Exposure to endotoxins during sensitization prevents further endotoxin-induced exacerbation of airway inflammation in a mouse model of allergic asthma.
We have shown previously that lipopolysaccharides (LPS) inhibited airway inflammation in allergen-sensitized and challenged mice when administered during sensitization, while exacerbating the inflammation when given upon challenge. We have here investigated the effect of LPS administered during both sensitization and challenge on airway inflammation, as well as on the profile of the T-helper (Th) response to allergen. Mice were sensitized and challenged with ovalbumin (OVA), in the presence or absence of effective doses of LPS, namely 1 mug during sensitization and 1 ng during challenge. Inflammation was assessed by measuring cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF). The profile of the Th response was determined by quantifying OVA-specific IgE and IgG2a in serum and Th1/Th2 cytokines in the culture medium of splenocytes and in BALF. Allergen-induced airway eosinophilia was increased in mice exposed to LPS during challenge only when compared with controls, whereas it was similarly reduced in animals exposed during sensitization only and during both sensitization and challenge. Mice exposed to LPS during sensitization only or during both sensitization and challenge also displayed a decrease in IgE and an increase in IgG2a, suggesting a switch in the immune response toward the Th1 profile. This was confirmed by quantification of Th1/Th2 cytokines in culture medium of splenocytes and in BALF. Our data demonstrate that exposure to endotoxins during sensitization prevents allergen-induced airway inflammation, as well as its exacerbation triggered by further exposure to endotoxins during challenge, while switching the immune response to allergen from a Th2 to a Th1 profile.


Explaining the latitudinal distribution of sunspots with deep meridional flow.
Sunspots, dark magnetic regions occurring at low latitudes on the Sun's surface, are tracers of the magnetic field generated by the dynamo mechanism. Recent solar dynamo models, which use the helioseismically determined solar rotation, indicate that sunspots should form at high latitudes, contrary to observations. We present a dynamo model with the correct latitudinal distribution of sunspots and demonstrate that this requires a meridional flow of material that penetrates deeper than hitherto believed, into the stable layers below the convection zone. Such a deep material flow may have important implications for turbulent convection and elemental abundance in the Sun and similar stars.


Heterologous Expression and Characterization of a Novel Chitinase (ChiEn1) from Coprinopsis cinerea and its Synergism in the Degradation of Chitin.
Chitinase ChiEn1 did not hydrolyze insoluble chitin but showed hydrolysis and transglycosylation activities toward chitin-oligosaccharides. Interestingly, the addition of ChiEn1 increased the amount of reducing sugars released from chitin powder by endochitinase ChiIII by 105.0%, and among the released reducing sugars the amount of (GlcNAc)2 was increased by 149.5%, whereas the amount of GlcNAc was decreased by 10.3%. The percentage of GlcNAc in the products of chitin powder with the combined ChiIII and ChiEn1 was close to that in the products of chitin-oligosaccharides with ChiEn1, rather than that with ChiIII. These results indicate that chitin polymers are first degraded into chitin oligosaccharides by ChiIII and the latter are further degraded to monomers and dimers by ChiEn1, and the synergistic action of ChiEn1 and ChiIII is involved in the efficient degradation of chitin in cell walls during pileus autolysis. The structure modeling explores the molecular base of ChiEn1 action.


Tomography of dark-field scatter including single-exposure Moiré fringe analysis with X-ray biprism interferometry-A simulation study.
In this work, we present tomographic simulations of a new hardware concept for X-ray phase-contrast interferometry wherein the phase gratings are replaced with an array of Fresnel biprisms, and Moiré fringe analysis is used instead of "phase stepping" popular with grating-based setups. Projections of a phantom consisting of four layers of parallel carbon microfibers is simulated using wave optics representation of X-ray electromagnetic waves. Simulated projections of a phantom with preferential scatter perpendicular to the direction of the fibers are performed to analyze the extraction of small-angle scatter from dark-field projections for the following: (1) biprism interferometry using Moiré fringe analysis; (2) grating interferometry using phase stepping with eight grating steps; and (3) grating interferometry using Moiré fringe analysis. Dark-field projections are modeled as projections of voxel intensities represented by a fixed finite vector basis set of scattering directions. An iterative MLEM algorithm is used to reconstruct, from simulated projection data, the coefficients of a fixed set of seven basis vectors at each voxel representing the small-angle scatter distribution. Results of reconstructed vector coefficients are shown comparing the three simulated imaging configurations. The single-exposure Moiré fringe analysis shows not only an increase in noise because of one-eighth the number of projection samples but also is obtained with less dose and faster acquisition times. Furthermore, replacing grating interferometry with biprism interferometry provides better contrast-to-noise. The simulations demonstrate the feasibility of the reconstruction of dark-field data acquired with a biprism interferometry system. With the potential of higher fringe visibility, biprism interferometry with Moiré fringe analysis might provide equal or better image quality to that of phase stepping methods with less imaging time and lower dose.


Self-assembly of giant bottlebrush block copolymer surfactants from luminescent organic electronic materials.
Bottlebrush copolymers have shown promise as building blocks for self-assembled nanomaterials due to their reduced chain entanglement relative to linear polymers and their ability to self-assemble with remarkably low critical micelle concentrations (CMCs). Concurrently, the preparation of bottlebrush polymers from organic electronic materials has recently been described, allowing multiple optoelectronic functions to be incorporated along the length of single bottlebrush strands. Here we describe the self-assembly of bottlebrush surfactants containing soluble n-butyl acrylate blocks and carbazole-based organic semiconductors, which self-assemble in selective solvent to give spherical micelles with CMCs below 54 nM. These narrowly dispersed structures were stable in solution at high dilution over periods of months, and could further be functionalized with fluorescent dyes to give micelles with quantum yields of 100%. These results demonstrate that bottlebrush-based nanostructures can be formed from organic semiconductor building blocks, opening the door to the preparation of fluorescent or redox-active micelles from giant polymeric surfactants.


Source of a micro-nutrient in a semi-synthetic basal diet as a causative factor in inducing urinary calculi in rats and its inhibition by PSC 833, a potent inhibitor of P-glycoprotein.
We report a serendipitous finding of urinary calculi in rats fed a semi-synthetic basal diet. This observation was made during ongoing studies to evaluate the inhibitory effect of PSC 833, a potent inhibitor of P-glycoprotein, on development of tumors in rodent tumor model systems. A large number of specific-pathogen-free (SPF) female Sprague-Dawley and SPF male Fischer 344 rats being fed the diet were euthanized when it became evident clinically that they were uremic. At necropsy, the renal pelvis, ureters, and urinary bladder contained numerous calculi. The presence of urinary calculi was determined to be related to the source of a Food Chemical Codex grade of choline bitartrate. Rats being fed the same basal diet containing the United States Pharmacopia grade of choline bitartrate failed to develop urinary calculi. Interestingly, rats treated with the P-glycoprotein inhibitor were at significantly reduced risk of developing urinary calculi. This finding highlights how something seemingly innocuous as a minor dietary constituent can have a profound impact and, thereby, affect experimental outcome.


Systematic Review of Appropriate Robotic Intervention for Gait Function in Subacute Stroke Patients.
The purpose of this study was to critically evaluate the effects of robot-assisted gait training (RAGT) on gait-related function in patients with acute/subacute stroke. We conducted a systematic review of randomized controlled trials published between May 2012 and April 2016. This search included 334 articles (Cochrane, 51 articles; Embase, 175 articles; PubMed, 108 articles). Based on the inclusion and exclusion criteria, 7 studies were selected for this review. We performed a quality evaluation using the PEDro scale. In this review, 3 studies used an exoskeletal robot, and 4 studies used an end-effector robot as interventions. As a result, RAGT was found to be effective in improving walking ability in subacute stroke patients. Significant improvements in gait speed, functional ambulatory category, and Rivermead mobility index were found with RAGT compared with conventional physical therapy (p < 0.05). Therefore, aggressive weight support and gait training at an early stage using a robotic device are helpful, and robotic intervention should be applied according to the patient's functional level and onset time of stroke.


Alpha-1-antitrypsin (PI) and vitamin-D binding globulin (GC) phenotypes in rheumatoid arthritis: absence of an association.
The distribution of alpha-1-antitrypsin (PI) and vitamin D-binding globulin (GC) phenotypes and gene frequencies has been examined in a homogenous group of clinically well-defined patients (N = 81) with rheumatoid arthritis. The distribution pattern of the two markers was then compared with two control groups consisting of 40 individuals with osteoarthritis and 192 randomly selected normal individuals, drawn from the same geographical area as the rheumatoid arthritis patients. No association was observed between alpha-1-antitrypsin subtypes or deficient alleles and any of clinical variables observed in rheumatoid arthritis cases. Although a slightly high frequency of the GC*2 allele and a low frequency of the GC*1S allele were observed in rheumatoid arthritis and osteoarthritis compared to controls, the differences were not statistically significant. However, within the patients two clinical variables were found to be significantly associated with a particular GC phenotype. Periarticular bony erosions and antinuclear antibody were positively and negatively associated with GC 1S-2 phenotype, respectively.


Whole exome sequencing identifies genetic variants in inherited thrombocytopenia with secondary qualitative function defects.
Inherited thrombocytopenias are a heterogeneous group of disorders characterized by abnormally low platelet counts which can be associated with abnormal bleeding. Next-generation sequencing has previously been employed in these disorders for the confirmation of suspected genetic abnormalities, and more recently in the discovery of novel disease-causing genes. However its full potential has not yet been exploited. Over the past 6 years we have sequenced the exomes from 55 patients, including 37 index cases and 18 additional family members, all of whom were recruited to the UK Genotyping and Phenotyping of Platelets study. All patients had inherited or sustained thrombocytopenia of unknown etiology with platelet counts varying from 11×109/L to 186×109/L. Of the 51 patients phenotypically tested, 37 (73%), had an additional secondary qualitative platelet defect. Using whole exome sequencing analysis we have identified "pathogenic" or "likely pathogenic" variants in 46% (17/37) of our index patients with thrombocytopenia. In addition, we report variants of uncertain significance in 12 index cases, including novel candidate genetic variants in previously unreported genes in four index cases. These results demonstrate that whole exome sequencing is an efficient method for elucidating potential pathogenic genetic variants in inherited thrombocytopenia. Whole exome sequencing also has the added benefit of discovering potentially pathogenic genetic variants for further study in novel genes not previously implicated in inherited thrombocytopenia.


Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy.
The induction of a strong cytotoxic T cell response is an important prerequisite for successful immunotherapy against many viral diseases and tumors. Nucleotide vaccines, including mRNA vaccines with their intracellular antigen synthesis, have been shown to be potent activators of a cytotoxic immune response. The intracellular delivery of mRNA vaccines to the cytosol of antigen presenting immune cells is still not sufficiently well understood. Here, we report on the development of a lipid nanoparticle formulation for the delivery of mRNA vaccines to induce a cytotoxic CD 8 T cell response. We show transfection of dendritic cells, macrophages, and neutrophils. The efficacy of the vaccine was tested in an aggressive B16F10 melanoma model. We found a strong CD 8 T cell activation after a single immunization. Treatment of B16F10 melanoma tumors with lipid nanoparticles containing mRNA coding for the tumor-associated antigens gp100 and TRP2 resulted in tumor shrinkage and extended the overall survival of the treated mice. The immune response can be further increased by the incorporation of the adjuvant LPS. In conclusion, the lipid nanoparticle formulation presented here is a promising vector for mRNA vaccine delivery, one that is capable of inducing a strong cytotoxic T cell response. Further optimization, including the incorporation of different adjuvants, will likely enhance the potency of the vaccine.


Isolation and characterization of Kingella negevensis sp. nov., a novel Kingella species detected in a healthy paediatric population.
We herein report the isolation and characterization of 21 Gram-stain-negative strains cultivated from the oropharynx of healthy children in Israel and Switzerland. Initially described as small colony variants of Kingella kingae, phenotypic analysis, biochemical analysis, phylogenetic analysis based on sequencing of the partial 16S rRNA gene and five housekeeping genes (abcZ, adk, G6PD, groEL and recA), and whole genome sequencing and comparison between members of the genera Kingella and Neisseria provided evidence for assigning them to the genus Kingella. Cellular fatty acids included important amounts of C12 : 0, C14 : 0, C16 : 0 and C16 : 1n7. Digital DNA-DNA hybridization between the isolates Sch538T and K. kingae ATCC 23330T revealed relatedness of 19.9 %. Comparative analysis of 16S rRNA gene sequences available in GenBank allowed matches to strains isolated in the USA, suggesting a wider geographical distribution. A novel species named Kingella negevensis sp. nov. is proposed, as most strains have been isolated in the Negev, a desert region of southern Israel. The type strain is Sch538T (=CCUG 69806T=CSUR P957).


Comparison of the haemocytometer and tube modifications of the leucocyte adherence inhibition assay.
The haemocytometer and the tube modifications of the leucocyte adherence inhibition assay were compared in guinea pigs immunized with bovine gamma globulin or bovine serum albumin. In the direct test, both modifications yielded positive results. In the indirect test, which is dependent on a cell-free mediator of the lymphokine nature, the haemocytometer LAI assay only gave positive results. The factor produced by immune guinea pig lymphocytes and responsible for LAI reactions in the haemocytometer modification was also able to inhibit adherence of human and rat leucocytes, but not of mouse leucocytes. The results confirm the earlier suggestion that the tube and haemocytometer LAI assays have a different mechanism.


Matching marine reserve design to reserve objectives.
Recent interest in using marine reserves for marine resource management and conservation has largely been driven by the hope that reserves might counteract declines in fish populations and protect the biodiversity of the seas. However, the creation of reserves has led to dissension from some interested groups, such as fishermen, who fear that reserves will do more harm than good. These perceived differences in the effect of marine reserves on various stakeholder interests has led to a contentious debate over their merit. We argue here that recent findings in marine ecology suggest that this debate is largely unnecessary, and that a single general design of a network of reserves of moderate size and variable spacing can meet the needs and goals of most stakeholders interested in marine resources. Given the high fecundity of most marine organisms and recent evidence for limited distance of larval dispersal, it is likely that reserves can both maintain their own biodiversity and service nearby non-reserve areas. In particular, spillover of larger organisms and dispersal of larvae to areas outside reserves can lead to reserves sustaining or even increasing local fisheries. Ultimately, the success of any reserve network requires attention to the uncertainty and variability in dispersal patterns of marine organisms, clear statements of goals by all stakeholder groups and proper evaluation of reserve performance.


Probing Anisotropic Surface Properties and Surface Forces of Fluorite Crystals.
Fluorite is the most important mineral source for producing fluorine-based chemicals and materials in a wide range of engineering and technological applications. In this work, atomic force microscopy was employed, for the first time, to probe the surface interactions and adhesion energy of model oleic acid (a commonly used surface modification organics for fluorite) molecules on fluorite surfaces with different orientations in both air and aqueous solutions at different pH conditions. Fitted with the Derjaguin-Landau-Verwey-Overbeek theory, the force results during surface approaching demonstrate the anisotropy in the surface charge of different orientations, with the {111} surface exhibiting a higher magnitude of surface charge, which could be attributed to the difference in the atomic composition. The adhesion measured during surface retraction shows that model oleic acid molecules have a stronger adhesion with the {100} surface than with the {111} surface in both air and aqueous solutions. The anisotropic adhesion energy was analyzed in relation to the surface atom (especially calcium) activity, which was supported by the surface free energy results calculated based on a three-probe-liquid method. Each calcium atom on the {100} surface with four dangling bonds is more active than the calcium atom on the {111} surface with only one dangling bond, supported by a larger value of the Lewis acid component for the {100} surface. The model oleic acid molecules present in the ionic form at pH 9 exhibit a higher adhesion energy with fluorite surfaces as compared to their molecular form at pH 6, which was related to the surface activity of different forms. The adhesion energy measured in solution is much lower than that in air, indicating that the solvent exerts an important influence on the interactions of organic molecules with mineral surfaces. The results provide useful information on the fundamental understanding of surface interactions and adhesion energy of organic molecules on mineral surfaces with different orientations, and the methodology can be extended to many other crystal surfaces in various interfacial processes.


A comparison of conventional versus locking plates in intraarticular calcaneus fractures: a biomechanical study in human cadavers.
Internal fixation of displaced intraarticular calcaneal fractures in patients older than 50 years remains controversial. This is, in many cases, due to fear of loss of fixation and the risk of implant failure in osteoporotic bone. It is the objective of this study to compare the fixation strength obtained using calcaneal plates with and without locking screws, in the fixation of osteoporotic cadaveric intraarticular calcaneal fractures. In seven pairs of fresh frozen lower limbs cadavers, intraarticular calcaneal fractures were created with a dynamic single impact loading device and stabilized using either the low profile locking plate, or the conventional calcaneus plate. Radiographs were obtained to assess reduction. The specimens were then subjected to cyclic loading followed by loading to failure, using matched pairs of cadaveric lower limbs. The Wilcoxon signed rank test was used to test for differences in the results. The locking plate showed a significant lower irreversible deformation during cyclic loading and a significant higher load to failure. The difference between the ultimate displacement, and work to failure was not significant. A low bone mineral content in the area of the posterior facet correlated only in the conventional plate group with increased irreversible deformation. This study supports the mechanical viability of using locking calcaneal plates for the fixation of intraarticular calcaneal fractures in elderly patients.


Tuning Li-Ion Diffusion in α-LiMn1-xFexPO4 Nanocrystals by Antisite Defects and Embedded β-Phase for Advanced Li-Ion Batteries.
Olivine-structured LiMn1-xFexPO4 has become a promising candidate for cathode materials owing to its higher working voltage of 4.1 V and thus larger energy density than that of LiFePO4, which has been used for electric vehicles batteries with the advantage of high safety but disadvantage of low energy density due to its lower working voltage of 3.4 V. One drawback of LiMn1-xFexPO4 electrode is its relatively low electronic and Li-ionic conductivity with Li-ion one-dimensional diffusion. Herein, olivine-structured α-LiMn0.5Fe0.5PO4 nanocrystals were synthesized with optimized Li-ion diffusion channels in LiMn1-xFexPO4 nanocrystals by inducing high concentrations of Fe2+-Li+ antisite defects, which showed impressive capacity improvements of approaching 162, 127, 73, and 55 mAh g-1 at 0.1, 10, 50, and 100 C, respectively, and a long-term cycling stability of maintaining about 74% capacity after 1000 cycles at 10 C. By using high-resolution transmission electron microscopy imaging and joint refinement of hard X-ray and neutron powder diffraction patterns, we revealed that the extraordinary high-rate performance could be achieved by suppressing the formation of electrochemically inactive phase (β-LiMn1-xFexPO4, which is first reported in this work) embedded in α-LiMn0.5Fe0.5PO4. Because of the coherent orientation relationship between β- and α-phases, the β-phase embedded would impede the Li+ diffusion along the [100] and/or [001] directions that was activated by the high density of Fe2+-Li+ antisite (4.24%) in α-phase. Thus, by optimizing concentrations of Fe2+-Li+ antisite defects and suppressing β-phase-embedded olivine structure, Li-ion diffusion properties in LiMn1-xFexPO4 nanocrystals can be tuned by generating new Li+ tunneling. These findings may provide insights into the design and generation of other advanced electrode materials with improved rate performance.


Isolation and characterization of a beta-primeverosidase-like endo-manner beta-glycosidase from Aspergillus fumigatus AP-20.
A novel beta-glycosidase-producing microorganism was isolated from soil and identified as Aspergillus fumigatus AP-20 based on its taxonomical characteristics. The enzyme was found to be an extracellular protein in the culture of the isolated fungus and was purified 88-fold by fractionation with ammonium sulfate followed by successive column chromatographies on phenyl-Sepharose HP and Mono P HR. The molecular mass was estimated to be 47 kDa by SDS-PAGE and the isoelectric point to be pH 6.0 by isoelectric focusing. The purified enzyme was highly specific for a substrate, p-nitrophenyl beta-primeveroside (6-O-beta-D-xylopyranosyl-beta-D-glucopyranoside), which was cleaved in an endo-manner into primeverose and p-nitrophenol.


