization of ethnocultural factors as a means to promote recovery from alcohol- and drug-use-associated problems is a feature of culturally congruent interventions. Mäori are the indigenous people of New Zealand, and this paper outlines the background to the increasing inclusion of customary Mäori values, beliefs, and practices in interventions in the development of culturally congruent programs.


Optical emission from C60-molecule-coupled Si nanocrystallites.
Using C60 molecule as a kind of surface-passivated agent to modify the electronic structure of Si nanocrystallites in porous silicon, we disclose that this kind of C60/nanocrystalline Si coupling system can show a strong blue emission at approximately 460 nm when stored in air for more than one year. After a full characterization of the photoluminescence properties, we propose a luminescent center in the SiOx layer at the surface of a Si nanocrystallite. It is a pair consisting of an oxygen vacancy and an interstitial oxygen. The interstitial oxygen also forms a peroxy linkage with a neighboring lattice oxygen. Radiative recombination of carriers photogenerated from Si nanocrystallite cores in the luminescent centers results in the observed blue photoluminescence. Neutron irradiation experiments support our assignment of the blue emission mechanism. This work improves the understanding of the origin of blue emission from silicon/oxygen-related nanostructured materials.


Electron transfer properties of dual self-assembled architectures based on specific recognition and electrostatic driving forces: its application to control substrate inhibition in horseradish peroxidase-based sensors.
This work describes the synergistic combination of ionic self-assembly and recognition-directed assembly with the aim of creating highly functional bioelectrochemical interfaces compatible with the supramolecular design of a wide variety of biosensing platforms. A recently synthesized glycopolyelectrolyte constituted of polyallylamine bearing redox-active osmium complexes and glycosidic residues (lactose) is used to create a self-assembled structure with sodium dodecylsulfate. In turn, this supramolecular thin films bearing redox-active and biorecognizable carbohydrate units enable the facile assembly of functional lectins as well as the subsequent docking and "wiring" of glycoenzymes, like horseradish peroxidase (HRP) (an elusive enzyme to immobilize via noncovalent interactions). The assembly of this system was followed by quartz crystal microbalance and grazing-incidence small-angle X-ray scattering (GISAXS) studies confirming that spin-coated ionically self-assembled films exhibit mesostructured architectures according to the formation of self-organized lamellar structures. In-depth characterization of the electrocatalytic properties of the biosupramacromolecular assemblies confirmed the ability of this kind of interfacial architecture to efficiently mediate electron transfer processes between the glycoenzyme and the electrode surface. For instance, our experimental electrochemical evidence clearly shows that tailor-made interfacial configurations of the ionic self-assemblies can prevent the inhibition of the glycoenzyme (typically observed in HRP) leading to bioelectrocatalytic currents up to 0.1 mA cm(-2). The presence of carbohydrate moieties in the ionic domains promotes the biorecognition-driven assembly of lectins adding a new dimension to the capabilities of ionic self-assembly.


Base-Induced Transformation of 2-Acyl-3-alkyl-2H-azirines to Oxazoles: Involvement of Deprotonation-Initiated Pathways.
An experimental study of base-induced transformation reaction of 2-acyl-3-alkyl-2H-azirines to oxazoles indicated that a deprotonation-initiated mechanism is involved, in addition to nucleophilic addition to the imine functionality. Calculations suggested the participation of a ketenimine (ethenimine) intermediate generated by azirine ring opening of the carbanion intermediate formed by α-deprotonation of 2H-azirine. The ketenimine intermediate possessing methyl substituents at C(3) appears to be more stable than the tautomeric nitrile ylide which was proposed to be involved in photoinduced and pyrolysis reactions of 2-acyl-3-alkyl-2H-azirines to afford oxazoles. Thus, intermediacy of ketenimine is consistent with both experimental and computational results, at least under strongly basic reaction conditions.


TPSSI-Net: Fast and Enhanced Two-Path Iterative Network for 3D SAR Sparse Imaging.
The emerging field of combining compressed sensing (CS) and three-dimensional synthetic aperture radar (3D SAR) imaging has shown significant potential to reduce sampling rate and improve image quality. However, the conventional CS-driven algorithms are always limited by huge computational costs and non-trivial tuning of parameters. In this article, to address this problem, we propose a two-path iterative framework dubbed TPSSI-Net for 3D SAR sparse imaging. By mapping the AMP into a layer-fixed deep neural network, each layer of TPSSI-Net consists of four modules in cascade corresponding to four steps of the AMP optimization. Differently, the Onsager terms in TPSSI-Net are modified to be differentiable and scaled by learnable coefficients. Rather than manually choosing a sparsifying basis, a two-path convolutional neural network (CNN) is developed and embedded in TPSSI-Net for nonlinear sparse representation in the complex-valued domain. All parameters are layer-varied and optimized by end-to-end training based on a channel-wise loss function, bounding both symmetry constraint and measurement fidelity. Finally, extensive SAR imaging experiments, including simulations and real-measured tests, demonstrate the effectiveness and high efficiency of the proposed TPSSI-Net.


The contributions of color to recognition memory for natural scenes.
The authors used a recognition memory paradigm to assess the influence of color information on visual memory for images of natural scenes. Subjects performed 5%-10% better for colored than for black-and-white images independent of exposure duration. Experiment 2 indicated little influence of contrast once the images were suprathreshold, and Experiment 3 revealed that performance worsened when images were presented in color and tested in black and white, or vice versa, leading to the conclusion that the surface property color is part of the memory representation. Experiments 4 and 5 exclude the possibility that the superior recognition memory for colored images results solely from attentional factors or saliency. Finally, the recognition memory advantage disappears for falsely colored images of natural scenes: The improvement in recognition memory depends on the color congruence of presented images with learned knowledge about the color gamut found within natural scenes. The results can be accounted for within a multiple memory systems framework.


Allometric scaling of flight energetics in Panamanian orchid bees: a comparative phylogenetic approach.
The relationship between body size and flight energetics was studied in the clade of tropical orchid bees, in order to investigate energy metabolism and evolution. Body mass, which varied from 47 to 1065 mg, was found to strongly affect hovering flight mass-specific metabolic rates, which ranged from 114 ml CO(2) h(-1) g(-1) in small species to 37 ml CO(2) h(-1) g(-1) in large species. Similar variation of wingbeat frequency in hovering flight occurred among small to large species, and ranged from 250 to 86 Hz. The direct relationship between such traits was studied by the comparative method of phylogenetically independent contrasts (PIC), using a new molecular phylogeny generated from the cytochrome b gene partial sequences. We found wingbeat frequency variation is satisfactorily explained by variation in wing loading, after corrections for body mass and phylogeny. The correlated evolution of mass-specific metabolic rate, wingbeat frequency and wing loading was also revealed after correcting for phylogeny and body mass. Further, the effect of body size on flight energetics can be understood in terms of a relationship between wing form and kinematics, which directly influence and explain the scaling of metabolic rate in this group of bees.


Aspergillus petrous apicitis associated with cerebral and peritubular abscesses in an immunocompetent man.
Petrous apex aspergillosis is an uncommon and dangerous condition, with only four previously reported cases. As with other forms of petrous apicitis, the clinical symptoms are often non-specific and this contributes to diagnostic delay. This paper presents the first reported case of Aspergillus petrous apicitis associated with an intracranial or nasopharyngeal abscess. A 72-year-old man with chronic otorrhoea developed neuralgic headaches and progressive lower cranial nerve palsies despite antibiotic therapy. Imaging revealed petrous apicitis, a temporal lobe abscess and nasopharyngeal abscess. Analysis of biopsy tissue indicated invasive aspergillosis. The patient recovered on a protracted course of voriconazole in addition to medium-term antibiotic therapy. Invasive fungal disease should be considered early in the course of skull base osteomyelitis that is clinically unresponsive to empirical broad spectrum antibiotics. This paper highlights the role of tissue biopsy in diagnosis, and the efficacy of voriconazole therapy without the need for radical surgery.


