Whey Protein Hydrolysate Ameliorated High-Fat-Diet Induced Bone Loss via Suppressing Oxidative Stress and Regulating GSK-3β/Nrf2 Signaling Pathway.
Long-term hypercaloric intake such as a high-fat diet (HFD) could act as negative regulators on bone remodeling, thereby inducing bone loss and bone microarchitecture destruction. Currently, food-derived natural compounds represent a promising strategy to attenuate HFD-induced bone loss. We previously prepared a whey protein hydrolysate (WPH) with osteogenic capacity. In this study, we continuously isolated and identified an osteogenic and antioxidant octapeptide TPEVDDA from WPH, which significantly promoted the alkaline phosphatase activities on MC3T3-E1 cells and exerted DPPH radical scavenging capacity. We then established an HFD-fed obese mice model with significantly imbalanced redox status and reduced bone mass and further evaluated the effects of different doses of WPH on ameliorating the HFD-induced bone loss and oxidative damages. Results showed that the administration of 2% and 4% WPH for 12 weeks significantly restored perirenal fat mass, improved serum lipid levels, reduced oxidative stress, and promoted the activity of antioxidant enzymes; meanwhile, WPH significantly preserved bone mass and bone mechanical properties, attenuated the degradation of trabecular microstructure, and regulated serum bone metabolism biomarkers. The protein levels of Runx2, Nrf2, and HO-1, as well as the phosphorylation level of GSK-3β in tibias, were notably activated by WPH. Overall, we found that the potential mechanism of WPH on ameliorating the HFD-induced bone loss mainly through its antioxidant and osteogenic capacity by activating Runx2 and GSK-3β/Nrf2 signaling pathway, demonstrating the potential of WPH to be used as a nutritional strategy for obesity and osteoporosis.


Targeting USP8 Inhibits O-GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT.
Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB-IN-3 shows the most effective anti-cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB-IN-3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O-GlcNAc transferase (OGT) via inhibiting K48-specific poly-ubiquitination process on OGT protein at K117 site, and STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O-GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.


Small-particle aerosols of antiviral compounds in treatment of type A influenza pneumonia in mice.
Three chemotherapeutic drugs active against type A influenza virus (amantadine, rimantadine, and ribavirin) were tested as therapeutic agents against established infections with influenza virus in mice. The drugs were administered intraperitoneally or as aerosols either from 6 hr to four days or from three to seven days after infection. Small-particle aerosols were administered continuously 24 hr per day. Continuous dissemination of aerosols was superior to intraperitoneal administration, as evidenced by higher survival rates at 21 days. Rimantadine, amantadine, and ribavirin were effective when treatment was delayed for three days. Ribavirin was the most efficacious if therapy was initiated as an aerosol 6 hr after infection. In contrast to amantadine, ribavirin given in samll-particle aerosols at 6 hr prevented the development of pneumonia and decreased titers of virus in lung.


Effects of hypertonicity on cAMP production in cultured renal epithelial cells (LLC-PK1).
The activation of adenylate cyclase by vasopressin in the renal medulla takes place in a hypertonic environment whose osmolality fluctuates widely under varying physiologic conditions. We utilized the cultured renal epithelial cell line, LLC-PK1 as a model system to study the effects of hypertonic electrolyte and nonelectrolyte solutes on the vasopressin-adenylate cyclase interaction. These cells do not produce prostaglandins, thus permitting separate evaluation of the direct effects of hypertonic solutes on the adenylate cyclase response. In intact cells, 40-400 mM NaCl and 600 mM sucrose and mannitol increased basal and vasopressin-sensitive cAMP production 2 to 4-fold. Urea in a concentration range of 300-1,200 mM blunted the stimulatory effect of hypertonic NaCl in intact cells. In order to distinguish direct effects of solutes on the adenylate cyclase response, from effects related to hypertonic cell shrinkage, the influence of these same electrolyte and nonelectrolyte solutes on adenylate cyclase activity in membrane particulate fractions was also examined. Increasing NaCl in the concentration range of 25-100 mM increased basal and vasopressin-sensitive adenylate cyclase. This effect was not specific to sodium, since similar degrees of stimulation were seen with the addition of KCl. Addition of higher concentrations of NaCl, sucrose, and mannitol directly in the adenylate cyclase assay were inhibitory. These findings suggested that the stimulatory effect of hypertonicity in the intact cells was not due to a direct effect of these solutes on the enzyme, but rather to hypertonic cell shrinkage.(ABSTRACT TRUNCATED AT 250 WORDS)


Ternary Copper (II) Complex Induced Apoptosis and Cell Cycle Arrest in Colorectal Cancer Cells.
The lack of specificity, severe side effects, and development of drug resistance have largely limited the use of platinum-based compounds in cancer treatment. Therefore, copper complexes have emerged as potential alternatives to platinum-based compounds. Ternary copper (II) complex incorporated with 1-10-phenanthroline and L-tyrosine was investigated for its anti-cancer effects in HT-29 colorectal cancer cells. Cytotoxic effects of ternary copper (II) complex in HT-29 cells was evaluated using MTT assay, Real-Time Cell Analysis (RTCA) and lactate dehydrogenase (LDH) assay. Cell cycle analysis was performed using flow cytometry. Apoptosis induction was studied by Annexin V-FITC/Propidium Iodide (PI) staining and mitochondrial membrane potential analysis (JC-10 staining) using flow cytometry. Intracellular Reactive Oxygen Species (ROS) were detected by DCFH-DA assay. The expression of proteins involved in the apoptotic signalling pathway (p53, caspases, and PARP-1) was evaluated by western blot analysis. Ternary copper (II) complex reduced the cell viability of HT-29 cells in a time- and dose-dependent manner, with IC50 of 2.4 ± 0.4 and 0.8 ± 0.04 μM at 24 and 48 hours, respectively. Cell cycle analysis demonstrated induction of S-phase cell cycle arrest. Morphological evaluation and Annexin V-FITC/PI flow cytometry analysis confirmed induction of apoptosis that was further supported by cleavage and activation of caspase-8, caspase-9, caspase-3, and PARP- 1. Mutant p53 was also downregulated in a dose-dependent manner. No LDH release, mitochondrial membrane potential disruption, and ROS production were observed. Ternary copper (II) complex holds great potential to be developed for colorectal cancer treatment.


T-cell and plasma cell populations in coeliac small intestinal mucosa in relation to dermatitis herpetiformis.
Differential lymphocyte and plasma cell counts and measurements of mucosal architecture were studied in small intestinal biopsies from 17 controls and 17 patients with untreated uncomplicated coeliac disease of whom five also had dermatitis herpetiformis. Intraepithelial T-cell and plasma cell counts and measurements of mucosal architecture were not significantly different in the two coeliac groups but both groups differed from the controls. Lamina propria T-cell counts were significantly higher in the patients who also had dermatitis herpetiformis than in uncomplicated coeliac disease, with a significant increase in the Leu 2 (CD8) positive (cytotoxic/suppressor) T-cell subset. This suggests a specific abnormality of T-cell control of immune responsiveness in the pathogenesis of the skin manifestations of dermatitis herpetiformis which is not found in uncomplicated coeliac disease.


Bridging the ICD11 and the DSM-5 personality disorders classification systems: The role of the PID5BF + M.
In both the ICD-11 Classification of Personality Disorders and the DSM-5 Alternative Model of Personality Disorders (AMPD) personality disorders (PD) are characterized by impairments in self- and interpersonal functioning which distinguish the various levels of dysfunction. Moreover, pathological traits are used by these classification systems to define the stylistic expression of personality dysfunction. Negative affectivity, detachment, antagonism/dissociality, and disinhibition feature as trait domains in each of these models. However, there are also differences between the two models, namely, in the psychoticism domain, which does not feature as a personality trait domain in the ICD-11, and in the anankastia domain, corresponding to compulsivity in the DSM-5, which was removed from the final AMPD model. Furthermore, facets are acknowledged by the DSM-5 within each trait domain, while this does not occur in the ICD-11. In view of the similarity between these classification systems, their harmonization would be beneficial for the clinical profession. With this goal in mind, the PID5BF + M, an algorithm that assesses the DSM-5 and ICD-11 six trait domains and 18 facets, was developed and has proven to adequately characterize the ICD-11 trait domains by means of DSM-5 trait facets. The current study compares a community sample (N = 280, M age = 48.01, 53.2% females) with a PD sample (N = 131, M age = 42.66, 45.0% females) along with the PID5BF + M, the LPFS-SR and the PID-5. Given that the PID5BF + M total can be seen as a measure of the level of personality dysfunction, strong relations between the PID5BF + M total and the LPFS-SR total are expected. Strong relations between the trait specifiers measured by the PID5BF + M and the PID-5 are also expected. Finally, the community and clinical samples are expected to differentiate by means of the dimensions assessed through the three afore-mentioned measures. The Spearman rank-order correlation coefficient was used to measure the strength and direction of associations between the PID5BF + M total and the LPFS-SR total and between the PID5BF + M and the PID-5 traits. Group differences were explored using the Mann-Whitney U test for independent samples. As expected, there were strong, significant, and positive relations between the measures. Furthermore, higher scores were observed in all the variables for the PD group against the community group. Although this study has limitations, its findings sustain that the PID5BF + M has potential to assess the severity of personality disfunction and to characterize the stylistic features of PD as they are conceived by both the ICD-11 and the DSM-5. Although more research is needed regarding the convergent validity of the PID5BF + M, this new test contributes to the harmonization of both systems and to parsimony in the assessment of PD, which is the main objective of clinical practice.