Predicting adverse drug reactions in older adults; a systematic review of the risk prediction models.
Adverse drug reaction (ADR) risk-prediction models for use in older adults have been developed, but it is not clear if they are suitable for use in clinical practice. This systematic review aimed to identify and investigate the quality of validated ADR risk-prediction models for use in older adults. Standard computerized databases, the gray literature, bibliographies, and citations were searched (2012) to identify relevant peer-reviewed studies. Studies that developed and validated an ADR prediction model for use in patients over 65 years old, using a multivariable approach in the design and analysis, were included. Data were extracted and their quality assessed by independent reviewers using a standard approach. Of the 13,423 titles identified, only 549 were associated with adverse outcomes of medicines use. Four met the inclusion criteria. All were conducted in inpatient cohorts in Western Europe. None of the models satisfied the four key stages in the creation of a quality risk prediction model; development and validation were completed, but impact and implementation were not assessed. Model performance was modest; area under the receiver operator curve ranged from 0.623 to 0.73. Study quality was difficult to assess due to poor reporting, but inappropriate methods were apparent. Further work needs to be conducted concerning the existing models to enable the development of a robust ADR risk-prediction model that is externally validated, with practical design and good performance. Only then can implementation and impact be assessed with the aim of generating a model of high enough quality to be considered for use in clinical care to prioritize older people at high risk of suffering an ADR.


Mesenchymal Stem Cell Conditioned Medium Modulates Inflammation in Tenocytes: Complete Conditioned Medium Has Superior Therapeutic Efficacy than Its Extracellular Vesicle Fraction.
Tendinopathy, a prevalent overuse injury, lacks effective treatment options, leading to a significant impact on quality of life and socioeconomic burden. Mesenchymal stem/stromal cells (MSCs) and their secretome, including conditioned medium (CM) and extracellular vesicles (EVs), have shown promise in tissue regeneration and immunomodulation. However, it remains unclear which components of the secretome contribute to their therapeutic effects. This study aimed to compare the efficacy of CM, EVs, and the soluble protein fraction (PF) in treating inflamed tenocytes. CM exhibited the highest protein and particle concentrations, followed by PF and EVs. Inflammation significantly altered gene expression in tenocytes, with CM showing the most distinct separation from the inflamed control group. Treatment with CM resulted in the most significant differential gene expression, with both upregulated and downregulated genes related to inflammation and tissue regeneration. EV treatment also demonstrated a therapeutic effect, albeit to a lesser extent. These findings suggest that CM holds superior therapeutic efficacy compared with its EV fraction alone, emphasizing the importance of the complete secretome in tendon injury treatment.


IL-12 producing monocytes and IFN-gamma and TNF-alpha producing T-lymphocytes are increased in placentas infected by Plasmodium falciparum.
Placental Plasmodium falciparum sequestration is associated with dysregulated immune function. Placental inflammatory responses via IFN-gamma and TNF-alpha are implicated in functional damage. However, they are needed during placental infection to control asexual stage parasites. To test the hypothesis that placental immunomodulation associated with malaria disturbs cytokine secretion differently in monocytes and lymphocytes, we have determined the proportion of monocytes and/or lymphocytes secreting IFN-gamma, TNF-alpha, IL-10 and IL-12. Intervillous and peripheral blood monocyte (CD14+) and lymphocyte (CD3/CD4+; CD3/CD8+) cytokine production was compared between 17 P. falciparum-infected and 12 non-infected Senegalese women. After culture with phorbolmyristate acetate/ionomycin (PMA/iono), lipopolysaccharide (LPS) or P. falciparum-infected erythrocytes (IE), the intracellular expression of cytokines in lymphocytes (IFN-gamma, TNF-alpha) and monocytes (IL-10, IL-12, TNF-alpha), was detected. In response to IE, CD4+ and CD8+ T-cells produced IFN-gamma and TNF-alpha at similar rates in both compartments. In response to PMA/iono, the frequencies of CD4+ and CD8+ T-cells producing IFN-gamma and TNF-alpha were similar in both compartments, but increased in P. falciparum-infected placentas. In response to LPS or IE, IL-12 secreting monocytes were increased in infected women, while the frequency of TNF-alpha secreting monocytes was decreased compared to that in non-infected placenta. The monocyte IL-12 response is not impaired in infected women. IL-12 is an important factor for inducing IFN-gamma in T-cells. Thus, IL-12 and IFN-alpha responses may synergistically allow a protective immune response in placental malaria. TNF-alpha production by CD4+ and CD8+ T-cells is up-regulated in P. falciparum-infected placentas, suggesting that T-cells actively participate to inflammatory responses.


Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency.
Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5-42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI.


Cloning and characterization of a flavanone 3-hydroxylase gene from Saussurea medusa.
Flavanone 3-hydroxylase (F3H) is a key enzyme in the flavonoid biosynthetic pathway, providing a branching point for the biosynthesis of different flavonoids, including the formation of 3-deoxy and 3-hydroxy flavonoids found in the silks of maize. Here, we report the cloning and characterization of a F3H gene (Smf3h) from a cDNA library derived from a red line callus of Saussurea medusa, a traditional Chinese medicinal plant. The cDNA contains a 1032 bp open reading frame (ORF) encoding a protein of 343 amino acid residues, a 149 bp long 5'untranslated regions (UTR) and a 163 bp long 3'UTR containing three putative polyadenylation signals (AATAAA) and an ATTTA element. The secondary structure of the mRNA predicted by MFOLD is very complex, suggesting a role in a post-transcriptional mechanism of regulation of Smf3h. The genomic structure of Smf3h includes four exons and three introns within the coding region, with all the splice donor/acceptor site sequences in accordance with the "GU-AG" consensus rule. The deduced SmF3H protein is 343 amino acid residues in length and has 40% and 39% identity and 60% and 58% similarity to the F3H of Arabidopsis and rice, respectively. Strikingly, the identity of SmF3H is higher to the H6H (hyoscyamine 3beta-hydroxylase, 45%) from Atropa belladonna. However, the analysis of the active center and the predicted protein secondary structure are more related to F3H than H6H. Together, our studies provide the first identification of a S. medusa flavonoid gene and its similarities to metabolic enzymes from other plants.


Recent progress of proteomic analysis on spermatogenesis†.
Testis, the only organ responsible for generating sperm, is by far the organ with the largest variety of proteins and tissue-specific proteins in humans. In testis, spermatogenesis is a multi-step complex process well-accepted that protein and mRNA are decoupled in certain stages of spermatogenesis. With the fast development of mass spectrometry-based proteomics, it is possible to systemically study protein abundances and modifications in testis and sperm to help us understand the molecular mechanisms of spermatogenesis. This review provides an overview of the recent progress of proteomics analysis on spermatogenesis, including protein expression and multiple post-translational modifications, such as phosphorylation, glycosylation, ubiquitylation, and acetylation.


Applying a theory of change approach to interagency planning in child mental health.
This paper describes the use of a theory of change approach to community-based cross-agency service planning for children with serious emotional disturbance and their families. Public agency planners in Contra Costa County, California used the theory of change approach to organize service planning for a population of youth who had been arrested and involved with juvenile probation. The theory of change process described in this paper links community outcomes with planned activities with the assumptions or principles that underlie the community planning efforts. When complete, a theory of change logic model can serve as a guide for implementation, ensuring that community plans for service delivery remain true to their intent. The theory of change development process includes twelve stages and is based on a step-by-step approach. Theory of change logic models establish a context for articulating a community's shared beliefs and prompt local stakeholders to establish logical connections between the population to be served, expected results, and strategies intended to achieve those results.


Comparison of the compliance of pharmacy patients.
This issue is an attempt to be compared the compliance, respectively non-compliance among pharmacy patients between the years 1998 and 2001. The authors make an attempt to elucidate the factors that influence the non-compliance of the patients in order to improve it and to increase the rate of compliance among them. A questionnaire is applied for assessment the state of compliance and non-compliance among the pharmacy patients. The results of the analysis of the received data show that the level of compliance was 69% in 1998 and has decreased to 53% in 2001. The main reasons that influence the non-adherence of the patients are shown.


Improved purification of human lactate dehydrogenase isoenzyme-3 and studies with its fluorescein isothiocyanate and biotin conjugates.
Lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 188.8.131.52) isoenzyme-3 (LD-3) has been isolated in milligram quantities from human erythrocytes. Using an improved procedure--which involves complete hemolysis of the erythrocytes, diethylaminoethyl (DEAE)-Sephacel column chromatography, and 5'-AMP-Sepharose 4B affinity chromatography--we obtained 23,000-fold purified isoenzyme from the crude hemolysate (overall yield about 90%). The final product was homogeneous on polyacrylamide disc gel electrophoresis and had a specific activity of about 435 kU/g. Its amino acid composition is presented. With the eventual aim to make visible and isolate IgA kappa antibody-secreting B lymphocytes, we developed reproducible methods for preparing fluorescein isothiocyanate isomer-1-conjugated LD-3 with a fluorescein/LD-3 molar ratio between 1.3 and 3.3, and biotinylated LD-3 with a biotin/LD-3 molar ratio between 1.3 and 2.5. In evaluating the stability of these two conjugates, we determined that they still can react with IgA kappa to form the IgA kappa (LD-3)2 complex.