Mycobacterial recA is cotranscribed with a potential regulatory gene called recX.
The recA gene of Mycobacterium smegmatis has been cloned and sequenced. The amino acid sequence of the RecA protein is highly homologous to other RecA proteins. Three other potential open reading frames were identified. One of these showed extensive homology to a protein, HypB, involved in the incorporation of nickel into hydrogenases. Another, found downstream of and overlapping recA, was similar to a gene, recX, which has been proposed to play a regulatory role related to recA function. The homology between the M. smegmatis sequence and that of Mycobacterium tuberculosis extended upstream of the recA coding region for 140 bp including a motif identical to the Cheo-box consensus sequence which has been shown to bind LexA. In addition, the transcriptional start sites were found to be identical to those identified previously for M. tuberculosis. Transcriptional fusions to the reporter gene chloramphenicol acetyltransferase (CAT) revealed that recA was DNA-damage inducible and that expression required sequences at some distance from the mapped transcriptional start sites. Although a motif with only one mismatch to the Cheo box was found in the intergenic region between orf1 and orf2 these open reading frames were not DNA-damage inducible, nor was this motif required for regulation of recA expression. Gel retardation assays revealed that the reason for this was that LexA did not bind to this sequence containing a mismatch. Reverse transcription/polymerase chain reaction analysis of M. smegmatis RNA demonstrated that recA and orf3 (recX) are within the same transcriptional unit.


The intended and unintended consequences of clinical guidelines.
First, we examine whether clinical guidelines, designed to improve health care and reduce disparities in clinical practice, are achieving their intended consequences. Second, we contemplate potential unintended consequences of clinical guidelines. As part of a factorial experiment we presented primary care doctors (n = 192) with clinically authentic vignettes of a 'patient' with already diagnosed diabetes with an emerging foot neuropathy. Their proposed clinical actions were compared with established practice guidelines for this clinical situation. After establishing the existence of consistent socioeconomic disparities in the proposed management of the case presented, we found that reported use of practice guidelines had no measurable effect towards their reduction (one intended consequence). However, the reported use of practice guidelines appeared to precipitate more clinical actions, without eliminating documented disparities. Consistent with other research we find that clinical practice guidelines are not producing a principal intended result, and may even produce unintended consequences.


Minimally Invasive Surgery of Pancreatic Cancer: Feasibility and Rationale.
Minimally invasive pancreatic procedures, in particular minimally invasive pancreaticoduodenectomy, are amongst the most technically challenging procedures in general surgery. Accordingly, a high number of cases is required to master the procedures. Minimally invasive pancreatic surgery is well established for benign and premalignant lesions of the pancreas. Borderline resectable tumors with infiltration of the portal vein are also resected minimally invasively in specialized centers with appropriate expertise. Retrospective and registry studies demonstrate an equivalent long-term survival compared to conventional surgery. Perioperative morbidity and mortality are also equivalent, whereas minimally invasive surgery significantly reduces hospital stay. We expect more widespread use of minimally invasive pancreatic procedures in large centers.


Molecular characterization of the gerbil C5a receptor and identification of a transmembrane domain V amino acid that is crucial for small molecule antagonist interaction.
Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.


Hydrogen-bond-directed highly stereoselective synthesis of Z-enamides via Pd-catalyzed oxidative amidation of conjugated olefins.
An efficient procedure for the preparation of Z-enamides has been developed, involving the reaction of primary amides with conjugated olefins using a Pd/Cu cocatalyst system. It was found that certain additives, such as phosphine oxides and phosphonates, increase the efficiency of the reaction in nonpolar solvents under an oxygen atmosphere, thus producing a variety of Z-enamides in high yields with excellent stereoselectivity under Wacker-type conditions. The oxidative amidation reaction has a broad substrate scope, allowing alkyl, aryl, and vinyl amides to react with olefins conjugated with ester, amide, phosphonate, and ketone groups. The notable preference for the formation of Z-enamides is presumably due to the presence of an intramolecular hydrogen bond between the amido proton and the carbonyl oxygen. The energy difference between two plausible sigma-alkylamidopalladium intermediates, leading to Z- and E-isomeric enamide products, respectively, was calculated to be 4.18 kcal/mol. The beta-hydride elimination step is assumed to be a stereochemistry-determining step in the overall oxidative amidation process, with the energy level for the transition state leading to the Z-enamide being 5.35 kcal/mol lower than that leading to the E-isomer. The efficiency of photoisomerization between Z- and E-enamides was observed to be largely dependent on the substrates' substituents, and certain E-enamides could be obtained in synthetically useful yields by photoirradiation of Z-isomers. Synthetic application of the present method was successfully demonstrated by a direct formal synthesis of cis-CJ-15,801.


Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients.
Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.


Multiple Cranial Nerve Palsies in Giant Cell Arteritis.
Giant cell arteritis (GCA) is a systemic vasculitis of medium and large arteries often with ophthalmic involvement, including ischemic optic neuropathy, retinal artery occlusion, and ocular motor cranial nerve palsies. This last complication occurs in 2%-15% of patients, but typically involves only 1 cranial nerve. We present 2 patients with biopsy-proven GCA associated with multiple cranial nerve palsies.


Coexistence of chronic neutrophilic leukemia with multiple myeloma.
A case report of simultaneous presentation of chronic neutrophilic leukemia and multiple myeloma (IgG kappa) in a 71-year-old male is described. The patient showed mature neutrophilic leukocytosis, hepatosplenomegaly, high neutrophil alkaline phosphatase score, hyperuricemia, neutrophils with toxic granulation and Döhle bodies, absence of Philadelphia chromosome and of the bcr-abl fusion gene. Moreover, a monoclonal IgG kappa paraproteinemia (36.93 g l(-1)) was detected. Bence-Jones proteinuria was 3.84 g l(-1). The bone marrow was grossly hypercellular with marked myeloid hyperplasia and aggregates of plasma cells. The patient died of severe bronchopneumonia after the transformation of chronic neutrophilic leukemia to acute myelomonocytic leukemia, 1.5 years following diagnosis.


Case report: Robust response of metastatic clear cell sarcoma treated with cabozantinib and immunotherapy.
Clear Cell Sarcoma (CCS), also referred to as malignant melanoma of soft parts, is a rare and aggressive malignant tumor. It comprises 1% of all soft tissue sarcomas and is known to be radio- and chemotherapy resistant. CCS shares morphological and immunohistochemical features with malignant melanoma, including melanin biosynthesis and melanocytic markers. However, it is distinct for the presence of EWSR1-ATF1 translocation which activates MITF transcription factor. We report here of an aggressive case of CCS in a 9-year-old patient, which demonstrates the critical role of molecular analysis in the diagnosis and treatment of uncommon cancer variants in the era of personalized medicine. The EWSR1-ATF1 translocation induces pathological c-Met activation, and so, following unsuccessful CTLA4 and PD-1 blockade immunotherapy, the child received cabozantinib, a small molecule tyrosine kinase inhibitor, with the intent to block c-Met oncogenic effect. In parallel, active immunization, using hapten di-nitrophenyl modified autologous tumor cells was administered with monotherapy PD-1 inhibitor nivolumab. Under this "triplet" therapy, the patient attained an initial partial response and was progression-free for 2 years, in good performance status and resumed schooling. Based on our observation, cabozantinib can be used as an effective and potentially life-prolonging treatment in CCS. We suggest that priming the child's immune system using her autologous tumor and combating T cell exhaustion with PD-1 blockade may have synergized with the targeted therapy. Combining targeted and immunotherapy is a rapidly growing practice in solid tumors and provides a glimpse of hope in situations that previously lacked any treatment option.