Loss of cytochrome cM stimulates cyanobacterial heterotrophic growth in the dark.
Although cyanobacteria are photoautotrophs, they have the capability for heterotrophic metabolism that enables them to survive in their natural habitat. However, cyanobacterial species that grow heterotrophically in the dark are rare. It remains largely unknown how cyanobacteria regulate heterotrophic activity. The cyanobacterium Leptolyngbya boryana grows heterotrophically with glucose in the dark. A dark-adapted variant dg5 isolated from the wild type (WT) exhibits enhanced heterotrophic growth in the dark. We sequenced the genomes of dg5 and the WT to identify the mutation(s) of dg5. The WT genome consists of a circular chromosome (6,176,364 bp), a circular plasmid pLBA (77,793 bp) and two linear plasmids pLBX (504,942 bp) and pLBY (44,369 bp). Genome comparison revealed three mutation sites. Phenotype analysis of mutants isolated from the WT by introducing these mutations individually revealed that the relevant mutation is a single adenine insertion causing a frameshift of cytM encoding Cyt c(M). The respiratory oxygen consumption of the cytM-lacking mutant grown in the dark was significantly higher than that of the WT. We isolated a cytM-lacking mutant, ΔcytM, from another cyanobacterium Synechocystis sp. PCC 6803, and ΔcytM grew in the dark with a doubling time of 33 h in contrast to no growth of the WT. The respiratory oxygen consumption of ΔcytM grown in the dark was about 2-fold higher than that of the WT. These results suggest a suppressive role(s) for Cyt cM in regulation of heterotrophic activity.


Shape- and size-controlled synthesis of monoclinic ErOOH and cubic Er2O3 from micro- to nanostructures and their upconversion luminescence.
A general approach has been developed for the synthesis of monoclinic ErOOH and cubic Er2O3 structures with high yield and controlled size and shape via the solvo-hydrothermal reaction of erbium nitrate in water/ethanol/decanoic acid media. The monoclinic ErOOH phase was formed at relatively low temperature (120-140 degrees C); however, the cubic Er2O3 phase was obtained at higher temperature (160-180 degrees C). By simply tuning different experimental parameters, such as the reaction temperature, the concentration of decanoic acid and erbium precursor etc., different sizes from 3 nm to 3 microm, and a variety of shapes including cores/dots to spheres, wrinkle-surfaced spheres, flowers, dog bonds, wires, rods, bundles, straw sheaves, and brooms can be achieved. The particle size of products decreased from micro- to nanometer as the decanoic acid concentration increased from 0.038 to 0.190 M. Furthermore, by using anhydrous ethanol instead of water-ethanol solvents, the particle size significantly decreased from 18 nm spheres to 3 nm cores. At high precursor monomer concentrations (76.25-152.50 mM), the nanorods were also obtained due to the anisotropic growth. On the basis of this study, a correlation between the experimental parameters and the phase, shape, and size of the products was proposed. The upconversion luminescence properties depend not only on crystalline phase but also on particle size of the products. The luminescence intensity increases with the decrease of particle size from micro- to nanometers.


Transition to motherhood in women with eating disorders: A qualitative study.
The aim of this study was to examine in depth the individual experience of transition from pregnancy to motherhood, among women with current eating disorders (EDs), focusing on differences between the first and subsequent pregnancies. We analysed the narratives of 12 women with severe ED during pregnancy using interpretative phenomenological analysis. We employed a sequential structure, and the emerging themes were ordered according to consecutive pregnancy stages. Our results indicate that experiences of pregnancy vary across pregnancy stages and in the first pregnancy compared to subsequent pregnancies. In particular, during their first pregnancy women with an ED seem to experience an inner conflict and questioned the continuity of their ED identity leading them to be more open to change. The first pregnancy, during its early stages, should be considered a potentially unique window for intervention for women with current ED. Eating disorders (EDs) are known to seriously affect fertility, pregnancy, and pregnancy outcomes. Our research sheds a light on experiences of pregnancy in women with ED and ultimately helps to define a window for intervention. Our findings have important implications in understanding mechanisms of relapse in the post-partum period and consequently could help in tailoring an adequate intervention for women with ED and in preventing ED relapse.


Complex Visual Adaptations in Squid for Specific Tasks in Different Environments.
In common with their major competitors, the fish, squid are fast moving visual predators that live over a great range of depths in the ocean. Both squid and fish show a variety of adaptations with respect to optical properties, receptors and their underlying neural circuits, and these adaptations are often linked to the light conditions of their specific niche. In contrast to the extensive investigations of adaptive strategies in fish, vision in response to the varying quantity and quality of available light, our knowledge of visual adaptations in squid remains sparse. This study therefore undertook a comparative study of visual adaptations and capabilities in a number of squid species collected between 0 and 1,200 m. Histology, magnetic resonance imagery (MRI), and depth distributions were used to compare brains, eyes, and visual capabilities, revealing that the squid eye designs reflect the lifestyle and the versatility of neural architecture in its visual system. Tubular eyes and two types of regional retinal deformation were identified and these eye modifications are strongly associated with specific directional visual tasks. In addition, a combination of conventional and immuno-histology demonstrated a new form of a complex retina possessing two inner segment layers in two mid-water squid species which they rhythmically move across a broad range of depths (50-1,000 m). In contrast to their relatives with the regular single-layered inner segment retina live in the upper mesopelagic layer (50-400 m), the new form of retinal interneuronal layers suggests that the visual sensitivity of these two long distance vertical migrants may increase in response to dimmer environments.


A physical-biological coupled model for algal dynamics in lakes.
A coupled model is presented for simulating physical and biological dynamics in fresh water lakes. The physical model rests upon the assumption that the turbulent kinetic energy in a water column of the lake is fully contained in a mixed layer of variable depth. Below this layer the mechanical energy content is assumed to vanish. Additionally, the horizontal currents are ignored. This one-dimensional two-layered model describes the internal conversion of the mechanical and thermal energy input from the atmosphere into an evolution of the mixed layer depth by entrainment and detrainment mechanisms. It is supposed to form the physical domain in which the simulation of the biological processes takes place. The biological model describes mathematically the typical properties of phyto- and zooplankton, their interactions and their response to the physical environment. This description then allows the study of the behaviour of Lagrangian clusters of virtual plankton that are subjected to such environments. The essence of the model is the dynamical simulation of an arbitrary number of nutrient limited phytoplankton species and one species of zooplankton. The members of the food web above and below affect the model only statically. The model is able to reproduce the typical progression of a predator-prey interaction between phyto- and zooplankton as well as the exploitative competition for nutrients between two phytoplankton species under grazing pressure of Daphnia. It suggests that the influence of the biological system on the physical system results in a weak increase of the surface temperature for coupled simulations, but a considerably higher seasonal thermocline in spring and a lower one in autumn.


Sympathetic and vascular responses to head-down neck flexion in humans.
Animal studies have demonstrated increases in sympathetic nerve outflow with vestibular stimulation. The purpose of the present study was to determine whether vestibulosympathetic reflexes are engaged in humans. Muscle sympathetic nerve activity (MSNA), heart rate, arterial pressure, calf blood flow (CBF), and calculated calf vascular resistance (CVR; mean arterial pressure/CBF) were determined during 10 min of baseline (laying prone with chin supported) and 10 min of head-down neck flexion (HDNF). MSNA responses were measured in nine subjects, and calf vascular responses were determined in seven of these subjects. Heart rate increased during the first minute of HDNF (71 +/- 2 to 76 +/- 3 beats/min; P < 0.05) and remained slightly elevated (71 +/- 2 to 74 +/- 3 beats/min; P < 0.05) for the duration of HDNF. Diastolic and mean arterial pressures also increased slightly with HDNF (80 +/- 3 to 82 +/- 3 and 96 +/- 3 to 98 +/- 3 mmHg, respectively; P < 0.05). Systolic arterial pressure did not change significantly during HDNF. CBF decreased 14% (4.63 +/- 0.78 to 3.97 +/- 0.60 ml x min(-1) x 100 ml(-1); P < 0.05), and CVR increased 12% (24.0 +/- 4.3 to 27.4 +/- 4.7 units; P < 0.05) during HDNF. These changes corresponded with significant increases in MSNA during HDNF. MSNA, expressed as burst frequency, increased from 14 +/- 2 to 20 +/- 2 bursts/min (P < 0.05) and increased 63 +/- 23% (P < 0.05) when expressed as the percent change in total activity. All variables returned to baseline during recovery. Thoracic impedance measured in five subjects did not change during HDNF (19.6 +/- 1.2 to 19.7 +/- 1.5 omega), suggesting no major change in central blood volume. The results indicate that HDNF elicits increases in CVR that are mediated by the augmentation of MSNA. Arterial pressure responses and thoracic impedance data suggest that high and low pressure baroreflexes were not the mechanism for sympathetic activation. The immediate increase in MSNA with HDNF suggests a role for vestibulosympathetic reflexes.