Vascularized Bone Grafting in Scaphoid Nonunion: A Review of Patient-Centered Outcomes.
Background: The radiographic and clinical outcomes following vascularized bone grafting (VBG) for scaphoid nonunion have previously been reported in the literature; however, few studies report on patient-derived outcomes. The purpose of this study was to determine the effect of VBG for scaphoid nonunion on patient-derived outcomes. Methods: The MEDLINE and PubMed databases were queried for the use of VBG in scaphoid nonunion. We included studies that reported on patient-derived outcomes. We excluded studies with less than 10 patients or less than 6 months of follow-up. The primary outcomes assessed included functionality, percent and time to return to preinjury activity, postoperative pain, and patient satisfaction. Results: Twenty-six articles described the outcomes of 520 patients with an average of 19.3 patients per study. Functionality was most commonly assessed by the Mayo Modified Wrist Score and Disabilities of the Arm, Shoulder and Hand scores, which improved by 53.1% and 81.7% postoperatively, respectively. Within 16 weeks, 90.3% of patients returned to their previous occupation or sporting activity. Pain was most commonly reported using a 0 to 10 visual analog scale and improved 4-fold postoperatively. Complete satisfaction was reported by 92% of patients. The most common complications were superficial infections (1.56%), neuropathic pain (1.56%), and complex regional pain syndrome (1.25%). Conclusions: VBG for scaphoid nonunion results in the improvement of patient-derived outcomes, and high rates of return to preinjury activity levels and patient satisfaction. Multiple metrics of patient-derived outcomes were utilized by the studies in our review without a clear consensus as to which metric is most responsive and accurate.


Reductive Coupling of CO2 , Primary Amine, and Aldehyde at Room Temperature: A Versatile Approach to Unsymmetrically N,N-Disubstituted Formamides.
We present a simple, metal-free, and versatile route to synthesize unsymmetrically N,N-disubstituted formamides (NNFAs) from CO2 , primary amine, and aldehyde promoted by an ionic liquid (1-butyl-3-methylimidazolium chloride) at room temperature. This approach features wide scopes of amines and aldehydes, and various unsymmetrical NNFAs could be obtained in good to excellent yields. The ionic liquid can be reused for at least five runs without obvious activity loss.


Arthur Conan Doyle, Sherlock Holmes, and gout.
Arthur Conan Doyle, the creator of Sherlock Holmes, was an experienced physician who treated gouty patients. A gouty character appears in The Adventure of the Missing Three-Quarter, a Sherlock Holmes novel. This offers the possibility of discussing gout from the peculiar perspective of a medical writer in light of the historical-medical context of the time. This study was conducted using Conan Doyle's autobiographical, scientific, and literary primary sources, as well as past and current medical literature. The Adventure of the Missing Three-Quarter was autobiographical. Conan Doyle himself was a rugby player and his wife died of tuberculosis. Furthermore, in 1884, in The Lancet, he described the hereditary case of a female gouty patient, presenting with ocular manifestations. In agreement with the concept of rich man's gout, the gouty patient of Sherlock Holmes' story, Lord Mount James, was a rich irascible noble but he was not addicted to the pleasures of food and sex. Following the usual funny representation of gouty patients, Conan Doyle made fun of Lord Mount James, but he misquoted a true case of gout cited in the literature. In his scientific and literary production on gout, Conan Doyle stuck to the most updated medical concepts of the time, demonstrating an uncommon knowledge of scientific literature.


[Acute kidney injury secondary to the first intravenous administration of acyclovir].
Acute kidney injury secondary to precipitation of acyclovir crystals in the kidneys is well known and mainly observed in the setting of dehydration or pre-existing renal impairment. We describe a case of acute kidney injury secondary to intravenous administration of acyclovir in a 64-year-old female with trans-versal myelitis and no prior medical history. She developed a rapid rise in the plasma creatinine level only seven hours after the primary drug administration. Acyclovir was discontinued and a urinary flow rate was maintained at 100-200 ml/h with IV fluids. The kidney function returned to normal within five days.


Prdm proto-oncogene transcription factor family expression and interaction with the Notch-Hes pathway in mouse neurogenesis.
Establishment and maintenance of a functional central nervous system (CNS) requires a highly orchestrated process of neural progenitor cell proliferation, cell cycle exit, and differentiation. An evolutionary conserved program consisting of Notch signalling mediated by basic Helix-Loop-Helix (bHLH) transcription factor activity is necessary for both the maintenance of neural progenitor cell character and the progression of neurogenesis; however, additional players in mammalian CNS neural specification remain largely unknown. In Drosophila we recently characterized Hamlet, a transcription factor that mediates Notch signalling and neural cell fate. Hamlet is a member of the Prdm (PRDI-BF1 and RIZ homology domain containing) proto-oncogene transcription factor family, and in this study we report that multiple genes in the Prdm family (Prdm6, 8, 12, 13 and 16) are expressed in the developing mouse CNS in a spatially and temporally restricted manner. In developing spinal cord Prdm8, 12 and 13 are expressed in precise neuronal progenitor zones suggesting that they may specify discrete neuronal subtypes. In developing telencephalon Prdm12 and 16 are expressed in the ventricular zone in a lateral to medial graded manner, and Prdm8 is expressed in a complementary domain in postmitotic neurons. In postnatal brain Prdm8 additionally shows restricted expression in cortical layers 2/3 and 4, the hippocampus, and the amygdala. To further elucidate roles of Prdm8 and 16 in the developing telencephalon we analyzed the relationship between these factors and the bHLH Hes (Hairy and enhancer of split homolog) effectors of Notch signalling. In Hes null telencephalon neural differentiation is enhanced, Prdm8 expression is upregulated, and Prdm16 expression is downregulated; conversely in utero electroporation of Hes1 into the developing telencephalon upregulates Prdm16 expression. Our data demonstrate that Prdm genes are regulated by the Notch-Hes pathway and represent strong candidates to control neural class specification and the sequential progression of mammalian CNS neurogenesis.


New Pinane Derivatives Found in Essential Oils of Calocedrus decurrens.
The main objective of this study was to determine the chemical composition of essential oils (EOs) obtained from leaf, old branches, and young branches of a coniferous species Calocedrus decurrens acclimated to Corsica. The analytical investigation was conducted by GC(RI), GC-MS, pc-GC, and NMR. C. decurrens leaf, old branches, and young branches EOs contained α-pinene (11.2; 56.6; 22.3%), myrcene (13.4; 8.4; 9.7%), Δ-3-carene (31.3; 5.2; 11.1%), limonene (6.4; 5.1; 5.5%), terpinolene (6.9; 1.5; 3.2%), and pin-2-en-8-ol (4.2; 4.5; 10.4%) as major components, respectively. Special attention was paid to purifying and identifying four unusual pinane derivatives: pin-2-en-8-ol, pin-2-en-8-yl Acetate, pin-2-en-8-al, and methyl pin-2-en-8-oate. The last two are reported for the first time.


Melanoma arising in a giant nevus spilus maculosus.
Melanoma arising in a nevus spilus is rare. There are two distinct types of nevus spilus characterized by macular or papular speckles, respectively. We report the case of a melanoma that arose in association with a giant nevus spilus maculosus.


Autoamputation of the Appendix Presenting as a Calcified Abdominal Mass Following Necrotizing Enterocolitis.
Autoamputation of the appendix has previously been reported in the literature, but it is likely an unusual event. We report a 2-year-old male child who had previously undergone laparotomy and bowel resection for necrotizing enterocolitis. Two years later a calcified intra-abdominal mass was identified on abdominal radiography and ultrasonography. Eventual laparotomy revealed a densely calcified mass within the transverse mesocolon. The mass was uneventfully resected. Pathologic evaluation showed appendiceal tissue, consistent with prior autoamputation of the vermiform appendix. Autoamputation of the appendix has not to our knowledge previously been associated with a calcified mass nor been associated with a history of necrotizing enterocolitis, and these factors distinguish this case as noteworthy.


The MISSED score, a new scoring system to predict Mortality In Severe Sepsis in the Emergency Department: a derivation and validation study.
To derive and validate a new scoring system to predict in-hospital mortality in septic patients in the emergency department (ED). Septic patients admitted to the ICU and those in whom early goal-directed therapy (EGDT) was carried out in the ED were identified from the ED record. Univariate and multivariate regression analyses identified independent variables associated with mortality. The variables were given a score weighted by the odds ratio, the sum of which yielded the Mortality In Severe Sepsis in the Emergency Department (MISSED) score. The performance of the MISSED score in predicting mortality was compared with that of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, the EGDT criteria and the severe sepsis criteria. The Hosmer-Lemeshow test was performed to calibrate the model. Independent variables identified were age at least 65 years, albumin level up to 27 g/l and international normalized ratio of 1.2 or more. The MISSED score ranged from 0-9; cut-off point 5.5. Mortality rates associated with a score of 0, less than 5.5 and 5.5 or more were 7.4, 17.7 and 40.6%, respectively. The sensitivity of the score was 96.8% (95% confidence interval 87.8-99.4%). The mortality rate and specificity associated with a score of 9 were 62.9 and 91.6% respectively. The area under the curve for the MISSED score and the APACHE II score were equal. The performance of the MISSED score of 5.5 or more in predicting mortality was similar to that of the EGDT criteria. The sensitivity of the score was equal to that for the severe sepsis criteria. The Hosmer-Lemeshow test confirmed good calibration. The MISSED score should be used in the ED.


Asthma exacerbations . 3: Pathogenesis.
Asthma exacerbations are an exaggerated lower airway response to an environmental exposure. Respiratory virus infection is the most common environmental exposure to cause a severe asthma exacerbation. Airway inflammation is a key part of the lower airway response in asthma exacerbation, and occurs together with airflow obstruction and increased airway responsiveness. The patterns of airway inflammation differ according to the trigger factor responsible for the exacerbation. The reasons for the exaggerated response of asthmatic airways are not completely understood, but recent studies have identified a deficient epithelial type 1 interferon response as an important susceptibility mechanism for viral infection.