An alternative synthesis method for [Os(NN)(CO)(2)X(2)] complexes (NN = 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine; X = Cl, Br, I). Electrochemical and photochemical properties and behavior.
A novel synthesis method is introduced for the preparation of [Os(NN)(CO)(2)X(2)] complexes (X = Cl, Br, I, and NN = 2,2'-bipyridine (bpy) or 4,4'-dimethyl-2,2'-bipyridine (dmbpy)). In the first step of this two-step synthesis, OsCl(3) is reduced in the presence of a sacrificial metal surface in an alcohol solution. The reduction reaction produces a mixture of trinuclear mixed metal complexes, which after the addition of bpy or dmbpy produce a trans(Cl)-[Os(NN)(CO)(2)Cl(2)] complex with a good 60-70% yield. The halide exchange of [Os(bpy)(CO)(2)Cl(2)] has been performed in a concentrated halidic acid (HI or HBr) solution in an autoclave, producing 30-50% of the corresponding complex. All of the synthesized trans(X)-[Os(bpy)(CO)(2)X(2)] (X = Cl, Br, I) complexes displayed a similar basic electrochemical behavior to that found in the ruthenium analog trans(Cl)-[Ru(bpy)(CO)(2)Cl(2)] studied previously, including the formation of an electroactive polymer [Os(bpy)(CO)(2)](n) during the two-electron electrochemical reduction. The absorption and emission properties of the osmium complexes were also studied. Compared to the ruthenium analogues, these osmium complexes display pronounced photoluminescence properties. The DFT calculations were made in order to determine the HOMO-LUMO gaps and to analyze the contribution of the individual osmium d-orbitals and halogen p-orbitals to the frontier orbitals of the molecules. The electrochemical and photochemical induced substitution reactions of carbonyl with the solvent molecule are also discussed.


Human amyloid-β enriched extracts: evaluation of in vitro and in vivo internalization and molecular characterization.
Intracerebral inoculation of extracts from post-mortem human Alzheimer's disease brains into mice produces a prion-like spreading effect of amyloid-β. The differences observed between these extracts and the synthetic peptide, in terms of amyloid-β internalization and seed and cell-to-cell transmission of cytosolic protein aggregates, suggest that brain extracts contain key contributors that enhance the prion-like effect of amyloid-β. Nevertheless, these potential partners are still unknown due to the complexity of whole brain extracts. Herein, we established a method based on sequential detergent solubilization of post-mortem samples of human brains affected by Alzheimer's disease that strongly enrich amyloid-β aggregates by eliminating 92% of the remaining proteins. Internalization of Aβ1-42 from the enriched AD extracts was evaluated in vitro, and internalization of fluorescent-labeled AD extracts was also investigated in vivo. Furthermore, we carried out a molecular characterization of the Aβ-enriched fraction using label-free proteomics, studying the distribution of representative components in the amygdala and the olfactory cortex of additional human AD brain samples by immunohistochemistry. Aβ1-42 from the enriched AD extracts are internalized into endothelial cells in vitro after 48 h. Furthermore, accumulation of fluorescent-labeled Aβ-enriched extracts into mouse microglia was observed in vivo after 4 months of intracerebral inoculation. Label-free proteomics (FDR < 0.01) characterization of the amyloid-β-enriched fraction from different post-mortem samples allowed for the identification of more than 130 proteins, several of which were significantly overrepresented (i.e., ANXA5 and HIST1H2BK; p < 0.05) and underrepresented (i.e., COL6A or FN1; p < 0.05) in the samples with Alzheimer's disease. We were also able to identify proteins exclusively observed in Alzheimer's disease (i.e., RNF213) or only detected in samples not affected by the disease (i.e., CNTN1) after the enrichment process. Immunohistochemistry against these proteins in additional tissues revealed their particular distribution in the amygdala and the olfactory cortex in relation to the amyloid-β plaque. Identification and characterization of the unique features of these extracts, in terms of amyloid-β enrichment, identification of the components, in vitro and in vivo cell internalization, and tissue distribution, constitute the best initial tool to further investigate the seeding and transmissibility proposed in the prion-like hypothesis of Alzheimer's disease.


Initiation timing effect of levothyroxine treatment on subclinical hypothyroidism in pregnancy.
The aim of this study is to estimate the timing impact on levothyroxine replacement among pregnant women with subclinical hypothyroidism (SCH). Ninety-eight pregnant women diagnosed as SCH in the first trimester were randomly divided into three groups: Group A, instantly initiated levothyroxine after diagnosis; Group B, administrated treatment in the second trimester, and Group C, received no prescription. Incidence of pregnancy complications and pregnancy outcomes were compared among three groups and subgroup analysis were performed stratified with TPO status in Group B. Group A exhibited lower rate of pregnancy complications (9.7%) and adverse outcome (3.2%) than Group B (41.9% and 32.3%) and Group C (64.5% and 38.7%). But the late initiation treatment group shared a comparable complication and maternal outcome with untreated women (p = .075 and .596, respectively). After stratified with TPOAb status in Group B, TPOAb+ women experienced a remarkable lower complication (14.2%) and adverse outcome rate (7.1%) compared with negative subjects (64.7% and 45%, respectively). Our data suggest that levothyroxine administrated in the first trimester was associated with decreased risk of adverse obstetric event. Additionally, pregnant women with TPOAb positive could also benefit from thyroid hormone therapy even initiated in the second trimester.


Extending chemoselective ligation to sugar chemistry: convergent assembly of bioactive neoglycoconjugates.
Glycoproteins and glycolipids play central roles in human health and disease, and their mimetics are primary candidates for drug development. Our understanding of the molecular level of phenomena based on molecular recognition of oligosaccharides by specific receptors has taken tremendous advantage from their chemical synthesis, which provides homogeneous material not attainable from biosynthetic systems. This review summarizes chemoselective approaches for the assembly of neoglycoconjugates. The objective of these methods is to make glycoconjugate synthesis accessible to a broader community, thus accelerating progress in biotechnology.


The interplay between heart failure, metabolism and body composition.
A complex interplay exists between heart failure, metabolic status and body composition. The idiosyncrasies of these relationships are poorly understood, but they offer prognostic value and potential clinical utility. Current understanding of this relationship and known clinical value are discussed in this article.


Ecological correlates of suicide in the United States and Hungary.
Ecological correlates of suicide were explored for the counties of Hungary and the states of the United States. Only one common correlate was identified (divorce rates). The remaining social indicators that were associated with suicide rates in the United States were not associated with suicide rates in Hungary. The importance of replicating ecological studies in several countries was noted.


