2,6-Bis(azaindole)pyridine: reactivity with iron(III) and copper(II) salts.
1-[6-(1H-Pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl]-1H-pyrrolo[2,3-b]pyridin-7-ium tetrachloridoferrate(III), (C(19)H(14)N(5))[FeCl(4)], (II), and [2,6-bis(1H-pyrrolo[2,3-b]pyridin-1-yl-kappaN(7))pyridine-kappaN]bis(nitrato-kappaO)copper(II), [Cu(NO(3))(2)(C(19)H(13)N(5))], (III), were prepared by self-assembly from FeCl(3).6H(2)O or Cu(NO(3))(2).3H(2)O and 2,6-bis(1H-pyrrolo[2,3-b]pyridin-1-yl)pyridine [commonly called 2,6-bis(azaindole)pyridine, bap], C(19)H(13)N(5), (I). Compound (I) crystallizes with Z' = 2 in the P\overline{1} space group, with both independent molecules adopting a trans-trans conformation. Compound (II) is a salt complex with weak C-H...Cl interactions giving rise to a zigzag network with pi-stacking down the a axis. Complex (III) lies across a twofold rotation axis in the C2/c space group. The Cu(II) center in (III) has an N(3)O(2) trigonal-bipyramidal environment. The nitrate ligand coordinates in a monodentate fashion, while the bap ligand adopts a twisted tridentate binding mode. C-H...O interactions give rise to a ribbon motif.


Multiple functions of stress granules in viral infection at a glance.
Stress granules (SGs) are distinct RNA granules induced by various stresses, which are evolutionarily conserved across species. In general, SGs act as a conservative and essential self-protection mechanism during stress responses. Viruses have a long evolutionary history and viral infections can trigger a series of cellular stress responses, which may interact with SG formation. Targeting SGs is believed as one of the critical and conservative measures for viruses to tackle the inhibition of host cells. In this systematic review, we have summarized the role of SGs in viral infection and categorized their relationships into three tables, with a particular focus on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Moreover, we have outlined several kinds of drugs targeting SGs according to different pathways, most of which are potentially effective against SARS-CoV-2. We believe this review would offer a new view for the researchers and clinicians to attempt to develop more efficacious treatments for virus infection, particularly for the treatment of SARS-CoV-2 infection.


The Synthesis of B2(SIDip)2 and its Reactivity Between the Diboracumulenic and Diborynic Extremes.
A new compound with the formula L-B2-L wherein the stabilizing ligand (L) is 1,3-bis[diisopropylphenyl]-4,5-dihydroimidazol-2-ylidene (SIDip) has been synthesized, isolated, and characterized. The π-acidity of the SIDip ligand, intermediate between the relatively non-acidic IDip (1,3-bis[diisopropylphenyl]imidazol-2-ylidene) ligand and the much more highly acidic CAAC (1-[2,6-diisopropylphenyl]-3,3,5,5-tetramethylpyrrolidin-2-ylidene) ligand, gives rise to a compound with spectroscopic, electrochemical, and structural properties between those of L-B2-L compounds stabilized by CAAC and IDip. Reactions of all three L-B2-L compounds with CO demonstrate the differences caused by their respective ligands, as the π-acidities of the CAAC and SIDip carbenes enabled the isolation of bis(boraketene) compounds (L(OC)B-B(CO)L), which could not be isolated from reactions with B2(IDip)2. However, only B2(IDip)2 and B2(SIDip)2 could be converted into bicyclic bis(boralactone) compounds.


Optical Coherence Angiographic Demonstration of Retinal Changes From Chronic Optic Neuropathies.
Glaucoma causes a decrease in peripapillary perfused capillary density on optical coherence tomography (OCT) angiography. However, other chronic optic neuropathies have not been explored with OCT angiography to see if these changes were specific to glaucoma. The authors evaluated OCT angiography in 10 patients who suffered various kinds of chronic optic neuropathies, including optic neuritis and ischaemic optic neuropathy, and found that all optic neuropathies showed a decrease in peripapillary vessel density on OCT angiography, regardless of the aetiology of the optic neuropathy. The peripapillary vessel loss on OCT angiography correlated well with the areas of retinal nerve fibre layer thinning seen on OCT.


Porphyromonas gingivalis lipopolysaccharide lipid A heterogeneity differentially modulates the expression of IL-6 and IL-8 in human gingival fibroblasts.
Porphyromonas gingivalis lipopolysaccharide (LPS) displays a significant amount of structural heterogeneity, containing both tetra- (LPS(1435/1449) ) and penta-acylated (LPS(1690) ) lipid A structures. This study investigated the effects of the two isoforms of P. gingivalis LPS on the expression of IL-6, IL-8 and TNF-α in human gingival fibroblasts (HGFs). HGFs were stimulated with P. gingivalis LPS(1435/1449) and LPS(1690) in both dose- (1 ng-10 μg/ml) and time-dependent (2-48 h) experiments. Total RNA and protein were extracted and used for analysis of the IL-6, IL-8 and TNF-α transcripts as well as IL-6 and IL-8 proteins, by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. P. gingivalis LPS(1690) significantly up-regulated the mRNA and protein expression of IL-6 and IL-8, whereas P. gingivalis LPS(1435/1449) did not induce significant host response. The expression levels of IL-6 and IL-8 up-regulated by P. gingivalis LPS(1690) continuously increased with time course. In contrast, TNF-α transcript expression was up-regulated promptly by P. gingivalis LPS(1690) after 2 h of stimulation and gradually declined afterwards. This study suggests that P. gingivalis LPS heterogeneity may differentially modulate the pro-inflammatory cytokine expression in HGFs, which may contribute to periodontal pathogenesis.


Unusual, but important, peri- and extra-articular manifestations of rheumatoid arthritis: a pictorial essay.
Ultrasonography is a useful technique to detect soft tissue changes of rheumatoid arthritisnot only synovitis, but also tenosynovitis, bursitis, and enthesitis-even at a subclinical stage. However, radiologists tend to focus on synovitis in daily practice, and unusual peri- or extraarticular manifestations of rheumatoid arthritis are difficult to detect at the initial presentation. This pictorial essay describes a broad spectrum of ultrasonographic findings in tendons, bursae, ligaments, subcutaneous tissues, bones, and nerves to assist in the accurate diagnosis of rheumatoid arthritis.


Preparation of Mn, Ni, Co ferrite highly porous silica nanocomposite aerogels by an urea-assisted sol-gel procedure.
The preparation of highly porous MnFe2O4-SiO2 and NiFe2O4-SiO2 nanocomposite aerogels with high purity and homogeneity was successfully achieved by a sol-gel procedure involving urea-assisted co-gelation of the precursor phases firstly applied for the synthesis of CoFe2O4-SiO2. This method allows fast gelation, giving rise to aerogels with 97% porosity. The structural, morphological and textural characterization as a function of thermal treatments was carried out by a multitechnique approach confirming that, as in the case of CoFe2O4-SiO2, the formation of single nanocrystals of manganese ferrite and nickel ferrite with spinel structure occurs after heating at 750 degrees C and is complete at 900 degrees C when the high porosity typical of aerogels is still retained. Thermogravimetric analysis (TG), differential thermal analysis (DTA), N2-physisorption at 77 K, powder X-ray diffraction (XRD), and transmission electron microscopy (TEM) indicate that the compositional homogeneity, crystallite size, thermal stability, and porosity are controlled by the sol-gel parameters of the preparation.


Use of Psychotropic Drugs among Children and Adolescents with Autism Spectrum Disorders in Denmark: A Nationwide Drug Utilization Study.
Children with autism spectrum disorder (ASD) have a considerable use of psychotropics. Leveraging nationwide registry data, we aimed to describe the use of psychotropics among children and adolescents with ASD in Denmark. Use of melatonin and attention-deficit/hyperactivity disorder (ADHD) medication increased from 2010 to 2017, while there were limited changes in use of antidepressants and antipsychotics. Thirty percent of the identified children used psychotropics in 2017 most commonly ADHD medication (17%) and melatonin (13%). Methylphenidate, sertraline and risperidone were most often prescribed. Most children filled more than one prescription and, across drug classes, at least 38% received treatment two years after treatment initiation. Use of psychotropics followed psychiatric comorbidities. Comorbidities did not affect age at treatment initiation. Use of psychotropics varied according to age and sex with limited use in the youngest children. In summary, psychotropic drug use has increased in children with ASD mainly due to an increase in the use of ADHD medication and melatonin. In accordance with previous studies, use seems to follow comorbidities. The long treatment duration underlines the need to investigate long-term effects of psychotropic drug use in children with ASD.


IL-17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice.
IL-17 is a signature cytokine of Th17 cells implicated in the induction and progression of chronic inflammatory diseases. Several studies in C57BL/6 mice, immunized with soluble schistosome egg Ags (SEA) in complete Freund's adjuvant (CFA), and subsequently infected with Schistosoma mansoni (S. mansoni) have shown that severe hepatic granulomatous inflammation is correlated with high levels of IL-17. Here, using a Schistosoma japonicum (S. japonicum) larvae infection model in C57BL/6 mice, we analyzed the dynamic expression of IL-17 in infected livers by RT-qPCR and ELISA. Our results showed that IL-17 expression was elevated during the course of infection. The temporal expression of IL-17 and cytokines/chemokines involved in the induction and effector function of Th17 cells was paralleled with hepatic granulomatous inflammation. Treatment of S. japonicum infected mice with IL-17-neutralizing mAb resulted in significant downmodulation of granulomatous inflammation and hepatocyte necrosis. The protection was associated with lower expression of proinflammatory cytokines/chemokines, such as IL-6, IL-1β, CXCL1, and CXCL2 and a reduced number of infiltrating neutrophils. Anti-IL-17 mAb significantly ameliorated hepatic granulomatous inflammation, partly through the downregulation of proinflammatory cytokines/chemokines and recruitment of neutrophils. Our data indicate a pathogenic role of Th17/IL-17 in hepatic immunopathology in S. japonicum infected mice.


