Differential effects of selective and non-selective nitric oxide synthase inhibitors on the blood perfusion of ischemia-reperfused myocardium in dogs.
Nitric oxide (NO) is protective for the cardiovascular system, and excessive NO exerts negative effects on the circulatory system. This study aimed to compare the effects of selective or non-selective NO synthase (NOS) inhibitors on blood flow perfusion of ischemia-reperfused myocardium. Male mongrel dogs were randomly assigned to 4 groups: only ischemia-reperfusion (control), ischemia-reperfusion plus Nù-nitro-L-arginine methyl ester (NAME) treatment, ischemia-reperfusion plus aminoguanidine (AMD) treatment, and sham operation group. Myocardial contrast echocardiography (MCE) was performed. Blood samples were taken for measurement of NO. Background-subtracted peak videointensity (PVI) and PVI ratio in myocardium were measured. In the NAME-treated group, the PVI at 5 min reperfusion did not significantly differ from pre-LAD-occlusion, but declined to and retained at a level obviously lower than the pre-LAD-occlusion. In the AMD-treated group, the PVI at 5 min reperfusion was significantly higher than at pre-LAD-occlusion, and then restored to and remained at the pre-LAD-occlusion level. The changes of PVI ratios in the 3 groups were similar to PVI values. In the AMD-treated group, the curve width increased in the early reperfusion, but returned to the pre-LAD-occlusion level at 90 min reperfusion. The plasma NO concentration in the NAME-treated group greatly decreased and remained low during the whole period of reperfusion. In the AMD-treated group, there were only slight increases in NO concentrations during reperfusion. NAME totally inhibited NO production and attenuated myocardial blood flow perfusion. Aminoguanidine significantly relieved the increase in NO production and alleviated the congestion of reperfused myocardium. Selective inhibitors of iNOS might be useful in the management of certain diseases associated with ischemia-reperfusion.


Motor cortical activity during drawing movements: population representation during lemniscate tracing.
Activity was recorded extracellularly from single cells in motor and premotor cortex as monkeys traced figure-eights on a touch-sensitive computer monitor using the index finger. Each unit was recorded individually, and the responses collected from four hemispheres (3 primary motor and 1 dorsal premotor) were analyzed as a population. Population vectors constructed from this activity accurately and isomorphically represented the shape of the drawn figures showing that they represent the spatial aspect of the task well. These observations were extended by examining the temporal relation between this neural representation and finger displacement. Movements generated during this task were made in four kinematic segments. This segmentation was clearly evident in a time series of population vectors. In addition, the (2)/(3) power law described for human drawing was also evident in the neural correlate of the monkey hand trajectory. Movement direction and speed changed continuously during the task. Within each segment, speed and direction changed reciprocally. The prediction interval between the population vector and movement direction increased in the middle of the segments where curvature was high, but decreased in straight portions at the beginning and end of each segment. In contrast to direction, prediction intervals between the movement speed and population vector length were near-constant with only a modest modulation in each segment. Population vectors predicted direction (vector angle) and speed (vector length) throughout the drawing task. Joint angular velocity and arm muscle EMG were well correlated to hand direction, suggesting that kinematic and kinetic parameters are correlated in these tasks.


Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy.
Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α-synuclein (α-syn), demyelination, inflammation and neuronal loss. To date, no disease-modifying therapy is available. Targeting α-syn-driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood-brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α-syn specifically in oligodendrocytes (MBP29 mouse line), a well-described MSA model, and non-transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin-specific proteins in control and α-syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.


beta-Funaltrexamine inactivates ORL1 receptors in BE(2)-C human neuroblastoma cells.
The potential interactions of natively expressed mu-opioid and opioid receptor-like (ORL1) receptors were studied by exposing intact BE(2)-C cells to agonists or antagonists for 1 h. Pretreatment with the mu-opioid receptor agonist, [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), or the ORL1 receptor agonist, orphanin FQ/nociceptin desensitized both mu-opioid and ORL1 receptor responses. beta-Funaltrexamine (beta-FNA) pretreatment also blocked both mu-opioid and ORL1 receptor responses, but only mu-opioid receptor binding was reduced. Moreover, beta-FNA (1 microM) failed to inhibit specific ORL1 receptor binding.


Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864.
Ro 5-4864 (4'-chlorodiazepam) elicited convulsions in mice with a CD50 of 23.5 mg/kg (i.p.) and increased the firing rate of substantia nigra zona reticulata neurons in a dose dependent fashion (0.5-4 mg/kg i.v.). Diazepam and clonazepam, but not Ro 15-1788, were potent inhibitors of Ro 5-4864 induced convulsions. Ro 15-1788 was also ineffective in reversing Ro 5-4864 induced increases in cell firing of zone reticulata neurons. Muscimol potently inhibited the seizures and reversed increases in cell firing elicited by Ro 5-4864. Phenobarbital and pentobarbital inhibited Ro 5-4864 induced convulsions with moderate potencies, while phenytoin and carbamazepine were ineffective at doses of up to 100 mg/kg. These observations suggest that Ro 5-4864 does not elicit its pharmacologic actions through a direct action at a 'brain-type' benzodiazepine receptor. However, both the profile and potency of compounds effective in inhibiting the electrophysiological and pharmacological effects of Ro 5-4864 suggest that this compound may act by perturbation of a component of the GABA-benzodiazepine receptor chloride ionophore complex. These findings do not, however, rule out a direct involvement of the high affinity 'peripheral-type' benzodiazepine receptors found in brain.


The metabolism of fluoroacetate in lettuce.
1. Whole lettuce plants were incubated with (1) [1-(14)C]acetate, (2) fluoroacetate followed by [1-(14)C]acetate, (3) fluoro[1-(14)C]acetate, (4) fluoro[2-(14)C]acetate or (5) S-carboxy[(14)C]methylglutathione. 2. Fluoroacetate did not affect the expiration of (14)CO(2) from [1-(14)C]acetate and only a small amount of (14)CO(2) was produced from either fluoro[1-(14)C]-acetate or fluoro[2-(14)C]acetate in 43h. 3. Fluoroacetate at 50mg/kg wet wt. doubled the plant citrate concentration after 43h incubation, and depending on the age and size of the plant 50-100% of the compound was metabolized. 4. With both fluoro[1-(14)C]acetate and fluoro[2-(14)C]acetate all the radioactivity except that in the CO(2) was found in the water-soluble acid fraction. About 2% was in fluorocitrate and the remainder, apart from unchanged fluoroacetate, was in a number of compounds devoid of fluorine but containing nitrogen and sulphur. These were peptide-like and could be separated by chromatography on an amino acid analyser. 5. Identical compounds were obtained from the spontaneous reaction between iodo[2-(14)C]acetate and glutathione, the major product being S-carboxymethylglutathione. 6. S-Carboxymethylcysteine was also isolated and its mass spectrum compared with a commercial sample. 7. Reaction rates of all the monohaloacetates with glutathione were studied at pH7 at 25 degrees C. No reaction was observed with fluoroacetate. 8. The metabolism of fluoroacetate by lettuce is discussed in relation to that of aliphatic and aromatic halogen compounds, including fluoroacetate, by mammalian liver and to the metabolism of fluoroacetate by different plants reported by other workers.


Artemisia annua extracts, artemisinin and 1,8-cineole, prevent fruit infestation by a major, cosmopolitan pest of apples.
Extracts of Artemisia annua (L.) (Asteraceae) and artemisinins are used for treatment of malaria, parasitic infections and have potent anticancer properties in cell lines. Eucalyptus oil and 1,8-cineole have antimicrobial, immune-stimulatory, anti-inflammatory, antioxidant, analgesic, and spasmolytic effects. Codling moth, Cydia pomonella, (L.) (Tortricidae), is a major cosmopolitan pest of the apple, potentially causing damage translating to 40 billion US dollars per year, globally. Currently used control measures are either hazardous to agricultural workers and harmful to environment, or ineffective. The potential of plant-derived semiochemicals for codling moth control is heavily understudied. This study evaluated the potential of A. annua extracts, and two chemicals that this plant contains, artemisinin and 1,8-cineole, for preventing apple feeding and infestation by neonate Cydia pomonella larvae. We studied effects of A. annua extracts, artemisinin and 1,8-cineole on apple infestation by neonate codling moth larvae using fruit choice assay in laboratory experiments. Preference of fruit treated with test solutions versus fruit treated with solvent was recorded and analyzed. Crude A. annua extracts prevented fruit feeding at 1, 3, and 10 mg/ml. Artemisinin had feeding deterrent effects at 10 and 30 mg/ml, and 1,8-cineole at 100 and 300 mg/ml. A. annua contains chemicals that prevent apple infestation by codling moth neonates. Artemisinin and 1,8-cineole are among them, but there are other, polar constituents of A. annua, which have similar effects. There is a potential of using our findings in codling moth control and production of codling moth-resistant apples.


Prescribing patterns of polypharmacy in Korean pediatric patients.
Several studies have examined the risk and health outcomes related to polypharmacy among the elderly. However, information regarding polypharmacy among pediatric patients is lacking. The aim of this study was to investigate the prevalence of polypharmacy and its related factors among the pediatric population of South Korea. We used national claim data from the Health Insurance Review and Assessment Service-Pediatric Patients Sample (HIRA-PPS) in Korea originating from 2012 through 2016. Polypharmacy was defined as a daily average of two or more drugs used yearly. Complex chronic conditions (CCCs) were examined to evaluate concomitant chronic diseases in pediatric patients. Age-specific contraindications and potential drug-drug interactions were assessed according to criteria established by the Korea Institute of Drug Safety & Risk Management (KIDS). Descriptive statistics and logistic regression were conducted to analyze the status of polypharmacy and its associated risk factors in pediatric patients. The 5-year prevalence of pediatric polypharmacy in pediatric patients was 3.7%. The prevalence of polypharmacy was much higher in younger pediatric patients: 9.5% for patients between the ages of 1-7 years, 0.9% for ages 6-11 years, and 1.1% for ages 12-19 years. Pediatric patients with CCCs, Medical Aid benefits, or a hospital admission history had a significantly higher prevalence of polypharmacy when compared to their counterparts without those conditions. The most commonly prescribed drugs were respiratory agents (29%) followed by anti-allergic drugs (18.7%), central nervous system agents (15.9%), antibiotics (10.1%), and gastrointestinal drugs (7.7%). There was a positive correlation between the daily average number of inappropriate prescriptions and the degree of polypharmacy, especially in pediatric patients between the ages of 1-7 years. Contraindications and potential drug-drug interactions occurred in 11.0% and 10.1% of patients exposed to polypharmacy, respectively. One in ten pediatric patients under the age of 7 years was prescribed two or more concurrent drugs on average per day. Furthermore, pediatric patients exposed to polypharmacy showed an increased risk of inappropriate drug use. The implementation of a medication review system that considers pediatric patient polypharmacy exposure would reduce inappropriate drug use and prevent unwanted adverse outcomes.