Social stress alters inhibitory synaptic input to distinct subpopulations of raphe serotonin neurons.
Anxiety disorders are among the most prevalent psychiatric disorders, yet much is unknown about the underlying mechanisms. The dorsal raphe (DR) is at the crux of the anxiety-inducing effects of uncontrollable stress, a key component of models of anxiety. Though DR serotonin (5-HT) neurons play a prominent role, anxiety-associated changes in the physiology of 5-HT neurons remain poorly understood. A 5-day social defeat model of anxiety produced a multifaceted, anxious phenotype in intruder mice that included increased avoidance behavior in the open field test, increased stress-evoked grooming, and increased bladder and heart weights when compared to control mice. Intruders were further compared to controls using electrophysiology recordings conducted in midbrain slices wherein recordings targeted 5-HT neurons of the ventromedial (vmDR) and lateral wing (lwDR) subfields of the DR. Though defining membrane characteristics of 5-HT neurons were unchanged, γ-aminobutyric-acid-mediated (GABAergic) synaptic regulation of 5-HT neurons was altered in a topographically specific way. In the vmDR of intruders, there was a decrease in the frequency and amplitude of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs). However, in the lwDR, there was an increase in the strength of inhibitory signals due to slower sIPSC kinetics. Synaptic changes were selective for GABAergic input, as glutamatergic synaptic input was unchanged in intruders. The distinct inhibitory regulation of DR subfields provides a mechanism for increased 5-HT output in vmDR target regions and decreased 5-HT output in lwDR target regions, divergent responses to uncontrollable stress that have been reported in the literature but were previously poorly understood.


An automated film reader for DNA sequencing based on homomorphic deconvolution.
An automated reader for electrophoresis based DNA sequencing methods is described that provides fast and accurate sequence determination. Digitized sequencing lanes are processed with homomorphic blind deconvolution in preparation for peak detection, interlane alignment, peak refinement and base calling. Initial reads from direct blot sequencing films have error rates of about 1% at the rate of 5 nucleotides/s. Typical read lengths are 500-600 nucleotides. The described reader is a significant improvement over existing readers and could be an essential component in the sequencing efforts of the Human Genome Project.


Quantification and Comparison of Anti-Fibrotic Therapies by Polarized SRM and SHG-Based Morphometry in Rat UUO Model.
Renal interstitial fibrosis (IF) is an important pathologic manifestation of disease progression in a variety of chronic kidney diseases (CKD). However, the quantitative and reproducible analysis of IF remains a challenge, especially in experimental animal models of progressive IF. In this study, we compare traditional polarized Sirius Red morphometry (SRM) to novel Second Harmonic Generation (SHG)-based morphometry of unstained tissues for quantitative analysis of IF in the rat 5 day unilateral ureteral obstruction (UUO) model. To validate the specificity of SHG for detecting fibrillar collagen components in IF, co-localization studies for collagens type I, III, and IV were performed using IHC. In addition, we examined the correlation, dynamic range, sensitivity, and ability of polarized SRM and SHG-based morphometry to detect an anti-fibrotic effect of three different treatment regimens. Comparisons were made across three separate studies in which animals were treated with three mechanistically distinct pharmacologic agents: enalapril (ENA, 15, 30, 60 mg/kg), mycophenolate mofetil (MMF, 2, 20 mg/kg) or the connective tissue growth factor (CTGF) neutralizing antibody, EX75606 (1, 3, 10 mg/kg). Our results demonstrate a strong co-localization of the SHG signal with fibrillar collagens I and III but not non-fibrillar collagen IV. Quantitative IF, calculated as percent cortical area of fibrosis, demonstrated similar response profile for both polarized SRM and SHG-based morphometry. The two methodologies exhibited a strong correlation across all three pharmacology studies (r2 = 0.89-0.96). However, compared with polarized SRM, SHG-based morphometry delivered a greater dynamic range and absolute magnitude of reduction of IF after treatment. In summary, we demonstrate that SHG-based morphometry in unstained kidney tissues is comparable to polarized SRM for quantitation of fibrillar collagens, but with an enhanced sensitivity to detect treatment-induced reductions in IF. Thus, performing SHG-based morphometry on unstained kidney tissue is a reliable alternative to traditional polarized SRM for quantitative analysis of IF.


Sleep Difficulties are Associated with Parent Report of Sluggish Cognitive Tempo.
Sleep disturbance is considered both a behavioral symptom of and a contributor to functional difficulties in children with attention-deficit/hyperactivity disorder (ADHD). The construct of sluggish cognitive tempo (SCT) has also been linked to ADHD; however, little is known regarding the effects of sleep specifically on SCT symptoms. This study examined the association between parent-reported sleep disturbance and parent- and teacher-reported SCT, while controlling for the effects of ADHD and mood symptoms. Participants included 746 clinically referred children (65% male, age range: 5-18 years) with both parent and teacher ratings assessing symptoms of ADHD, mood symptoms (depression, anxiety), and SCT. Parents/caregivers also rated their child's sleep problems with regard to 4 core concerns: falling asleep, sleep restlessness, difficulty waking, and breathing difficulties. The SCT scale included three empirically derived subscales: sleepy/sluggish, low initiation/persistence, and daydreamy. After accounting for age, medication status, ADHD symptoms, depressive symptoms, and anxiety, sleep problems accounted for a small but significant proportion of additional variance in the prediction of parent-reported sleepy/sluggish SCT. Difficulty waking showed the strongest associations with parent-reported SCT. There were no significant relationships found between parent-reported sleep difficulties and teacher-reported SCT. Some elements of sluggishness and lethargy inherent to the SCT construct may be associated with sleep difficulties, even after accounting for ADHD and mood symptoms; however, these associations are not consistent across SCT subscales and sleep problem domains.


The Genetic Regulation of Alternative Splicing in Populus deltoides.
Alternative splicing (AS) is a mechanism of regulation of the proteome via enabling the production of multiple mRNAs from a single gene. To date, the dynamics of AS and its effects on the protein sequences of individuals in a large and genetically unrelated population of trees have not been investigated. Here we describe the diversity of AS events within a previously genotyped population of 268 individuals of Populus deltoides and their putative downstream functional effects. Using a robust bioinformatics pipeline, the AS events and resulting transcript isoforms were discovered and quantified for each individual in the population. Analysis of the AS revealed that, as expected, most AS isoforms are conserved. However, we also identified a substantial collection of new, unannotated splice junctions and transcript isoforms. Heritability estimates for the expression of transcript isoforms showed that approximately half of the isoforms are heritable. The genetic regulators of these AS isoforms and splice junction usage were then identified using a genome-wide association analysis. The expression of AS isoforms was predominately cis regulated while splice junction usage was generally regulated in trans. Additionally, we identified 696 genes encoding alternatively spliced isoforms that changed putative protein domains relative to the longest protein coding isoform of the gene, and 859 genes exhibiting this same phenomenon relative to the most highly expressed isoform. Finally, we found that 748 genes gained or lost micro-RNA binding sites relative to the longest protein coding isoform of a given gene, while 940 gained or lost micro-RNA binding sites relative to the most highly expressed isoform. These results indicate that a significant fraction of AS events are genetically regulated and that this isoform usage can result in protein domain architecture changes.


Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson's Disease.
Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson's disease (PD). Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson's Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers. In patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD. Genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.


Effects of dopamine D1 and dopamine D2 antagonists on the free feeding and drinking patterns of rats.
In male rats with food and water freely available, the specific dopamine D2 antagonist YM-09151-2 had little effect on total food or water intake across a 24-hr period. However, it produced a substantial dose-related decrease in feeding rate during meals and an enhancement of both meal size and duration. The equivalent parameters for water intake were affected to a much lesser extent. A second dopamine D2 antagonist, remoxipride, had similar effects on feeding patterns and, in addition, raised food intake during the 2 hr after drug administration. A third dopamine D2 antagonist, raclopride, produced a short-lived rise in food intake and a slowing of feeding rate with a nonsignificant increase in meal size at intermediate doses. Higher doses increased the latency to feed and drink. The specific D1 antagonist SCH 23390 had small effects on both total food intake and feeding patterns. Water intake was substantially reduced in the first 2-4 hr after drug administration by an increased latency to drink. The results are interpreted, first of all, in terms of two separate effects of dopamine D2 receptors on feeding behavior: the first mediating positive feedback processes important at meal initiation and the second mediating the preabsorptive effects of food on meal termination. D1 receptors, in contrast, are of greater importance in controlling water intake.


Evaluation of treatment modalities in perioral electrical burns.
A retrospective analysis of 29 patients who sustained perioral electrical burns was undertaken. Children were divided into three groups: (group 1) no surgery and no splint (n = 21), (group 2) nonsurgical management with splint appliance (n = 8), and (group 3) commissuroplasty (n = 9). Mean age was 3 years, and minimum follow-up was 1 year. Subjective evaluation of standard photographs was performed by six surgeons. Group 2 had a less noticeable scar and more normal lip parameters. Group 3 and group 1 had similar percent scar involvement and overall poor subjective scores. All evaluators felt that commissuroplasty (group 3) improved patients' appearance compared with no surgery and no splint (group 1). Therefore the application of our easily constructed splint alone yielded the best cosmetic results.