Echinacea pupurea extracts promote murine dendritic cell maturation by activation of JNK, p38 MAPK and NF-κB pathways.
Dendritic cells (DCs) comprise a system of highly professional antigen presenting cells (APCs) which connect innate and adaptive immunity by undergoing dramatic shift in their maturation state. Phytomedicine Echinacea purpurea extracts (EE) could modulate murine dendritic cell fate and function. However, the underlying mechanism of EE on DCs development and maturation remains limited. In this study, immature DCs were induced phenotypic maturation with up-regulated expression of key accessory molecules and the phagocytic activity was decreased after being treated with EE (400 μg/ml) for 48 h. We found that TLR1/2, JNK, p38-MAPK and NF-κB pathways were activated following EE exposure. Notably, JNK activation was demonstrated to be associated with increased IFN-γ response while p38-MAPK pathway exhibited immuno-regulatory effects via induction of IL-10 and TGF-β1. Furthermore, it was verified that NF-κB signaling was responsible for EE-induced synthesis of IFN-γ, IL-12 and TGF-β1, but not for IL-10 induction. These results indicate that EE have the immunomodulatory potency to promote both phenotypic and functional maturation of BMDCs via modulating the activation of JNK, p38-MAPK and NF-κB pathways. Our findings contributed to the current understanding of the immunoregulatory function of EE and the mechanism of DCs maturation.


Reduced DNA damage induced in human melanoma cells by dacarbazine in the presence of deoxyribonucleosides.
Decarbazine induces DNA lesions in replicating DNA. We show here that deoxyribonucleosides, with the exception of thymidine, in doses of 250 microM or higher, prevent dacarbazine-induced DNA lesions. The DNA lesions that appear in the presence of thymidine can be prevented by aphidicolin, an inhibitor of DNA synthesis. Cytotoxicity analyses confirm that the combination thymidine-dacarbazine prevents cell outgrowth only partially, while other deoxyribonucleosides completely abolish the dacarbazine effect.


Challenges in diagnosing a metabolic disorder: error of pyruvate metabolism or drug induced?
Certain drugs are known to cause metabolic changes resulting in altered metabolic profiles. We report here a case where a combination of antiepileptic drugs resulted in a profile that mimicked a metabolic disorder. A 16month-old female child on antiepileptic drugs (valproate and topiramate) was suspected to have the inherited metabolic disorder, dihydrolipoamide dehydrogenase deficiency, based on clinical symptoms and metabolic profile showing hyperalaninemia, elevated branched-chain amino acids, and lactate-pyruvate ratio. Suspecting that the observed metabolic changes could have also arised from medication, current medication was weaned off and replaced with levetiracetam, clonazepam, and levocarnitine (supportive therapy). Metabolic profiling conducted after 47 days showed normal alanine, branched-chain amino acids, ornithine, and lactate-pyruvate ratio, suggesting that the earlier abnormalities could have been medication induced. We stress that metabolic changes resulting from chronic medication should be considered while interpreting a positive result when investigating an inherited metabolic disorder.


[The risk evaluation and response to the spread of hydatid disease after Yushu earthquake in Qinghai Province].
Yushu of Qinghai Province is the mixed endemic area for cystic and alveolar hydatid diseases. Reviewing the previous data on the prevalence of the disease and the information from the communicable disease surveillance network during 2004 to April 15, 2010, possible impact of the Yushu earthquake was evaluated. It revealed that post-earthquake conditions might bring about risk factors for an increase of disease transmission, which included more deaths of livestock, increase of the number of stray dogs, poorer hygienic condition for local residents, etc. Countermeasures are proposed for preventing the spread of the disease in the disaster area.


A case study of anomaly detection: shallow semantic processing and cohesion establishment.
Although the establishment of a coherent mental representation depends on semantic analysis, such analysis is not necessarily complete. This is illustrated by failures to notice the anomaly in questions such as, "When an airplane crashes, where should the survivors be buried?" Four experiments were carried out to extend knowledge of what determines the incidental detection of the critical item. Detection is a function of the goodness of global fit of the item (Experiments 1 and 2) and the extent to which the scenario predicts the item (Experiment 3). Global good fit appears to result in shallow processing of details. In Experiment 4, it is shown that if satisfactory coherence can be established without detailed semantic analysis, through the recruitment of suitable information from a sentence, then processing is indeed shallow. The studies also show that a text is not understood by first producing a local semantic representation and then incorporating this into a global model, and that semantic processing is not strictly incremental.


Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes.
Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF. To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two-photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down-regulated compared with these from sham-operated animals, and the mitochondrial network structure altered. The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF.


Antimicrobial resistance: One Health, one problem.
The roles that the medical and veterinary professions can play in tackling antimicrobial resistance were discussed at the BVA Congress at the London Vet Show last week. It was clear from the debate that, while action is already being taken, much more needs to be done by both professions in the UK and overseas. Kathryn Clark reports.


Who deserves the credit for discovering ether's use as a surgical anesthetic?
This paper discusses the controversy based around the discovery of inhalation anesthesia. Although many contributors claim to be the discoverer, deeper research into the events leading to anesthesia can award credit to a select few. It can be determined that anesthesia in animals was discovered by Paracelsus back in the fifteenth century and that the first person to demonstrate ether's use as a surgical anesthetic was Dr. William Morton in 1846.


Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice.
Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the first-line regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.


Biogenesis and Homeostasis of Nicotinamide Adenine Dinucleotide Cofactor.
Universal and ubiquitous redox cofactors, nicotinamide adenine dinucleotide (NAD) and its phosphorylated analog (NADP), collectively contribute to approximately 12% of all biochemical reactions included in the metabolic model of Escherichia coli K-12. A homeostasis of the NAD pool faithfully maintained by the cells results from a dynamic balance in a network of NAD biosynthesis, utilization, decomposition, and recycling pathways that is subject to tight regulation at various levels. A brief overview of NAD utilization processes is provided in this review, including some examples of nonredox utilization. The review focuses mostly on those aspects of NAD biogenesis and utilization in E. coli and Salmonella that emerged within the past 12 years. The first pyridine nucleotide cycle (PNC) originally identified in mammalian systems and termed the Preiss-Handler pathway includes a single-step conversion of niacin (Na) to NaMN by nicotinic acid phosphoribosyltransferase (PncB). In E. coli and many other prokaryotes, this enzyme, together with nicotinamide deamidase (PncA), compose the major pathway for utilization of the pyridine ring in the form of amidated (Nm) or deamidated (Na) precursors. The existence of various regulatory mechanisms and checkpoints that control the NAD biosynthetic machinery reflects the importance of maintaining NAD homeostasis in a variety of growth conditions. Among the most important regulatory mechanisms at the level of individual enzymes are a classic feedback inhibition of NadB, the first enzyme of NAD de novo biosynthesis, by NAD and a metabolic regulation of NadK by reduced cofactors.


Different time scales of common-cause evidence shape multisensory integration, recalibration and motor adaptation.
Perceptual coherence in the face of discrepant multisensory signals is achieved via the processes of multisensory integration, recalibration and sometimes motor adaptation. These supposedly operate on different time scales, with integration reducing immediate sensory discrepancies and recalibration and motor adaptation reflecting the cumulative influence of their recent history. Importantly, whether discrepant signals are bound during perception is guided by the brains' inference of whether they originate from a common cause. When combined, these two notions lead to the hypothesis that the time scales on which integration and recalibration (or motor adaptation) operate are associated with different time scales of evidence about a common cause underlying two signals. We tested this prediction in a well-established visuo-motor paradigm, in which human participants performed visually guided hand movements. The kinematic correlation between hand and cursor movements indicates their common origin, which allowed us to manipulate the common-cause evidence by titrating this correlation. Specifically, we dissociated hand and cursor signals during individual movements while preserving their correlation across the series of movement endpoints. Following our hypothesis, this manipulation reduced integration compared with a condition in which visual and proprioceptive signals were perfectly correlated. In contrast, recalibration and motor adaption were not affected by this manipulation. This supports the notion that multisensory integration and recalibration deal with sensory discrepancies on different time scales guided by common-cause evidence: Integration is prompted by local common-cause evidence and reduces immediate discrepancies, whereas recalibration and motor adaptation are prompted by global common-cause evidence and reduce persistent discrepancies.


Use of genomics to explore AMR persistence in an outdoor pig farm with low antimicrobial usage.
Food animals may be reservoirs of antimicrobial resistance (AMR) passing through the food chain, but little is known about AMR prevalence in bacteria when selective pressure from antimicrobials is low or absent. We monitored antimicrobial-resistant Escherichia coli over 1 year in a UK outdoor pig farm with low antimicrobial usage (AMU) compared to conventional pig farms in the United Kingdom. Short and selected long-read whole-genome sequencing (WGS) was performed to identify AMR genes, phylogeny and mobile elements in 385 E. coli isolates purified mainly from pig and some seagull faeces. Generally, low levels of antimicrobial-resistant E. coli were present, probably due to low AMU. Those present were likely to be multi-drug resistant (MDR) and belonging to particular Sequence Types (STs) such as ST744, ST88 or ST44, with shared clones (<14 Single Nucleotide Polymorphisms (SNPs) apart) isolated from different time points indicating epidemiological linkage within pigs of different ages, and between pig and the wild bird faeces. Although importance of horizontal transmission of AMR is well established, there was limited evidence of plasmid-mediated dissemination between different STs. Non-conjugable MDR plasmids or large AMR gene-bearing transposons were stably integrated within the chromosome and remained associated with particular STs/clones over the time period sampled. Heavy metal resistance genes were also detected within some genetic elements. This study highlights that although low levels of antimicrobial-resistant E. coli correlates with low AMU, a basal level of MDR E. coli can still persist on farm potentially due to transmission and recycling of particular clones within different pig groups. Environmental factors such as wild birds and heavy metal contaminants may also play important roles in the recycling and dissemination, and hence enabling persistence of MDR E. coli. All such factors need to be considered as any rise in AMU on low usage farms, could in future, result in a significant increase in their AMR burden.