Host-location behavior of the tea green leafhopper Empoasca vitis Göthe (Hemiptera: Cicadellidae): olfactory and visual effects on their orientation.
The tea green leafhopper, Empoasca vitis Göthe, is one of the most serious pests in tea growing areas. This study investigated the roles played by olfaction and vision in host orientation behavior. The compound eye of E. vitis was found to be a photopic eye; few olfactory sensilla were found on the antennae, while abundant gustatory sensilla were recorded on the mouthparts. Three opsin genes (EV_LWop, EV_UVop, EV_Bop) were isolated and found to be mainly expressed in the compound eye compared with other parts of the body. Immunolocalization indicated that the opsins mainly located in the different regions of rhabdom. The transcription levels of EV_LWop, EV_Bop and EV_UVop were reduced by 77.3, 70.0 and 40.0%, respectively, by RNA interference induced by being fed a special RNA-rich diet for 6 days. The rate of tropism to host color was effectively impaired by 67.6 and 29.5% in the dsEV_LWop and dsEV_Bop treatment groups, but there was no significant change in the dsEV_UVop group. The determination of the cause of the tropism indicated that odors from the host over long distances were unable to attract E. vitis and were only detected when the insects were close to the host. The developed compound eye of E. vitis plays a leading role in host location, and the long-wavelength opsin significantly affects the tropism to host color; the lack of olfactory sensilla results in long-distance odors not being able to be detected until the insect is near to the host-plant. The understanding of these behavioral mechanisms, especially the importance of opsin genes is expected to be useful for pest management.


The HARE-HTH and associated domains: novel modules in the coordination of epigenetic DNA and protein modifications.
Human ASXL proteins, orthologs of Drosophila Additional Sex combs, have been implicated in conjunction with TET2 as a major target for mutations and translocations leading to a wide range of myeloid leukemias, related myelodysplastic conditions (ASXL1 and ASXL2) and the Bohring-Opitz syndrome, a developmental disorder (ASXL1). Using sensitive sequence and structure comparison methods, we show that most animal ASXL proteins contain a novel N-terminal domain that is also found in several other eukaryotic chromatin proteins, diverse restriction endonucleases and DNA glycosylases, the RNA polymerase delta subunit of Gram-positive bacteria and certain bacterial proteins that combine features of the RNA polymerase α-subunit and sigma factors. This domain adopts the winged helix-turn-helix fold and is predicted to bind DNA. Based on its domain architectural contexts, we present evidence that this domain might play an important role, both in eukaryotes and bacteria, in the recruitment of diverse effector activities, including the Polycomb repressive complexes, to DNA, depending on the state of epigenetic modifications such as 5-methylcytosine and its oxidized derivatives. In other eukaryotic chromatin proteins, this predicted DNA-binding domain is fused to a region with three conserved motifs that are also found in diverse eukaryotic chromatin proteins, such as the animal BAZ/WAL proteins, plant HB1 and MBD9, yeast Itc1p and Ioc3, RSF1, CECR2 and NURF1. Based on the crystal structure of Ioc3, we establish that these motifs in conjunction with the DDT motif constitute a structural determinant that is central to nucleosomal repositioning by the ISWI clade of SWI2/SNF2 ATPases. We also show that the central domain of the ASXL proteins (ASXH domain) is conserved outside of animals in fungi and plants, where it is combined with other domains, suggesting that it might be an ancient module mediating interactions between chromatin-linked protein complexes and transcription factors via its conserved LXLLL motif. We present evidence that the C-terminal PHD finger of ASXL protein has certain peculiar structural modifications that might allow it to recognize internal modified lysines other than those from the N terminus of histone H3, making it the mediator of previously unexpected interactions in chromatin.


Sympathoinhibition evoked from caudal midline medulla is mediated by GABA receptors in rostral VLM.
The present study was performed to determine whether the powerful depressor and sympathoinhibitory response that can be evoked from neurons in the caudal midline medulla is mediated by gamma-aminobutyric acidergic (GABAergic) inhibition of sympathoexcitatory neurons in the rostral part of the ventrolateral medulla (VLM). In anesthetized barointact and barodenervated rabbits, bilateral micro-injections of bicuculline into sympathoexcitatory sites in the rostral VLM resulted in a sustained increase in renal sympathetic nerve activity and abolished or reversed the depressor and sympathoinhibitory response evoked by glutamate micro-injection into the caudal midline medulla. By contrast, the sympathoinhibitory response evoked from the caudal midline medulla persisted when the background level of renal sympathetic nerve activity was reflexly raised by baroreceptor unloading. The results indicate that 1) the depressor and sympathoinhibitory response evoked by stimulation of neurons in the caudal midline medulla is mediated by a GABAergic synapse in the rostral VLM and 2) there are also sympathoexcitatory neurons in the caudal midline medulla whose presence is revealed by blockade of the more powerful sympathoinhibitory response.


Nilotinib therapy in chronic myelogenous leukemia.
Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) is a highly effective inhibitor of the deregulated kinase activity of BCR-ABL in chronic myelogenous leukemia (CML) and represents the current standard of care for patients with this disease. Mutations within the ABL kinase domain that interfere with drug binding have been identified as the main mechanism of resistance to imatinib. Currently, more than 50 different BCR-ABL mutants conferring varying degrees of resistance to tyrosine kinase inhibitors have been identified. Nilotinib (Tasigna; Novartis) is a second-generation tyrosine kinase inhibitor with 30-fold higher potency against BCR-ABL kinase than imatinib. Notably, nilotinib is active against a wide range of imatinib-resistant or-intolerant patients, except for T315I. Results from the pivotal phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy indicate that nilotinib has a favorable toxicity profile and is highly efficacious in this setting. Studies exploring the efficacy of nilotinib as front-line therapy for patients with newly diagnosed CML are ongoing. Here, we review the preclinical and clinical development of nilotinib for the treatment of CML.


Longitudinal changes and body composition assessment using bioelectrical impedance in elderly patients with mild disequilibrium and different care needs.
[Purpose] This study involved performing longitudinal measurements of muscle mass in elderly patients with mild disequilibrium using a body composition meter. The rate of change and characteristics were determined according to the level of care needed. [Participants and Methods] Bioelectrical impedance was used to measure body composition in 20 elderly females in Care Needs Category 1 (n=10) and 2 (n=8); body composition was measured every 3 months for 1 year. [Results] Compared to Category 1, the muscle mass at each body site was lower in Category 2 and the muscle mass of the whole body and thighs in Category 2 decreased throughout the year. [Conclusion] Muscle mass in elderly patients needing assistance depended on the level of care, as suggested by the decrease in muscle mass in the whole body and thighs in Category 2 over time. In addition, effective rehabilitation intervention for the trunk is important.


Anterior Cruciate Ligament Reconstruction With Concomitant Meniscal Repair: Is Graft Choice Predictive of Meniscal Repair Success?
When meniscal repair is performed during anterior cruciate ligament (ACL) reconstruction (ACLR), the effect of ACL graft type on meniscal repair outcomes is unclear. The authors hypothesized that meniscal repairs would fail at the lowest rate when concomitant ACLR was performed with bone--patellar tendon--bone (BTB) autograft. Cohort study; Level of evidence, 3. Patients who underwent meniscal repair at primary ACLR were identified from a longitudinal, prospective cohort. Meniscal repair failures, defined as any subsequent surgical procedure addressing the meniscus, were identified. A logistic regression model was built to assess the association of graft type, patient-specific factors, baseline Marx activity rating score, and meniscal repair location (medial or lateral) with repair failure at 6-year follow-up. A total of 646 patients were included. Grafts used included BTB autograft (55.7%), soft tissue autograft (33.9%), and various allografts (10.4%). We identified 101 patients (15.6%) with a documented meniscal repair failure. Failure occurred in 74 of 420 (17.6%) isolated medial meniscal repairs, 15 of 187 (8%) isolated lateral meniscal repairs, and 12 of 39 (30.7%) of combined medial and lateral meniscal repairs. Meniscal repair failure occurred in 13.9% of patients with BTB autografts, 17.4% of patients with soft tissue autografts, and 19.4% of patients with allografts. The odds of failure within 6 years of index surgery were increased more than 2-fold with allograft versus BTB autograft (odds ratio = 2.34 [95% confidence interval, 1.12-4.92]; P = .02). There was a trend toward increased meniscal repair failures with soft tissue versus BTB autografts (odds ratio = 1.41 [95% confidence interval, 0.87-2.30]; P = .17). The odds of failure were 68% higher with medial versus lateral repairs (P < .001). There was a significant relationship between baseline Marx activity level and the risk of subsequent meniscal repair failure; patients with either very low (0-1 points) or very high (15-16 points) baseline activity levels were at the highest risk (P = .004). Meniscal repair location (medial vs lateral) and baseline activity level were the main drivers of meniscal repair outcomes. Graft type was ranked third, demonstrating that meniscal repairs performed with allograft were 2.3 times more likely to fail compared with BTB autograft. There was no significant difference in failure rates between BTB versus soft tissue autografts. NCT00463099 (ClinicalTrials.gov identifier).