Suprachoroidal CLS-TA with and without Systemic Corticosteroid and/or Steroid-Sparing Therapy: A Post-Hoc Analysis of the Phase 3 PEACHTREE Clinical Trial.
To study the efficacy and safety of suprachoroidal CLS-TA (proprietary suspension of triamcinolone acetonide) in uveitic macular edema (UME) with and without concurrent systemic corticosteroid or steroid-sparing therapy (ST). Post hoc analysis of the PEACHTREE phase 3 randomized trial. Among UME patients receiving no ST, at week 24, mean BCVA change was +15.6 letters in 68 CLS-TA patients versus +4.9 letters in 49 sham-control patients (p < .001), while mean CST change was -169.8 µm versus -10.3 µm, respectively (p < .001). Among patients receiving ST, at week 24, mean BCVA change was +9.4 letters in 28 CLS-TA patients versus -3.2 letters in 15 sham-control patients (p = .019), while mean CST change was -108.3 µm versus -43.5 µm, respectively (p = .190). No SAEs related to treatment were reported. A clinically meaningful benefit of CLS-TA was noted in UME patients, regardless of concurrent ST usage.Abbreviation and AcronymsCST = central subfield thickness; BCVA = best corrected visual acuity; ME = macular edemaI; IVT = intravitreal; AE = adverse event; FA = fluocinolone acetonide; SD-OCT = spectral-domain optical coherence tomography; NIU = noninfectious uveitis; SAE = serious adverse event; TEAE = treatment emergent adverse event; ITT = intent to treat; CI = confidence interval.


Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.
Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.


Evaluation of amino acid analysis as reference method to quantitate highly purified proteins.
The applicability of amino acid analysis for accurate quantitation of reference standard preparations of proteins has been evaluated. This approach is very useful since, in addition to absolute quantitative information, it also provides a measure of composition, partial identity, and purity in a single experiment. Comparisons with Kjeldahl nitrogen assay and/or UV measurements shows that amino acid analysis is reliable for the quantitation of small-to-medium size proteins in the molecular weight range of 6-22 kDa. For larger proteins such as immunoglobulins (150 kDa), amino acid analysis may "underestimate" the total protein concentration. These results also show the effect of recovery of individual residues on protein quantitation. As expected, the recovery of more than one stable residue could be used to calculate total protein content of samples, which is in good agreement with the results obtained by Kjeldahl nitrogen assay. However, the protein concentrations calculated from the total mass of the recovered residues appear to give relatively low estimates in almost all cases. Thus, it is concluded that amino acid analysis is an appropriate reference method only when stable residues are employed for quantitation, particularly for highly purified proteins of rDNA origin.


Superconducting radio-frequency resonator in magnetic fields up to 6 T.
We have measured the characteristics of a superconducting radio-frequency resonator in an external magnetic field. The magnetic field strength has been varied with 10 mT resolution between zero and 6 T. The resonance frequency and the quality factor of the resonator have been found to change significantly as a function of the magnetic field strength. Both parameters show a hysteresis effect which is more pronounced for the resonance frequency. Quantitative knowledge of such behaviour is particularly important when experiments require specific values of resonance frequency and quality factor or when the magnetic field is changed while the resonator is in the superconducting state.


Prognostic significance of elevated troponin I after percutaneous coronary intervention.
We sought to assess the incidence and clinical significance of elevated cardiac troponin I (cTnI) after percutaneous coronary intervention (PCI). Elevated creatine kinase-MB (CK-MB) is prognostically important after PCI, but the prognostic significance of elevated cTnI after PCI is uncertain. In a prospective substudy of the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) trials, which randomized patients with acute coronary syndromes (ACS) to receive aspirin or sibrafiban, we measured cTnI (positive, > or =1.5 ng/ml) and CK-MB (positive, > or =7 ng/ml) in 481 patients with PCI. Samples were collected immediately before and at 0, 8 and 16 h after PCI and analyzed by a core laboratory. The primary end point was the Kaplan-Meier estimate of death, myocardial infarction or severe, recurrent ischemia at 90 days. Overall, 230 patients (48%) had elevated cTnI after PCI. Such patients underwent PCI sooner and were more likely to have coronary stenting. Elevated cTnI was associated with nonsignificantly higher risks of the primary end point (11.5% vs. 8.7%; p = 0.15) and of death (1.8% vs. 0.4%; p = 0.4) and a significantly higher risk of death or infarction (10.6% vs. 4.2%; p = 0.005). This pattern was more pronounced for patients who became positive only after PCI: primary end point, 20.7% vs. 10.1% for patients who remained negative after PCI (p = 0.05); death, 5.2% vs. 0% (p = 0.02); death or infarction, 18.1% vs. 4.1% (p = 0.007). Elevated cTnI, often observed after PCI in patients with ACS, is associated with worse 90-day clinical outcomes. This marker, therefore, is a useful prognostic indicator in such patients.


Molecular Structure of Glycogen in Escherichia coli.
Glycogen, a randomly branched glucose polymer, provides energy storage in organisms. It forms small β particles which in animals bind to form composite α particles, which give better glucose release. Simulations imply β particle size is controlled only by activities and sizes of glycogen biosynthetic enzymes and sizes of polymer chains. Thus, storing more glucose requires forming more β particles, which are expected to sometimes form α particles. No α particles have been reported in bacteria, but the extraction techniques might have caused degradation. Using milder glycogen extraction techniques on Escherichia coli, transmission electron microscopy and size-exclusion chromatography showed α particles, consistent with this hypothesis for α-particle formation. Molecular density and size distributions show similarities with animal glycogen, despite very different metabolic processes. These general polymer constraints are such that any organism which needs to store and then release glucose will have similar α and β particle structures: a type of convergent evolution.


Particle-Hole Symmetry and the Fractional Quantum Hall Effect in the Lowest Landau Level.
We report on detailed experimental studies of a high-quality heterojunction insulated-gate field-effect transistor (HIGFET) to probe the particle-hole symmetry of the fractional quantum Hall effect (FQHE) states about half-filling in the lowest Landau level. The HIGFET is specially designed to vary the density of a two-dimensional electronic system under constant magnetic fields. We find in our constant magnetic field, variable density measurements that the sequence of FQHE states at filling factors ν=1/3,2/5,3/7… and its particle-hole conjugate states at filling factors 1-ν=2/3,3/5,4/7… have a very similar energy gap. Moreover, a reflection symmetry can be established in the magnetoconductivities between the ν and 1-ν states about half-filling. Our results demonstrate that the FQHE states in the lowest Landau level are manifestly particle-hole symmetric.


Characteristics of Telephone Crisis Hotline Callers with Suicidal Ideation in Japan.
Hotline callers do not always have suicidal ideation and previous studies have noted that the rate of such callers is limited. Crisis hotline counselors must be able to identify high-risk callers in order to provide appropriate support. This study investigated the characteristics of Japanese crisis hotline callers in 2012 (N = 541,694) and is the first to analyze crisis hotline data for all parts of Japan over 1 year. About 14% of the callers had suicidal ideation and 6% had a history of attempted suicide. The odds ratio for suicidal ideation among those with a history of attempted suicide was 15.5. The suicidal ideation rate was much smaller compared to previous studies in other countries. There is a psychological barrier that must be broken for high-risk people to use support hotlines. In addition, attempted suicide is a strong exclusive predisposing factor for death due to suicide; therefore, counselors should pay careful attention to callers with a history of attempted suicide. The characteristics of Japanese crisis hotline callers and the features of suicidal ideation revealed in the present study are expected to be useful in developing telephone crisis hotline strategies.


Malignant Melanoma of Oral Cavity.
Primary malignant melanoma of oral cavity is very rare. A case of oral melanoma who died due to metastasis a year after the excision of the primary lesion is reported along with a brief review of the literature.


Substrate specificity of homogeneous monkeypox virus uracil-DNA glycosylase.
Weak or nonexistent smallpox immunity in today's human population raises concerns about the possibility of natural or provoked genetic modifications leading to re-emergence of variola virus and other poxviruses. Thus, the development of new antiviral strategies aimed at poxvirus infections in humans is a high priority. The DNA repair protein uracil-DNA glycosylase (UNG) is one of the viral enzymes important for poxvirus pathogenesis. Consequently, the inhibition of UNG is a rational therapeutic strategy for infections with poxviruses. Monkeypox virus, which occurs naturally in Africa, can cause a smallpox-like disease in humans. Here, the monkeypox virus UNG (mpUNG) is characterized and compared to vaccinia virus UNG (vUNG) and human UNG (hUNG). The mpUNG protein excises uracil preferentially from single-stranded DNA. Furthermore, mpUNG prefers the U.G pair over the U.A pair and does not excise oxidized bases. Both mpUNG and vUNG viral proteins are strongly inhibited by physiological concentrations of NaCl and MgCl2. Although the two viral DNA repair enzymes have similar substrate specificities, the kcat/KM values of mpUNG are higher than those of vUNG. The mpUNG protein was strongly inhibited by 5-azauracil and to a lesser extent by 4(6)-aminouracil and 5-halogenated uracil analogues, whereas uracil had no effect. To develop antiviral drugs toward mpUNG, we also validated a repair assay using the molecular beacons containing multiple uracil residues. Potential targets and strategies for combating pathogenic orthopoxviruses, including smallpox, are discussed.


[New fall prediction score for the prevention of fall fractures in the elderly].
Elderly fracture is a critical public health issue for older adults, and falls risk assessment is an expected competency for medical worker. The prevention from fall fracture is one of the important items of medical safety, and although fall assessment is carried out, it is not much effective. One of the reasons is that there is not the simple and easy tool of the fall prediction. The aim of this study was to design an innovative method of falls risk assessment using standing ability of the elderly. We devised new fall assessment score (Mimamori score) that scored lifting assistance movement. We incorporate it in real duties after 2011, inflect for the fall prevention.