Reconstituted skin in culture: a simple method with optimal differentiation.
Human skin is a unique organ, which can be reconstituted in vitro and represents an interesting system for studying cell proliferation and differentiation. A simple technique for producing reconstituted skin with optimal epidermal differentiation is described and characterized. A 4-mm punch biopsy of normal human skin is deposited on the epidermal side of mortified de-epidermized human dermis maintained at the air-liquid interface with a metallic support. The culture medium contains insulin, epidermal growth factor (EGF), cholera toxin, hydrocortisone, penicillin/streptomycin and fungizone. A well-differentiated epidermis develops within 15 days. Morphological and ultrastructural studies show a neoepidermis resembling normal skin. Differentiation markers such as involucrin, filaggrin, and various cytokeratins detected with pancytokeratin antibody are present and confirm this resemblance. The keratin profile is comparable to that observed in other skin culture models. A basement-membrane-like structure is reconstituted with hemidesmosomes and anchoring-filament formation. Bullous pemphigoid (BP) antigen is observed at the dermo-epidermal junction after 21 days of culture. Moreover, both dermal substrates and punch biopsies can be kept frozen for long-term storage, with little or no loss of epidermal growth kinetics and morphology. This skin culture technique is rapid, simple, economical and reproducible. Characterization has here shown high-quality epidermal differentiation. Scientists interested in epidermal in vitro studies should take interest in all these advantages.


Detection and identification of food-borne pathogens of the genera Campylobacter, Arcobacter and Helicobacter by multiplex PCR in poultry and poultry products.
The objective of this study was to develop a multiplex polymerase chain reaction (PCR) to detect and differentiate food-borne pathogens of the three genera Campylobacter, Arcobacter and Helicobacter in a single step procedure. One common reverse primer and three genus-specific forward primers were designed by hybridizing to the 16S rRNA of selected reference strains. Besides the species with significance as food-borne pathogens isolated from poultry meat--Campylobacter jejuni, Campylobacter coli, Arcobacter butzleri and Helicobacter pullorum--several other members of these genera were tested to determine the specificity of the designed multiplex PCR. In total, 20 ATCC and NCTC reference strains of Campyobacter, Arcobacter and Helicobacter were used to evaluate the PCR. Specific amplificates were obtained from all thermophilic species of Campylobacter as well as from species of Arcobacter and Helicobacter. No amplification product was obtained from the non-thermophilic Campylobacter, C. hyointestinalis and C. fetus. Furthermore, a total of 43 field strains of the three genera isolated from poultry, pigs, cattle and humans were investigated using this PCR. To confirm the classification of 10 H. pullorum strains the 16S rRNAs were sequenced. The developed PCR is a helpful diagnostic tool to detect and differentiate Campylobacter, Arcobacter and Helicobacter isolated from poultry and poultry products.


Normal variation of talar tilt of the ankle in children.
Sixty normal children were examined clinically and radiologically, using a special apparatus with a goniometer and a tensometer to standardize stress tests when applying valgus and varus forces to the ankle. It was noted that the clinical movement of inversion is not entirely due to a subtalar movement; indeed a talar tilt appears to be physiological. The range of normal in these patients, age range 6 to 15 years, was 0 to 27 degrees with an average talar tilt of 7 degrees . The talar tilt is not necessarily the same in both ankles of any one individual and it is never noted in eversion. The talar tilt is more marked in younger children in the position of equinus.When interpreting radiographs of recently injured ankles, it is wise to recall that a talar tilt need not be the result of trauma and that it may be physiological and yet unequal on both sides.


Broadening access to medical care during a severe influenza pandemic: the CDC nurse triage line project.
The impact of a severe influenza pandemic could be overwhelming to hospital emergency departments, clinics, and medical offices if large numbers of ill people were to simultaneously seek care. While current planning guidance to reduce surge on hospitals and other medical facilities during a pandemic largely focuses on improving the "supply" of medical care services, attention on reducing "demand" for such services is needed by better matching patient needs with alternative types and sites of care. Based on lessons learned during the 2009 H1N1 pandemic, the Centers for Disease Control and Prevention and its partners are currently exploring the acceptability and feasibility of using a coordinated network of nurse triage telephone lines during a pandemic to assess the health status of callers, help callers determine the most appropriate site for care (eg, hospital ED, outpatient center, home), disseminate information, provide clinical advice, and provide access to antiviral medications for ill people, if appropriate. As part of this effort, the integration and coordination of poison control centers, existing nurse advice lines, 2-1-1 information lines, and other hotlines are being investigated.


Regulation of cell division in Escherichia coli K-12: probable interactions among proteins FtsQ, FtsA, and FtsZ.
In Escherichia coli, the FtsQ, FtsA, and FtsZ proteins are believed to play essential roles in the regulation of cell division. Of the three proteins, FtsZ has received the most attention, particularly because of its interactions with SfiA. Double mutants which carry mutations located in the ftsQ, ftsA, or ftsZ gene in combination with the lon-1 mutation were constructed. In the presence of the lon-1 mutation, which is known to stabilize SfiA, the ftsQ1 mutant cells were not capable of forming colonies on a rich agar medium, whereas mutant cells harboring either one of the mutations grew well on this medium. Examination of lon-1 fts double-mutant cells for sensitivity to UV light revealed that those carrying the ftsA10 allele were resistant. It was also observed that in the presence of a multicopy plasmid containing a wild-type ftsZ gene, the ftsQ1 mutant filamented markedly following a nutritional shift-up and that the division rate of ftsZ84 mutant cells was slightly reduced when they harbored a wild-type ftsQ-containing plasmid. The possibility that the Fts proteins are interacting with one another and forming a molecular complex is discussed.


Hyperbranched Triphenylamine Polymer for UltraFast Battery Cathode.
A novel hyperbranched poly(triphenylamine) (PHTPA) was synthesized, and the electrochemical properties of this material were studied. PHTPA was synthesized by a facile method in a one-step reaction from affordable monomers. Despite all aromatic structures, PHTPA showed good solubility in several organic solvents. The battery performance test of PHTPA showed a high discharge voltage, an ultrafast charge-discharge performance of 100-300 C, and a long cycle life of more than 5000 cycles. Moreover, the addition of the PHTPA to LiFePO4 (LFP) improved the charge-transfer resistance and Warburg coefficient, which is related to the diffusion of lithium ions in LFP, and consequently improved the charge-discharge performance of LFP itself at a high C rate (20-100 C). This behavior is understood to be the result of the organic-inorganic charge transfer. The superior cycle performance of the PHTPA-LFP hybrid cathode was also found. PHTPA will serve as an additive for a high-performance LIB.