Stromal interactions as regulators of tumor growth and therapeutic response: A potential target for photodynamic therapy?
It has become increasingly widely recognized that the stroma plays several vital roles in tumor growth and development and that tumor-stroma interactions can in many cases account poor therapeutic response. Inspired by an emerging body of literature, we consider the potential role of photodynamic therapy (PDT) for targeting interactions with stromal fibroblasts and mechano-sensitive signaling with the extracellular matrix as a means to drive tumors toward a more therapeutically responsive state and synergize with other treatments. This concept is particularly relevant for cancer of the pancreas, which is characterized by tumors with a profoundly dense, rigid fibrous stroma. Here we introduce new in vitro systems to model interactions between pancreatic tumors and their mechanical microenvironment and restore signaling with stromal fibroblasts. Using one such model as a test bed it is shown here that PDT treatment is able to destroy fibroblasts in an in vitro 3D pancreatic tumor-fibroblast co-culture. These results and the literature suggest the further development of PDT as a potential modality for stromal depletion.


Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
Fragile histidine triad protein (Fhit) is a diadenosine triphosphate (ApppA) hydrolase encoded at the human chromosome 3 fragile site which is frequently disrupted in tumors. Reintroduction of FHIT coding sequences to cancer cell lines with FHIT deletions suppressed the ability of these cell lines to form tumors in nude mice even when the reintroduced FHIT gene had been mutated to allow ApppA binding but not hydrolysis. Because this suggested that the tumor suppressor activity of Fhit protein depends on substrate-dependent signaling rather than ApppA catabolism, we prepared two crystalline forms of Fhit protein that are expected to model its biologically active, substrate-bound state. Wild-type and the His96Asn forms of Fhit were overexpressed in Escherichia coli, purified to homogeneity and crystallized in the presence and absence of ApppA and an ApppA analog. Single crystals obtained by vapor diffusion against ammonium sulfate diffracted X-rays to beyond 2.75 A resolution. High quality native synchrotron X-ray data were collected for an orthorhombic and a hexagonal crystal form.


[Placental growth hormone. Significance relative to growth hormone and lactogen hormone].
Normal human placenta secretes within maternal compartment a pregnancy associated protein, placental growth hormone (PGH). This entity, agonist of pituitary GH, appears responsible for the elevated IGF I blood levels observed in the mother during pregnancy, while pituitary GH is no longer secreted. PGH could thus play a significant role in the anabolic processes of pregnancy. The biochemical mechanism responsible for PGH production is the expression of the GH-V gene at the placental level. This has been demonstrated by the positive probing of GH-V mRNA in this tissue, by the establishment of the restriction map and sequence of its cDNA as well as by the NH2-terminal sequence determination of both 22 and 25K PGH forms. The positive aspect of this function for human reproduction gains weight in that a placenta deleted for the CS-A, GH-V and CS-B gene expresses alternative genes coding for protein similar or related to pituitary GH or hPL, respectively.


[Study on the genotyping of 113 Mycobacterium tuberculosis strains isolated in Beijing based on 13 variable number of tandem DNA repeats].
Variable Number of Tandem Repeats (VNTRs) analysis was a recently developed method which could serve as a 'real-time' genotyping tool for Mycobacterium tuberculosis. One hundred and thirteen M. tuberculosis isolates from the patients with tuberculosis in Beijing were analysed using the reference method to study the characters of genetic diversity and genotype. Thirteen tandem repeat loci (ETR-A, ETR-C, ETR-D, MIRU10, MIRU16, MIRU27, MIRU31, MIRU40, Mtub21, Mtub30, Mtub38, Qublla, Qubllb) in the total genome of MTB were analyzed by PCR and agarose gel electrophoresis method. The characters of the polymorphism of DNA fingerprinting of one hundred and thirteen MTB strains were analyzed with Gel-Pro analyzer 3.1 software and BioNumerics 3.0 software. Results One hundred and thirteen MTB strains were characterized and classified in to four genotype families(type I , type II , type NV, type V ) based on thirteen tandem repeat loci. One hundred and four isolates(92.0%) belonged to type I , the other three genotypes scattered, five strains(4.4%) remaining with type II , while type IV and type V having the same quantity 1.8% (2/113). M. tuberculosis H37Rv belonged to a unattached genotype(type ll ). Conclusion There was obvious length polymorphism in the M. tuberculosis isolates which implied that type I was the epidemic strain clusters in M. tuberculosis in Beijing. VNTRs analysis seemed to be a simple, rapid, sensitive and valuable tool for epidemiological studies of M. tuberculosis complex organisms.


[Uterine perforation by an intrauterine device].
The intrauterine device (IUD) is a widely used, effective and reversible means of birth control. Its insertion can be associated with perforation of the utuerus. This is a rare complication, but with possible serious clinical consequences. There is an increased risk of uterine perforation if the IUD is inserted during 6 months of post-partum or after uterine evacuation. A follow up by sonography is essential. The surgical removal of the ectopic IUD is imperious.


Azadirachtin effects on mating success, gametic abnormalities and progeny survival in Drosophila melanogaster (Diptera).
Azadirachtin is a prominent natural pesticide and represents an alternative to conventional insecticides. It has been successfully used against insect pests. However, its effects on reproduction require further analysis. Here we investigated lethal and sublethal effects of azadirachtin, on treated adults in a model insect, Drosophila melanogaster (Meigen). Dose-mortality relationships as well as several parameters of reproduction (mating, spermatogenesis, oogenesis and fertility) were examined. Neem-Azal, a commercial formulation of azadirachtin, applied topically on newly emerged adults, increased mortality with a positive dose-dependent relationship. The LD50 (0.63 μg) was determined 24 h after treatment using a non-linear regression. Adults surviving this dose had a mating success that was divided by 3 and a progeny production reduced by half when males were treated, and even more when females were treated. When combining probability of survival, of mating and reduced progeny, it appeared that LD50 induced a 98% reduction in reproductive rates. Reduced progeny was partially explained by the effect of adult treatment on gametes number and abnormalities. The number of cysts and the apical nuclei positions within the cysts decreased by 29.7% and 20%, respectively, in males. In females, the number of oocytes per ovary and the volume of basal oocytes also decreased by 16.1% and 32.4%, respectively. Azadirachtin causes significant toxic effects in both sexes and decreases the fecundity and fertility of D. melanogaster. Females are more sensitive to azadirachtin. © 2017 Society of Chemical Industry.


Association of Matrix Metalloproteinase1-1607 1G>2G Polymorphism and Lung Cancer Risk: An Update by Meta-Analysis.
Objective: The association between matrix metalloproteinase1 (MMP1)-1607 1G>2G polymorphism and lung cancer risk is still inconclusive and inconsistent. We conducted a meta-analysis to estimate the potential relationship between MMP1-1607 1G>2G polymorphism and lung cancer risk. Methods: The comprehensive searches of the PubMed, Web of Science, Medline, CBM, CNKI, Weipu, and Wanfang databases, published up to Nov 10, 2018. Statistical analyses were performed with Review Manager 5.3 software. Results: A total of 14 relevant studies containing 6068 cases and 5860 controls were included in the study. The results indicated that MMP1-1607 1G>2G polymorphism was significantly associated with increased lung cancer risk under four models: 2G vs. 1G model (pooled OR = 1.19, 95% CI = 1.05-1.34, P < 0.0001); 2G/2G vs. 1G/1G (pooled OR = 1.34, 95% CI = 1.09-1.64, P = 0.003); 2G/2G vs. 1G/1G+1G/2G (pooled OR = 1.26, 95% CI = 1.06-1.49, P < 0.0001); 2G/2G+1G/2G vs. 1G/1G (pooled OR = 1.21, 95% CI = 1.05-1.40, P = 0.01). Subgroup analyses showed that there was a higher increase in smoking status under three models: 2G/2G vs. 1G/1G (pooled OR = 2.07, 95% CI = 1.14-3.77, P = 0.02); 2G/2G vs. 1G/1G+1G/2G (pooled OR = 1.71, 95% CI = 1.17-2.52, P = 0.006); 2G/2G+1G/2G vs. 1G/1G (pooled OR = 2.03, 95% CI = 1.14-3.62, P = 0.02). In addition, subgroup analyses by ethnicity further identified the significant association in Asians. Non-smoking population and ethnicity among Caucasian had no relationship with lung cancer susceptibility in four models. Conclusion: Our study suggested that MMP1-1607 1G>2G polymorphism was a risk factor for developing lung cancer risk.


Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Patients with Advanced Cancer.
Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies.Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles.Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a grade 3-4 treatment-related adverse event (fatigue), and no clinically relevant elevations in transaminases were noted. Utomilumab demonstrated linear pharmacokinetics at doses ranging from 0.006 to 10 mg/kg, with similar safety and pharmacokinetics in anti-drug antibody (ADA)-negative and ADA-positive patients. The overall objective response rate was 3.8% (95% CI, 0.5%-13.0%) in patients with solid tumors and 13.3% in patients with Merkel cell carcinoma, including a complete response and a partial response. Circulating biomarkers support 4-1BB/CD137 engagement by utomilumab and suggest that circulating lymphocyte levels may influence probability of clinical benefit.Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816-23. ©2018 AACR.