Autoregulation of canonical Wnt signaling controls midbrain development.
After the primary anterior-posterior patterning of the neural plate, a subset of wnt signaling molecules including Xwnt-1, Xwnt-2b, Xwnt-3A, Xwnt-8b are still expressed in the developing brain in a region spanning from the posterior part of the diencephalon to the mesencephalon/metencephalon boundary. In this expression field, they are colocalized with the HMG-box transcription factor XTcf-4. Using antisense morpholino loss-of-function strategies, we demonstrate that the expression of this transcription factor depends on Xwnt-2b, which itself is under the control of XTcf-4. Marker gene analyses reveal that this autoregulatory loop is important for proper development of the midbrain and the isthmus. Staining for NCAM reveals a lack of dorsal neural tissue in this area. This reduction is caused by a reduced proliferation rate as shown by staining for PhosphoH3 positive nuclei. In rescue experiments, we demonstrate that individual isoforms of XTcf-4 control the development of different parts of the brain. XTcf-4A restored the expression of the mesencephalon marker genes pax-6 and wnt-2b but not the isthmus marker gene en-2. XTcf-4C, in contrast, restored en-2, but had only weak effects on pax-6 and wnt-2b. Thus, autoregulation of canonical Wnt signaling and alternative expression of different isoforms of XTcf-4 is essential for specifying the developing CNS.


Computational Structural Genomics Unravels Common Folds and Novel Families in the Secretome of Fungal Phytopathogen Magnaporthe oryzae.
Structural biology has the potential to illuminate the evolution of pathogen effectors and their commonalities that cannot be readily detected at the primary sequence level. Recent breakthroughs in protein structure modeling have demonstrated the feasibility to predict the protein folds without depending on homologous templates. These advances enabled a genome-wide computational structural biology approach to help understand proteins based on their predicted folds. In this study, we employed structure prediction methods on the secretome of the destructive fungal pathogen Magnaporthe oryzae. Out of 1,854 secreted proteins, we predicted the folds of 1,295 proteins (70%). We showed that template-free modeling by TrRosetta captured 514 folds missed by homology modeling, including many known effectors and virulence factors, and that TrRosetta generally produced higher quality models for secreted proteins. Along with sensitive homology search, we employed structure-based clustering, defining not only homologous groups with divergent members but also sequence-unrelated structurally analogous groups. We demonstrate that this approach can reveal new putative members of structurally similar MAX effectors and novel analogous effector families present in M. oryzae and possibly in other phytopathogens. We also investigated the evolution of expanded putative ADP-ribose transferases with predicted structures. We suggest that the loss of catalytic activities of the enzymes might have led them to new evolutionary trajectories to be specialized as protein binders. Collectively, we propose that computational structural genomics approaches can be an integral part of studying effector biology and provide valuable resources that were inaccessible before the advent of machine learning-based structure prediction.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia.
Induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Therapeutic applications of oral tolerance to autoimmunities are in progress both experimentally and clinically, while those to allergies have been poorly investigated. We examined the induction of CD4+ T cells with suppressive properties by oral tolerance and the mechanism by which these cells down-regulated Ag-induced eosinophilia in the trachea. Feeding of mice transgenic for anti-OVA TCR with high doses of OVA inhibited the airway eosinophilic inflammation induced by the intratracheally administered Ag. This inhibition reflected the mechanism of active suppression, since the inhibitory effect was adoptively transferred by splenic CD4+ T cells from the transgenic mice fed with high doses of OVA. The Ag specificity of the suppressor T cells was documented by the failure of spleen cells from mice that were orally tolerant of OVA to suppress irrelevant Ag, KLH-specific airway eosinophilic inflammation. The suppressive effect of the transferred T cells on eosinophil recruitment was neutralized by anti-TGF-beta mAb, but not anti-IFN-gamma mAb, indicating that the suppression is due to the inhibitory effect by secreted TGF-beta, but not to the dominance of the transferred Th1 cells over Th2 cells. This is the first study to reveal a link between oral tolerance and the regulation of Th2-mediated experimental tracheal eosinophilia through TGF-beta. Our experimental model suggests possible therapeutic applications of oral tolerance for the treatment of allergic disorders such as bronchial asthma.


The Role of Subinhibitory Concentrations of Daptomycin and Tigecycline in Modulating Virulence in Staphylococcus aureus.
Staphylococcus aureus (S. aureus) infections are notoriously complicated by the ability of the organism to grow in biofilms and are difficult to eradicate with antimicrobial therapy. The purpose of the current study was to clarify the influence of sub-inhibitory concentrations (sub-MICs) of daptomycin and tigecycline antibiotics on biofilm adhesion factors and exoproteins expressions by S. aureus clinical isolates. Six clinical isolates representing positive biofilm S. aureus clones (3 methicillin-sensitive S. aureus (MSSA) and 3 methicillin-resistant S. aureus (MRSA)) were grown with sub-MICs (0.5 MIC) of two antibiotics (daptomycin and tigecycline) for 12 h of incubation. RNA extracted from culture pellets was used via relative quantitative real-time-PCR (qRT-PCR) to determine expression of specific adhesion (fnbA, fnbB, clfA, clfB, fib, ebps, cna, eno) and biofilm (icaADBC) genes. To examine the effect of sub-MIC of these antibiotics on the expression of extracellular proteins, samples from the culture supernatants of six isolates were collected after 12 h of treatment with or without tigecycline in order to profile protein production via 2D gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2D gel-SDS-PAGE). Sub-MIC treatment of all clinical MRSA and MSSA strains with daptomycin or tigecycline dramatically induced or suppressed fnbA, fnbB, clfA, clfB, fib, ebps, cna, eno, and icaADBC gene expression. Furthermore, sub-MIC use of tigecycline significantly reduced the total number of separated protein spots across all the isolates, as well as decreasing production of certain individual proteins. Collectively, this study showed very different responses in terms of both gene expression and protein secretion across the various isolates. In addition, our results suggest that sub-MIC usage of daptomycin and tigecycline could signal virulence induction by S. aureus via the regulation of biofilm adhesion factor genes and exoproteins. If translating findings to the clinical treatment of S. aureus, the therapeutic regimen should be adapted depending on antibiotic, the virulence factor and strain type.


Surgical Skills Feedback and myTIPreport: Is There Construct Validity?
To initiate construct validity testing of myTIPreport for procedural skill assessment in a prospective multicenter evaluation study. Teachers and learners from a convenience-based site selection of obstetrics and gynecology (OBGYN) and female pelvic medicine and reconstructive surgery (FPMRS) training programs performed procedural assessments in myTIPreport. The specifically defined 5-point Dreyfus rating scale describing ability levels from novice to expert was used. Defined as the degree to which a test or measure assesses what it was designed to measure, construct validity of myTIPreport was tested by comparing the medians of procedure-specific overall assessments, by both teachers and learners themselves, of senior learners with junior learners. To minimize type I error, comparisons were performed only when a threshold of 10 or greater feedback encounters per learner group was met. Correlation of teacher assessments and learner self-assessments was examined for myTIPreport. From November 2014 to May 2016, 12 OBGYN and 7 FPMRS training programs participated. There were 440 learners and 443 teachers. Feedback was recorded on 5,093 surgical procedures; 4,567 for OBGYN residents and 526 for FPMRS fellows. Each OBGYN procedure had two categories of teacher and learner assessments comparing postgraduate year (PGY)-4 with PGY-1 learner performance. This yielded 48 possible assessment comparisons for the included 24 OBGYN procedures. In all, 28 of these 48 (58%) met the threshold number of observations per learner group. In 28 of these 28 (100%) comparison categories, PGY-4s rated significantly higher than PGY-1s. Similarly, in 16 of 18 (89%) comparison categories meeting inclusion criteria, FPMRS PGY-7s rated significantly higher than FPMRS PGY-5s. Strong correlation was noted of teacher assessments and learner self-assessments in myTIPreport with a Spearman correlation coefficient of 0.89 (P<.001). As noted for the majority of compared teacher assessments and learner self-assessments, myTIPreport appeared to detect differences between senior and junior learners. These data support the emerging construct validity of myTIPreport for procedural skills assessment.


[Lanthanide fluorescent immune analysis for determination of hormone thyroxine in dry blood spots].
The determination of thyroxin (T4) is a basic confirmative test for congenital hypothyroidism. 70% cases of this period inborn disease are taking asymptomatic course. We developed immunofluorescent T4-assay in dried blood spots with anti-T4 monoclonal antibody and europium chelate (dianhydride of diethylentriaminipentaacetic acid (DA-DTPA)). This method requires DELFIA Plate Fluorometer 1232 (Wallac, Finland) or its sub modifications. Panel of monoclonal antibodies for T4 has been obtained. Type/subtype (IgG2b, IgG1), affinity constants (10(7)-10(8) M-1), cross reactivity to homologous structures (0-2%) were determined. Stable clones with high affinity and viability were selected for the development of the assay. Conjugates of thyroxin and europium chelate were synthesized. Inclusion of sodium salicylate (2 mg/ml) and EDTA (2 mM) into the buffer reduced the nonspecific signal. Limit for T4 detection (T4 standarts) was 10 nM with not more than 15% variation coefficient. Accuracy was estimated by Bio-Rad Lipochek Immunoassay Plus Control Kit. Obtained results were within control confidence interval.


Sulfonate ester hydroxamic acids as potent and selective inhibitors of TACE enzyme.
Sulfonamide hydroxamate derivatives of anthranilic acids are known to be potent inhibitors of cell-free TACE enzyme. However, compounds of this structural class with both high potency and high selectivity for TACE over matrix metalloproteinases (MMPs) are uncommon. Replacement of the sulfonamide functionality with an isosteric sulfonate ester has resulted in a series of sulfonate ester hydroxamates, 2a-e, with excellent activity against TACE and excellent selectivity over MMP-1 and MMP-13. Although compounds 2a-e possess good permeability in a PAMPA assay, they are only weakly active as inhibitors of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production in human monocytic THP-1 cells. Protein binding affinity also does not predict the lack of cellular activity for these analogs.