Syncope as the first sign of complete heart block in a military aviator.
Syncope in an aviator may lead to abrupt loss or impairment of control of an aircraft and is thus a threat to safety of flight. Consequently, it is vital to conduct a thorough medical evaluation of any syncopal episode in a pilot or other flight crewmember. A 28-yr-old male Naval Flight Officer experienced loss of consciousness at a morning briefing, but immediately returned to normal except for tachycardia. He suffered a second episode at a base hospital while on a cardiac monitor. The rhythm was diagnosed as complete heart block and a permanent pacemaker was inserted. This condition is considered disqualifying for U.S. Navy aviation duty. It is easy to dismiss a single episode of syncope in this age group as due to orthostasis, hangover, or other benign causes. Serious underlying pathology such as complete heart block is rare. The threat to safety of flight, however, dictates that all episodes of syncope in aviators receive a thorough diagnostic work-up.


[Detection of HPV DNA and its relationship with peripheral T cell subsets in patients with condyloma acuminata].
To study the relationship between presence of HPV DNA related sequence and cellular-immune responses in patients with condyloma acuminata (CA). HPV DNA related sequences in biopsy material of 30 CA patients were determined by using Southern blot hybridization, and typed according to the restricted fragment length polymorphism (RFLP) analysis. At the same time, the T-cell subpopulations in peripheral blood of 30 patient with CA were also measured by using anti-CD3, CD4, CD8 monoclonal antibody labeled SERC direct rosette assay. HPV DNA positive results were revealed in 19 of 30 patients with CA(63.3%). Among them, 3 cases possessed HPV 6 DNA homologous sequence (15.8%), 15 had HPV 11 DNA homologous sequence(78.9%), and only one case had a sequence homologous to HPV 16 DNA(5.2%). The percentages of CD3 and CD4 cells were significantly lower (P< 0.01) in CA patients than those in controls. However the percentage of CD8 cell was strikingly higher (P< 0.001) in CA patients than that in controls. Consequently the CD4/CD8 ratio was noticeably lower (P<0.001) in patients with CA than that in controls. The decrease of CD3 cell and the lowering of C D4/CD8 ratio were closely related to the positivity of HPV DNA homologous sequence (P =0.008 02, P=0.004 17). Conclusion The presence of HPV DNA in the patients with CA results in inhibitory effects on a series of cellular-immune responses, which may play an important role in the pathogenesis of CA.


Three-dimensional structural labeling microscopy of cilia and flagella.
Locating a molecule within a cell using protein-tagging and immunofluorescence is a fundamental technique in cell biology, whereas in three-dimensional electron microscopy, locating a subunit within a macromolecular complex remains challenging. Recently, we developed a new structural labeling method for cryo-electron tomography by taking advantage of the biotin-streptavidin system, and have intensively used this method to locate a number of proteins and protein domains in cilia and flagella. In this review, we summarize our findings on the three-dimensional architecture of the axoneme, especially the importance of coiled-coil proteins. In addition, we provide an overview of the technical aspects of our structural labeling method.


Pathway involving the N155H mutation in HIV-1 integrase leads to dolutegravir resistance.
Dolutegravir, an integrase strand-transfer inhibitor (STI), shows a high genetic barrier to resistance. Dolutegravir is reported to be effective against viruses resistant to raltegravir and elvitegravir. In this study, we report the case of a patient treated with dolutegravir monotherapy. Failure of dolutegravir treatment was observed concomitant with the appearance of N155H-K211R-E212T mutations in the integrase (IN) gene in addition to the polymorphic K156N mutation that was present at baseline in this patient. The impact of N155H-K156N-K211R-E212T mutations was studied in cell-free, culture-based assays and by molecular modelling. Cell-free and culture-based assays confirm that selected mutations in the patient, in the context of the polymorphic mutation K156N present at the baseline, lead to high resistance to dolutegravir requiring that the analysis be done at timepoints longer than usual to properly reveal the results. Interestingly, the association of only N155H and K156N is sufficient for significant resistance to dolutegravir. Modelling studies showed that dolutegravir is less stable in IN/DNA complexes with respect to the WT sequence. Our results indicate that the stability of STI IN/DNA complexes is an important parameter that must be taken into account when evaluating dolutegravir resistance. This study confirms that a pathway including N155H can be selected in patients treated with dolutegravir with the help of the polymorphic K156N that acts as a secondary mutation that enhances the resistance to dolutegravir.


Binary Solvent Extraction of Tocols, γ-Oryzanol, and Ferulic Acid from Rice Bran Using Alkaline Treatment Combined with Ultrasonication.
Alkaline treatment (Alk) combined with ultrasound-assisted extraction (UAE) (Alk+UAE) was examined as a means of extracting tocols and γ-oryzanol from rice bran into an organic phase while simultaneously recovering ferulic acid into an aqueous phase. The tocols and γ-oryzanol/ferulic acid yields were determined using high-performance liquid chromatography with fluorescence and UV detection. The effects of extraction conditions were evaluated by varying the Alk treatment temperature and extraction duration. The maximum yields of tocols and γ-oryzanol were obtained at 25 °C over a time span of 30 min. When the temperature was increased to 80 °C, the yield of ferulic acid increased dramatically, whereas the recovery of γ-oryzanol slightly decreased. Employing the Alk+UAE procedure, the recovered concentrations of tocols, γ-oryzanol, and ferulic acid were in the ranges of 146-518, 1591-3629, and 352-970 μg/g, respectively. These results are in good agreement with those reported for rice bran samples from Thailand.


Rapid characterization of Mycobacterium fortuitum-chelonei complex by restriction fragment length polymorphism of ribosomal RNA genes.
Using labelled, gamma-32P rRNA of mycobacteria as a probe restriction fragment length polymorphism (RFLP) of rRNA genes of strains belonging to the Mycobacterium fortuitum-chelonei complex was analysed. Each DNA sample was cleaved with EcoRI restriction endonuclease, the fragments were separated by agarose gel electrophoresis and transferred to nitrocellulose membrane. Fragments of DNA containing rRNA genes were identified by hybridization with gamma-32P-labelled rRNA. Patterns were found to be species specific and both the species were distinguishable from each other. Results indicate that this approach can be used for rapid genomic characterization of the Mycobacterium fortuitum-chelonei complex.


Chemically engineered extracts as an alternative source of bioactive natural product-like compounds.
The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for library development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.


[Evaluation of activity and the electron microscope picture in Paget's disease].
Thirteen patients with Paget's disease followed-up for prolonged periods of time were subjected to a series of biological tests and to studies of radionuclides incorporation into skeletal tissues. Bone alkaline phosphatase showed an osteoblastic activity, and tartarate -resistant acid phosphatases an osteoclastic function. Hydroxyproline in urine corresponded to the osteoclastic destruction. The X-ray pattern did not agree necessarily with the local metabolic bone activity of phosphates ( 99mTechnetium pyrophosphate), or of glycoproteins (85Sr). The use of scanning was recommended for studies of local activity and to correlate the results obtained with the clinical and biochemical syndromology . The electronoptic pattern was similar to that observed in inclusions of the paramyxovirus or papova virus. The problems associated with the differential diagnosis were discussed.


Functional and esthetic considerations for single-tooth Ankylos implant-crowns: 8 years of clinical performance.
Following the loss of an anterior natural tooth, the mucogingival complex begins to collapse. The early placement of endosseous dental implants can prevent or reduce the extent of this collapse. If there is a long interval between the loss of the natural tooth and the placement of the implant prosthetic replacement, this collapse tends to increase significantly. This paper will report on the clinical success of this implant product in the fabrication of esthetic, functional, and harmonious replacements for missing single, natural teeth for a period of 8 years. A total of 275 single Ankylos implant tooth restorations in the anterior and posterior jaw regions were placed and monitored for 8 years. Of these, 264 implants were restored using the titanium Balance abutments, and only 11 were restored using ceramic abutments. The final restorations were either metal-ceramic or full-ceramic crowns and were cemented with glass ionomer cement. The survival rate was 98.2%, with only 5 implants being lost during the healing phase. There were no other implant losses in the postloading period that averaged 3.2 years. To date, there have been no mechanical complications associated with the prosthetic components (ie, screw loosening, screw breaking, or crown breaking) for either the titanium or the ceramic abutments. Experience with the Ankylos system with single-tooth replacement indications may be considered positive with regard to the esthetic and functional results of the treatment. The lack of mechanical complications and problems with the hard and soft tissue in the loading phase of the implants suggests the functional safety of the tapered connection between implant and abutment.


Structural and genetic analysis of protein stability.
One very encouraging development has been the freedom with which amino acid replacements can be introduced in a protein of interest. This has made it possible to obtain detailed structural and thermodynamic data on a wide variety of mutants that modify protein stability. Substitutions of solvent-exposed amino acids on the surfaces of proteins are seen to have little if any effect on protein stability or structure, leading to the view that it is the rigid parts of proteins that are critical for folding and stability. There is every reason to expect that it will be possible to rationalize the stabilities of mutant proteins from accurate knowledge of their structures. Substantial progress is being made in quantitating the interactions that determine and stabilize protein structures. Although not specifically the subject of this review, substantial progress is also being made in developing methods to engineer proteins of enhanced stability.