The Effect of Hydrofluoric Acid Surface Treatment on the Cyclic Fatigue Resistance of K3 NiTi Instruments.
The aim of this study was to investigate the effect of 50% hydrofluoric acid (HF) surface treatment on the cyclic fatigue resistance (CFR) of K3 NiTi instruments. Twenty as-received and twenty HF-treated K3 NiTi instruments were compared in CFR. The surface texture and fracture surface of two instrument groups were examined with a scanning electron microscope (SEM). Additionally, any change of Ni and Ti composition from both instrument groups was investigated using energy dispersive spectrometry. The results were analyzed with t-test. The HF-treated K3 group showed statistically higher cyclic fatigue resistance than as-received K3 group (P < 0.05). HF-treated K3 instruments showed smoother and rounded surface compared to as-received K3 under SEM observation. The fracture surfaces of both groups showed typical patterns of cyclic fatigue fracture. There was no difference in surface Ni and Ti composition between two groups. HF treatment of K3 instruments smoothed the file surface and increased the cyclic fatigue resistance, while it had no effect on surface ion composition and the file fracture pattern.


Expression of Human Trefoil Factor 3 in Pichia pastoris and Its Biological Activity Analysis.
The human TFF3 (trefoil factor 3) DNA fragment was amplified by polymerase chain reaction (PCR) from human fetal placenta cDNA. The gene was cloned into the Pichia pastoris expression vector pPIC9K containing AOX 1 promoter and alpha-factor leader sequence. Multi-copies insertion transformants were screened on G418 plates. After the induction by 2% methanol for 48 hours, the expression of dimeric hTFF3 came up to 45% of total proteins in medium, as identified by SDS-PAGE and Western blot assay. The recombinant protein was further purified by S-Sepharose, Q-Sepharose ion-exchange chromatography and Sephacryl-S-100 gel filtration chromatography to the 95% purity, as shown by densitometric scanning. The N-terminus and molecular weight of the recombinant hTFF3 was in good agreement with the native hTFF3. The recombinant protein was proved to have good biological activity of preventing rats from the gastric ulcer induced by hydrochloric acid.


Necessity for a national carcinogen list in Korea, based on international harmonization.
Cancer has been the leading cause of death in Korea for the last 30 years. Cancer patients' 5-year survival rate between 2005 and 2009 was 62.0%, representing a highly advanced standard of care, as much as developed countries in the EU and the US. The Korean government formulated its first 10-year plan for cancer control in 1996 and has been carrying out a second 10-year plan for cancer control since 2006. But despite the Korean government's efforts, the cancer burden in Korea continues to increase. Many separate laws have gone into effect concerning the management of carcinogen exposure. However, there are no integrated regulatory laws or management systems against carcinogen exposure in Korea. Dead zones remain where carcinogen exposure cannot be controlled properly in Korea. In this paper, we suggest the need to establish a national carcinogen list based on international harmonization as a prerequisite for a paradigm shift in cancer control policy from treatment to primary prevention.


Immunoglobulins and circulating immune complexes in nephrotic syndrome.
Serum immunoglobulin (IgG, IgA and IgM) levels were measured in 40 children with idiopathic nephrotic syndrome and 20 healthy controls. Significantly decreased IgG (P < 0.001), normal IgA and increased IgM (P < 0.05), averaging 92 per cent, 99 per cent and 104 per cent of normal mean, respectively, were observed in active nephrotic syndrome (ANS). The mean immunoglobulin levels did not differ significantly among different subgroups of ANS cases. In remission, a significant increase in IgG (P < 0.01), a decrease in IgA (P < 0.05) and in IgM (P < 0.01) levels were found in comparison to their corresponding ANS values. Their concentrations were significantly abnormal also when compared with controls. The circulating immune complexes (CIC), detected by polyethylene glycol (PEG) per cent index, demonstrated that overall mean serum level was significantly higher (P < 0.01, 168 per cent of normal) in ANS patients. Among different subgroups, the mean level was significantly elevated (P < 0.001, 205 per cent of normal) only in relapsing nephrotic syndrome cases. Thus, the abnormal levels of immunoglobulins were found both in active as well as in remission stage of the disease, while elevated levels of CIC were seen only in patients with relapse.


Phylogeny and species delineation in the marine diatom Pseudo-nitzschia (Bacillariophyta) using cox1, LSU, and ITS2 rRNA genes: A perspective in character evolution.
Analyses of the mitochondrial cox1, the nuclear-encoded large subunit (LSU), and the internal transcribed spacer 2 (ITS2) RNA coding region of Pseudo-nitzschia revealed that the P. pseudodelicatissima complex can be phylogenetically grouped into three distinct clades (Groups I-III), while the P. delicatissima complex forms another distinct clade (Group IV) in both the LSU and ITS2 phylogenetic trees. It was elucidated that comprehensive taxon sampling (sampling of sequences), selection of appropriate target genes and outgroup, and alignment strategies influenced the phylogenetic accuracy. Based on the genetic divergence, ITS2 resulted in the most resolved trees, followed by cox1 and LSU. The morphological characters available for Pseudo-nitzschia, although limited in number, were overall in agreement with the phylogenies when mapped onto the ITS2 tree. Information on the presence/absence of a central nodule, number of rows of poroids in each stria, and of sectors dividing the poroids mapped onto the ITS2 tree revealed the evolution of the recently diverged species. The morphologically based species complexes showed evolutionary relevance in agreement with molecular phylogeny inferred from ITS2 sequence-structure data. The data set of the hypervariable region of ITS2 improved the phylogenetic inference compared to the cox1 and LSU data sets. The taxonomic status of P. cuspidata and P. pseudodelicatissima requires further elucidation.


Imaging of sleep-disordered breathing in adults.
Sleep-disordered breathing (SDB) is a term that includes several chronic conditions in which partial or complete cessation of breathing occurs multiple times throughout the night. Central sleep apnoea (CSA) is uncommon and defined by the episodic cessation of airflow without respiratory effort. Lesions involving the respiratory centre in the brainstem or the origin of the phrenic nerve from the mid-cervical cord are the commonest structural causes of CSA; magnetic resonance imaging (MRI) will demonstrate the lesion and frequently suggest the likely aetiology. In contrast, obstructive sleep apnoea (OSA) is defined as upper airway obstruction despite ongoing respiratory effort. Repetitive episodes of narrowing or closure of the upper airway are the predominant cause leading to snoring and OSA, respectively. OSA affects 33-40% of the adult population and is associated with multiple adverse health consequences, including a significantly increased risk of serious morbidity and mortality. The incidence is increasing proportionally to the worldwide rise in obesity. Imaging, performed primarily without the involvement of radiologists, has been integral to understanding the anatomical basis of SDB and especially OSA. This article will review the pathophysiology, imaging findings, and sequelae of these common conditions. The role of imaging both in suggesting the incidental diagnoses of SDB and in the investigation of these conditions when the diagnosis is suspected or has been established are also discussed.


Urinary response to an oxalic acid load is influenced by the timing of calcium loading in rats.
Dietary intake of calcium or dairy products has been shown to decrease urinary oxalate excretion by limiting its intestinal absorption. However, not enough attention has been given to whether there is any benefit from altering the schedule of ingesting calcium and oxalate. Therefore, we investigated the effects of changes in the timing of calcium and oxalate loading on urinary oxalate excretion. Male Wistar rats weighing 180 to 200 gm were fasted and randomized into several groups. They were then administered normal saline or oxalic acid with or without calcium or milk. Calcium or milk was given immediately, or 5, 10, 15 or 30 minutes before or after the oxalate load. All treatments were given via gastrostomy. Urine samples were collected by bladder puncture just before administration and at hourly intervals up to 5 hours afterward. Urinary oxalate was measured by capillary electrophoresis. Urinary oxalate increased after the administration of oxalate alone, while it decreased when oxalate was combined with calcium or milk. Urinary oxalate showed a smaller increment when calcium or milk was given before than after oxalate loading, and it was much smaller when calcium or milk was given immediately before oxalate. Prior calcium loading appears to have a positive influence on decreasing oxalic acid absorption from the intestinal tract. Therefore, calcium or dairy products should always be ingested before a meal rich in oxalate to prevent oxalate absorption and decrease urinary oxalate excretion.


Small and medium-sized enterprises failure in providing workers' rights concerning Sustainable Development Goals-2030 in Pakistan.
Small and medium-sized enterprises (SMEs) play an enormously crucial part in the modern world economy, demonstrating the most unique and incredible ground-breaking system. SMEs' employment statistics and future worker needs make it a focus of policies among rising economies, and Pakistan is no exception. The working conditions in SMEs diverge from industry to industry; however, irrespective of the industrial categorization, the SMEs are failing to protect the workers' rights in the perspective of Sustainable Development Goals (SDGs). The interpretivism paradigm and purposive sampling, narrative inquiry, and analysis method have been adopted to gain in-depth knowledge of workers' rights in SMEs concerning the SDGs. Results revealed that Pakistan-based SMEs argue to be financially weak and perceived as less equipped to adhere to the world's standards. Highlighted issues in failure to adhere to worker's rights include lack of financial resources, top management's commitment, regulatory framework, SDG awareness, strategic planning, and the dire need for expert guidance and consultation in translating goals to work environments.