Masking in three pinnipeds: underwater, low-frequency critical ratios.
Behavioral techniques were used to determine underwater masked hearing thresholds for a northern elephant seal (Mirounga angustirostris), a harbor seal (Phoca vitulina), and a California sea lion (Zalophus californianus). Octave-band white noise maskers were centered at five test frequencies ranging from 200 to 2500 Hz; a slightly wider noise band was used for testing at 100 Hz. Critical ratios were calculated at one masking noise level for each test frequency. Above 200 Hz, critical ratios increased with frequency. This pattern is similar to that observed in most animals tested, and indicates that these pinnipeds lack specializations for detecting low-frequency tonal sounds in noise. However, the individual pinnipeds in this study, particularly the northern elephant seal, detected signals at relatively low signal-to-noise ratios. These results provide a means of estimating zones of auditory masking for pinnipeds exposed to anthropogenic noise sources.


Autoantibodies to human citrullinated fibrinogen and their subfamilies to the α36-50Cit and β60-74Cit fibrin peptides similarly predict radiographic damages: a prospective study in the French ESPOIR cohort of very early arthritides.
To investigate whether subfamilies of the RA-specific autoantibodies to human citrullinated fibrinogen (AhFibA) differentially associate with the RA risk factors, HLA-DRB1 shared epitope containing alleles (SE alleles) and cigarette smoking, and thus help to predict the disease outcome. AhFibA and their anti-α36-50Cit and anti-β60-74Cit subfamilies were assayed by ELISA, at baseline, in the French ESPOIR (Etude et Suivi des Polyarthrites Indifférenciées Récentes) cohort composed of undifferentiated arthritides and RA patients of < 6 months' duration. Cigarette smoking, SE alleles' presence, DAS28, HAQ and modified Sharp-van der Heijde Score data were obtained at baseline, and after follow-up. After 3 years, 701 patients were classified as having RA according to the ACR/EULAR 2010 criteria. Among them, 349 (50%), 203 (29%) and 257 (37%) were AhFibA-, anti-α36-50Cit- and anti-β60-74Cit-positive, respectively. The presence and titres of AhFibA and their subfamilies similarly associated with SE alleles, irrespective of their fine specificity, without significant effect of smoking. Neither their presence nor their titre was associated with DAS28 or HAQ. The presence of at least one subfamily was associated with a faster Sharp/van der Heijde score progression, albeit without correlation with the titre. AhFibA and their main subfamilies are similarly associated with SE alleles without additional effect of smoking. Whatever their fine specificity was, their presence (but not their titre) similarly constituted a marker of faster joint destruction.


Effect of oxytocin infusion on luteal blood flow and progesterone secretion in dairy cattle.
The objective of this study was to investigate the effects of oxytocin infusion on corpus luteum (CL) function during early to mid-diestrus by measuring luteal size (LS) and luteal blood flow (LBF) along with plasma levels of progesterone (P4) and prostaglandin metabolites (13,14-dihydro-15-keto-prostaglandin F(2α), PGFM). On day (D) 7 of the estrus cycle (D1 = ovulation), seven cows received 100 IU of oxytocin (OXY) or placebo (PL) following a Latin square design. LS and LBF increased in both groups over time and no differences were observed between the groups. PGFM did not differ either within the groups over time or between the groups at any time point. P4 of the OXY group was higher compared to that of the the PL group 360 min after the infusion (p = 0.01) and tended to be higher at the time points 450 min, 48 h, and 72 h (all p = 0.08). Results from this study support the hypothesis that OXY is not directly involved in the mechanism(s) governing blood flow of the CL and has no remarkable effects either on luteal size or P4 and PGFM plasma levels. Further investigation is needed to elucidate the role of OXY in CL blood flow during early and late luteal phases.


Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor.
The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy. Pregnenolone sulfate, a neurosteroid, specifically enhances NMDA-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids glycine and gamma-aminobutyric acid, as well as non-NMDA glutamate receptors. This observation is consistent with the hypothesis that neurosteroids such as pregnenolone sulfate are involved in regulating the balance between excitation and inhibition in the central nervous system.


Prioritizing allocation of COVID-19 vaccines based on social contacts increases vaccination effectiveness.
We study allocation of COVID-19 vaccines to individuals based on the structural properties of their underlying social contact network. Even optimistic estimates suggest that most countries will likely take 6 to 24 months to vaccinate their citizens. These time estimates and the emergence of new viral strains urge us to find quick and effective ways to allocate the vaccines and contain the pandemic. While current approaches use combinations of age-based and occupation-based prioritizations, our strategy marks a departure from such largely aggregate vaccine allocation strategies. We propose a novel approach motivated by recent advances in (i) science of real-world networks that point to efficacy of certain vaccination strategies and (ii) digital technologies that improve our ability to estimate some of these structural properties. Using a realistic representation of a social contact network for the Commonwealth of Virginia, combined with accurate surveillance data on spatiotemporal cases and currently accepted models of within- and between-host disease dynamics, we study how a limited number of vaccine doses can be strategically distributed to individuals to reduce the overall burden of the pandemic. We show that allocation of vaccines based on individuals' degree (number of social contacts) and total social proximity time is significantly more effective than the currently used age-based allocation strategy in terms of number of infections, hospitalizations and deaths. Our results suggest that in just two months, by March 31, 2021, compared to age-based allocation, the proposed degree-based strategy can result in reducing an additional 56-110k infections, 3.2- 5.4k hospitalizations, and 700-900 deaths just in the Commonwealth of Virginia. Extrapolating these results for the entire US, this strategy can lead to 3-6 million fewer infections, 181-306k fewer hospitalizations, and 51-62k fewer deaths compared to age-based allocation. The overall strategy is robust even: (i) if the social contacts are not estimated correctly; (ii) if the vaccine efficacy is lower than expected or only a single dose is given; (iii) if there is a delay in vaccine production and deployment; and (iv) whether or not non-pharmaceutical interventions continue as vaccines are deployed. For reasons of implementability, we have used degree, which is a simple structural measure and can be easily estimated using several methods, including the digital technology available today. These results are significant, especially for resource-poor countries, where vaccines are less available, have lower efficacy, and are more slowly distributed.


HEPeak: an HMM-based exome peak-finding package for RNA epigenome sequencing data.
Methylated RNA Immunoprecipatation combined with RNA sequencing (MeRIP-seq) is revolutionizing the de novo study of RNA epigenomics at a higher resolution. However, this new technology poses unique bioinformatics problems that call for novel and sophisticated statistical computational solutions, aiming at identifying and characterizing transcriptome-wide methyltranscriptome. We developed HEP, a Hidden Markov Model (HMM)-based Exome Peak-finding algorithm for predicting transcriptome methylation sites using MeRIP-seq data. In contrast to exomePeak, our previously developed MeRIP-seq peak calling algorithm, HEPeak models the correlation between continuous bins in an m6A peak region and it is a model-based approach, which admits rigorous statistical inference. HEPeak was evaluated on a simulated MeRIP-seq dataset and achieved higher sensitivity and specificity than exomePeak. HEPeak was also applied to real MeRIP-seq datasets from human HEK293T cell line and mouse midbrain cells and was shown to be able to recapitulate known m6A distribution in transcripts and identify novel m6A sites in long non-coding RNAs. In this paper, a novel HMM-based peak calling algorithm, HEPeak, was developed for peak calling for MeRIP-seq data. HEPeak is written in R and is publicly available.


Chirped lasers dispersion spectroscopy implemented with single- and dual-sideband electro-optical modulators.
We report new approaches for signal generation in Chirped Laser Dispersion Spectroscopy (CLaDS). Two optical arrangements based on electro-optical modulators significantly reduce CLaDS system complexity and enable optimum performance when applied to detection of GHz-wide molecular transitions. Proof-of-principle experiments in the near-infrared spectral range are presented and potential strategies for application in the mid-infrared are discussed.


Refrigeration beyond weak internal coupling.
We investigate the performance of a three-spin quantum absorption refrigerator using a refined open quantum system model valid across all interspin coupling strengths. It describes the transition between previous approximate models for the weak and the ultrastrong coupling limit, and it predicts optimal refrigeration for moderately strong coupling, where both approximations are inaccurate. Two effects impede a more effective cooling: the coupling between the spins no longer reduces to a simple resonant energy exchange (the rotating wave approximation fails), and the interactions with the thermal baths become sensitive to the level splitting, thus opening additional heat channels between the reservoirs. We identify the modified conditions of refrigeration as a function of the interspin coupling strength, and we show that, contrary to intuition, a high-temperature work reservoir thwarts refrigeration in the strong coupling regime.


Maternal high-fat diet during pregnancy with concurrent phthalate exposure leads to abnormal placentation.
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical commonly used for its plasticizing capabilities. Because of the extensive production and use of DEHP, humans are exposed to this chemical daily. Diet is a significant exposure pathway and fatty food contain the highest level of phthalates. The impact on pregnancy following DEHP exposure and the associated interaction of high fat (HF) diet remains unknown. Here we report that exposure of pregnant mice to an environmentally relevant level of DEHP did not affect pregnancy. In contrast, mice fed a HF diet during gestation and exposed to the same level of DEHP display marked impairment in placental development, resulting in poor pregnancy outcomes. Our study further reveals that DEHP exposure combined with a HF diet interfere with the signaling pathway controlled by nuclear receptor PPARγ to adversely affect differentiation of trophoblast cells, leading to compromised vascularization and glucose transport in the placenta. Collectively, these findings demonstrate that maternal diet during pregnancy is a critical factor that determines whether exposure to an environmental toxicant results in impaired placental and fetal development, causing intrauterine growth restriction, fetal morbidity, and mortality.