Role of Hematological Parameters in the Grading of COVID-19 and a Model to Predict the Outcome in Inpatients.
Introduction Human coronaviruses, identified in the 1960s, are known culprits of respiratory infections. Classified into alpha, beta, gamma, and delta subgroups, these viruses have the capacity to transition from animal reservoirs to causing severe respiratory ailments in humans. Notable outbreaks like the 2003 severe acute respiratory distress syndrome (SARS) epidemic and the ongoing coronavirus disease 2019 (COVID-19) pandemic underscore the recurring emergence of novel coronaviruses with severe human infection potential. COVID-19, driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a leading global cause of severe acute respiratory syndrome. Immune system disruptions and cytokine imbalances contribute to severe cases, necessitating early diagnosis and precise severity assessment. Methodology This retrospective cross-sectional study encompassed 211 COVID-19 patients admitted to AIIMS Patna from May to July 2020. Clinical and hematological parameters, including neutrophils, eosinophils, basophils, lymphocytes, monocytes, red and white blood cell counts, platelet count, C-reactive protein (CRP), serum ferritin, and d-dimer, were meticulously recorded. Patients were categorized into non-severe and severe groups using the National Early Warning Score (NEWS) 2. Results Our findings underscore the pivotal role of hematological markers in gauging COVID-19 severity. Notably, markers such as neutrophil-to-lymphocyte ratio (NLR), derived NLR, lymphocyte monocyte ratio, platelet lymphocyte ratio, d-dimer, CRP, and serum ferritin exhibited notable elevation in severe cases. Survival analysis further established the predictive potential of these markers in assessing disease progression and mortality risk. We advocate for the integration of these markers into existing severity assessment frameworks to foster objective clinical evaluations. Conclusion In conclusion, our study unravels the intricate connection between COVID-19 severity and hematological parameters. We emphasize the early warning capabilities of NLR, derived NLR, platelet lymphocyte ratio, and other markers in predicting disease progression. This research underscores the imperative need to incorporate hematological markers into the evaluation of COVID-19 severity, thereby providing invaluable insights for enhancing clinical practice and patient outcomes.


Endogenous expression of CD80 co-stimulatory molecule facilitates in vivo tumor regression of oral squamous carcinoma.
Most tumor tissues, especially those of non-hematopoietic origin, do not express CD80 co-stimulatory molecules, possibly as a mechanism to evade immune surveillance. The objective of this study was to determine whether abundant endogenous CD80 expression on oral squamous cell carcinoma (SCC) early during tumor progression can facilitate immune elimination and reverse immune tolerance. The growth of regressor and progressor oral SCC lines with differing endogenous CD80 expression were examined in immune-competent and -deficient mice. Immune effectors were determined by T-cell depletion experiments and immunohistochemistry. Our studies show regression of early tumor growth when immunocompetent animals are inoculated with oral SCC progressor cell lines expressing abundant endogenous CD80. The CD80-induced antitumor response was due largely to induced T-cell responses. Our findings suggest that inadequate CD80 expression during early oral SCC formation may contribute to the escape of tumors from immune elimination. This information can be useful in the design of new approaches to generate more effective immunotherapy against this disease.


(131)I therapy in patients with benign thyroid disease does not conclusively lead to a higher risk of subsequent malignancies.
Due to its excellent tolerability and low incidence of side effects, 131I therapy has been the treatment of choice for benign thyroid diseases for over 60 years. A potentially increased risk of malignancies due to this therapy is however still subject of debate. To review the literature pertaining to 131I therapy of benign thyroid diseases in order to establish whether there is an increased incidence of, or increased mortality due to malignancies of the thyroid or other organs. In order to allow for sufficient long-term follow-up time after 131I therapy, only literature after 1990 was reviewed. Two criteria were applied to consider an increased incidence of malignancies linked to 131I therapy: a) there should be a latency period of at least 5 years between 131I therapy and the observation of an increased risk b) an elevated risk should increase with increasing radiation exposure. A total of 7 studies reporting cancer incidence and / or mortality in 4 different patient collectives spanning a total of 54510 patients over an observation period varying from 2-49 years were found. Although some studies detected a slightly increased risk for malignancies of the thyroid or the digestive system, others did not find these effects - while other studies even reported a slightly lower risk of malignant (thyroid) disease after 131I therapy for benign thyroid diseases. As over 60 years of experience has thus far failed to produce conclusive evidence to the contrary, it can be concluded that there is no increased risk of malignancies after 131I therapy for benign thyroid disease.


Infrared spectroscopy with heated attenuated total internal reflectance enabling precise measurement of thermally induced transitions in complex biological polymers.
We report an improved tool for acquiring temperature-resolved fourier transform infrared (FT-IR) spectra of complex polymer systems undergoing thermal transitions, illustrated by application to several phenomena related to starch gelatinization that have proved difficult to study by other means. Starch suspensions from several botanical origins were gelatinized using a temperature-controlled attenuated total reflectance (ATR) crystal, with IR spectra collected every 0.25 °C. By following the 995/1022 cm(-1) peak ratio, clear transitions occurring between 59 and 70 °C were observed, for which the midpoints could be determined accurately by sigmoidal fits. The magnitude of the change in peak ratio was found to be strongly correlated to the enthalpy of gelatinization as measured by differential scanning calorimetry (DSC, R(2) = 0.988). An important advantage of the technique, compared to DSC, is that the signal-to-noise ratio is not reduced when measuring very broad transitions. This has the potential to allow more precise determination of the gelatinization parameters of high-amylose starches, for which gelatinization may take place over several tens of °C.


Bone scintigraphy in acetabular labral tears.
Acetabular labral tears are an increasingly recognized cause of hip pain in young adults with hip dysplasia and older patients with degenerative disease of the hips. The authors analyzed retrospectively bone scintigraphy in 27 patients with acetabular labral tears diagnosed by MRI/arthroscopy. Analysis was also made of scintigraphy in 30 patients without labral tears being investigated for other causes of hip pain for comparison. Patients with labral tears had hyperemia of the superior or superomedial aspect of the acetabulum and increased delayed uptake in either a focal superior pattern or in an "eyebrow" pattern of a superomedial tear. This pattern was not seen in any other sources of hip pathology. Uptake in the superior or superomedial aspect of the acetabular rim is characteristic of a labral tear. Absence of this pattern carries a high negative predictive value for the diagnosis.


Gratitude as moral sentiment: emotion-guided cooperation in economic exchange.
Economic exchange often pits options for selfish and cooperative benefit against one another. Decisions favoring communal profit at the expense of self-interest have traditionally been thought to stem from strategic control aimed at tamping down emotional responses centered on immediate resource acquisition. In the present article, evidence is provided to argue against this limited view of the role played by emotion in shaping prosociality. Findings demonstrate that the social emotion gratitude functions to engender cooperative economic exchange even at the expense of greater individual financial gains. Using real-time inductions, increased gratitude is shown to directly mediate increased monetary giving within the context of an economic game, even where such giving increases communal profit at the expense of individual gains. Moreover, increased giving occurred regardless of whether the beneficiary was a known individual or complete stranger, thereby removing the possibility that it stemmed from simple awareness of reciprocity constraints.


Perineural Invasion is a Strong Prognostic Factor in Colorectal Cancer: A Systematic Review.
Perineural invasion (PNI) is a possible route for metastatic spread in various cancer types, including colorectal cancer (CRC). PNI is linked to poor prognosis, but systematic analyses are lacking. This study systematically reviews the frequency and impact of PNI in CRC. A literature search was performed using PubMed database from inception to January 1, 2014. Data were analyzed using Review Manager 5.3. A quality assessment was performed on the basis of modified REMARK criteria. Endpoints were local recurrence (LR), 5-year disease-free survival (5yDFS), 5-year cancer-specific survival (5yCSS), and 5-year overall survival (5yOS). Meta-analysis was performed in terms of risk ratios (RR) and hazard ratios (HR) with 95% confidence interval (95% CI). In this meta-analysis, 58 articles with 22,900 patients were included. PNI was present in 18.2% of tumors. PNI is correlated with increased LR (RR 3.22, 95% CI, 2.33-4.44) and decreased 5yDFS (RR 2.35, 95% CI, 1.66-3.31), 5yCSS (RR 3.61, 95% CI, 2.76-4.72), and 5yOS (RR 2.09, 95% CI, 1.68-2.61). In multivariate analysis PNI remains an independent prognostic factor for 5yDFS, 5yCSS, and 5yOS (HR 2.35, 95% CI, 1.97-3.08; HR 1.91, 95% CI, 1.50-2.42; and HR 1.85, 95% CI, 1.63-2.12, respectively). We confirmed the strong impact of PNI for LR and survival in CRC. The prognostic value of PNI is similar to that of well-established prognostic factors as depth of invasion, differentiation grade, lymph node metastases, and lymphatic and extramural vascular invasion. Therefore, PNI should be one of the factors in the standardized reporting of CRC and might be considered a high-risk feature.


[The characteristics of plasma lipids in silicosis rat models were studied based on lipid metabolomics].
Objective: To screen the differential metabolites and metabolic pathways in silicosis model by analyzing plasma metabolomics of silicosis rats. Methods: In May 2021, twenty male SD rats were randomly divided into control group (C), 1-week silicosis group (S1W), 2-week silicosis group (S2W) and 4-week silicosis group (S4W), with 5 rats in each group. Rats were intratracheally instillated with 1ml crystalline SiO(2) suspension (50 mg/ml) or normal saline and were sacrificed after 1 week, 2 weeks and 4 weeks, HE staining was used to observe the lung pathology of rats. The plasma samples were analyzed by UPLC-IMS-QTOF mass spectrometer to screen out potential differential metabolites in silicosis models and analyze their lipid enrichment. Results: HE results showed that nodules formed in the silicosis model group, and with the extension of time, nodules gradually increased and alveolar structure was gradually destroyed. Metabolomics screened out 14 differential metabolites in S1W, 24 in S2W, and 28 in S4W, and found that the differential metabolites were mainly enriched in the metabolism of glycerophospholipid metabolism, fatty acid degradation, Glycosylphosphatidylinositol (GPI) -anchor biosynthesis, fatty acid elongation and other metabolic pathways. Conclusion: There are significant changes in plasma lipid metabolites in silicosis rat models.