Molecular control of steady-state dendritic cell maturation and immune homeostasis.
Dendritic cells (DCs) are specialized sentinels responsible for coordinating adaptive immunity. This function is dependent upon coupled sensitivity to environmental signs of inflammation and infection to cellular maturation-the programmed alteration of DC phenotype and function to enhance immune cell activation. Although DCs are thus well equipped to respond to pathogens, maturation triggers are not unique to infection. Given that immune cells are exquisitely sensitive to the biological functions of DCs, we now appreciate that multiple layers of suppression are required to restrict the environmental sensitivity, cellular maturation, and even life span of DCs to prevent aberrant immune activation during the steady state. At the same time, steady-state DCs are not quiescent but rather perform key functions that support homeostasis of numerous cell types. Here we review these functions and molecular mechanisms of suppression that control steady-state DC maturation. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune and inflammatory disease.


COVID-19 Vaccine as a Potential Triggering Factor for Anti-Glomerular Basement Membrane (GBM) Disease: A Case Report and Literature Review.
Coronavirus 2019 (COVID-19) is considered one of the most significant medical pandemics of this century, with high morbidity and mortality associated with the pandemic. The virus was recognized initially as a cause of pneumonia, but subsequent studies showed significant association with gastrointestinal, neurological, and autoimmune diseases. By 2020, several vaccines became available for use, significantly reducing the infection rate. A good safety profile supported most of the studies related to vaccines. However, this area is still under study, and some reports linked the COVID-19 vaccine to the development of thrombocytopenia, thrombosis, Guillain-Barre syndrome, autoimmune diseases, and myocarditis. These side effects need to be reported to VAERS (Vaccine Adverse Event Reporting System). The exact etiology of anti-glomerular basement (Anti-GBM) disease remains unknown, but the disease is thought to be triggered by environmental factors in genetically predisposed individuals. It is considered one of the serious diseases that could lead to permanent kidney impairment if not treated early and adequately. That's why a great effort is being made by health care practitioners to figure out and avoid the risk and triggering factors. Few previously published papers linked the COVID-19 vaccine and the development of anti-GBM disease, which raised concerns about digging more into this area. Herein, we are reporting a case of a patient who developed rapidly progressive glomerulonephritis (RPGN) due to anti-glomerular basement membrane (GBM) antibody disease two days after receiving the second dose of the COVID-19 vaccine.


Looking for middle ground in cultural attraction theory.
In their article, Thom Scott-Phillips, Stefaan Blancke, and Christophe Heintz do a commendable job summarizing the position and misunderstandings of "cultural attraction theory" (CAT). However, they do not address a longstanding problem for the CAT framework; that while it has an encompassing theory and some well-worked out case studies, it lacks tools for generating models or empirical hypotheses of intermediate generality. I suggest that what the authors diagnose as misunderstandings are instead superficial interpretive errors, resulting from researchers who have attempted to extract generalizable hypotheses from CAT and bring them into contact with the analytical and inferential models of contemporary cultural evolutionary research.


Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology.
To determine the correspondence of in vivo quantitative estimates of brain uptake of fluorine 18-labeled flutemetamol with immunohistochemical estimates of amyloid levels in patients who underwent previous biopsy. Cross-sectional study of ¹⁸F-flutemetamol positron emission tomography (PET) findings in patients with prior cortical biopsy specimen stained for the presence or absence of amyloid plaques. University hospital. Patients Seven patients who previously had a prior right frontal cortical biopsy at the site of ventriculoperitoneal placement for presumed normal pressure hydrocephalus were recruited. Inclusion criteria included an adequate biopsy specimen for detection and quantification of β-amyloid pathology and age older than 50 years. Intervention All patients underwent an ¹⁸F-flutemetamol PET scan. Quantitative measures of ¹⁸F-flutemetamol uptake (standardized uptake value ratio, a ratio of mean target cortex activity divided by that in a cerebellar reference region) were made at a location contralateral to the biopsy site and compared with estimates of amyloid load based on immunohistochemical and histological staining. There was complete agreement between visual reads of ¹⁸F-flutemetamol PET scans (3 blinded readers with majority rule) and histology. A regression model, including time from biopsy as a covariate, demonstrated a significant relationship (P = .01) between ¹⁸F-flutemetamol uptake and percentage of area of amyloid measured by a monoclonal antibody raised against amyloid (NAB228). Similar results were found with the amyloid-specific monoclonal antibody 4G8 and Thioflavin S. To our knowledge, these data are the first to demonstrate the concordance of ¹⁸F-flutemetamol PET imaging with histopathology, supporting its sensitivity to detect amyloid and potential use in the study and detection of Alzheimer disease.


Modulation of glucocorticoid receptor function via phosphorylation.
The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone-dependent manner. It has been suggested that GR phosphorylation affects turnover, subcellular trafficking, or the transcriptional regulatory functions of the receptor, yet the contribution of individual GR phosphorylation sites to the modulation of GR activity remains enigmatic. This review critically evaluates the literature on GR phosphorylation and presents more recent work on the mechanism of GR phosphorylation from studies using antibodies that recognize GR only when it is phosphorylated. In addition, we present support for the notion that GR phosphorylation modifies protein-protein interactions, which can stabilize the hypophosphorylated form of the receptor in the absence of ligand, as well as facilitate transcriptional activation by the hyperphosphorylation of GR via cofactor recruitment upon ligand binding. Finally, we propose that GR phosphorylation also participates in the nongenomic activation of cytoplasmic signaling pathways evoked by GR. Thus, GR phosphorylation is a versatile mechanism for modulating and integrating multiple receptor functions.


Mid-term results of patterned laser trabeculoplasty for uncontrolled ocular hypertension and primary open angle glaucoma.
To describe the safety and efficacy of patterned laser trabeculoplasty (PLT) as an adjunctive treatment in primary open angle glaucoma (POAG) and ocular hypertension (OHT) after 18-month follow-up in Hispanic population. A single-center, retrospective study was conducted. All patients with OHT or POAG undergoing PLT from June 2016 to August 2016 were included in the study. Investigated parameters were intraocular pressure (IOP), the number of IOP-lowering medications, best corrected visual acuity (BCVA), laser parameters and postoperative adverse events. Primary efficacy outcome measures were the proportion of eyes achieving an IOP reduction ≥20% at 18mo versus baseline medicated IOP or a reduction in the number of medications while maintaining IOP values. From 40 PLT-treated eyes (mean baseline IOP 20.3±1.7 mm Hg), 24 patients were analyzed (age 63.4±7.3y). The mean IOP reductions from baseline across visits (months 1, 3, 6, 9, 12, and 18) ranged from 14.1% to 20.8%. Success rate after 18-month follow-up was 61.7% with a mean IOP of 16±3.2 mm Hg (P<0.001). The number of glaucoma IOP-lowering medications per eye (preoperative 2.1±1.1 and postoperative 2.3±1.1, P=0.86) and the mean BCVA (preoperative 0.10±0.22 and postoperative 0.11±0.22 logMAR, P=0.42) remained stable. Adverse events comprised transitory IOP spikes in 4 eyes (10%) and peripheral anterior synechiae in 7 eyes (17.5%). Mid-term results of PLT show that this procedure may be an efficacious and safe technique to approach medically uncontrolled OHT or POAG patients.


Implementation and Evaluation of a Large-Scale Teleretinal Diabetic Retinopathy Screening Program in the Los Angeles County Department of Health Services.
Diabetic retinopathy (DR) is the leading cause of blindness in adults of working age in the United States. In the Los Angeles County safety net, a nonvertically integrated system serving underinsured and uninsured patients, the prevalence of DR is approximately 50%, and owing to limited specialty care resources, the average wait times for screening for DR have been 8 months or more. To determine whether a primary care-based teleretinal DR screening (TDRS) program reduces wait times for screening and improves timeliness of needed care in the Los Angeles County safety net. Quasi-experimental, pretest-posttest evaluation of exposure to primary care-based TDRS at 5 of 15 Los Angeles County Department of Health Services safety net clinics from September 1, 2013, to December 31, 2015, with a subgroup analysis of random samples of 600 patients before and after the intervention (1200 total). Primary care clinic-based teleretinal screening for DR. Annual rates of screening for DR before and after implementation of the TDRS program across the 5 clinics, time to screening for DR in a random sample of patients from these clinics, and a description of the larger framework of program implementation. Among the 21 222 patients who underwent the screening (12 790 female, 8084 male, and 348 other gender or not specified; mean [SD] age, 57.4 [9.6] years), the median time to screening for DR decreased from 158 days (interquartile range, 68-324 days) before the intervention to 17 days (interquartile range, 8-50 days) after initiation of the program (P < .001). Overall annual screening rates for DR increased from 5942 of 14 633 patients (40.6%) before implementation to 7470 of 13 133 patients (56.9%) after initiation of the program at all 15 targeted clinics (odds ratio, 1.9; 95% CI, 1.3-2.9; P = .002). Of the 21 222 patients who were screened, 14 595 (68.8%) did not require referral to an eye care professional, 4160 (19.6%) were referred for treatment or monitoring of DR, and 2461 (11.6%) were referred for other ophthalmologic conditions. A digital TDRS program was successfully implemented for the largest publicly operated county safety net population in the United States, resulting in the elimination of the need for more than 14 000 visits to specialty care professionals, a 16.3% increase in annual rates of screening for DR, and an 89.2% reduction in wait times for screening. Teleretinal DR screening programs have the potential to maximize access and efficiency in the safety net, where the need for such programs is most critical.