Evaluating ureteral patency in the post-indigo carmine era: a randomized controlled trial.
Many gynecologic, urologic, and pelvic reconstructive surgeries require accurate intraoperative evaluation of ureteral patency. We performed a randomized controlled trial to compare surgeon satisfaction with 4 methods of evaluating ureteral patency during cystoscopy at the time of benign gynecologic or pelvic reconstructive surgery: oral phenazopyridine, intravenous sodium fluorescein, mannitol bladder distention, and normal saline bladder distention. We conducted an unblinded randomized controlled trial of the method used to evaluate ureteral patency during cystoscopy at time of benign gynecologic or pelvic reconstructive surgery. Subjects were randomized to receive 200 mg oral phenazopyridine, 25 mg intravenous sodium fluorescein, mannitol bladder distention, or normal saline bladder distention during cystoscopy. The primary outcome was surgeon satisfaction with the method, assessed via a 100-mm visual analog scale with 0 indicating strong agreement and 100 indicating strong disagreement with the statement. Secondary outcomes included comparing visual analog scale responses about ease of each method and visualization of ureteral jets, bladder mucosa and urethra, and operative information, including time to surgeon confidence in the ureteral jets. Adverse events were evaluated for at least 6 weeks after the surgical procedure, and through the end of the study. All statistical analyses were based on the intent-to-treat principle, and comparisons were 2-tailed. In all, 130 subjects were randomized to phenazopyridine (n = 33), sodium fluorescein (n = 32), mannitol (n = 32), or normal saline (n = 33). At randomization, patient characteristics were similar across groups. With regard to the primary outcome, mannitol was the method that physicians found most satisfactory on a visual analog scale. The median (range) scores for physicians assessing ureteral patency were 48 (0-83), 20 (0-82), 0 (0-44), and 23 (3-96) mm for phenazopyridine, sodium fluorescein, mannitol, and normal saline, respectively (P < .001). Surgery length, cystoscopy length, and time to surgeon confidence in visualization of ureteral jets were not different across the 4 randomized groups. During the 189-day follow-up, no differences in adverse events were seen among the groups, including urinary tract infections. The use of mannitol during cystoscopy to assess ureteral patency provided surgeons with the most overall satisfaction, ease of use, and superior visualization without affecting surgery or cystoscopy times. There were no differences in adverse events, including incidence of urinary tract infections.


Optical Fourier transform based in-plane vibration characterization for MEMS comb structure.
On-line and on-wafer characterizations of mechanical properties of Micro-Electro-Mechanical-System (MEMS) with efficiency are very important to the mass production of MEMS foundry in the near future. However, challenges still remain. In this paper, we present an in-plane vibration characterizing method for MEMS comb using optical Fourier transform (OFT). In the experiment, the intensity distribution at the focal plane was captured to characterize the displacement of the vibrator in the MEMS comb structure. A typical MEMS comb was tested to verify the principle. The shape and the movement of MEMS comb was imitated and tested to calibrate the measurement by using a spatial light modulator (SLM). The relative standard deviations (RSD) of the measured displacements were better than 5%, where the RSD is defined as the ratio of the standard deviation to the mean. It is convinced that the presented method is feasible for on-line and on-wafer characterizations for MEMS with great convenience, high efficiency and low cost.


Low bone mineral density and its predictors in type 1 diabetic patients evaluated by the classic statistics and artificial neural network analysis.
To investigate factors associated with bone mineral density (BMD) in type 1 diabetes by classic statistic and artificial neural networks. A total of 175 eugonadal type 1 diabetic patients (age 32.8 ± 8.4 years) and 151 age- and BMI-matched control subjects (age 32.6 ± 4.5 years) were studied. In all subjects, BMI and BMD (as Z score) at the lumbar spine (LS-BMD) and femur (F-BMD) were measured. Daily insulin dose (DID), age at diagnosis, presence of complications, creatinine clearance (ClCr), and HbA(1c) were determined. LS- and F-BMD levels were lower in patients (-0.11 ± 1.2 and -0.32 ± 1.4, respectively) than in control subjects (0.59 ± 1, P < 0.0001, and 0.63 ± 1, P < 0.0001, respectively). LS-BMD was independently associated with BMI and DID, whereas F-BMD was associated with BMI and ClCr. The cutoffs for predicting low BMD were as follows: BMI <23.5 kg/m(2), DID >0.67 units/kg, and ClCr <88.8 mL/min. The presence of all of these risk factors had a positive predictive value, and their absence had a negative predictive value for low BMD of 62.9 and 84.2%, respectively. Data were also analyzed using the TWIST system in combination with supervised artificial neural networks and a semantic connectivity map. The TWIST system selected 11 and 12 variables for F-BMD and LS-BMD prediction, which discriminated between high and low BMD with 67 and 66% accuracy, respectively. The connectivity map showed that low BMD at both sites was indirectly connected with HbA(1c) through chronic diabetes complications. In type 1 diabetes, low BMD is associated with low BMI and low ClCr and high DID. Chronic complications negatively influence BMD.


Depot risperidone in the outpatient management of bipolar disorder: a 2-year study of 10 patients.
Nonadherence with pharmacotherapy occurs frequently in bipolar patients, and is a common cause of relapse. Depot formulations of first-generation antipsychotic medications have been shown to reduce manic relapses during maintenance therapy in bipolar patients, but appear to increase liability for depressive episodes. A depot formulation of risperidone has recently become commercially available, but to date there is little evidence regarding its efficacy or safety in bipolar patients. Ten outpatients with bipolar I or II disorder, with a predominantly depressive course of illness, were prescribed risperidone Consta as an adjunct to mood stabilizing and other medications in routine clinical practice, and were followed during 2 years of maintenance therapy. The number of mood episodes, including depressive episodes, decreased in all patients compared with an equivalent pretreatment period. No patient required hospitalization for a mood episode. The number and doses of concomitant medications was reduced in most patients risperidone Consta was well tolerated, with minimal to modest weight gain, absent or reduced extrapyramidal symptoms, and few other side effects. Clinicians may consider risperidone Consta as an option in patients with refractory bipolar illness, including those with a predominantly depressive course, and particularly in patients' nonadherence with prescribed medications.


Sex- and age-dependent contribution of System xc- to cognitive, sensory, and social behaviors revealed by comprehensive behavioral analyses of System xc- null mice.
System xc- (Sxc-) is an important heteromeric amino acid cystine/glutamate exchanger that plays a pivotal role in the CNS by importing cystine into cells while exporting glutamate. Although certain behaviors have been identified as altered in Sxc- null mutant mice, our understanding of the comprehensive impact of Sxc- on behavior remains incomplete. To address this gap, we compared motor, sensory and social behaviors of male and female mice in mice null for Sxc- (SLC7A11sut/sut) with wildtype littermates (SLC7A11+/+) in a comprehensive and systematic manner to determine effects of genotype, sex, age, and their potential interactions. Motor performance was not affected by loss of Sxc- in both males and females, although it was impacted negatively by age. Motor learning was specifically disrupted in female mice lacking Sxc- at both 2 and 6 months of age. Further, female SLC7A11sut/sut mice at both ages exhibited impaired sociability, but normal spatial and recognition memory, as well as sensorimotor gating. Finally, pronounced open-space anxiety was displayed by female SLC7A11sut/sut when they were young. In contrast, young SLC7A11sut/sut male mice demonstrated normal sociability, delayed spatial learning, increased open-space anxiety and heightened sensitivity to noise. As they aged, anxiety and noise sensitivity abated but hyperactivity emerged. We find that the behavioral phenotypes of female SLC7A11sut/sut are similar to those observed in mouse models of autism spectrum disorder, while behaviors of male SLC7A11sut/sut resemble those seen in mouse models of attention deficit hyperactivity disorder. These results underscore the need for further investigation of SLC7A11 in neurodevelopment. By expanding our understanding of the potential involvement of Sxc-, we may gain additional insights into the mechanisms underlying complex neurodevelopmental conditions.


Exams disadvantage women in introductory biology.
The gender gap in STEM fields has prompted a great deal of discussion, but what factors underlie performance deficits remain poorly understood. We show that female students underperformed on exams compared to their male counterparts across ten large introductory biology course sections in fall 2016 (N > 1500 students). Females also reported higher levels of test anxiety and course-relevant science interest. Results from mediation analyses revealed an intriguing pattern: for female students only, and regardless of their academic standing, test anxiety negatively impacted exam performance, while interest in the course-specific science topics increased exam performance. Thus, instructors seeking equitable classrooms can aim to decrease test anxiety and increase student interest in science course content. We provide strategies for mitigating test anxiety and suggestions for alignment of course content with student interest, with the hope of successfully reimagining the STEM pathway as one that is equally accessible to all.


Dual role of BKI1 and 14-3-3 s in brassinosteroid signaling to link receptor with transcription factors.
The plasma membrane-localized plant steroid hormone receptor, BRASSINOSTEROID INSENSITIVE 1 (BRI1), is quiescent in the absence of steroids, largely due to a negative regulator, BRI1 KINASE INHIBITOR 1 (BKI1). Here, we report that the steroid-induced, plasma membrane-dissociated and phosphorylated BKI1 also plays positive roles in BR signaling by interacting with a subset of 14-3-3 proteins. The cytosolic fraction of BKI1 carboxyl terminal region enhances BR signaling. Mutations of two serine residues in this region lead to reduced phosphorylation by the BRI1 kinase and constitutive plasma membrane localization. The 14-3-3 proteins can interact with the phosphorylated BKI1 through a motif that contains the two phosphorylation sites to release inhibition of BRI1 by BKI1. Meanwhile, the cytosolic BKI1 antagonizes the 14-3-3 s and enhances accumulation of BRI1 EMS SUPPRESSOR 1 (BES1)/BRASSINAZOLE RESISTANT 1 (BZR1) in the nucleus to regulate BR-responses.


Documentation as a defense to legal claims.
Proper documentation and record keeping serve to protect the professional, as well as the patient. Complete and accurate records are the foundation of an optometrist's practice, as well as the best source of defense in the event of litigation.