A case of an unusual subtrochanteric fracture in a patient receiving denosumab.
Bisphosphonates are the most common class of medications used to treat osteoporosis. Their widespread use has uncovered rare complications, including atypical femoral fractures (AFF). The pathogenesis of AFF is incompletely understood; however, if oversuppression of bone remodeling contributes to AFF, it is plausible that other potent antiresorptive agents, such as denosumab, could be associated with AFF as well. We report a case of an 81-year-old woman with densitometric osteopenia, chronic kidney disease, and hyperparathyroidism, who was initiated on denosumab for elevated fracture risk. Approximately 6 months after her initial denosumab injection, she developed severe right groin and thigh pain without prior trauma. A femoral radiograph was normal, without cortical thickening, but a magnetic resonance imaging revealed a transverse subtrochanteric insufficiency fracture with a medial defect involving 25% of the femoral cortex. She did not receive any further doses of denosumab. Bone turnover markers did not suggest oversuppression. Her fracture was treated conservatively with nonweight bearing status with resultant full recovery. This fracture does not meet the current definition of an AFF as, for that definition, a lateral femoral location is required. This case does not provide conclusive evidence for a causal relationship between treatment with denosumab and this unusual fracture. It clearly illustrates, however, the occurrence of an unusual, nontraumatic subtrochanteric fracture in a patient treated with the potent antiresorptive agent denosumab with many features in common with bisphosphonate-associated AFF.


Effects of perfluorination on thiophene and pyrrole oligomers.
The effect of perfluorination on thiophene and pyrrole oligomers in neutral, cationic, and anionic states was investigated with density functional theory at the (TD)B3P86-30%/6-31G* level. For the title compounds fluorination leads to planarization. For pyrroles a band gap reduction of 0.58 eV results, as unsubstituted pyrroles are nonplanar and disordered in the solid state. For thiophene the band gap is slightly increased as long thiophene oligomers are almost planar. Ionization energies and electron affinities increase upon fluorination by 0.65 and 0.60 eV for polythiophene and by 0.45 and 0.90 eV for polypyrrole. Conduction band widths increase by 0.5 for polythiophene and by 0.7 eV for polypyrrole. Spectra of charged (doped) forms are almost identical to those of the parent systems. Like parent systems, fluorinated oligomers with chain lengths of more than six rings develop a third UV absorption that increases in strength and decreases in energy upon chain length increase.


Infrared spectra of CH3-CrH, CH3-WH, CH2=WH2, and CH[triple bond]WH3 formed by activation of CH4 with Cr and W atoms.
Laser-ablated W atoms react with CH4 in excess argon to form the CH3-WH, CH2=WH2, and CH[triple bond]WH3 molecules with increasing yield in this order of product stability. These molecules are identified from matrix infrared spectra by isotopic substitution. Tungsten methylidene and methylidyne hydride molecules are reversibly interconverted by alpha-H transfers upon visible and ultraviolet irradiations. Matrix infrared spectra and DFT/B3LYP calculations show that CH[triple bond]WH3 is a stable molecule with C3v symmetry, but other levels of theory were required to describe agostic distortion for CH2=WH2. Analogous reactions with Cr gave only CH3-CrH, which is calculated to be by far the most stable product.


EGFR rs11506105 and IFNL3 SNPs but not rs8099917 are strongly associated with treatment responses in Iranian patients with chronic hepatitis C.
Interferon lambda 3 (IFNL3) and epidermal growth factor receptor (EGFR) single nucleotide polymorphisms (SNPs) may play a key role in the spontaneous clearance of hepatitis C virus (HCV) and treatment responses. The aim of this study was to evaluate the effect of IFNL3 SNPs and EGFR rs11506105 on treatment outcomes in patients with chronic HCV (CHC). IFNL3 SNPs and EGFR rs11506105 were genotyped by PCR-restriction fragment length polymorphism and PCR-sequencing, respectively, in 235 naïve patients with CHC infection. The frequency of rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) were 52.3%, 76.2% and 64.7% respectively. The results of this study showed that RVR was associated with ALT (P=0.015), AST (P=0.020), IFNL3 rs12979860 (CC) (P=0.043), rs12980275 (AA) (P=1 × 10-4), and EGFR rs11506105 (AA) (P=0.010), and IFNL3 rs12979860 (CC) (P=0.048), rs12980275 (AA) (P=0.022), and EGFR rs11506105 (AA) (P=0.006) were correlated with cEVR. HCV genotype (P=0.007), IFNL3 rs12979860 (CC) (P=0.023), IFNL3 rs12980275 (AA) (P=1 × 10-4), EGFR rs11506105 (AA) (P=0.005), RVR (P=1 × 10-4), and cEVR (P=0.003) were significant predictors for SVR. These results, for the first time, revealed that beside IFNL3 SNPs, EGFR rs11506105 is strongly associated with RVR, cEVR and SVR. EGFR rs11506105 besides IFNL3 SNPs could predict treatment responses in CHC patients.


Reply to "Validity of five MMPI alcoholism scales: a critique and reanalysis".
Replied to Hays and Stacy's critique of an article by Holmes, Dungan and McLaughlin in which the validity of MMPI alcoholism scales was questioned. Hays and Stacy asserted that the original authors misinterpreted the results of the statistical analyses. The present article presents support for the original conclusions and comments on Hays and Stacy's reanalysis.


Photochemical mass balance of 2,3,7,8-TeCDD in aqueous solution under UV light shows formation of chlorinated dihydroxybiphenyls, phenoxyphenols, and dechlorination products.
Polychlorinated dibenzo-p-dioxins (PCDDs) are a class of halogenated diaryl compounds that are environmentally important because of their high toxicity and bioaccumulatory properties. There is an incomplete understanding of their photochemistry because the majority of photoproducts, as indicated by incomplete mass balances, have not been identified. We studied the photochemical transformation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TeCDD) in aqueous solution using 302 nm light. Our results allow for the first photochemical mass balance (92-99%) for this compound and confirm the operation of a novel photochemical pathway, which gives rise to 2,2'-dihydroxy-4,4',5,5'-tetrachlorobiphenyl (4,4',5,5'-TeCDHBP) at >50% conversion from the starting material. Rearrangement from 2,3,7,8-TeCDD to 4,4',5,5'-TeCDHBP takes place following preferential homolytic C-O bond cleavage via a proposed mechanism analogous to the parent dibenzo-p-dioxin system. Photochemical conversion from the starting material to dechlorinated PCDDs or chlorinated phenoxyphenols are minor pathways, although the exact contribution of the strictly dechlorination pathways remains uncertain because of the complexity of the system. The results suggest that the photochemical conversion of PCDDs to chlorinated dihydroxybiphenyls, which are also polychlorinated biphenyl (PCB) metabolites, may be an important part of their environmental fate.


Magnetic diagnostics for the lithium tokamak experiment.
The lithium tokamak experiment (LTX) is a spherical tokamak with R(0)=0.4 m, a=0.26 m, B(TF) approximately 3.4 kG, I(P) approximately 400 kA, and pulse length approximately 0.25 s. The focus of LTX is to investigate the novel low-recycling lithium wall operating regime for magnetically confined plasmas. This regime is reached by placing an in-vessel shell conformal to the plasma last closed flux surface. The shell is heated and then coated with liquid lithium. An extensive array of magnetic diagnostics is available to characterize the experiment, including 80 Mirnov coils (single and double axis, internal and external to the shell), 34 flux loops, 3 Rogowskii coils, and a diamagnetic loop. Diagnostics are specifically located to account for the presence of a secondary conducting surface and engineered to withstand both high temperatures and incidental contact with liquid lithium. The diagnostic set is therefore fabricated from robust materials with heat and lithium resistance and is designed for electrical isolation from the shell and to provide the data required for highly constrained equilibrium reconstructions.


Inhibition of P2X4 and P2X7 receptors improves histological and behavioral outcomes after experimental traumatic brain injury in rats.
Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naïve group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury.


Meta-analysis of case-referent studies of specific environmental or occupational pollutants on lung cancer.
Meta-analysis is a statistical tool for combining and integrating the results of independent studies of a given scientific issue. The present investigation was initiated to investigate case-referent studies of lung cancer risk from specific environmental and occupational pollutants, using detailed individual exposure data. To examine the risk of lung cancer associated with environmental and occupational pollutants, a meta-analysis of published case-control studies was undertaken using a random effects model. For this study, the papers were selected for review from electronic search of PubMed, Medline and Google Scholar during 1990-2006. The principal outcome measure was the odds ratio for the risk of lung cancer. Twelve study reports detailing the relationship between the lung cancer and the type of exposure were identified. The odds ratio of asbestos, cooking fuel, cooking fumes, motor and diesel exhaust related to lung cancer were 1.67, 1.99, 2.52 and 1.42 (P < 0.001), respectively. The odds ratio of metal fumes related to lung cancer was 1.28 (0.001 P < 0.01). The combined odds ratio for the environmental and occupational exposure related to lung cancer was 1.67 (P < 0.001). The meta-analysis of the present study shows the magnitude association between asbestos, cooking fumes, cooking fuels, motor and diesel exhaust, with lung cancer risk. Lung cancer risk may be reduced by controlling exposure levels.


PrimaDORAC: A Free Web Interface for the Assignment of Partial Charges, Chemical Topology, and Bonded Parameters in Organic or Drug Molecules.
We present PrimaDORAC, a simple and freely accessible web interface for generating the topology and the parameter files of organic or drug molecules to be used in molecular mechanics or molecular dynamics calculations. The interface relies on our in-house FORTRAN90 parser, working on the recently released Generalized Amber Force Field parameter set (GAFF2). AM1/BCC charges are computed using the Public Domain MOPAC7 program and the bond charge corrections (BCC) reported in Jakalian, A.; Jack, D. B.; Bayly, C. I.; J. Comp. Chem., 2002, 23, 1623-1641. The interface has been tested on about 52,000 compounds (identified with a CAS registry number) taken from the National Cancer Institute (NCI) Open Database. PrimaDORAC has been found to be very reliable, producing GAFF2 minimized structures bearing a mean root square displacement of about 0.01-0.02 nm with respect to the original CORINA-generated 3D NCI structures. As a demonstrative example, we release the full topology and parameter files, along with the AM1/BCC-GAFF2 computed in vacuo IR spectrum, for some recently discovered PARP/MCL1 inhibitors. The web interface and parser, including the sources, are part of the ORAC code (Procacci, P.; J. Chem. Inf. , 2016, 56, 1117-1121), distributed under the General Public License at www.chim.unifi.it/orac.