Intergenerational impact of paternal lifetime exposures to both folic acid deficiency and supplementation on reproductive outcomes and imprinted gene methylation.
Do paternal exposures to folic acid deficient (FD), and/or folic acid supplemented (FS) diets, throughout germ cell development adversely affect male germ cells and consequently offspring health outcomes? Male mice exposed over their lifetimes to both FD and FS diets showed decreased sperm counts and altered imprinted gene methylation with evidence of transmission of adverse effects to the offspring, including increased postnatal-preweaning mortality and variability in imprinted gene methylation. There is increasing evidence that disruptions in male germ cell epigenetic reprogramming are associated with offspring abnormalities and intergenerational disease. The fetal period is the critical time of DNA methylation pattern acquisition for developing male germ cells and an adequate supply of methyl donors is required. In addition, DNA methylation patterns continue to be remodeled during postnatal spermatogenesis. Previous studies have shown that lifetime (prenatal and postnatal) folic acid deficiency can alter the sperm epigenome and increase the incidence of fetal morphological abnormalities. Female BALB/c mice (F0) were placed on one of four amino-acid defined diets for 4 weeks before pregnancy and throughout pregnancy and lactation: folic acid control (Ctrl; 2 mg/kg), 7-fold folic acid deficient (7FD; 0.3 mg/kg), 10-fold high FS (10FS, 20 mg/kg) or 20-fold high FS (20FS, 40 mg/kg) diets. F1 males were weaned to their respective prenatal diets to allow for diet exposure during all windows of germline epigenetic reprogramming: the erasure, re-establishment and maintenance phases. F0 females were mated with chow-fed males to produce F1 litters whose germ cells were exposed to the diets throughout embryonic development. F1 males were subsequently mated with chow-fed female mice. Two F2 litters, unexposed to the experimental diets, were generated from each F1 male; one litter was collected at embryonic day (E)18.5 and one delivered and followed postnatally. DNA methylation at a global level and at the differentially methylated regions of imprinted genes (H19, Imprinted Maternally Expressed Transcript (Non-Protein Coding)-H19, Small Nuclear Ribonucleoprotein Polypeptide N-Snrpn, KCNQ1 Opposite Strand/Antisense Transcript 1 (Non-Protein Coding)-Kcnq1ot1, Paternally Expressed Gene 1-Peg1 and Paternally Expressed Gene 3-Peg3) was assessed by luminometric methylation analysis and bisulfite pyrosequencing, respectively, in F1 sperm, F2 E18.5 placenta and F2 E18.5 brain cortex. F1 males exhibited lower sperm counts following lifetime exposure to both folic acid deficiency and the highest dose of folic acid supplementation (20FS), (both P < 0.05). Post-implantation losses were increased amongst F2 E18.5 day litters from 20FS exposed F1 males (P < 0.05). F2 litters derived from both 7FD and 20FS exposed F1 males had significantly higher postnatal-preweaning pup death (both P < 0.05). Sperm from 10FS exposed males had increased variance in methylation across imprinted gene H19, P < 0.05; increased variance at a few sites within H19 was also found for the 7FD and 20FS groups (P < 0.05). While the 20FS diet resulted in inter-individual alterations in methylation across the imprinted genes Snrpn and Peg3 in F2 E18.5 placenta, ≥50% of individual sites tested in Peg1 and/or Peg3 were affected in the 7FD and 10FS groups. Inter-individual alterations in Peg1 methylation were found in F2 E18.5 day 10FS group brain cortex (P < 0.05). Not applicable. The cause of the increase in postnatal-preweaning mortality was not investigated post-mortem. Further studies are required to understand the mechanisms underlying the adverse effects of folic acid deficiency and supplementation on developing male germ cells. Genome-wide DNA and histone methylome studies as well as gene expression studies are required to better understand the links between folic acid exposures, an altered germ cell epigenome and offspring outcomes. The findings of this study provide further support for paternally transmitted environmental effects. The results indicate that both folic acid deficiency and high dose supplementation can be detrimental to germ cell development and reproductive fitness, in part by altering DNA methylation in sperm. This study was supported by a grant to J.M.T. from the Canadian Institutes of Health Research (CIHR #89944). The authors declare they have no conflicts of interest.


Levofloxacin-induced Achilles tendinitis in a young adult in the absence of predisposing conditions.
Fluoroquinolones (FQs) represent a major class of antimicrobials that have a high potential as therapeutic agents. Although FQs are generally safe for the use as antimicrobials, they may induce tendinopathic complications such as tendinitis and tendon rupture. A number of factors have been suggested to further predispose a patient to such injuries. Hitherto, a few published cases on tendon disorders have implicated levofloxacin, a more recently introduced FQ. Here, we report a patient with levofloxacin-induced Achilles tendinitis, who exhibited no known predisposing factors. A 20-year-old man without any history of disease or medication presented with community-acquired pneumonia. Levofloxacin was administered and 3 days later, he complained of pain in the left Achilles tendon and revealed redness and swelling in the area. On suspecting Achilles tendinitis, levofloxacin treatment was discontinued, and the tendinitis subsequently improved. To our knowledge, this is the first case report on FQ-induced Achilles tendinitis in Korea.


Actions of BAFF in B cell maturation and its effects on the development of autoimmune disease.
BAFF, a member of the family of tumour necrosis factor (TNF) ligands, is essential for the development of peripheral mature, long lived B lymphocytes. It binds to three different receptors, BCMA, TACI, and BAFF-R, which are all members of the family of TNF receptors. Defects in the genes encoding BAFF or BAFF-R abolish the generation of mature B cells. BAFF is made by myeloid cells whereas BAFF-R is expressed preferentially on B cells. BAFF induces polyclonal maturation of resting, short lived immature B cells to resting, long lived mature B cells without proliferation. Lupus erythematodes prone mice have elevated blood levels of BAFF, and treatment of these mice with the BAFF decoy receptor (BCMA-Ig) prevents the onset of this systemic autoimmune disease. Human lupus patients also have elevated blood levels of BAFF. Treatment with BAFF neutralising agents (decoy receptors, monoclonal antibodies) should prevent, delay, or, at least, slow down the disease.


Investigation of hematological blood values in COVID-19 patients according to discharge and exitus groups.
The investigation was conducted on hematological blood values examined in COVID-19 patients in order to assess whether these values could provide a prediction about the severity and course of the disease. In this way, the study aims to help determine the treatment plans of patients and monitor the recovery process with simple and common tests such as hematological blood values. This was a retrospective study. The study group consisted of patients with positive PCR test results registered in the Patient Automation System of the Emergency Department of Malatya Training and Research Hospital between 1 January and 30 April 2021. The patients were divided in discharge (n=187) and exitus (n=52) groups. The study showed that Neutrophil (AUC=0.889, p<0.05), Lymphocyte (AUC=0.805, p<0.05) and mean corpuscular hemoglobin concentration (MCHC) (AUC=0.739, p<0.05) values may be a good predictive factor for disease severity and mortality risk of COVID-19 patients. Neutrophil, Lymphocyte and MCHC blood test samples can be used as a biomarker in the effective fight against COVID-19.


Adsorption of Staphylococcus viruses S13' and S24-1 on Staphylococcus aureus strains with different glycosidic linkage patterns of wall teichoic acids.
The group of phages belonging to the family Podoviridae, genus P68virus, including Staphylococcus viruses S13' and S24-1, are important because of their benefits in phage therapy against Staphylococcus aureus infections. The O-glycosidic linkage patterns of wall teichoic acids (WTAs) in S. aureus cell walls seem to be important for adsorption of this phage group. In this study, the adsorption of Staphylococcus viruses S13' and S24-1 to S. aureus was examined using strains with modified WTA glycosidic linkage patterns. We found that the β-O-N-acetylglucosamine of WTAs was essential for S13' adsorption, while N-acetylglucosamine, regardless of the α- and β-O-glycosidic linkages of the WTAs, was essential for S24-1 adsorption. Next, examining the binding activities of their receptor-binding proteins (RBPs) to cell walls with different WTA glycosidic patterns, the β-O-N-acetylglucosamine of the WTAs was essential for S13' RBP binding, while N-acetylglucosamine, regardless of the α- and β-O-glycosidic linkages of the WTAs, was essential for S24-1 RBP binding. Therefore, the results of the RBP binding assays were consistent with those of the phage adsorption assays. Bioinformatic analysis suggested that the RBPs of Staphylococcus viruses S13' and S24-1 were structurally similar to the RBPs of phage phi11 of thefamily Siphoviridae. Phylogenetic analysis of the RBPs indicated that two phylogenetic subclusters in the family Podoviridae were related to the glycosidic linkage patterns required for phage adsorption, possibly mediated by RBPs. We hope that this study will encourage the future development of therapeutic phages.