Interpretation of urinary concentrations of pseudoephedrine and its metabolite cathine in relation to doping control.
Until the end of 2003 a urinary concentration of pseudoephedrine exceeding 25 microg/mL was regarded as a doping violation by the World Anti-Doping Agency. Since its removal from the prohibited list in 2004 the number of urine samples in which pseudoephedrine was detected in our laboratory increased substantially. Analysis of 116 in-competition samples containing pseudoephedrine in 2007 and 2008, revealed that 66% of these samples had a concentration of pseudoephedrine above 25 microg/mL. This corresponded to 1.4% of all tested in competition samples in that period. In the period 2001-2003 only 0.18% of all analysed in competition samples contained more than 25 microg/mL. Statistical comparison of the two periods showed that after the removal of pseudoephedrine from the list its use increased significantly. Of the individual sports compared between the two periods, only cycling is shown to yield a significant increase.Analysis of excretion urine samples after administration of a therapeutic daily dose (240 mg pseudoephedrine) in one administration showed that the threshold of 25 microg/mL can be exceeded. The same samples were also analysed for cathine, which has currently a threshold of 5 microg/mL on the prohibited list. The maximum urinary concentration of cathine also exceeded the threshold for some volunteers. Comparison of the measured cathine and pseudoephedrine concentrations only indicated a poor correlation between them. Hence, cathine is not a good indicator to control pseudopehedrine intake. To control the (ab)use of ephedrines in sports it is recommended that WADA reintroduce a threshold for pseudoephedrine.


Like (CO)4, Do (CS)4 and (CSe)4 have a triplet ground state?
Cyclobutane-1,2,3,4-tetraone, (CO)4, was computationally predicted and, subsequently, experimentally confirmed to have a triplet ground state, in which a b2g σ MO and an a2u π MO were each singly occupied. In contrast, the (U)CCSD(T) calculations reported herein found that cyclobutane-1,2,3,4-tetrathione, (CS)4, and cyclobutane-1,2,3,4-tetraselenone, (CSe)4, both had singlet ground states, in which the b2g σ MO was doubly occupied and the a2u π MO was empty. Our calculations showed that both the longer C=X distances and smaller coefficients on the carbon atoms in the b2g and a2u MOs of (CS)4 and (CSe)4 contributed to the difference between the ground states of these two molecules and the ground state of (CO)4. An experimental test of the prediction of a singlet ground state for (CS)4 is proposed.


Bullous pemphigoid antigen concentration in normal human skin in relation to body area and age.
The amount of bullous pemphigoid antigen (BPA) in normal human skin on different areas of the body and in bodies of different ages was determined by making endpoint titer estimations using the indirect immunofluorescence technique. Two sera with bullous pemphigoid antibodies were tested with 36 specimens of normal human skin from six cadavers. The greatest expression of BPA was found in plantar sites, whereas the lowest endpoint titers were seen in flexural arm biopsy specimens. Age-dependent differences in BPA expression were detected as well. The oldest individuals tested produced the highest endpoint titers in contrast to the lowest endpoint titers in the youngest. This study suggests that the amount of BPA depends not only on the body region where the biopsy specimen is taken but also on the age of the donor. This is important to know in connection with indirect immunofluorescence assays for BP antibodies on human skin.


The causal relationship between air pollution, obesity, and COVID-19 risk: a large-scale genetic correlation study.
Observational evidence reported that air pollution is a significant risk element for numerous health problems, such as obesity and coronavirus disease 2019 (COVID-19), but their causal relationship is currently unknown. Our objective was to probe the causal relationship between air pollution, obesity, and COVID-19 and to explore whether obesity mediates this association. We obtained instrumental variables strongly correlated to air pollutants [PM2.5, nitrogen dioxide (NO2) and nitrogen oxides (NOx)], 9 obesity-related traits (abdominal subcutaneous adipose tissue volume, waist-to-hip ratio, body mass index, hip circumference, waist circumference, obesity class 1-3, visceral adipose tissue volume), and COVID-19 phenotypes (susceptibility, hospitalization, severity) from public genome-wide association studies. We used clinical and genetic data from different public biological databases and performed analysis by two-sample and two-step Mendelian randomization. PM2.5 genetically correlated with 5 obesity-related traits, which obesity class 1 was most affected (beta = 0.38, 95% CI = 0.11 - 0.65, p = 6.31E-3). NO2 genetically correlated with 3 obesity-related traits, which obesity class 1 was also most affected (beta = 0.33, 95% CI = 0.055 - 0.61, p = 1.90E-2). NOx genetically correlated with 7 obesity-related traits, which obesity class 3 was most affected (beta = 1.16, 95% CI = 0.42-1.90, p = 2.10E-3). Almost all the obesity-related traits genetically increased the risks for COVID-19 phenotypes. Among them, body mass index, waist circumference, hip circumference, waist-to-hip ratio, and obesity class 1 and 2 mediated the effects of air pollutants on COVID-19 risks (p < 0.05). However, no direct causal relationship was observed between air pollution and COVID-19. Our study suggested that exposure to heavy air pollutants causally increased risks for obesity. Besides, obesity causally increased the risks for COVID-19 phenotypes. Attention needs to be paid to weight status for the population who suffer from heavy air pollution, as they are more likely to be susceptible and vulnerable to COVID-19.


Construction and Evaluation of a Murine Calvarial Osteolysis Model by Exposure to CoCrMo Particles in Aseptic Loosening.
Wear particle-induced osteolysis is a major cause of aseptic loosening in arthroplasty failure, but the underlying mechanism remains unclear. Due to long follow-ups necessary for detection and sporadic occurrence, it is challenging to assess the pathogenesis ofparticle-induced osteolysis in clinical cases. Hence, optimal animal models are required for further studies. The murine model of calvarial osteolysis established by exposure to CoCrMo particles is an effective and valid tool for assessing the interactions between particles and various cells in aseptic loosening. In this model, CoCrMo particles were first obtained by high-vacuum three-electrode direct current and resuspended in phosphate-buffered saline at a concentration of 50 mg/mL. Then, 50 µL of the resulting suspension was applied to the middle of the murine calvaria after separation of the cranial periosteum by sharp dissection. After two weeks, the mice were sacrificed, and calvaria specimens were harvested; qualitative and quantitative evaluations were performed by hematoxylin and eosin staining and micro computed tomography. The strengths of this model include procedure simplicity, quantitative evaluation of bone loss, rapidity of osteolysis development, potential use transgenic or knockout models, and a relatively low cost. However, this model cannot to be used to assess the mechanical force and chronic effects of particles in aseptic loosening. Murine calvarial osteolysis model generated by exposure to CoCrMo particles is an ideal tool for assessing the interactions between wear particles and various cells, e.g., macrophages, fibroblasts, osteoblasts and osteoclasts, in aseptic loosening.


An unusual cause of lower gastrointestinal haemorrhage.
A previously unreported cause of lower gastrointestinal haemorrhage in a 63-year-old female patient on clopidogrel for cardiac comorbidities is presented. Endoscopy suggested a small bowel or colonic aetiology but failed to accurately localise the source. The patient became haemodynamically unstable despite conservative management and temporary cessation of clopidogrel. CT angiography demonstrated a pseudoaneurysm arising from the superior rectal artery. Percutaneous embolisation using coils was performed to successfully occlude the pseudoaneurysm, prevent further haemorrhage and avoid emergency colonic resection.


[Alterations of β-γ coupling of scalp electroencephalography during epilepsy].
Uncovering the alterations of neural interactions within the brain during epilepsy is important for the clinical diagnosis and treatment. Previous studies have shown that the phase-amplitude coupling (PAC) can be used as a potential biomarker for locating epileptic zones and characterizing the transition of epileptic phases. However, in contrast to the θ-γ coupling widely investigated in epilepsy, few studies have paid attention to the β-γ coupling, as well as its potential applications. In the current study, we use the modulation index (MI) to calculate the scalp electroencephalography (EEG)-based β-γ coupling and investigate the corresponding changes during different epileptic phases. The results show that the β-γ coupling of each brain region changes with the evolution of epilepsy, and in several brain regions, the β-γ coupling decreases during the ictal period but increases in the post-ictal period, where the differences are statistically significant. Moreover, the alterations of β-γ coupling between different brain regions can also be observed, and the strength of β-γ coupling increases in the post-ictal period, where the differences are also significant. Taken together, these findings not only contribute to understanding neural interactions within the brain during the evolution of epilepsy, but also provide a new insight into the clinical treatment.


Magnetic resonance cholangiopancreatography: the ABC of MRCP.
Magnetic resonance cholangiopancreatography (MRCP) is a technique that has evolved over the past two decades. It continues to have a fundamental role in the non-invasive investigation of many pancreatico-biliary disorders. The purpose of this review is to summarise the key concepts behind MRCP, the different techniques that are currently employed (including functional and secretin-stimulated MRCP), the pitfalls the reader should be aware of, and the main clinical indications for its use.


Modality effect on text processing as a function of ability to comprehend.
The present study had two purposes. One was to examine the prediction that the modality effect on processing text is influenced by subjects' comprehension. The other was to confirm the assumption that this effect arises not only in the processing of each work in texts but also in the processing of the relations between words (comprehension). The same text was presented to 28 good and 28 poor comprehenders at a fixed pace, auditorily or visually. After presentation of the text, subjects answered two kinds of tests, Memory Test and Comprehension Test. The performance on both tests showed superiority of auditory over visual presentation. These results were discussed in terms of a visual disadvantage: visually presented texts are translated into an auditory form and this extra process leads to insufficient processing of a text when the text is difficult for a processor.