Adverse Childhood Experiences and Building Resilience With the JoyPop App: Evaluation Study.
The effects of adverse childhood experiences (ACEs) on mental health, self-regulatory capacities, and overall resilience are well-known. Given such effects, ACEs may play a role in how individuals adjust to challenges later in life. Of interest in this study is the transition to university, a time of heightened stress when adapting to circumstances is required and when those with ACEs may need additional in-the-moment support to exercise resilience. A smartphone app may provide a worthwhile and readily accessible medium for a resilience intervention, provided behavioral outcomes are adequately evaluated. This study evaluates the impact of an innovative, smartphone app-based resilience intervention. The JoyPop app was designed to promote resilience through the use of self-regulatory skills such as emotion regulation and executive functioning. Among a sample of first-year undergraduate students, we explored whether use of the app would be associated with positive changes in resilience and related outcomes, and whether these benefits were influenced by level of childhood adversity. Participants (N=156) were requested to use the JoyPop app for 4 weeks, at least twice daily. Changes in resilience, emotion regulation, executive functioning, and depression were assessed after 2 and 4 weeks of app usage using multilevel modeling. The sample of 156 participants included 123 females and 33 males, with a mean age of 19.02 years (SD 2.90). On average participants used the app on 20.43 of the possible 28 days (SD 7.14). App usage was associated with improvements in emotion regulation (χ21=44.46; P<.001), such that it improved by 0.25 points on the 18-point scale for each additional day of app usage, and symptoms of depression (χ21=25.12; P<.001), such that depression symptoms were reduced by .08 points on the 9-point scale with each additional day of app usage. An interaction between ACEs and days of app usage existed for emotion regulation, such that participants with more adversity evidenced a faster rate of change in emotion regulation (P=.02). Results highlight that daily incorporation of an app-based resilience intervention can help youth who have experienced adversity to improve emotion regulation skills and experience reductions in depression. The JoyPop app represents an important step forward in the integration of resilience intervention research with a technology-based medium that provides in-the-moment support.


Ophthalmoplegic migraine: reversible enhancement and thickening of the cisternal segment of the oculomotor nerve on contrast-enhanced MR images.
Ophthalmoplegic migraine is a rare condition characterized by the association of headaches and an oculomotor nerve palsy. We report six patients with typical clinical features of this disorder in whom enhancement of the cisternal segment of the oculomotor nerve developed during the acute phase, followed by resolution of enhancement over several weeks as the symptoms resolved. Six patients, ages 3 to 27 years, underwent MR imaging during the acute phase of ophthalmoplegic migraine and at the time of recovery several weeks later. The MR studies, performed on a 1.5-T MR unit, included noncontrast and contrast-enhanced axial and coronal T1-weighted sequences. Sagittal images were obtained in two patients, with and without contrast enhancement. Enhancement of the cisternal segment of the oculomotor nerve was seen in all patients at initial presentation. Contrast-enhanced studies also showed focal thickening at the exit of the nerve in the interpeduncular cistern in five of six patients. No patient had enhancement of the cavernous sinus or adjacent dura. Enhancement was almost completely resolved on follow-up studies 7 to 9 weeks later. Our findings confirm an intrinsic transient abnormality in the cisternal segment of the third nerve in patients with a typical clinical presentation of ophthalmoplegic migraine.


Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix.
Epithelial sheets define organ architecture during development. Here, we employed an iterative multiscale computational modeling and quantitative experimental approach to decouple direct and indirect effects of actomyosin-generated forces, nuclear positioning, extracellular matrix, and cell-cell adhesion in shaping Drosophila wing imaginal discs. Basally generated actomyosin forces generate epithelial bending of the wing disc pouch. Surprisingly, acute pharmacological inhibition of ROCK-driven actomyosin contractility does not impact the maintenance of tissue height or curved shape. Computational simulations show that ECM tautness provides only a minor contribution to modulating tissue shape. Instead, passive ECM pre-strain serves to maintain the shape independent from actomyosin contractility. These results provide general insight into how the subcellular forces are generated and maintained within individual cells to induce tissue curvature. Thus, the results suggest an important design principle of separable contributions from ECM prestrain and actomyosin tension during epithelial organogenesis and homeostasis.


The Next Step in the Treatment of Stroke.
Although many patients do not receive reperfusion therapy because of delayed presentation and/or severity and location of infarct, new reperfusion approaches are expanding the window of intervention. Novel application of neuroprotective agents in combination with the latest methods of reperfusion provide a path to improved stroke intervention outcomes. We examine why neuroprotective agents have failed to translate to the clinic and provide suggestions for new approaches. New developments in recanalization therapy in combination with therapeutics evaluated in parallel animal models of disease will allow for novel, intra-arterial deployment of therapeutic agents over a vastly expanded therapeutic time window and with greater likelihood success. Although the field of neuronal, endothelial, and glial protective therapies has seen numerous large trials, the application of therapies in the context of newly developed reperfusion strategies is still in its infancy. Given modern imaging developments, evaluation of the penumbra will likely play a larger role in the evolving management of stroke. Increasingly more patients will be screened with neuroimaging to identify patients with adequate collateral blood supply allowing for delayed rescue of the penumbra. These patients will be ideal candidates for therapies such as reperfusion dependent therapeutic agents that pair optimally with cutting-edge reperfusion techniques.


Bayesian networks and imaging-derived phenotypes highlight the role of fat deposition in COVID-19 hospitalisation risk.
Objective: Obesity is a significant risk factor for adverse outcomes following coronavirus infection (COVID-19). However, BMI fails to capture differences in the body fat distribution, the critical driver of metabolic health. Conventional statistical methodologies lack functionality to investigate the causality between fat distribution and disease outcomes. Methods: We applied Bayesian network (BN) modelling to explore the mechanistic link between body fat deposition and hospitalisation risk in 459 participants with COVID-19 (395 non-hospitalised and 64 hospitalised). MRI-derived measures of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat were included. Conditional probability queries were performed to estimate the probability of hospitalisation after fixing the value of specific network variables. Results: The probability of hospitalisation was 18% higher in people living with obesity than those with normal weight, with elevated VAT being the primary determinant of obesity-related risk. Across all BMI categories, elevated VAT and liver fat (>10%) were associated with a 39% mean increase in the probability of hospitalisation. Among those with normal weight, reducing liver fat content from >10% to <5% reduced hospitalisation risk by 29%. Conclusion: Body fat distribution is a critical determinant of COVID-19 hospitalisation risk. BN modelling and probabilistic inferences assist our understanding of the mechanistic associations between imaging-derived phenotypes and COVID-19 hospitalisation risk.


[Our variant of the prerequisites for the conversion of the otorhinolaryngological services to the cost-accountable system].
At the basis of disproportions existing in the otorhinolaringological service of the Region, and the necessity to eliminate them, the author suggests a variant of organizational prerequisites for making ENT service cost accountable. The technological links in the process of transition, as viewed by the author, should be such analytical parts of work as: testing performance of ENT clinics by central regional, city and district hospitals, assessment of the amount and quality of performance of regional, city and district ENT-specialists in accordance with the idea of the optimum model of regional ENT service, diagnostically related groups of ENT diseases permitting to make analysis with allowances made for the latter, and also variants of incentive payments for the staff participating in the cost-accounting activity.


Cellular localisation of structurally diverse diphenylacetylene fluorophores.
Fluorescent probes are increasingly used as reporter molecules in a wide variety of biophysical experiments, but when designing new compounds it can often be difficult to anticipate the effect that changing chemical structure can have on cellular localisation and fluorescence behaviour. To provide further chemical rationale for probe design, a series of donor-acceptor diphenylacetylene fluorophores with varying lipophilicities and structures were synthesised and analysed in human epidermal cells using a range of cellular imaging techniques. These experiments showed that, within this family, the greatest determinants of cellular localisation were overall lipophilicity and the presence of ionisable groups. Indeed, compounds with high log D values (>5) were found to localise in lipid droplets, but conversion of their ester acceptor groups to the corresponding carboxylic acids caused a pronounced shift to localisation in the endoplasmic reticulum. Mildly lipophilic compounds (log D = 2-3) with strongly basic amine groups were shown to be confined to lysosomes i.e. an acidic cellular compartment, but sequestering this positively charged motif as an amide resulted in a significant change to cytoplasmic and membrane localisation. Finally, specific organelles including the mitochondria could be targeted by incorporating groups such as a triphenylphosphonium moiety. Taken together, this account illustrates a range of guiding principles that can inform the design of other fluorescent molecules but, moreover, has demonstrated that many of these diphenylacetylenes have significant utility as probes in a range of cellular imaging studies.


Effects of long-term phenobarbital treatment on the liver in dogs.
Long-term administration of phenobarbital has been reported to cause hepatic injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to distinguish the effect of enzyme induction on serum liver enzyme activities from actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of enzyme induction on serum liver enzyme activity were investigated prospectively in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h, resulting in therapeutic serum phenobarbital concentrations (20-40 microg/mL). Serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin were determined before and during treatment. Lateral abdominal radiographs, abdominal ultrasounds, and histopathologic examinations of liver tissue obtained by ultrasound-guided biopsy were performed before and during treatment. Radiographs revealed a moderate increase in liver size in most dogs. Ultrasonographic examination revealed no change in liver echogenicity or architecture. No evidence of morphologic liver damage was observed histopathologically. ALP and ALT increased significantly (P < .05), GGT increased transiently, and albumin decreased transiently during the study. There were no significant changes in AST, bilirubin, and fBA. These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.