Trichotillomania: Bizzare Patern of Hair Loss at 11-Year-old Girl.
Trichotillomania (TTM) is defined by the Diagnostics and Statistic Manual of Mental Disorders, 4th edition (DMS-IV) as hair loss from a patient`s repetitive self-pulling of hair. The disorder is included under anxiety disorders because it shares some obsessive-compulsive features. Patients have the tendency towards feelings of unattractiveness, body dissatisfaction, and low self-esteem (1,2). It is a major psychiatric problem, but many patients with this disorder first present to a dermatologist. An 11-year-old girl came to our department with a 2-month history of diffuse hair loss on the frontoparietal and parietotemporal area (Figure 1). She had originally been examined by a pediatrician with the diagnosis of alopecia areata. The patient`s personal history included hay fever and shortsightedness, and she suffered from varicella and mononucleosis. Nobody in the family history suffered from alopecia areata, but her father has male androgenetic alopecia (Norwood/Hamilton MAGA C3F3). The mother noticed that the child had had changeable mood for about 2 months and did not want to communicate with other persons in the family. The family did not have any pet at home. At school, her favorite subjects were Math and Computer Studies. She did not like Physical Education and did not participate in any sport activities during her free time. This was very strange because she was obese (body-mass index (BMI) 24.69). She was sometimes angry with her 13-year-old sister who had better results at school. The girl had suddenly started to wear a blue scarf. The parents did not notice that she pulled out her hair at home. Dermatological examination of the capillitium found a zone of incomplete alopecia in the frontoparietal and parietotemporal area, without inflammation, desquamation, and scaring. Hairs were of variable length (Figure 1). There was a patch of incomplete alopecia above the forehead between two stripes of hair of variable length (Figure 2). The hair pull test was negative along the edges of the alopecia. Mycological examination from the skin capillitium was negative. The trichoscopy and skin biopsy of the parietotemporal region of the capillitium (Figure 3) confirmed trichotillomania. Laboratory tests (blood count, iron, ferritin, transferrin, selenium, zinc, vitamin B12, folic acid, serology and hormones of thyroid gland) were negative. We referred the girl for ophthalmologic and psychological examination. Ophthalmologic examination proved that there was no need to add any more diopters. The psychological examination provided us with a picture in which she drew her family (Figure 4). The strongest authority in the family was the mother because she looked after the girls for most of the day. She was in the first place in the picture. The father had longer working hours and spent more time outside the home. He worked as a long vehicle driver. He was in the second place in the picture. There was sibling rivalry between the girls, but the parents did not notice this problem and preferred the older daughter. She was successful at school and was prettier (slim, higher, curly brown hair, without spectacles). Our 11-years-old patient noticed all these differences between them, but at her level of mental development was not able to cope with this problem. She wanted to be her sister's equal. The sister is drawn in the picture in the third place next to father, while the patient's own figure was drawn larger and slim even though she was obese. Notably, all three female figures had very nice long brown hair. It seemed that the mother and our patient had better quality of hair and more intense color than the sister in the drawing. The only hairless person in the picture was the father. The girl did not want to talk about her problems and feelings at home. Then it was confirmed that our patient was very sensitive, anxious, willful, and withdrawn. She was interested in her body and very perceptive of her physical appearance. From the psychological point of view, the parents started to pay more interest to their younger daughter and tried to understand and help her. After consultation with the psychiatrist, we did not start psychopharmacologic therapy for trichotillomania; instead, we started treatment with cognitive behavioral therapy, mild shampoo, mild topical steroids (e.g. hydrocortisone butyrate 0.1%) in solution and methionine in capsules. With parents' cooperation, the treatment was successful. The name trichotillomania was first employed by the French dermatologist Francois Henri Hallopeau in 1889, who described a young man pulling his hair out in tufts (3-5). The word is derived from the Greek thrix (hair), tillein (to pull), and mania (madness) (5). The prevalence of TTM in the general adult population ranges from 0.6% to 4%, and 2-4% of the general psychiatric outpatient population meet the criteria for TTM (2-5). The prevalence among children and adolescents has been estimated at less than 1% (5). The disease can occur at any age and in any sex. The age of onset of hair pulling is significantly later for men than for women (3). There are three subsets of age: preschool children, preadolescents to young adults, and adults. The mean age of onset is pre-pubertal. It ranges from 8 to 13 years (on average 11.3 years) (2-5). The occurrence of hair-pulling in the first year of life is a rare event, probably comprising <1% of cases (5). The etiology of TTM is complex and may be triggered by a psychosocial stressor within the family, such as separation from an attachment figure, hospitalization of the child or parent, birth of a younger sibling, sibling rivalry, moving to a new house, or problems with school performance. It has been hypothesized that the habit may begin with "playing" with the hair, with later chronic pulling resulting in obvious hair loss (2). Environment is a factor because children usually pull their hair when alone and in relaxed surroundings. The bedroom, bathroom, or family room are "high-risk" situations for hair-pulling (5). Men and women also differed in terms of the hair pulling site (men pull hair from the stomach/back and the moustache/beard areas, while women pull from the scalp) (3). Pulling hair from siblings, pets, dolls, and stuffed animals has also been documented, often occurring in the same pattern as in the patient (5). Genetic factors contributing to the development of TTM are mutations of the SLITRK1 gene, which plays a role in cortex development and neuronal growth. The protein SAPAP3 has been present in 4.2% of TTM cases and patients with obsessive-compulsive disorder (OCD). It may be involved in the development of the spectrum of OCD. A significantly different concordance rate for TTM was found in monozygotic (38.1%) compared with dizygotic (0%) twins in 34 pairs (3). The core diagnostic feature is the repetitive pulling of hairs from one`s own body, resulting in hair loss. The targeted hair is mostly on the scalp (75%), but may also be from the eyebrows (42%), eyelashes (53%), beard (10%), and pubic area (17%) (3,5). There are three subtypes of hair pulling - early onset, automatic, and focused. Diagnostic criteria for TTM according to DSM-IV criteria are (2,3,5): 1) recurrent pulling of one`s hair resulting in noticeable hair loss; 2) an increasing sense of tension immediately prior to pulling out the hair or when attempting to resist the behavior; 3) pleasure, gratification, or relief when pulling out the hair; 4) the disturbance is not better accounted for by another mental disorder and is not due to a general medical condition (e.g., a dermatologic condition); 5) the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The differential diagnosis includes alopecia areata (Table 1) (6), tinea capitis, telogen effluvium, secondary syphilis, traction alopecia, loose anagen syndrome, lichen planopilaris, alopecia mucinosa, and scleroderma (2-5). Biopsy of an involved area (ideally from a recent site of hair loss) can help to confirm the diagnosis (5). On histologic examination, there are typically increased numbers of catagen and telogen hairs without evidence of inflammation. Chronic hair pulling induces a catagen phase, and more hairs will be telogen hairs. Pigment casts and empty anagen follicles are often seen. Perifollicular hemorrhage near the hair bulb is an indicator of TTM (2). Complications of TTM are rare, but they comprise secondary bacterial infections with regional lymphadenopathy as a result of picking and scratching at the scalp. Many patients play with and ingest the pulled hairs (e.g. touching the hair to lips, biting, and chewing). Trichophagia (ingestion of the hair) can lead to a rare complication named trichobezoar (a "hair ball" in stomach). This habit is present in approximately 5% to 30% of adult patients, but it is less frequent in children. Patient with trichophagia present with pallor, nausea, vomiting, anorexia, and weight loss. Radiologic examination and gastroscopy should not be delayed (2,4,5). The management of the disease is difficult and requires strong cooperation between the physician, patient, and parents. The dermatologist cannot take part in the therapy, strictly speaking, but without the psychological, psychopharmacologic, and topic dermatologic treatment a vicious circle will be perpetuated.