The effect of periodontal treatment on serum leptin, interleukin-6, and C-reactive protein.
Previous studies suggest that periodontitis is closely related to obesity and metabolic syndrome. Leptin, a pleiotrophic hormone produced by adipose tissue, has been reported to be related to periodontitis. This study investigates the effects of periodontal treatment on the serum levels of leptin and other cytokines in patients with chronic periodontitis (CP). Serum samples were taken from 33 CP patients (22 non-smokers, 11 smokers) and 18 healthy subjects. The serum leptin, adiponectin, tumor necrosis factor-alpha, interleukin (IL)-6, and C-reactive protein (CRP) levels were measured before and after non-surgical periodontal treatment. Significant differences between healthy and CP patients were found in serum leptin, IL-6, and CRP levels (P = 0.0018, P = 0.0064, and P = 0.0095, respectively). The serum leptin level was associated with mean probing depth, mean clinical attachment level, mean alveolar bone loss, and body mass index. There were significant associations between serum leptin levels and IL-6 and CRP levels. After non-surgical periodontal treatment, serum leptin, IL-6, and CRP levels were significantly decreased (mean +/- SD before and after, P value, respectively: leptin, 8.02 +/- 5.5, 7.10 +/- 4.4, P = 0.015; IL-6, 1.73 +/- 1.02, 1.36 +/- 0.73, P = 0.048; and CRP, 802.0 +/- 1065, 491.2 +/- 479.3, P = 0.047). Periodontal treatment is effective in reducing serum leptin, IL-6, and CRP levels. The results suggest that leptin, IL-6, and CRP could be mediating factors that connect metabolic syndrome and periodontitis.


Diversity of fungi and bacteria in species-rich grasslands increases with plant diversity in shoots but not in roots and soil.
Microbial communities in roots and shoots of plants and in soil are important for plant growth and health and take part in important ecosystem processes. Therefore, understanding the factors that affect their diversity is important. We have analyzed fungal and bacterial communities associated with plant shoots, roots and soil over a 1 km2 area in a semi-natural temperate grassland with 1-43 plant species per 0.1 m2, to describe the relationships between plant and microbial diversity and to identify the drivers of bacterial and fungal community composition. Microbial community composition differed between shoots, roots and soil. While both fungal and bacterial species richness in shoots increased with plant species richness, no correlation was found between plant and microbial diversity in roots and soil. Chemistry was a significant predictor of bacterial and fungal community composition in soil as was also the spatial location of the sampled site. In this species-rich grassland, the effects of plants on the microbiome composition seemed to be restricted to the shoot-associated taxa; in contrast, the microbiomes of roots or soil were not affected. The results support our hypothesis that the effect of plants on the microbiome composition decreases from shoots to roots and soil.


Randomised comparison of the effects of Sprinkles and Foodlets with the currently recommended supplement (Drops) on micronutrient status and growth in Iranian children.
Multiple micronutrient supplementation with Sprinkles powder and crushable Foodlets tablets may be effective means of controlling micronutrient deficiencies in infants. Their efficacy has not been tested in countries like Iran where wheat as the staple food may affect nutrient bioavailability. This study aimed to compare the efficacy of Sprinkles, Foodlets and the current supplement (Drops) for improving micronutrient status and growth among Iranian infants. Infants of 6-18 months of age, living in an urban district of Iran were randomised to receive daily Sprinkles (n=120), Foodlets (n=121) or Drops (n=121) for 4 months. Haemoglobin (Hb), serum ferritin, serum retinol, serum zinc, 25(OH) D concentration and anthropometry were assessed at baseline and at 4 months. Iron status improved with all treatments. Drops showed significantly greater changes in Hb and serum ferritin, though changes in anaemia prevalence were not different across groups. Infants having Foodlets and Sprinkles had significantly greater reductions in proportion of children with zinc deficiency compared with Drops. No significant differences in treatment effects were observed for mean serum 25(OH) D and retinol, or for growth of infants across groups. The study was the first efficacy trial with Sprinkles and Foodlets in the Middle East where wheat or rice is the principal complementary foods. Differences across treatment groups were largely consistent with supplement micronutrient composition for iron and zinc, with no benefit in this population for serum retinol, 25(OH) D, growth or anthropometric status. The trial identified trade-offs in combining multiple micronutrients in a single delivery mechanism.


Comparative Emulsifying Properties of Octenyl Succinic Anhydride (OSA)-Modified Starch: Granular Form vs Dissolved State.
The emulsifying ability of OSA-modified and native starch in the granular form, in the dissolved state and a combination of both was compared. This study aims to understand mixed systems of particles and dissolved starch with respect to what species dominates at droplet interfaces and how stability is affected by addition of one of the species to already formed emulsions. It was possible to create emulsions with OSA-modified starch isolated from Quinoa as sole emulsifier. Similar droplet sizes were obtained with emulsions prepared at 7% (w/w) oil content using OSA-modified starch in the granular form or molecularly dissolved but large differences were observed regarding stability. Pickering emulsions kept their droplet size constant after one month while emulsions formulated with OSA-modified starch dissolved exhibited coalescence. All emulsions stabilized combining OSA-modified starch in granular form and in solution showed larger mean droplet sizes with no significant differences with respect to the order of addition. These emulsions were unstable due to coalescence regarding presence of free oil. Similar results were obtained when emulsions were prepared by combining OSA-modified granules with native starch in solution. The degree of surface coverage of starch granules was much lower in presence of starch in solution which indicates that OSA-starch is more surface active in the dissolved state than in granular form, although it led to unstable systems compared to starch granule stabilized Pickering emulsions, which demonstrated to be extremely stable.


Glucose-Triggered Insulin Release from Fe3+ -Cross-linked Alginate Hydrogel: Experimental Study and Theoretical Modeling.
We study the mechanisms involved in the release, triggered by the application of glucose, of insulin entrapped in Fe3+ -cross-linked alginate hydrogel particles further stabilized with a polyelectrolyte. Platelet-shaped alginate particles are synthesized containing enzyme glucose oxidase conjugated with silica nanoparticles, which are also entrapped in the hydrogel. Glucose diffuses in from solution, and production of hydrogen peroxide is catalyzed by the enzyme within the hydrogel. We argue that, specifically for the Fe3+ -cross-linked systems, the produced hydrogen peroxide is further converted to free radicals via a Fenton-type reaction catalyzed by the iron cations. The activity of free radicals, as well as the reduction of Fe3+ by the enzyme, and other mechanisms contribute to the decrease in density of the hydrogel. As a result, while the particles remain intact, void sizes increase and release of insulin ensues and is followed experimentally. A theoretical description of the involved processes is proposed and utilized to fit the data. It is then used to study the long-time properties of the release process that offers a model for designing new drug-release systems.


A step at a time.
In this issue of Families, Systems, and Health are two articles that inch us on our winding way forward as we try to help people become healthier. This article takes stock of where we are now, starting from the start, equipped with three of our foundational guiding principles, and sighting our polestar to see what our best next moves might be. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Rape: Is it a lifestyle or behavioral problem?
In India, girl is raped every 20 min. The majority of reports reveals youth is vulnerable group for rape victimization. A set of prejudicial, stereotyped, or false beliefs about rape, rape victims, and rapist exist in the community. To study the attitude and myths toward rape among college going students of Surat City. College students of various streams were participated in the study based on attitude toward rape scale (21 items) and updated Illinois Rape Myth Acceptance Scale (22 items). A total of 332 participants from three different colleges of the city took part in the survey. Data analysis was done with the SPSS version 19. Among the responders, 61.75% were female. Mean age of participants was 20.22 ± 1.27 years. Almost two-third (73%) of female participants and 42% of the male participants disagreed with the myth that "When a woman says 'no' she really means 'yes'." Around 30% of the participants were uncertain about the myth that "A woman cannot be raped by someone she previously knew or had sex with." While almost 35% of participants believed that "Most rapes are carried out by strangers." Strong sexual desire of guys, drunkenness, and girl's clothes were reported to be factors that provoke rape by 50%, 40%, and 33% of respondents, respectively, around 95% of female and 92% of male participants think that 7-year imprisonment for rape is not enough. Rape myths are found to be highly prevalent among youth and higher among males.


MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking.
Meningioma expressed antigen 6 (MEA6), also called cutaneous T cell lymphoma-associated antigen 5 (cTAGE5), was initially found in tumor tissues. MEA6 is located in endoplasmic reticulum (ER) exit sites and regulates the transport of collagen, very low density lipoprotein, and insulin. It is also reported that MEA6 might be related to Fahr's syndrome, which comprises neurological, movement, and neuropsychiatric disorders. Here, we show that MEA6 is critical to cerebellar development and motor performance. Mice with conditional knockout of MEA6 (Nestin-Cre;MEA6F/F) display smaller sizes of body and brain compared to control animals, and survive maximal 28 days after birth. Immunohistochemical and behavioral studies demonstrate that these mutant mice have defects in cerebellar development and motor performance. In contrast, PC deletion of MEA6 (pCP2-Cre;MEA6F/F) causes milder phenotypes in cerebellar morphology and motor behaviors. While pCP2-Cre;MEA6F/F mice have normal lobular formation and gait, they present the extensive self-crossing of PC dendrites and damaged motor learning. Interestingly, the expression of key molecules that participates in cerebellar development, including Slit2 and brain derived neurotrophic factor (BDNF), is significantly increased in ER, suggesting that MEA6 ablation impairs ER function and thus these proteins are arrested in ER. Our study provides insight into the roles of MEA6 in the brain and the pathogenesis of Fahr's syndrome.