Isotope fractionation of micropollutants during large-volume extraction: heads-up from a critical method evaluation for atrazine, desethylatrazine and 2,6-dichlorobenzamide at low ng/L concentrations in groundwater.
Micropollutants are frequently detected in groundwater. Thus, the question arises whether they are eliminated by natural attenuation so that pesticide degradation would be observed with increasing residence time in groundwater. Conventional analytical approaches rely on parent compound/metabolite ratios. These are difficult to interpret if metabolites are sorbed or further transformed. Compound-specific stable isotope analysis (CSIA) presents an alternative for identifying degradation based on the analysis of natural isotope abundances in pesticides and their changes during degradation. However, CSIA by gas chromatography-isotope ratio mass spectrometry is challenged by the low concentrations (ng/L) of micropollutants in groundwater. Consequently, large amounts of water need to be sampled requiring enrichment and clean-up steps from interfering matrix effects that must not introduce artefacts in measured isotope values. The aim of this study was to evaluate the accuracy of isotope ratio measurements of the frequently detected micropollutants atrazine, desethylatrazine and 2,6-dichlorobenzamide after enrichment from large water volumes (up to 100 L) by solid-phase extraction with consecutive clean-up by HPLC. Associated artefacts of isotope discrimination were found to depend on numerous factors including organic matter content and extraction volume. This emphasizes the necessity to perform a careful method evaluation of sample preparation and sample pre-treatment prior reliable CSIA.


Theoretical approaches to the evolution of development and genetic architecture.
Developmental evolutionary biology has, in the past decade, started to move beyond simply adapting traditional population and quantitative genetics models and has begun to develop mathematical approaches that are designed specifically to study the evolution of complex, nonadditive systems. This article first reviews some of these methods, discussing their strengths and shortcomings. The article then considers some of the principal questions to which these theoretical methods have been applied, including the evolution of canalization, modularity, and developmental associations between traits. I briefly discuss the kinds of data that could be used to test and apply the theories, as well as some consequences for other approaches to phenotypic evolution of discoveries from theoretical studies of developmental evolution.


Dodecyl gallate, permitted in food, is a strong sensitizer.
Additives are now an established part of our packaged food. Some, like colouring agents and flavouring compounds are hardly necessary or even redundant. Others, mainly antimicrobials and antioxidants, are very important. Antioxidants are not only added to food, but also to cosmetics, pharmaceuticals and industrial products. Dodecyl gallate belongs with propyl- and octyl-gallate to the synthetic esters of gallic acid. These lipid-soluble phenols are very effective antioxidants. We found contact allergy in 4 of 10 workers having only limited contact with dodecyl gallate in the very low concentration of 0.05%. It is important to recognize its strong sensitizing capacity. Workers working with dodecyl gallate should avoid direct skin contact.


Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus.
Seven arabinosyl, 2'-deoxyribosyl, and ribosyl pyrrolo[2,3-d]pyrimidines were evaluated in vitro for activity against human cytomegalovirus and for cytotoxicity in primary and established cell lines of human origin. The parent ribosyl analogs exhibited little antiviral selectivity owing to high cytotoxicity. In contrast, ara-tubercidin, ara-toyocamycin, ara-sangivamycin, and deoxysangivamycin exhibited selectivity between antiviral effect (measured by plaque or titer reduction or both) and cytotoxicity (measured microscopically and by incorporation of radioactive precursors into DNA, RNA, and protein). The selectivity (in vitro therapeutic indexes) for these four compounds ranged from 2 to 40. The two sangivamycin analogs were the most potent and selective. Ara-sangivamycin, for example, inhibited virus replication 10(5)-fold at a concentration (10 microM) which produced only partial inhibition of cell growth and labeled precursor incorporation. The four arabinosyl and deoxyribosyl nucleosides appeared to act by inhibition of viral DNA synthesis as quantitated by DNA-DNA dot blot hybridization. These four analogs also were tested for activity against two strains of type 1 herpes simplex virus by a plaque reduction assay. Unexpectedly, all compounds inhibited herpes simplex virus to a lesser extent than human cytomegalovirus.


Enhanced synthesis of 5-hydroxy-l-tryptophan through tetrahydropterin regeneration.
5-Hydroxy-l-tryptophan (5-HTP) is a naturally occurring aromatic amino acid present in the seeds of the African plant Griffonia simplicifolia. Although 5-HTP has therapeutic effects in various symptoms, efficient method of producing 5-HTP has not been established. In this study, we developed a novel cofactor regeneration process to achieve enhanced synthesis of 5-HTP by using modified l-phenylalanine 4-hydroxylase of Chromobacterium violaceum. For the synthesis of 5-HTP using Escherichia coli whole cell bioconversion, l-tryptophan and 5-HTP degradation by E. coli endogenous catabolic enzymes should be considered. The tryptophanase gene was disrupted using the λ red recombination system, since tryptophanase is postulated as an initial enzyme for the degradation of l-tryptophan and 5-HTP in E. coli. For regeneration of the cofactor pterin, we screened and investigated several key enzymes, including dihydropteridine reductase from E. coli, glucose dehydrogenase from Bacillus subtilis, and pterin-4α-carbinolamine dehydratase from Pseudomonas syringae. Genes encoding these three enzymes were overexpressed in an E. coli tryptophanase-deficient host, resulting in the synthesis of 0.74 mM 5-HTP in the presence of 0.1 mM pterin and the synthesis of 0.07 mM 5-HTP in the absence of regeneration of pterin. These results clearly indicated the successful regeneration of pterin. Following optimization of the reaction conditions, 2.5 mM 5-HTP was synthesized with cofactor regeneration, while 0.8 mM 5-HTP was recovered without cofactor regeneration under the same reaction conditions, suggesting that the principle described here provides a new method for cofactor regeneration.


OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients.
Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that chronic cancer pain as well as high-dose opioid use lead to mu-opioid receptor downregulation. In this study we explore downregulation of the mu-opioid receptor gene (OPRM1), as a mechanism for opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high-dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on 2 main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons. We demonstrate that epigenetic regulation of OPRM1 contributes to opioid tolerance in cancer patients, and that targeted gene therapy could treat cancer-induced nociception and opioid tolerance in a mouse cancer model.


Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity.
Paired immunofluorescent staining with antibodies specific for the major isotypes of mouse immunoglobulin was used to study the ontogenetic expression of diversity of cell surface immunoglobulin. The first B lymphocytes to emerge, derived from cytoplasmic IgM+ precursors, express sIgM exclusively. Between birth and 3 days of age separate populations of sIgM+ B lymphocyte acquire a second isotype: sIgD, one of the subclasses of sIgG, or sIgA. At 3 days, all splenic B lymphocytes that bear sIg or sIgA also express sIgM, but virtually none stain for sIgD. By 7 days, a substantial porportion of sIgG+ or sIgA+ lymphocytes in spleen and most of those in lymph node express both sIgM ans sIgD. Anti-mu antibody treatment from birth prevented development of B lymphocytes expressing any isotype. These observations suggest that the immature sIgM+ B lymphocyte is the pivotal cell in the generation of the different sublines of B cells and that sIgD ig or IgA. The frequency of lymphocytes bearing only sIgG or sIgA is higher in old than in young mice, suggesting that sIgD and sIgM may be lost after stimulation by antigens. The occurrence of a nearly identical distribution of sIg isotypes on B lymphocytes from athymic, pathogen-free mice suggests that primary expression of isotype diversity does not require T cells.


The impact of pre-donated autologous blood and intra-operative isovolaemic haemodilution on the outcome of transfusion in patients undergoing radical retropubic prostatectomy.
To assess the impact of pre-donated autologous blood and intra-operative isovolaemic haemodilution on the outcome of transfusions in patients undergoing radical retropubic prostatectomy. The charts and transfusion records of 192 consecutive patients undergoing radical retropubic prostatectomy were reviewed retrospectively. Of 192 patients, 14% required homologous transfusions, the rate of which varied significantly depending upon blood availability (autologous, haemodilution or homologous) (P < 0.001): 66% of patients with only autologous blood available were transfused a mean of 1.96 units (range 1-6) of blood, of which 87% received autologous alone. 12% both autologous and homologous and 1% homologous blood only. Of the pre-donated autologous units, 44% were wasted. Both the pre-donation of autologous blood and intra-operative isovolaemic haemodilution lower the risk of homologous blood transfusion. It is recommended that patients pre-donate 2 units of autologous blood and undergo intra-operative isovolaemic haemodilution before radical prostatectomy.


The endocannabinoid system drives neural progenitor proliferation.
The discovery of multipotent neural progenitor (NP) cells has provided strong support for the existence of neurogenesis in the adult brain. However, the signals controlling NP proliferation remain elusive. Endocannabinoids, the endogenous counterparts of marijuana-derived cannabinoids, act as neuromodulators via presynaptic CB1 receptors and also control neural cell death and survival. Here we show that progenitor cells express a functional endocannabinoid system that actively regulates cell proliferation both in vitro and in vivo. Specifically, NPs produce endocannabinoids and express the CB1 receptor and the endocannabinoid-inactivating enzyme fatty acid amide hydrolase (FAAH). CB1 receptor activation promotes cell proliferation and neurosphere generation, an action that is abrogated in CB1-deficient NPs. Accordingly, proliferation of hippocampal NPs is increased in FAAH-deficient mice. Our results demonstrate that endocannabinoids constitute a new group of signaling cues that regulate NP proliferation and thus open novel therapeutic avenues for manipulation of NP cell fate in the adult brain.


Electrocardiographic changes in acute pancreatitis.
Electrograms recorded during 50 episodes of acute pancreatitis were analyzed and compared to those recorded during an asymptomatic period. Ten episodes of acute pancreatitis occurred in eight patients with normal ECGs during an asymptomatic period. Nonspecific ST-T changes were recorded in only two of them (one with mild hypokalemia). ECGs recorded during 40 episodes of acute pancreatitis in 24 patients who had ECG abnormalities during an asymptomatic period revealed no significant changes during 33 of the episodes. The seven episodes associated with significant ECG changes occurred in patients with previous ECG abnormalities. Review of the literature and of our cases strongly suggests that significant ECG alterations during acute pancreatitis usually occur in patients with previous cardiac abnormalities.