Frustration Tolerance and Personality Traits in Patients With Substance Use Disorders.
Previous research has suggested the prevalence of certain personality traits, some of which are related to a disorganized attachment, in substance abuse disorders. Further, frustration tolerance (FT) has been proposed as an important factor in addiction, both at the inception-following the "self-medication" hypothesis-and regarding treatment compliance. In turn, an inadequate response to frustrating events has been also associated with a disrupted attachment. Our goal is to explore the mediational role of FT in the relationship between personality traits and two different treatments for substance addiction: therapeutic community (TC) and ambulatory treatment (AT). Eighty-four subjects with substance abuse disorder were recruited in total (22 female), including 46 volunteers (13 female) in TC and 38 (9 female) in AT. They were assessed with Rosenzweig's test for FT and the Millon Clinical Multiaxial Inventory-III (MCMI-III) test to evaluate personality factors. By comparing with a control sample (335 volunteers, 268 female), we found that FT was lower in patients. Between therapeutic groups, FT was significantly lower in TC. Depressive, antisocial, sadistic, negativistic, schizotypal, borderline, paranoid, anxiety, dysthymia, alcohol use, drug use, posttraumatic stress disorder (PTSD), thought disorder, and delusional disorder traits were suggestive of pathology in the clinical samples and were significantly different between control, AT, and TC groups. Further, anxiety and PTSD traits were higher in TC than in AT. A mediational analysis revealed that the effect of anxiety and PTSD scales on therapeutic group was partially mediated by FT. In conclusion, FT and its interplay with personality traits commonly related to disorganized attachment (anxiety and PTSD) might be important factors to consider within therapeutic programs for persons with substance addiction.


Blood monitoring of granzyme B and perforin expression after intestinal transplantation: considerations on clinical relevance.
The use of biomarkers for rejection monitoring represents a major goal in intestinal transplantation. We analyzed the blood expression of Granzyme B (GB) and Perforin (PF) in the following pathological conditions after intestinal transplantation: acute rejection (AR), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). The diagnostic accuracy and the clinical utility of these tests are finally discussed. GB and PF levels were measured by real time polymerase chain reaction on peripheral blood samples from 32 intestinal recipients. Blood samples (n=494) after comparison of clinical, histological, and microbiological data were assigned to the following groups: normal (n=307), AR (n=30), EBV infection (n=107), CMV infection (n=25), and PTLD (n=25). Mean levels of GB and PF in the AR (GB=279.7; PF=256.7), PTLD (GB=199; PF=185.9), EBV (GB=133.2; PF=143.7), and CMV (GB=151.3; PF=144) groups were significantly higher than in the normal group (GB=100.1; PF=101.1) (all P<0.05, except for PF in CMV infection). The best accuracy was obtained for the diagnosis of AR with sensitivity and specificity of 80% and 79% for GB and 70% and 79% for PF, respectively. The area under the receiver-operator characteristics curve was 0.87 for GB and 0.82 for PF. GB and PF are diagnostic molecular markers of AR. GB and PF blood levels are also increased in case of viral infections or PTLD. Serial blood testing for GB and PF might be predictive of early intestinal graft dysfunction and should be interpreted in the context of the histological and virological analyses.


Changes in the frequency and size of smooth muscle tumors in Japanese quail lines differing in body weight.
The purpose of this investigation was to study the incidence and size of smooth muscle tumors in several Japanese quail lines and to report recent correlated changes in mature BW and egg production. Laying females from lines selected solely (HW) or partly (HW-HP; HW-LP) for increased 4-wk BW or for decreased 4-wk BW (LW) and from the corresponding randombred control (R1) were used. Lines HW-HP and HW-LP were sublines of Line HW in which males were selected for increased 4-wk BW and females were selected for high or low level of total plasma phosphorus, respectively. Laying hens were examined for the presence of smooth muscle tumors after about 170 d of egg production (240 d of age). During Generations 19 through 26, mature BW was increasing in the HW line and decreasing in the LW line. Selection for either increased or decreased 4-wk BW resulted in decreased egg production, but the only significant change with generations was a decrease of 2.7 eggs per hen for a 120-d laying period in the LW line. Frequency and weight of the smooth muscle tumors were greater for females from the large-bodied lines than females from Line R1. No tumors were detected in LW females. Based on the linear regression of response on generations, tumor frequency was increasing in Line HW-LP but tumor weight was decreasing in this line. Tumor weight was increasing in the HW line. No other changes in tumor frequency or size were noted across generations. Weight of the tumors was not correlated with egg production. The presence of tumors did not seem to affect mortality during the laying period. The Japanese quail lines may serve as a useful animal model for the study of smooth muscle tumors in humans, chickens, and turkeys.


Identification of O-glycosylation sites and partial characterization of carbohydrate structure and disulfide linkages of human insulin-like growth factor binding protein 6.
The actions of insulin-like growth factors (IGFs) are modulated by a family of high-affinity binding proteins (IGFBPs), including IGFBP-6, which preferentially binds IGF-II and is O-glycosylated. Glycosylated and nonglycosylated recombinant human IGFBP-6, expressed in Chinese hamster ovary cells and Escherichia coli, respectively, were purified using IGF-II affinity chromatography and reverse-phase medium-pressure chromatography. Electrospray ionization mass spectrometry (ESMS) of glycosylated IGFBP-6 revealed considerable heterogeneity of carbohydrate composition. Major glycoforms contained 8-16 monosaccharides, including N-acetylhexosamine, hexose, and N-acetylneuraminic acid. Glycosylation sites of IGFBP-6 were identified as Thr126, Ser144, Thr145, Thr146, and Ser152 by using a combination of ESMS and Edman sequencing of tryptic fragments separated by reverse-phase high-pressure liquid chromatography. One oligosaccharide chain contained 5-6 monosaccharides, whereas the others contained 2-4 monosaccharides. Glycosylated IGFBP-6 exhibited greater resistance to proteolysis by chymotrypsin and trypsin than nonglycosylated IGFBP-6. Native disulfide bond positions in IGFBP-6 were localized by means of observed disulfide-linked tryptic fragments, revealing that there are two disulfide-linked subdomains within each of the N- and C-terminal regions and confirming a previous suggestion that the latter regions are not interconnected. A model of IGFBP-6 is developed in which these distinct domains are separated by a central region which is O-glycosylated.


Exertional heat illness in a Marine training on the endurance course.
Exercise-induced heat stroke is defined as core temperature greater than 104 degrees F (400 degrees C) accompanied by signs or symptoms of organ system failure, most commonly CNS dysfunction. Exertional heatstroke is a life-threatening emergency that requires immediate whole-body cooling for a satisfactory outcome. Cooling should be initiated and, in the absence of life-threatening complications, completed on site prior to evacuation to an emergency department or other facility. Cool-water immersion provides the fastest whole body cooling rate and the lowest morbidity and mortality for exertional heat stroke. When water immersion is unavailable, ice water towels combined with ice packs on the head, trunk, and extremities provide effective but slower whole-body cooling. Medications, including antipyretics and dantrolene, are not effective in treating heatstroke and should not be used. Clinical observations indicate that prognosis is closely linked to the amount of time a patient's temperature remains elevated. Prevention strategies are essential to reducing the incidence of exertional heatstroke, heat exhaustion, and exercise-associated muscle cramping.


Long-reads reveal that Rhododendron delavayi plastid genome contains extensive repeat sequences, and recombination exists among plastid genomes of photosynthetic Ericaceae.
Rhododendron delavayi Franch. var. delavayi is a wild ornamental plant species in Guizhou Province, China. The lack of its plastid genome information seriously hinders the further application and conservation of the valuable resource. The complete plastid genome of R. delavayi was assembled from long sequence reads. The genome was then characterized, and compared with those of other photosynthetic Ericaceae species. The plastid genome of R. delavayi has a typical quadripartite structure, and a length of 202,169 bp. It contains a large number of repeat sequences and shows preference for codon usage. The comparative analysis revealed the irregular recombination of gene sets, including rearrangement and inversion, in the large single copy region. The extreme expansion of the inverted repeat region shortened the small single copy, and expanded the full length of the genome. In addition, consistent with traditional taxonomy, R. delavayi with nine other species of the same family were clustered into Ericaceae based on the homologous protein-coding sequences of the plastid genomes. Thus, the long-read assembly of the plastid genome of R. delavayi would provide basic information for the further study of the evolution, genetic diversity, and conservation of R. delavayi and its relatives.