Propelling plastics into the circular economy - weeding out the toxics first.
The Stockholm Convention bans toxic chemicals on its persistent organic pollutants (POPs) list in order to promote cleaner production and prevent POPs accumulation in the global environment. The original 'dirty dozen' set of POPs has been expanded to include some of the brominated diphenyl ether flame retardants (POP-BDEs). In addition to cleaner production, there is an urgent need for increased resource efficiency to address the finite amount of raw materials on Earth. Recycling plastic enhances resource efficiency and is part of the circular economy approach, but how clean are the materials we are recycling? With the help of a new screening method and detailed analyses, we set out to investigate where these largely obsolete BDEs were showing up in Dutch automotive and electronics waste streams, calculate mass flows and determine to what extent they are entering the new product chains. Our study revealed that banned BDEs and other toxic flame retardants are found at high concentrations in certain plastic materials destined for recycling markets. They were also found in a variety of new consumer products, including children's toys. A mass flow analysis showed that 22% of all the POP-BDE in waste electrical and electronic equipment (WEEE) is expected to end up in recycled plastics because these toxic, bioaccumulative and persistent substances are currently not effectively separated out of plastic waste streams. In the automotive sector, this is 14%, while an additional 19% is expected to end up in second-hand parts (reuse). These results raise the issue of delicate trade-offs between consumer safety/cleaner production and resource efficiency. As petroleum intensive materials, plastic products ought to be repaired, reused, remanufactured and recycled, making good use of the 'inner circles' of the circular economy. Keeping hazardous substances - whether they are well known POPs or emerging contaminants - out of products and plastic waste streams could make these cycles work better for businesses, people and nature.


Factors associated with having a medical marijuana card among Veterans with recent substance use in VA outpatient treatment.
Psychiatric symptoms, somatic problems, and co-occurring substance use have been associated with medical marijuana consumption among civilian patients with substance use disorders. It is possible that these factors may impact Veterans' ability to engage in or adhere to mental health and substance use disorder treatment. Therefore, we examined whether psychiatric functioning, substance use, and somatic problems were associated with medical marijuana use among Veterans receiving substance use disorder and/or mental health treatment. Participants (n=841) completed screening measures for a randomized controlled trial and 67 (8%) reported that they had a current medical marijuana card. Most of these participants (78%) reported using marijuana to treat severe/chronic pain. Significant bivariate differences revealed that, compared to participants without a medical marijuana card, those with a card were more likely to be in a middle income bracket, unemployed, and they had a significantly higher number of recent days of marijuana use, synthetic marijuana use, and using sedatives prescribed to them. Additionally, a significantly higher proportion of participants with a medical marijuana card scored above the clinical cutoff for posttraumatic stress disorder (PTSD) symptoms, had significantly higher severity of sleep-related problems, and reported a higher level of pain. These findings highlight the co-occurrence of substance use, PTSD symptoms, sleep-related problems, and chronic pain among Veterans who use medical marijuana. Future research should investigate the inter-relationships among medical marijuana use and other clinical issues (e.g., PTSD symptoms, sleep, pain) over time, and potential implications of medical marijuana use on treatment engagement and response.


Analysis of the inhibitory effects of miR-124 and miR-152 on human epithelial ovarian cancer xenografts in a nude mouse model.
This study investigated the inhibitory effects of miR-124 and miR-152 on the growth of human ovarian cancer (OC) SKOV3 cell line subcutaneous xenografts in nude mice. Twenty-eight healthy nude mice were selected and divided into the experimental group 1 (n=4), experimental group 2 (n=4), negative control group 1 (n=4), negative control group 2 (n=4), blank control group 1 (n=4), blank control group 2 (n=4) and observation group (n=4) according to the principle of similarity in body weight. The transfected SKOV3 cells were inoculated subcutaneously into the nape of the nude mice. After tumorigenesis, miR-124 mimics, miR-152 mimics, and their negative controls were transiently transfected into human OC SKOV3 cells via lipofection method. The expression levels of miR-124 and miR-152 were detected via reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and those of Ki-67 and caspase-3 were detected by western blotting. After transfection, the expression levels of miR-124 and miR-152 in the SKOV3 cells were significantly upregulated. The nude mice were sacrificed 36 days later, and tumor nodes of nude mice transfected with miR-124 and miR-152 grew slowly. Compared with that in the experimental groups, tumor size in the blank control and negative control groups was gradually increased with the increment of days (P<0.05). The volume of subcutaneous xenografts in nude mice of miR-124 and miR-152 experimental groups was obviously smaller than that in the blank control and negative control groups (P<0.05). Besides, the inhibition of tumor size in the observation group was more significant than that in the experimental groups (P<0.05). Thus, miR-124 and miR-152 inhibit the growth of human epithelial OC xenografts in nude mice, and they are expected to become new targets for gene-based therapy of OC.


Looking back and judging our predecessors.
The Advisory Committee on Human Radiation Experiments has correctly argued that persons and institutions can sometimes be held responsible for actions taken more than a half-century ago, when practices and policies on the use of research subjects were strikingly different. In reaching its conclusions, the Committee did not altogether adhere to the language and commitments of its own ethical framework. In its Final Report, the Committee emphasizes judgments of wrongdoing, to the relative neglect of culpability; it discusses mitigating conditions that are exculpatory, but does not provide a thoroughgoing assessment of either culpability or exculpation. However, the Committee's shortcomings are mild in comparison to the deficiencies in the "Report of the UCSF Ad Hoc Fact Finding Committee on World War II Human Radiation Experiments" of the University of California at San Francisco. The latter report reaches no significant judgments of either wrongdoing or culpability. The findings that should have been reached by both committees are discussed.


Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms.
Interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and also directly inhibit tumor growth. IFNα is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFNα and others do not. Here, we identify and characterize a pathway involving PKCδ-dependent phosphorylation of ULK1 on serine residues 341 and 495, required for subsequent activation of p38 MAPK. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from MPN patients, and that increased levels of ULK1 and p38 MAPK correlate with clinical response to IFNα therapy in these patients. We also demonstrate that IFNα treatment induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vitro and in vivo, triggering a negative feedback loop that suppresses IFN responses. Overexpression of ROCK1/2 is seen in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid precursors from MPN patients. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPNs.


Early protection events in swine immunized with an experimental live attenuated classical swine fever marker vaccine, FlagT4G.
Prophylactic vaccination using live attenuated classical swine fever (CSF) vaccines has been a very effective method to control the disease in endemic regions and during outbreaks in previously disease-free areas. These vaccines confer effective protection against the disease at early times post-vaccination although the mechanisms mediating the protection are poorly characterized. Here we present the events occurring after the administration of our in-house developed live attenuated marker vaccine, FlagT4Gv. We previously reported that FlagT4Gv intramuscular (IM) administered conferred effective protection against intranasal challenge with virulent CSFV (BICv) as early as 7 days post-vaccination. Here we report that FlagT4Gv is able to induce protection against disease as early as three days post-vaccination. Immunohistochemical testing of tissues from FlagT4Gv-inoculated animals showed that tonsils were colonized by the vaccine virus by day 3 post-inoculation. There was a complete absence of BICv in tonsils of FlagT4Gv-inoculated animals which had been intranasal (IN) challenged with BICv 3 days after FlagT4Gv infection, confirming that FlagT4Gv inoculation confers sterile immunity. Analysis of systemic levels of 19 different cytokines in vaccinated animals demonstrated an increase of IFN-α three days after FlagT4Gv inoculation compared with mock infected controls.


Escherichia coli aspartate transcarbamylase: the relation between structure and function.
The x-ray structures of the allosteric enzyme aspartate transcarbamylase from Escherichia coli have been solved and refined for both allosteric forms. The T form was determined in the presence of the heterotropic inhibitor cytidine triphosphate, CTP, while the R form was determined in the presence of the bisubstrate analog N-phosphonacetyl-L-aspartate. These two x-ray structures provide the starting point for an understanding of how allosteric enzymes are able to control the rates of metabolic pathways. Insights into the mechanisms of both catalysis and homotropic cooperativity have been obtained by using site-directed mutagenesis to probe residues thought to be critical to the function of the enzyme based on these x-ray structures.


Antibacterial Discovery: 21st Century Challenges.
It has been nearly 50 years since the golden age of antibiotic discovery (1945-1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.


The Effect of an HIV Self-Management Intervention on Neurocognitive Behavioral Processing.
People living with HIV (PLHIV) are increasingly diagnosed with comorbidities which require increasing self-management. We examined the effect of a self-management intervention on neurocognitive behavioral processing. Twenty-nine PLHIV completed a two-group, 3-month randomized clinical trial testing a self-management intervention to improve physical activity and dietary intake. At baseline and 3 months later, everyone completed validated assessments of physical, diet, and neurocognitive processing (functional magnetic resonance imaging [fMRI]-derived network analyses). We used linear mixed effects modeling with a random intercept to examine the effect of the intervention. The intervention improved healthy eating (p = .08) but did not improve other self-management behaviors. There was a significant effect of the intervention on several aspects of neurocognitive processing including in the task positive network (TPN) differentiation (p = .047) and an increase in the default mode network (DMN) differentiation (p = .10). Self-management interventions may influence neurocognitive processing in PLHIV, but those changes were not associated with positive changes in self-management behavior.


Feasibility and efficacy of microwave ablation for treating breast fibroadenoma.
To investigate the safety, efficacy, and follow-up outcomes of microwave ablation (MWA) in patients with breast fibroadenoma. An institutional review board-approved this study of patients treated with MWA for breast fibroadenoma from October 2017 to March 2019. Clinical features of patients and breast fibroadenoma were analyzed. At follow-up all patients received physical examination and ultrasound imaging. In total, 171 patients with 271 lesions were enrolled. The mean lesion diameter was 1.35 ± 0.47 cm. The results revealed differential lesion states, including stability, enlargement, reduction, and complete regression, at 1-6, 6-12, and >12 months of follow-up. The size was reduced in 22.14% (31/140), 26.36% (29/110), and 36.36% (16/44) of the lesions at 1-6, 6-12, and >12 months of follow-up, respectively. The proportion of lesions with complete regression was 24.29% (34/140) at 1-6 months, 45.45% (50/110) at 6-12 months, and 40.91% (18/44) at >12 months of follow up. There was no significant relationship between the curative effect and age, lesion location, and blood flow in patients with breast fibroadenoma after MWA (p > .05), but there was statistically significant relationship with lesion diameter (categorized as <1.5 cm and ≥1.5 cm) (p < .05). The current evidence indicates that MWA is a safe and effective method for treating breast fibroadenoma. Nevertheless, further large-scale prospective trials and well-designed future studies are warranted to validate our findings.