Diet-induced metabolic acidosis.
The modern Western-type diet is deficient in fruits and vegetables and contains excessive animal products, generating the accumulation of non-metabolizable anions and a lifespan state of overlooked metabolic acidosis, whose magnitude increases progressively with aging due to the physiological decline in kidney function. In response to this state of diet-derived metabolic acidosis, the kidney implements compensating mechanisms aimed to restore the acid-base balance, such as the removal of the non-metabolizable anions, the conservation of citrate, and the enhancement of kidney ammoniagenesis and urinary excretion of ammonium ions. These adaptive processes lower the urine pH and induce an extensive change in urine composition, including hypocitraturia, hypercalciuria, and nitrogen and phosphate wasting. Low urine pH predisposes to uric acid stone formation. Hypocitraturia and hypercalciuria are risk factors for calcium stone disease. Even a very mild degree of metabolic acidosis induces skeletal muscle resistance to the insulin action and dietary acid load may be an important variable in predicting the metabolic abnormalities and the cardiovascular risk of the general population, the overweight and obese persons, and other patient populations including diabetes and chronic kidney failure. High dietary acid load is more likely to result in diabetes and systemic hypertension and may increase the cardiovascular risk. Results of recent observational studies confirm an association between insulin resistance and metabolic acidosis markers, including low serum bicarbonate, high serum anion gap, hypocitraturia, and low urine pH.


A note on the variance of the number of loci having a given gene frequency.
In a recent not in this journal (MARUYAMA 1973), one of us has considered, for a certain genetic model, the variance of the distribution of the number of loci having a given gene frequency. The formula given is incorrect. This brief note considers this problem and notes the correct solution in one particular case.


Chemoenzymatic Synthesis of a Novel Borneol-Based Polyester.
Terpenes are a class of natural compounds that have recently moved into the focus as a bio-based resource for chemical production, owing to their abundance, their mostly cyclic structures, and the presence of olefin or single hydroxy groups. To apply this raw material in new industrial fields, a second hydroxy group is inserted into borneol by cytochrome P450cam (CYP101) enzymes in a whole-cell catalytic biotransformation with Pseudomonas putida KT2440. Next, a semi-continuous batch system was developed to produce 5-exo-hydroxyborneol with a final concentration of 0.54 g L-1 . The bifunctional terpene was then used for the synthesis of a bio-based polyester by a solvent-free polycondensation reaction. The resulting polymer showed a glass transition temperature of around 70 °C and a molecular weight in the range of 2000-4000 g mol-1 (Mw ). These results show that whole-cell catalytic biotransformation of terpenes could lead to bio-based, higher-functionalized monomers, which might be basic raw materials for different fields of application, such as biopolymers.


The role of surface charge in ionic germination of Clostridium perfringens spores.
The surface charge against pH behaviour of spores of Clostridium perfringens type A was determined using a colloid titration method in the pH range 4-9. The native spores as well as various ionic forms of the spores loaded with divalent cations were found to be negatively charged. A positive colloid, MGCh, inhibited the ionic germination of the spores and this inhibition was highly dependent on pH. However, another positive colloid, GCh, did not inhibit the germination. Chemical modification of carboxyl groups on the spore surface by use of a water-soluble carbodiimide with two nucleophiles, glycine ethyl ester and taurine, caused spores not only to have little or no colloidal charge but also to lose the ability to germinate. The modification of carboxyl groups in the spore coat protein also resulted in elimination of, or marked reduction in its negative charge. These results suggest that carboxyl groups in the spore coat protein are the major negatively charged species on the spore surface. The role of surface charge in the ionic germination of the spores is discussed.


Using family network data in child protection services.
Preventing child abuse is a unifying goal. Making decisions that affect the lives of children is an unenviable task assigned to social services in countries around the world. The consequences of incorrectly labelling children as being at risk of abuse or missing signs that children are unsafe are well-documented. Evidence-based decision-making tools are increasingly common in social services provision but few, if any, have used social network data. We analyse a child protection services dataset that includes a network of approximately 5 million social relationships collected by social workers between 1996 and 2016 in New Zealand. We test the potential of information about family networks to improve accuracy of models used to predict the risk of child maltreatment. We simulate integration of the dataset with birth records to construct more complete family network information by including information that would be available earlier if these databases were integrated. Including family network data can improve the performance of models relative to using individual demographic data alone. The best models are those that contain the integrated birth records rather than just the recorded data. Having access to this information at the time a child's case is first notified to child protection services leads to a particularly marked improvement. Our results quantify the importance of a child's family network and show that a better understanding of risk can be achieved by linking other commonly available datasets with child protection records to provide the most up-to-date information possible.


Spatial and temporal variation in Rhipicephalus appendiculatus size in eastern Zambia.
The size of Rhipicephalus appendiculatus collected at different altitudes in the Eastern Province of Zambia between February 1985 and May 1986 and between October 1994 and December 1996 showed distinct variation dependent on altitude and season. The ticks were smallest during the dry season and at the start of the rains, and specimens were larger as the rainy season progressed. Second-generation adults where on average smaller than first-generation ticks. At higher altitudes, where a one-generation-per-annum phenology dominates, ticks were larger than at intermediate altitudes, where two generations per year are common. Larger size, associated with increased survival, is also favoured in low-lying, drier areas. Selective mortality of smaller adult ticks in years with a delayed rainy season appears to play an important role in the variation in size between years.


The First Crested Duck Genome Reveals Clues to Genetic Compensation and Crest Cushion Formation.
The Chinese crested (CC) duck is a unique indigenous waterfowl breed, which has a crest cushion that affects its survival rate. Therefore, the CC duck is an ideal model to investigate the genetic compensation response to maintain genetic stability. In the present study, we first generated a chromosome-level genome of CC ducks. Comparative genomics revealed that genes related to tissue repair, immune function, and tumors were under strong positive selection, indicating that these adaptive changes might enhance cancer resistance and immune response to maintain the genetic stability of CC ducks. We also assembled a Chinese spot-billed (Csp-b) duck genome, and detected the structural variations (SVs) in the genome assemblies of three ducks (i.e., CC duck, Csp-b duck, and Peking duck). Functional analysis revealed that several SVs were related to the immune system of CC ducks, which further strongly suggests that genetic compensation in the anti-tumor and immune systems supports the survival of CC ducks. Moreover, we confirmed that the CC duck originated from the mallard ducks. Finally, we revealed the physiological and genetic bases of crest traits and identified a causative mutation in TAS2R40 that leads to crest formation. Overall, the findings of this study provide new insights into the role of genetic compensation in adaptive evolution.


Almotriptan increases sustained pain-free outcomes in acute migraine: results from three controlled clinical trials.
Evaluate the effect of almotriptan on sustained pain-free outcome in patients with acute migraine. Three randomized, double-blind, placebo-controlled trials of almotriptan for the treatment of acute migraine were examined. Two trials evaluated almotriptan 6.25 mg and 12.5 mg, and the third evaluated almotriptan 12.5 mg and sumatriptan 100 mg. Patients aged 18 to 65 years were instructed to take 1 dose of study medication at the onset of a moderate-to-severe migraine headache. A second dose was allowed for relapse. Sustained pain-free was defined as a decrease in pain severity from moderate or severe at baseline to no pain at 2 hours postdose and without relapse or the use of escape medication between 2 and 24 hours. A total of 1791 adult migraine sufferers were studied. The proportion of patients achieving a sustained pain-free state was significantly (P<.05) higher in the almotriptan 6.25-mg (21.7% to 22.5%) and 12.5-mg (24.6% to 27.6%) groups than in the placebo group (7.5% to 12.1%). The proportion of patients achieving a sustained pain-free state was comparable between almotriptan 12.5 mg (24.6%) and sumatriptan 100 mg (28.5%) and significantly (P<.05) greater than with placebo (12.1%). Among patients with severe baseline pain, a sustained pain-free state was achieved in significantly more patients (P<.05) with almotriptan 12.5 mg (17.3% to 20.9%) than with placebo (3.1% to 3.2%). Among those with moderate baseline pain, a sustained pain-free state was achieved in significantly more patients (P<.01) with almotriptan 12.5 mg (31.3% to 32.0%) than with placebo (10.2% to 16.1%). Almotriptan 12.5 mg is significantly better than placebo and comparable to sumatriptan 100 mg for achieving a sustained pain-free state.


Effects of inhaled fenoterol on the circadian rhythm of expiratory flow in allergic bronchial asthma.
Metered-dose aerosol treatment with fenoterol for three consecutive days, in eight patients suffering from allergic asthma, caused the disappearance of FEV1 and MEF50 circadian rhythm. We attribute such behavior to the suppression of the bronchomotor tone induced by fenoterol. The administration on different days of a single dose of fenoterol aerosol in another group of eight patients pointed out the variability of the effects of the drug at different hours of the day. We believe the results obtained are important for a better dosage and time distribution of the therapy with beta2 agonists.


Theta Oscillations Through Hippocampal/Prefrontal Pathway: Importance in Cognitive Performances.
Among various hippocampal rhythms, including sharp-wave ripples, gamma, and theta, theta rhythm is crucial for cognitive processing, particularly learning and memory. Theta oscillations are observable in both humans and rodents during spatial navigations. However, the hippocampus (Hip) is well known as the generator of current rhythm, and other brain areas, such as prefrontal cortex (PFC), can be affected by theta rhythm, too. The PFC is a core structure for the execution of diverse higher cortical functions defined as cognition. This region is connected to the hippocampus through the hippocampal/prefrontal pathway; hereby, theta oscillations convey hippocampal inputs to the PFC and simultaneously synchronize the activity of these two regions during memory, learning and other cognitive tasks. Importantly, thalamic nucleus reunions (nRE) and basolateral amygdala are salient relay structures modulating the synchronization, firing rate, and phase-locking of the hippocampal/prefrontal oscillations. Herein, we summarized experimental studies, chiefly animal researches in which the theta rhythm of the Hip-PFC axis was investigated using either electrophysiological assessments in rodent or integrated diffusion-weighted imaging and electroencephalography in human cases under memory-based tasks. Moreover, we briefly reviewed alterations of theta rhythm in some CNS diseases with the main feature of cognitive disturbance. Interestingly, animal studies implied the interruption of theta synchronization in psychiatric disorders such as schizophrenia and depression. To disclose the precise role of theta rhythm fluctuations through the Hip-PFC axis in cognitive performances, further studies are needed.