The eye of the beholder: Increased likelihood of prison sentences for people perceived to have Hispanic ethnicity.
Hispanic individuals are a growing proportion of the general and carceral populations in the United States. This study examined the relationship between the type of sentences (prison, jail/probation) given to White, non-Hispanic individuals and to similarly situated individuals who were perceived to be Hispanic (any race) or perceived to be White but, based on validated estimates, self-identified as Hispanic. Psychological theory indicates that, for group-based stereotypes and attitudes to impact decisions, decisionmakers must first identify and categorize target individuals as members of the relevant group. Following this theory, we predicted that individuals perceived by members of the criminal justice system to be Hispanic will be more likely to be sentenced to prison than similarly situated individuals perceived to be White. However, sentences of individuals predicted to have been misperceived as White but to self-identify as Hispanic will not differ from those of individuals accurately perceived as White. We analyzed official state records of more than 220,000 unique sentencing decisions for nearly 200,000 individuals under state correctional supervision between 2005 and 2018, including demographic characteristics, statutory crime-seriousness and criminal-history scores from state sentencing guidelines, and sentencing outcomes. Even after controlling for crime severity and criminal history, we found that individuals who were labeled as Hispanic in criminal justice records were nearly twice as likely to be sentenced to prison as those who were labeled as White (odds ratio [OR] = 1.95, 95% confidence interval [CI] [1.86, 2.04]). By comparison, individuals who were labeled in criminal justice records as White but, on the basis of validated estimates, were predicted to self-identify as Hispanic had the same likelihood of being sentenced to prison as individuals who were accurately perceived to be White (OR = 1.01, 95% CI [0.94, 1.07]). Results suggest that ethnic stereotypes or attitudes regarding Hispanic individuals may negatively impact criminal sentencing decisions regarding people perceived as Hispanic by actors in the legal system. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Role of plasma lipoproteins in modifying the biological activity of hydrophobic drugs.
The plasma lipoprotein distribution of potential drug candidates is not commonly studied. For some hydrophobic drug candidates, attainment of similar plasma free drug levels has not been associated with uniform production of pharmacological activity in different animal species. It is well-known that plasma lipoprotein lipid profiles vary considerably between different animal species. In addition, human disease states can significantly influence plasma lipoprotein profiles, resulting in altered therapeutic outcomes. Current research has shown that lipoprotein binding of drug compounds can significantly influence not only the pharmacological and pharmacokinetic properties of the drug, but the relative toxicity as well. Elucidation of drug distribution among plasma lipoproteins is expected to yield valuable insight into factors governing the pharmacological activity and potential toxicity of the drug. This paper will present an historical perspective and summarize the latest research in the area of lipoprotein-drug interactions.


DNA bending by the chromosomal protein HMG1 and its high mobility group box domains. Effect of flanking sequences.
HMG1 is an evolutionarily highly conserved chromosomal protein consisting of two folded DNA-binding domains, A and B ("high mobility group (HMG) boxes"), and an acidic C-terminal domain. Several lines of evidence suggest that previously reported sequence-independent DNA bending and looping by HMG1 and its HMG box domains might be important for the proposed role of the protein in transcription and recombination. We have used ligase-mediated circularization assays to investigate the contribution of the individual A and B HMG1 box domains and of the linker region between A/B- and B/C-domains, which flank the "minimal" B-domain (residues 92-162), to the ability of the HMG1 protein (residues 1-215) to bend DNA. Neither the minimal B-domain nor the minimal B-domain with a 7-residue N-terminal extension (85TKKKFKD91) bent the DNA. The attachment of an extra 18-residue C-terminal additional extension (residues 163-180) to the minimal B-domain had only a small effect on the ability of the HMG box to bend DNA. On the other hand, circularization assay with a B-domain having both 7-residue N-terminal and 18-residue C-terminal flanking sequences (residues 85-180) revealed a strong bending of the DNA, suggesting that both extensions are a prerequisite for efficient DNA bending by the B-domain. We have also shown that a single lysine residue (Lys90) in a short N-terminal sequence 90KD91 attached to the B-domain is sufficient for strong distortion of DNA by bending, provided that the B-domain is flanked by the 18-residue C-terminal flanking sequence. Although the DNA bending potential of HMG1 seems to be predominantly due to the B-domain flanked by basic sequences, covalent attachment of the A- and B-domains is necessary for efficient DNA flexure and the ability of the (A+B)-bidomain to bend DNA is further modulated in the native HMG1 protein by its acidic C-domain.


Detection of Acetaminophen-Protein Adducts in Decedents with Suspected Opioid-Acetaminophen Combination Product Overdose.
Acetaminophen overdose is a leading cause of drug-induced liver failure in the United States. Acetaminophen-protein adducts have been suggested as a biomarker of hepatotoxicity. The purpose of this study was to determine whether protein-derived acetaminophen-protein adducts are quantifiable in postmortem samples. Heart blood, femoral blood, and liver tissue were collected at autopsy from 22 decedents suspected of opioid-acetaminophen overdose. Samples were assayed for protein-derived acetaminophen-protein adducts, acetaminophen, and selected opioids found in combination products containing acetaminophen. Protein-derived APAP-CYS was detected in 17 of 22 decedents and was measurable in blood that was not degraded or hemolyzed. Heart blood concentrations ranged from 11 ng/mL (0.1 μM) to 7817 ng/mL (28.9 μM). Protein-derived acetaminophen-protein adducts were detectable in liver tissue for 20 of 22 decedents. Liver histology was also performed for all decedents, and no evidence of centrilobular hepatic necrosis was observed.


Glucose transporter isoform expression in Huntington's disease brain.
Several reports have suggested a characteristic decrease in glucose use in the striatum of patients with Huntington's disease (HD) may contribute to the cellular atrophy of the caudate and putamen. We examined the expression of the two major glucose transporter isoforms of brain, GLUT1 and GLUT3. GLUT1 is found largely in capillary endothelial cells and to a lesser extent in the brain parenchyma, whereas GLUT3 is localized primarily in neurons. Membranes prepared from postmortem samples of HD caudate and cortex and non-HD caudate and cortex were separated on 10% sodium dodecyl sulfate-polyacrylamide gels and probed with antisera to GLUT1 and GLUT3 by western blotting. Compared with controls, GLUT1 and GLUT3 transporter expression in caudate was decreased by three- and fourfold, respectively, in grade 3 of the disease. At earlier stages (grade 1), there was no significant difference in the expression of the two transporter isoforms compared with nondiseased controls. It is surprising that despite a substantial increase in glial fibrillary acidic protein immunoreactivity (an indicator of the extent of gliosis), glucose transporter expression was diminished significantly in HD caudate. The results suggest in the absence of a significant number of neurons, as in grade 3, glial cell GLUT1 and GLUT3 expression is down-regulated, perhaps reflecting the decreased metabolic demand of this brain region in HD.


Fostering sustainability: unveiling the impact of Internet development on carbon emissions in China.
The rapid development of the Internet has significantly impacted various socio-economic activities. Using Chinese Industrial Enterprise database and Industrial Enterprise Pollution database, this research examines the impact and mechanisms of Internet development on CO2 emissions. The key findings are as follows: (1) Internet development has substantially reduced the CO2 intensity of enterprises, and this conclusion remains robust even after performing a series of robustness analyses. (2) The major mechanisms responsible for the reduction in CO2 emissions are productivity improvement, technological innovation, and energy structure adjustment. (3) The analysis of heterogeneity reveals that the effect of Internet development on CO2 reduction is more pronounced in coastal areas, areas with a high share of secondary industry, low-carbon industries, clean industries, small-scale enterprises, and export enterprises. This study provides empirical evidence supporting China's "Internet+" strategy and its progress towards achieving the "Carbon Peaking and Carbon Neutrality Goals."


6,12-Diarylindeno[1,2-b]fluorenes: syntheses, photophysics, and ambipolar OFETs.
Herein we report the synthesis and characterization of a series of 6,12-diarylindeno[1,2-b]fluorenes (IFs). Functionalization with electron donor and acceptor groups influences the ability of the IF scaffold to undergo two-electron oxidation and reduction to yield the corresponding 18- and 22-π-electron species, respectively. A single crystal of the pentafluorophenyl-substituted IF can serve as an active layer in an organic field-effect transistor (OFET). The important finding is that the single-crystal OFET yields an ambipolar device that is able to transport holes and electrons.


Pulmonary lymphangioleiomyomatosis associated with retroperitoneal lymphangioleiomyomas.
A 36-year-old woman presented with worsening symptoms of abdominal pain, diarrhoea, low fever, dyspnoea on exertion and bilateral leg during the last 2 months. Chest radiograph showed mild diffuse reticular pattern with preserved lung volumes. Lung high resolution CT disclosed multiple thin-walled lung cysts throughout the lungs bilaterally with no zonal predominance and with normal intervening parenchyma and abdominal CT revealed bilateral retrocrural and retroperitoneal hypodense masses. Imaging findings were consistent with lymphangioleiomyomatosis.


Renin, cortisol and plasma volume in marine teleost fishes adapted to dilute media.
The renin-angiotensin system has been found in teleost fishes from both marine and fresh-water environments. In an attempt to define whether activity of the renin-angiotensin system is related to sodium balance in fishes, we transferred two euryhaline teleosts from seawater to hypo-osmotic media. Plasma renin activity decreased in American eels, Anguilla rostrata, after they were transferred from seawater to fresh water, and it did not change in the aglomerular toadfish, Opsanus tau, after transfer from 50% seawater to 5% seawater. Plasma sodium concentrations decreased significantly in toadfish in 5% seawater and in one group of eels in fresh water. Plasma levels of cortisol, a major mineralocorticoid in teleosts, and plasma volume, measured in eels, remained relatively constant. There are no clear correlations between plasma renin levels and those of plasma sodium or plasma cortisol. These results provide no evidence that the need of these fishes to conserve sodium when in hypo-osmotic media stimulates the renin-angiotensin system.