[The status of diagnosis of Barrett esophagus. An analysis of 1000 histologically diagnosed cases].
To evaluate the quality of diagnosis in cases of Barrett's oesophagus (BOe). It was examined whether: (1) there had been regular pre-treatment investigations;(2) characteristic mucosal changes had been recognized by endoscopy; (3) a diagnosis of intraepithelial neoplasia had been made more often than of advanced Barrett carcinoma. Endoscopic and associated bioptic reports on 1000 consecutive patients with histologically confirmed BOe, seen between 1990 and 1995, were analysed. (Average age was 63 +/- 14.3 years; male to female ratio: 2.2:1). In 85.1% of patients the histological diagnosis was BOe without dysplasia. The neoplasias consisted of carcinoma in 8.8%, suspected carcinoma in 0.5%, actual or suspected low-grade dysplasia in 4.6%, actual or high-grade dysplasia in 1.0%. Endoscopic diagnosis in cases without neoplasia was in 60.8% correct for actual BOe or suspected BOe. At endoscopy dysplasia was suspected in 5.4%. The diagnosis or suspected diagnosis of Barrett's carcinoma was correct in 69%. Repeat endoscopy a year after the initial diagnosis was performed in 9.4% with BOe and no neoplasia. Repeat endoscopy was performed in 37.5% of patients with an initial diagnosis of suspected low-grade dysplasia, in 43.3% with low-grade dysplasia, in 42.9% of suspected high-grade and in 100% of actual high-grade dysplasia. Neoplasia in Barrett's oesophagus is found too late. Only half of the histologically confirmed cases are found by endoscopy and follow-up is not sufficient.


Structured Graph Learning for Scalable Subspace Clustering: From Single View to Multiview.
Graph-based subspace clustering methods have exhibited promising performance. However, they still suffer some of these drawbacks: they encounter the expensive time overhead, they fail to explore the explicit clusters, and cannot generalize to unseen data points. In this work, we propose a scalable graph learning framework, seeking to address the above three challenges simultaneously. Specifically, it is based on the ideas of anchor points and bipartite graph. Rather than building an n×n graph, where n is the number of samples, we construct a bipartite graph to depict the relationship between samples and anchor points. Meanwhile, a connectivity constraint is employed to ensure that the connected components indicate clusters directly. We further establish the connection between our method and the K -means clustering. Moreover, a model to process multiview data is also proposed, which is linearly scaled with respect to n . Extensive experiments demonstrate the efficiency and effectiveness of our approach with respect to many state-of-the-art clustering methods.


Serum increase and liver overexpression of carbohydrate 19.9 antigen in patients with genetic haemochromatosis.
CA 19.9 antigen is mainly secreted by biliary and pancreatic duct cells. Its metabolism could be modified in genetic haemochromatosis by iron accumulation within these cells. Therefore, CA 19.9 was assayed in the serum samples of 84 patients with genetic haemochromatosis before and after iron depletion and immunolocalised in the liver of 24 untreated genetic haemochromatosis cases. The study showed that serum CA 19.9 (N < 37 IU/l) was increased (SD) before treatment (41.2 (34)) when compared with after the venesection period (16 (12)), and correlated, before treatment, with the amount of iron excess, transaminases, fibrosis, and biliary iron deposits. Hepatic CA 19.9 was located within the cytoplasm of bile duct and cholangiolar cells. In conclusion, this study shows that a mild, reversible, and non-specific increase in serum CA 19.9 is common in genetic haemochromatosis patients and shows that this increase is related to iron excess, directly or through associated liver damage. The unexplained finding of a mild increase in serum CA 19.9 should lead, in a patient with no diagnosis, to the search for liver iron overload, and, in a patient with untreated genetic haemochromatosis, not to further diagnostic procedures unless this finding persists after completion of the venesection treatment.


A Facile, Nonreactive Hydrogen Peroxide (H2O2) Detection Method Enabled by Ion Chromatography with UV Detector.
Hydrogen peroxide (H2O2) is ubiquitous in the natural environment, and it is now widely used for pollutant control in water and wastewater treatment processes. However, current analytical methods for H2O2 inevitably require reactions between H2O2 and other reactants to yield signals and are thus likely subjective to the interferences of coexisting colored, oxidative, and reductive compounds. In order to overcome these barriers, we herein for the first time propose to analyze H2O2 by ion chromatography (IC) using an ultraviolet (UV) detector. The proposal is based on two principles: first, that H2O2 can deprotonate to hydroperoxyl ion (HO2-) when eluent pH is higher than the acid-dissociation coefficient of H2O2 (pKa = 11.6); and second, that after separation from other compounds via IC column, H2O2 can be quantified by a UV detector. Under favorable operating conditions, this method has successfully achieved acceptable recoveries (>91%) of H2O2 dosed to ultrapure and natural waters, a calibration curve with R2 > 0.99 for a wide range of H2O2 concentrations from 0.1 to 50 mg/L and a method detection limit of 0.027 mg/L. In addition, this approach was shown to be capable of distinguishing H2O2 from anions (e.g., fluoride and chloride) and organics (e.g., glycolate) and monochloramine, suggesting that it is insensitive to many neighboring compounds as long as they do not react quickly with H2O2. Hence, this study proves the combination of IC and UV detector a facile and reliable method for H2O2 measurement.


Do consumer-directed health plans drive change in enrollees' health care behavior?
Using panel data from two surveys of employees at one large employer from 2004 and 2005, this paper examines consumer-directed health plans' (CDHPs') influence on the use of health-related information and health services. We compare enrollees in a high-deductible CDHP, a lower-deductible CDHP, and a preferred provider organization (PPO). Enrollees in the lower-deductible CDHP were more likely than enrollees in the other plans to start using information. Enrollees in the high-deductible CDHP were more likely than those in the PPO to start forgoing medical care to save money.


Dissemination of Extended-Spectrum β-Lactamases and Quinolone Resistance Genes Among Clinical Isolates of Uropathogenic Escherichia coli in Children.
Urinary tract infection (UTI) is one of the most common childhood bacterial infections and Escherichia coli is the major pathogen. Producing β-lactamase enzymes are the most common mechanism of bacterial resistance. This study aimed to determine the prevalence of Extended-Spectrum β-Lactamases (ESBLs) and Quinolone Resistance (qnr) genes in E. coli strains isolated from UTIs. In this study, a total of 120 isolates of E. coli from urinary tract infections of the children were collected at Besat Hospital in Hamadan, Iran, from October 2010 to October 2011. The bacterial isolates were identified by standard biochemical methods. Antimicrobial susceptibilities were determined by disk diffusion method, and ESBLs-producing was confirmed phenotypically using the double-disk synergy (DDS) test. The presence and identification of ESBLs and qnr genes were determined by Polymerase Chain Reaction (PCR). The highest sensitivity was seen to imipenem (96.7%), amikacin (92.5%), nitrofurantoin (93.3%), ofloxacin (81.7%), gentamicin norfloxacin (70.8%), and ciprofloxacin (79.2%). In contrast, the highest rate of resistance was seen to co-trimoxazole (77%) and nalidixic acid (40.9%). The results showed that 6 (2.18%) and 4 (1.12%) isolates of ESBL-producing E. coli were positive with respect to having qnrB and qnrS genes, respectively. No isolates was found to have qnrA. CTX-M was the most prevalent ESBL genotype in uropathogenic E. coli (UPEC) isolated from UTI. In addition, a high frequency of qnr genes among ESBL-producing E. coli was identified in this study. In order to avoid treatment failures, we recommend using phenotypic and molecular methods to diagnose these enzymes and qnr genes.


[Long-term effects of neonatal recurrent seizures on gamma-aminobutyric acid A receptor alpha1 and gamma2 subunit expressions in the rat brain].
To investigate the long-term effects of flurothyl-induced neonatal recurrent seizures on GABA A receptor (GABA(A)R) alpha1 and gamma2 subunit expressions in adult rat brain, and discuss the relationship between these alterations of GABA(A)R subunits in mature brain and the changes of spatial memory and seizure susceptibility in adult rats. Thirty-two of 7-day-old (P7) Sprague-Dawley rats were divided randomly into two groups: the control group and the seizure group. Seizures were induced by inhalant flurothyl daily for six consecutive days. Rats were tested for spatial memory by using the Morris water maze task from postnatal 61 d(P61) to P65. Seizure threshold was examined by intraperitoneal injection of pentylenetetrazol, and then the brains were sampled on P75. The expressions of GABA(A)R alpha1 and gamma2 subunits mRNA and protein in cerebral cortex and hippocampus were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry method. On P64, the escape latencies in water maze for the rats in the seizure group were significantly longer than those of the control rats [(82 424+/-35 622)ms vs (40 712+/-29 468)ms, P=0.001]. On P65, the frequency of crossing target within 120 s in water maze for the rats in the seizure group were significantly less than those of the control rats [(1.2+/-0.9) vs (3.1+/-1.3), P<0.001]. There was no difference in seizure threshold between the two groups on P75 [(1 487+/-662)s vs (1 841+/-648)s, P=0.137]. Compared to the control rats, the accumulated optical density (AOD) of GABA(A)R alpha1 subunit immunoreactivity in seizure rats decreased significantly in the parietal cortex, CA1-2 and CA4 region (P<0.05). The AOD of alpha1 subunit protein immunoreactivity in the frontal cortex, CA3 and dentate gyrus (DG) were of no significant difference between the two groups on P75 (P>0.05). There were also no differences in the AOD of gamma2 subunit protein immunoreactivity in the parietal lobe, DG, and CA1-3 region between the two groups (P>0.05). The AOD of gamma2 subunit protein immunoreactivity in the frontal lobe and CA4 region decreased significantly in the seizure group than those in the control group (P<0.05). The expressions of alpha1 subunits mRNA in the cerebral cortex and gamma2 subunit mRNA in the hippocampus were similar between the two groups (P>0.05), but the expressions of alpha1 subunits mRNA in the hippocampus and gamma2 subunit mRNA in the cerebral cortex in the seizure group decreased significantly as compared with those in the control group (P< 0.05). Recurrent seizures in neonatal rats modify GABA(A) receptor alpha1 and gamma2 subunits expression in the cerebral cortex and hippocampus of adult rats, and cause long-term cognitive deficit, Which suggests that abnormal GABA(A) receptor expression might play an important role in long-term cognitive deficit induced by early life recurrent seizures.