The importance and perspective of plant-based squalene in cosmetology.
Squalene is a highly unsaturated hydrocarbon from triterpenoid family, discovered as a major component of the liver oil of certain varieties of deep sea sharks. In the interest of protecting biodiversity, raw materials of animal origin must be replaced by alternative sources that respect our environment. Squalene is widely present as a component of the unsaponifiable fraction of vegetable oils (i.e., olive oil, amaranth oil). Amaranth oil seems to be the key source of squalene. Amaranth grains contains 7-7.7% lipids, and these lipids are extremely valuable because of the presence of ingredients like squalene, unsaturated fatty acids, vitamin E as tocopherols, tocotrienols, and phytosterols, which are not seen together in other common oils. In human skin physiology, squalene is not only used as an antioxidant, moisturizer, and material for topically applied vehicle, but is also used in treating skin disorders like seborrheic dermatitis, acne, psoriasis, or atopic dermatitis. Further studies on alternative sources are needed to explore the utility of squalene for treating skin.


Communication and swallowing training of stroke-specialized health professionals using transdisciplinary knowledge in a patient-actor scenario: A case report.
Most people with stroke exhibit a variety of impairments that need to be addressed by a multidisciplinary team. Communication and swallowing disorders are common and should be screened very early. To guarantee a patient-centred approach, all patients, even those with speech and language disorders, must be actively engaged in the healthcare process. Effective communication is essential to success in many of the needed interventions. However, healthcare professionals often do not receive formal training in communicating with these patients, thus increasing the risk of preventable adverse events. To describe the design, implementation and evaluation of a post-acute stroke multidisciplinary team training using patient actors in a simulation approach. A 2-day course focused on the transdisciplinary knowledge related to communication and swallowing that all members of the multidisciplinary stroke team should acquire was implemented. A case-based learning methodology used simulation and resorting to patients' actors. Learning outcomes were evaluated by comparing the results obtained in two knowledge tests, one for each topic, which participants performed before and after each day course. Reaction to the training was gathered concerning the content, teacher quality and course organization. The follow-up was performed 6 months later to assess training skills transfer to the workplace environment. All the participants considered that the programme objectives were relevant or truly relevant and revealed that the programme's dynamic, rhythm and scenarios set were excellent. After the end of the programme, both communication and swallowing knowledge increased. Most participants had the opportunity to employ the acquired training skills in their work environment. The main barriers identified to implementing these skills were the 'need for additional training', the 'lack of time' or 'the lack of opportunities'. Simulation is a central method to increase and improve health professionals' skills when intervening with stroke patients. Using simulation with patient actors allows flexibility and diversification of clinical situations under analysis, which can provide a multiplier effect of reflection and learning. The implemented training achieved its objectives. What is already known on this subject Simulation in the training of health professionals is increasingly used as a good practice, allowing the recreation of scenarios identical to those in the context of professional practice. This strategy is used not only in initial training but also for the development of advanced skills. What this study adds to the existing knowledge This study reports the use of simulation using actor patients for the development of transdisciplinary skills in the topics of communication and swallowing in people with stroke What are the clinical and practical implications of this work? The study demonstrates that in a short period of training, the use of simulation with actor patients favours the development of transdisciplinary skills in the topics of communication and swallowing in people with stroke. At the same time, the skills developed are transferable to professional practice.


A nanofluidic sensing platform based on robust and flexible graphene oxide/chitosan nanochannel membranes for glucose and urea detection.
We present the development of a health-monitoring nanofluidic membrane utilizing biocompatible and biodegradable graphene oxide, chitosan, and graphene quantum dots. The nanoconfinement provided by graphene oxide nanolayers encapsulates chitosan molecules, allowing for their conformational changes and switchable hydrophobic-hydrophilic behavior in response to pH variations. This low-dimensional membrane operates as an array of nanofluidic channels that can release quantum dots upon pH change. The photoluminescence emission from quantum dots enables rapid and reliable optical visualization of pH changes, facilitating efficient human health monitoring. To ensure fouling prevention and enable multiple usages, we adopt a design approach that avoids direct contact between biomarkers and the nanochannels. This design strategy, coupled with good mechanical properties (Young's modulus of 5.5 ± 0.7 GPa), preserves the integrity and functionality of the sensors for repeated sensing cycles. Furthermore, leveraging the memory effect, our sensors can be reloaded with graphene quantum dots multiple times without significant loss of selectivity, achieving reusability. The wide-ranging capabilities of 2D materials and stimuli-responsive polymers empower our sustainable approach to designing low-dimensional, robust, and flexible sensing materials. This approach allows for the integration of various biorecognition elements and signal transduction modes, expanding the versatility and applications of the designed materials.


Mechanical challenge causes alterations of rat colonic mucosa and released mucins. Alterations of mucosa and mucins.
The effect of intraluminal challenge on rat colonic mucin producing cells and the amount and composition of released mucins was investigated. Germfree rats (GF) were maintained on a commercial high fiber (HF) diet (37% of undigestable fiber, Altromin 1640 p), in order to increase volume, dry weight and abrasive effect of the ingesta. GF control rats were fed a standard (ST) laboratory diet with 4.5% fiber (Altromin 1314 f). In the HF diet group, histological sections of the proximal and distal colon revealed a significantly increased number of mucin secreting goblet cells and an elevated goblet cell replication activity, as determined by 5'-bromo-deoxyuridine incorporation. The total amount of colonic mucins, isolated by gel filtration, was increased versus the control group. According to the results of ion exchange chromatography, carbohydrate and amino acid analysis, mucins from rats, given the HF diet, had an elevated content of acidic mucin constituents with alterations in the carbohydrate and amino acid composition. In a parallel study with specified pathogen free rats (SPF), the additional influence of the microflora on mucin secreting cells and isolated mucins was determined. An increased number of mucin secreting cells predominantly was observed in rats given the standard diet. Due to bacterial degradation, significantly less mucin was isolated from both dietary groups. The increase of acidic mucin constituents was less pronounced than in GF rat mucin, coinciding with losses of terminally linked monosaccharides. Alterations of the core protein, accompanying the presence of the microflora, were not detected.


Interaction of organophosphorus insecticides phosphamidon & malathion on lipid profile & acetylcholinesterase activity in human erythrocyte membrane.
The organophosphorus insecticides phosphamidon and malathion were found to inhibit the activity of human acetylcholinesterase in vitro, in the human erythrocyte membrane. Lineweaver-Burk analysis indicated that the insecticide induced inhibition of acetylcholinesterase activity was uncompetitive in nature. The total lipid, cholesterol and phospholipid contents of erythrocyte membranes were reduced following phosphamidon and technical malathion treatment, while the level of lipid peroxidation was raised following malathion treatment.


The effect of early versus late antidepressant treatment on physical impairment associated with poststroke depression: is there a time-related therapeutic window?
Impairments in activities of daily living (ADL) are common after stroke and may be related to poststroke depression. We have demonstrated that remission of poststroke major depression was associated with improvement in ADL. The administration of antidepressants within the first 3 months after stroke has been shown to prevent poststroke depression, early administration might also improve recovery of ADL among patients with stroke. This study examines the effect of early versus late treatment with antidepressants on recovery in ADL. Among 62 patients after stroke, the therapeutic effect of a 3-month course of antidepressants begun during the first month after stroke was compared with the effect of treatment begun after 1 month. The severity of impairment was measured using the Functional Independence Measure (FIM) and post-treatment outcome was assessed over the following 21 months. Although both the early and late treatment groups showed improvements in FIM scores during the 3 months of treatment, the early treatment group improved significantly more than the late treatment group. After the treatment, the early treatment group maintained this improvement over 2 years while the late treatment group deteriorated over time. There were no significant differences in the 2 groups that would explain the findings. Recovery in ADL impairment after stroke appeared to be enhanced by the use of antidepressant medication if treatment was started within the first month after stroke. These findings are consistent with the hypothesis that there may be a time-related therapeutic window in the treatment of physical impairment associated with poststroke depression.