A Very Rare Association of Fuchs Heterochromic Uveitis and Ectropion Uvea in Usher Syndrome.
Usher syndrome is a heterogeneous genetic disease that is the most common cause of hereditary blindness-deafness. This syndrome is the most prevalent syndrome associated with retinitis pigmentosa. A 25-year-old man referred to us with hearing loss and vision diminution since childhood which has gradually worsened. Visual acuity of both eyes was 20/100. Slit lamp examination of the left eye revealed endothelial stellate keratic precipitates, mild anterior chamber reaction, iris heterochromia, ectropion of uvea, and mild posterior subcapsular cataract. There were also no crypts and abnormal vessels in the left eye iris. His intraocular pressure was 14 mmHg in the right eye and 18 mmHg in the left one. Funduscopy demonstrated waxy pallor optic nerve, marked arterial narrowing, and retinal bone spicule pigment formation in both eyes. We report for the first time a very rare association between Usher syndrome, Fuchs heterochromic uveitis (FHU), and ectropion uvea. To our knowledge, no association has been reported between ectropion uvea, FHU, and Usher syndrome.


Etiology of corneal striae accompanying hydrogel lens wear.
Vertical striae in the posterior cornea were produced experimentally in ten human subjects by depriving the anterior corneal surface of its normal oxygen supply and inducing corneal edema. These striae were similar in appearance and time of occurrence to those observed in gel lens wearers. Three subjects also wore gel lenses and developed vertical striae while wearing their lenses. These striae were eliminated by increasing the oxygen concentration at the anterior lens surface. The data confirm many clinical observations which have suggested that verical striae are caused by corneal edema accompanying gel lens wear.


Menstrual Cycle in Schizophrenic Patients: Review with a Case.
There are not enough studies about the relationship between menstrual psychosis and schizophrenia exacerbation during the menstrual cycle. In patients diagnosed with schizophrenia, it is important to examine the psychotic symptoms and depression and anxiety symptoms during the menstrual cycle and to adjust the treatment according to these symptoms. If depression and anxiety symptoms are present, selective serotonin reuptake inhibitors can be used. In patients with exacerbated psychotic symptoms, it may be effective to increase the dose of an antipsychotic drug, which has no effect on prolactin release, 3-5 days prior to menstruation. In addition, hormonal therapy or menstrual cycle suppression is an alternative option. In this article, a case of a schizophrenic patient whose psychotic symptoms exacerbated with the menstrual cycle is presented.


A simple method for anzlyzing multifactorial data.
A simple method of isolating significant factors from multifactorial data has been outlined. The factors must be at two levels, but any number of factors can be handled. Variable group sizes and empty groups do not invalidate the method.


Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix.
Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. Fifty-five healthy, regularly cycling premenopausal women participated. Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.


Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol.
Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (MYH7R403Q/+). We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes. R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.


Influence of onset density on spoken-word recognition.
Previous research has suggested that the initial portion of a word activates similar sounding words that compete for recognition. Other research has shown that the number of similar sounding words that are activated influences the speed and accuracy of recognition. Words with few neighbors are processed more quickly and accurately than words with many neighbors. The influences of the number of lexical competitors in the initial part of the word were examined in a shadowing and a lexical-decision task. Target words with few neighbors that share the initial phoneme were responded to more quickly than target words with many neighbors that share the initial phoneme. The implications of onset-density effects for models of spoken-word recognition are discussed.


The glucose/insulin system and vitamin C: implications in insulin-dependent diabetes mellitus.
The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM. The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.


Adipocytokine Regulation and Antiangiogenic Activity Underlie the Molecular Mechanisms of Therapeutic Effects of Phyllanthus niruri against Non-Alcoholic Fatty Liver Disease.
The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Sprague⁻Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.


Surveillance of the Efficacy of Artemisinin-Piperaquine in the Treatment of Uncomplicated Plasmodium falciparum Malaria Among Children Under 5 Years of Age in Est-Mono District, Togo, in 2017.
Malaria is a major public health concern in Togo. The Est-Mono district of Togo has a population of 150,000. Accordingly, the Guangzhou University of Chinese Medicine, China and the Ministry of Health and Social Security, Togo launched a nationwide Mass Drug Administration Project with artemisinin-piperaquine (AP) in Est-Mono. Before launching this project, the sensitivity test of AP was conducted in a general clinic in Elawagnon, Togo. With this background, we evaluated the efficacy and safety of AP for the treatment of uncomplicated falciparum malaria in children under the age of 5 years. Children aged 6-59 months with uncomplicated falciparum malaria were enrolled in this study. The selected patients were treated with a combination regime of artemisinin-piperaquine. The patients were followed up for 28 days, during which signs of the following were observed for: the duration for fever clearance, parasitemia density, gametophyte generation, cure rate, hemoglobin level, and merozoite surface protein-2 (msp-2) polymorphism. The primary end point was a 28-day cure rate and polymerase chain reaction (PCR)-corrected reinfection and recrudescence. This research followed the standardized World Health Organization (WHO) protocol for the assessment of the efficacy of antimalarial drugs. A total of 91 children with uncomplicated falciparum malaria were enrolled in this study. Adequate clinical and parasitological responses (ACPRs) before and after PCR-correction were 66 (73%) and 90 (99%), respectively. The average hemoglobin level in the patient increased by 0.05 g/dl per day (p < 0.0001) after the treatment. The gametophyte generation did not decline at the beginning of the treatment; however, after 14 days, it declined (day 21: p < 0.05; day 28: p < 0.01). In the msp-2 polymorphism study of 24 children treated for parasite infection, one case of msp-2 with 3D7 haplotype and FC27 haplotype was noted, indicating its recrudescence, with a frequency of 4%. The remaining 23 cases could have been of reinfection, with a frequency of 96%. No serious adverse reactions occurred, and AP was well-tolerated by all patients. Artemisinin-piperaquine was found to be an effective combination for treating uncomplicated falciparum malaria in children aged <5 years in Togo, and the drugs were well-tolerated. In Togo, Plasmodium falciparum remains sensitive to artemisinin-piperaquine, necessitating its trial in this region. Trial registration: ECGPHCM No. B2017-054-01; MHSST AVIS N° 0001/2016/CBRS du 07 janvier 2016. Registered 17 March 2014, http://www.chinadrugtrials.org.cn/eap/main.


Synthesis of novel dendritic 2,2'-bipyridine ligands and their application to Lewis acid-catalyzed diels-alder and three-component condensation reactions.
A series of dendritic ligands with a 2,2'-bipyridine core was synthesized through the coupling of 4,4'-dihydroxy-2,2'-bipyridine with poly(aryl ether) dendrons. The corresponding dendritic Cu(OTf)2 catalysts were used for Diels-Alder and three-component condensation reactions. The dendritic Cu(OTf)2-catalyzed Diels-Alder reaction proceeded smoothly, and these dendritic catalysts could be recycled without deactivation by reprecipitation. Three-component condensation reactions such as Mannich-type reactions also proceeded not only in dichloromethane but also in water. Furthermore, a positive dendritic effect on chemical yields was observed in both Diels-Alder reactions and aqueous-media three-component condensation reactions.


A unidirectional temperature gradient stage for solidification studies in aqueous solutions.
A low temperature light microscope stage has been designed and fabricated for quantitative analysis of the solidification of aqueous solutions. Thermal boundary conditions are controlled during freezing so as to enable direct comparison of data with complementary theoretical models. Evolution of the temperature distribution within the system is monitored by a one-dimensional thermocouple array, and growth of the phase interface is measured via a displacement transducer. The two-dimensional solution concentration field is assessed by computer densitometric analysis of the grey scale distribution for a light absorbing solute. Experimental and theoretical analyses of freezing processes with the stage correlate well, and the data base is shown to be internally consistent by independent thermal and mechanical measures of the interface velocity.


Biotherapeutics.
This Society for Medicines Research symposium was held on March 6, 2008, at the National Heart and Lung Institute, London, U.K. The meeting, organized by Kate Brown and David Fox reviewed the state-of-the-art in biotherapeutics. This is an area that is acquiring increasing importance in drug discovery and development portfolios, offering new and alternative ways of treating a wide range of conditions as well as opening up new and exciting areas of science and technology. Presentations ranged from the therapeutic potential of monoclonal and polyclonal antibodies, vaccines and oligonucleotides, through to the scientific basis of the emerging area of RNA interference. In addition, some of the technical aspects of delivering novel therapies and ensuring their quality were also discussed.


Potential multiple functions of the v-myc oncogene within a single cell clone of OK10 retrovirus-transformed quail fibroblasts.
Propagation of in vitro transformed OK10 QDP 9c cells, cloned in soft agar, results in selective amplification of the OK10 pro-viral genome to yield a 12-fold increase in v-myc oncogene expression. In addition, increased v-myc oncogene dosage correlates with an increase of the proliferative potential of already transformed cells and relieves dependence on high serum concentrations for optimal cell growth. The increased rate of cell proliferation is reflected by a much more rapid progression through all parts of the cell cycle. These results suggest that the attainment of transformed status on one hand and progressive increase in growth factor independence for optimal cell proliferation on the other hand, may be initiated by different myc oncogene dosages within the OK10 QDP 9c cell clone.


Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.
We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD. We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an APOE ε4 allele (OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least one APOE ε4 allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aβ42/Aβ40 ratio reflecting different pathways enriched in early and middle stages of disease. Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed an APOE ε4 dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.