Successful use of 1064 Nm Nd:YAG in conjunction with 2790 Nm YSGG ablative laser for traumatic scarring.
Patients with traumatic scarring often seek both aesthetic and functional improvement and can be a challenge to treat; however, advances in laser and light technologies have helped to treat many of these patients with rather minimally invasive approaches. A nineteen year old girl with Fitzpatrick skin type III skin presented for the evaluation of extensive traumatic scarring involving her right cheek, right chin, and right oral commissure that she sustained after a motor vehicle accident. We report the successful use of the 1064 nm Nd:YAG laser in conjunction with the ablative 2790 nm YSGG laser for the treatment of traumatic scarring in this patient. Our patient noted a notable improvement in the appearance of her traumatic scarring in addition to decrease in contracture of the right oral commissure. The treatment regimen described provides an effective option for clinicians to utilize when treating traumatic scarring and skin textural changes.


Fragility in p-spin models.
We investigate the relation between fragility and phase space properties - such as the distribution of states - in the mean-field p -spin model, a solvable model that has been frequently used in studies of the glass transition. By direct computation of all the relevant quantities, we find that (i) the recently observed correlation between fragility and vibrational properties at low temperature is present in this model and (ii) the total number of states is a decreasing function of fragility, at variance with what is currently believed. We explain these findings by taking into account the contribution to fragility coming from the transition paths between different states. Finally, we propose a geometric picture of the phase space that explains the correlation between properties of the transition paths, distribution of states, and their vibrational properties. However, our analysis may not apply to strong systems where inflection points in the configurational entropy as a function of the temperature are found.


[Contribution to the development of the union between the manubrium of the malleus and the tympanic membrane in human fetus].
The development of the union between the manubrium of the malleus and the tympanic membrane was studied in human embryo. For that purpose 25 temporal bones of human foetus, aged from 36 days (14 mm) to 29 weeks (270 mm) were analyzed. Samples were fixed in a 10% formaldehyde solution, decalcified with 2% nitric acid, embedded in Paraplast, cut in sections of 7 microns thick and stained with Martin's trichrome method. During the development a pseudojoint between the malleus and the tympanic membrane several stages were seen. In the first stage, the manubrium was adhered to membrane mesenchyme of primitive tympanum, in the second one this mesenchyme was loose and there appeared capillars in it, in the third one there were collagen fibers in a radial disposition, and in the forth stage, the hollow in the meatal plug gave independence to the tympanic membrane for the external acoustic meatus. The distal portion of the manubrium, included in tympanic membrane, has remained with a cartilaginous structure during end of the time it has been studied by us. The collagen fibers at the level of the umbo surround the manubrium, while the rest of it remains in its anterior edge.


Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.
Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.


Electron Donor-Acceptor (EDA) Complex between a Triarylamine and B(C6F5)3 for the Photocatalytic Dehydrogenative Cross-Coupling of Phenols.
In this article, an electron donor-acceptor (EDA) complex between a triarylamine and B(C6F5)3 that catalyzes the dehydrogenative cross-coupling of phenols is described. We demonstrate, for the first time, that the use of both components of the radical ion pairs generated by the photoexcitation of the EDA complex as co-catalysts, and the triarylaminium radical cation (+·NAr3) successfully promotes dehydrogenative cross-coupling between electron-rich phenols and 2-naphthols to provide electron-rich biphenol motifs using molecular oxygen as a terminal oxidant.


Delayed Posterior Urethroplasty Following Pelvic Fracture Urethral Injury: Do We Have to Wait 3 Months?
To compare outcomes with early vs delayed reconstruction following pelvic fracture urethral injury (PFUI) to determine if a traditional 3-month delay is necessary. This delay has been advocated to allow resolution of traumatic inflammation and hematoma but has never been validated. We proceed to reconstruction at 3-6 weeks if the associated injuries are stable, the perineum is soft on rectal palpation, and the fracture is stable for lithotomy positioning. PFUI patients treated with a suprapubic tube and delayed urethroplasty from October 1991 to August 2016 were included. Patients with initial catheter realignment were excluded. We compared reconstruction failure, incontinence, and erectile dysfunction rates in patients reconstructed within 6 weeks after injury with those reconstructed after the traditional ≥12 weeks. Thirty-nine patients were identified with a median age of 32 years (17 to 69). Overall, the median urethral gap was 2 cm (1-4.5) and median follow-up was 64 months (12-277). Stricture failure occurrence was 5.1%, incontinence rate was 7.7%, and erectile dysfunction rate was 56.4%. The 22 patients with urethroplasty ≤6 weeks post-injury were no more likely to experience erectile dysfunction (13 vs 9, P = .70), urinary incontinence (1 vs 2, P = .40) or reconstruction failure (2 vs 0, P = .20) than the 17 patients delayed ≥12 weeks. We report similar outcomes following urethral reconstruction for PFUI patients repaired ≤6 weeks after injury compared with those delayed ≥12 weeks. This suggests that in selected cases reconstruction at 3-6 weeks is feasible, minimizing the morbidity of a suprapubic tube.


A Rare Case of Solitary Giant Congenital Juvenile Xanthogranuloma: A Case Report.
Juvenile xanthogranuloma (JXG) is the most frequent form of non-Langerhans cell histiocytosis. We present a case of giant congenital JXG in a 7-week-old boy, who had a firm and incompressible lesion, measuring 3 × 4 cm in diameter, on his right flank. The clinical appearance of the lesion and the ultrasound results suggested a vascular tumor, such as a hemangioma. Histology confirmed a JXG, although there was an absence of Touton cells, which are usually pathognomonic of JXG. In light of these findings, it would be important to include JXG in the differential diagnosis of congenital tumours, particularly vascular lesions.


In vitro evaluation of CP-62,993, erythromycin, clindamycin, and tetracycline against Chlamydia trachomatis.
The antimicrobial activity of CP-62,993 against four Chlamydia trachomatis isolates was compared with those of erythromycin, clindamycin, and tetracycline. The MIC of CP-62,993 was 0.26 to 1.02 micrograms/ml for 100% inclusion inhibition and 0.031 to 0.063 microgram/ml for 50% inclusion inhibition. With pharmacokinetic and antimicrobial studies demonstrating prolonged half-life and in vitro effectiveness, CP-62,993 may make possible a single, short-course treatment regimen for C. trachomatis infection.


Additional value of integrated PET-CT in the detection and characterization of lung metastases: correlation with CT alone and PET alone.
The purpose was evaluating retrospectively the additional value of integrated positron emission tomography (PET) and computed tomography (CT) in the detection of pulmonary metastases in comparison with CT and PET alone. Fifty-six lung nodules, divided into three groups according their size, detected in 24 consecutive patients with a known primary tumor were retrospectively evaluated with integrated PET-CT, CT and PET. The nature of these nodules was determined by either histopathology or a follow-up of at least 6 months. The CT and PET images of the integrated PET-CT were evaluated separately by a radiologist and a nuclear medicine physician, the integrated PET-CT images were evaluated by a chest radiologist and nuclear medicine physician in consensus. The investigators were asked to search lung nodules and to determine whether these nodules were metastases or not. Sensitivity and accuracy for CT, PET and integrated PET-CT for characterization of all pulmonary nodules were, respectively: 100%, 90%, 100% and 57%, 55%, 55%. There was no significant difference in the characterization of pulmonary nodules between integrated PET-CT and CT alone (P=1.000) and PET alone (P=0.1306). An accurate evaluation is only possible for lesions larger than 1 cm.


Isolation of Cryptococcus gattii from Oregon soil and tree bark, 2010-2011.
In Oregon, human and animal infections by C. gattii were first identified in 2004. Cryptococcus gattii is considered to be an emerging non-zoonotic infection affecting animals and humans in Oregon. We report a longitudinal environmental isolation of C. gattii after an Oregon dog was diagnosed with the disease in 2009. Cryptococcus gattii was isolated twice from the same location with a span of one year between isolation dates. Cryptococcus gattii molecular types VGIIa and VGI were isolated in 2010 from soil and tree bark near the home of a 9-month-old dog which three months previously had an infection caused by C. gattii genotype VGIIa. The environment featured heavy growth of Douglas Fir trees. In 2011, a second set of soil and tree bark samples was collected in the same area and C. gattii VGIIa was again identified from the environment, along with genotypes VGIIb and VGIIc. The use of animal surveillance data to identify environmental niches of C. gattii should be considered to expand the understanding of this emerging pathogen. Understanding the ecology and how the environment and other factors might modify the existing niches is important for assessing risk and for designing measures to protect human and animal health.