The feasibility of genome-scale biological network inference using Graphics Processing Units.
Systems research spanning fields from biology to finance involves the identification of models to represent the underpinnings of complex systems. Formal approaches for data-driven identification of network interactions include statistical inference-based approaches and methods to identify dynamical systems models that are capable of fitting multivariate data. Availability of large data sets and so-called 'big data' applications in biology present great opportunities as well as major challenges for systems identification/reverse engineering applications. For example, both inverse identification and forward simulations of genome-scale gene regulatory network models pose compute-intensive problems. This issue is addressed here by combining the processing power of Graphics Processing Units (GPUs) and a parallel reverse engineering algorithm for inference of regulatory networks. It is shown that, given an appropriate data set, information on genome-scale networks (systems of 1000 or more state variables) can be inferred using a reverse-engineering algorithm in a matter of days on a small-scale modern GPU cluster.


Synthesis and Characterization of Micro/Nanoscale VO2(M) through Vanadylethylene Glycolate Decomposition.
Thanks to a homemade dynamic vacuum system, fully crystallized VO2 (M) is successfully synthesized in a merged step of vanadyl ethylene glycolate (VEG) decomposition and crystallization of VO2 at high temperatures (>500 °C). During the whole process, vanadium valence (+4) is well maintained, and VEG microstructure plays an important role in the end-product size and shape. Finally, the suggested route appears well suitable for the mass production of VO2 nanoparticles.


Prevalence and antimicrobial resistance of Campylobacter jejuni and Campylobacter coli isolated from raw chicken meat and human stools in Korea.
Prevalence of Campylobacter in raw chicken meat and human stools and subsequent antibiotic resistance profiles of the pathogenic isolates obtained from 2000 through 2002 were investigated. Campylobacter jejuni and Campylobacter coli were isolated from 570 of the 923 raw chicken meat samples collected from traditional markets, large retail stores, or department stores in Korea, resulting in the isolation rate of 61.8%. A total of 579 Campylobacter isolates were obtained from raw chicken (36.3% for C. jejuni and 26.4% for C. coli) with the average population of 335.6 CFU/g. From 513 human stool samples, 15 isolates of Campylobacter were detected. Seasonal variation in the quantification of C. coli was not noticeable throughout the year, while the isolation rate of C. jejuni was the highest in September through October (840 CFU/g) followed by that of July through August and May through June in decreasing order, showing a significant seasonal effect (P < 0.05). Contamination of Campylobacter was more severe in raw chicken meat sold in traditional markets than in those sold in large retail stores and department stores. Prevalence of Campylobacter in raw chicken sold in traditional markets was significantly influenced by seasonal changes (P < 0.05), whereas the samples obtained from other places was less affected by the seasonal changes. Susceptibilities of the 594 chicken isolates to ciprofloxaxin, chloramphenicol, erythromycin, kanamycin, nalidixic acid, and tetracycline were determined by an E-test. Campylobacter isolates were the most resistant to nalidixic acid (91.4%) followed by ciprofloxaxin (87.9%), tetracycline (87.2%), kanamycin (30.6%), erythromycin (19.4%), and chloramphenicol (1.3%). Human isolates showed a similar resistance to the six antibiotics tested. The proportion of Campylobacter isolates with multidrug resistance to four or more antimicrobials obtained from 2000 through 2002 ranged from 28 to 43.5%, indicating that it could be a serious health-threatening factor. This study suggests that it is prudent to establish an effective National Monitoring Program in Korea for the prevention and control of Campylobacter spp.


Progress in type II dehydroquinase inhibitors: from concept to practice.
Scientists are concerned by an ever-increasing rise in bacterial resistance to antibiotics, particularly in diseases such as malaria, toxoplasmosis, tuberculosis, and pneumonia, where the currently used therapies become progressively less efficient. It is therefore necessary to develop new, safe, and more efficient antibiotics. Recently, the existence of the shikimic acid pathway has been demonstrated in certain parasites such as the malaria parasite. These types of parasites cause more than a million casualties per year, and their effects are particularly strong in people with a compromised immune system such as HIV patients. In such cases it is possible that inhibitors of this pathway could be active against a large variety of microorganisms responsible for the more opportunistic infections in HIV patients. Interest in this pathway has resulted in the development of a wide variety of inhibitors for the enzymes involved. This review covers recent progress made in the development of inhibitors of the third enzyme of this pathway, i.e., the type II dehydroquinase. The X-ray crystal structures of several dehydroquinases (Streptomyces coelicolor, Mycobacterium tuberculosis, etc.) with an inhibitor bound in the active site have recently been solved. These complexes identified a number of key interactions involved in inhibitor binding and have shed light on several aspects of the catalytic mechanism. These crystal structures have also proven to be a useful tool for the design of potent and selective enzyme inhibitors, a feature that will also be discussed.


Circulating Levels of M30 and M65 Molecules in Transitional Cell Carcinoma of the Bladder and Their Relation to Tumor Progression.
Various markers are suggested for diagnosis and monitoring of transitional cell carcinoma of the bladder (TCC), including cytokeratins (CKs). In the present study, the circulating CK18 (M65) and its caspase-cleaved form, ccCK18 (M30), have been investigated in a group of patients with TCC. Serum samples were obtained from 60 patients before surgical resection, among which the samples of 26 patients after resection were also included. We measured the levels of soluble M30 and M65 molecules by enzyme-linked immunosorbent assay. The relation between these markers and patients' clinical characteristics was evaluated. M30 and M65 in total patient sera were 148 ± 16 U/L and 318 ± 34 U/L, respectively. A correlation existed between pre-operative M30 and M65 levels (P < 0.0001, Spearman r = 0.51). M65, but not M30, showed a significant relation to tumor stage and grade. The M65 quantity in patients with T3/T4 tumor stages (350 ± 42 U/L) was higher than that of patients with T1/T2 stages (293 ± 45U/L; P < 0.038). Patients with tumor grades III/IV also showed higher levels of M65 compared to patients with tumor grades I/II (P < 0.04). The M30:M65 ratio in all patients was 0.54 ± 0.04. There was a lower M30:M65 ratio in patients with T3/T4 stage tumors and those with tumor grades III/IV (P < 0.02). The M30 (133 ± 19 U/L) and M65 levels (240 ± 21 U/L) after surgery did not significantly differ compared to their pre-operative values. However, a correlation between the pre- and post-operative M30:M65 ratio in patients ≥ 70 years was seen (P = 0.009). These data suggested a relationship of both M65 and the M30:M65 ratio to tumor progression which might imply their importance in TCC monitoring.


Plant ureases: roles and regulation.
Both urea and urease were subjects of early scientific investigations. Urea was the first organic molecule to be synthesized and jack bean urease was the first enzyme ever to be crystallized. About 50 years later it was shown to be the first nickel metalloenzyme. Since then, nickel-dependent ureases have been isolated from many bacteria, fungi and higher plants. They have similar structures and mechanisms of catalysis. A urease apoenzyme needs to be activated. This process requires participation of several accessory proteins that incorporate nickel into the urease forming catalytic site. In this review, ureases from various organisms are briefly described and the similarities of their structures discussed. Moreover, the significance of urea recycling in plants is explained and recent literature data about the function and activation of plant ureases are presented.