Ketamine ameliorates depressive-like behaviors by tPA-mediated conversion of proBDNF to mBDNF in the hippocampus of stressed rats.
Some studies have indicated that ketamine has a rapid antidepressant effects, but the underlying molecular mechanism is still unclear. Researchers have found that mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF are related to depression; they elicit opposite effects on cellular functions. It is clear that tissue plasminogen activator (tPA) is a key regulatory element in the conversion of proBDNF to mBDNF. The chronic unpredicted mild stress (CUMS) procedure is a classical and reliable method to establish the model of depression. This study found that sucrose preference and locomotor activity were both reduced in CUMS-treated rats while were increased in those who were injected with ketamine. The hippocampal proBDNF/mBDNF ratio was downregulated after ketamine treatment in those rats, together with an increased level of tPA in the hippocampus. However, tPA activity was unaltered after ketamine intraperitoneal injection. Intrahippocampal injection of active plasminogen activator inhibitor-1 (inhibitor of tPA) before ketamine treatment reversed the antidepressant effects and upregulated the proBDNF/mBDNF ratio. The results of this study suggest that the antidepressant action induced by ketamine may be related to tPA-mediated conversion of proBDNF to mBDNF in the hippocampus.


Relative Rates of Surface and Volume Synthesis Set Bacterial Cell Size.
Many studies have focused on the mechanisms underlying length and width determination in rod-shaped bacteria. Here, we focus instead on cell surface area to volume ratio (SA/V) and demonstrate that SA/V homeostasis underlies size determination. We propose a model whereby the instantaneous rates of surface and volume synthesis both scale with volume. This model predicts that these relative rates dictate SA/V and that cells approach a new steady-state SA/V exponentially, with a decay constant equal to the volume growth rate. To test this, we exposed diverse bacterial species to sublethal concentrations of a cell wall biosynthesis inhibitor and observed dose-dependent decreases in SA/V. Furthermore, this decrease was exponential and had the expected decay constant. The model also quantitatively describes SA/V alterations induced by other chemical, nutritional, and genetic perturbations. We additionally present evidence for a surface material accumulation threshold underlying division, sensitizing cell length to changes in SA/V requirements.


An Environmental Scan of Existing Canadian Childcare Resources Targeting Improvements in Health Behaviours.
The objective was to conduct an environmental scan of existing Canadian childcare resources targeting nutrition, physical activity, sedentary behaviour, and/or sleep. A comprehensive search plan was conducted that involved four search strategies: (1) grey literature databases, (2) customized Google search engines, (3) targeted websites, and (4) consultation with content experts. A resource (i.e., information, materials) must have been created by government or an organization/agency within Canada, available in English, intended for childcare educators or directors working with children ≤ 5 years of age, and focused on targeting improvements in nutrition, physical activity, sedentary behaviour, and/or sleep. The quality of each included resource was assessed using a modified version of the Authority, Accuracy, Coverage, Objectivity, Date, Significance checklist. A total of 192 eligible resources were included. Most resources targeted only nutrition (n = 101) or physical activity (n = 60), and few resources targeted only sedentary behaviour (n = 2) or sleep (n = 1). The remaining 28 resources targeted more than one health behaviour. The 4 most common topics of resources were menu/meal planning (n = 55), healthy nutrition practices/environment (n = 37), physical activities/games (n = 33), and nutrition/food literacy (n = 20). Only 52 included resources cited evidence. One-third of the included resources (n = 64) were rated as high quality, including 55 that received a point for the significance criterion. Therefore, numerous high quality Canadian childcare resources exist for nutrition and physical activity. Future resource development is needed for sedentary behaviour and sleep. Findings can assist future intervention work and the database of resources can be utilized by relevant stakeholders to support other childcare initiatives. The online version contains supplementary material available at 10.1007/s10643-021-01266-2.


OLIG-1 and 2 gene expression and oligodendroglial tumours.
OLIG 1/2 genes encode basic helix-loop-helix transcription factors that play a critical role in motor neurone and oligodendrocyte fate specification during development. Two recent studies in which OLIG transcripts were detected by in situ hybridization have reported a high expression of the OLIG genes in oligodendrogliomas. This suggests that the detection of these lineage markers could become an adjunct to the classic morphological diagnosis of these tumours. There are problems in the diagnosis of oligodendroglioma. To date, all other known oligodendrocyte lineage markers have failed to label specifically neoplastic oligodendrocytes. Deletions on chromosome 1p and 19q are much more frequent in oligodendrogliomas than in astrocytomas but these molecular alterations are not constant. For the future, when routinely available, immunohistochemical techniques using anti-OLIG antibodies on paraffin embedded tissues will allow a systematic study of a large series of tumours so that we will know the specificity and sensitivity of this investigation in diagnosis. At another level, it is possible that expression of OLIG in neoplastic oligodendrocyte might participate in the oncogenesis of oligodendrogliomas. Initial work suggests that this is probably not the case. However further in vitro and in vivo studies analysing the functional consequence of OLIG overexpression in terms of proliferation and tumour progression are needed.


Evading apoptosis in cancer.
Carcinogenesis is a mechanistically complex and variable process with a plethora of underlying genetic causes. Cancer development comprises a multitude of steps that occur progressively starting with initial driver mutations leading to tumorigenesis and, ultimately, metastasis. During these transitions, cancer cells accumulate a series of genetic alterations that confer on the cells an unwarranted survival and proliferative advantage. During the course of development, however, cancer cells also encounter a physiologically ubiquitous cellular program that aims to eliminate damaged or abnormal cells: apoptosis. Thus, it is essential that cancer cells acquire instruments to circumvent programmed cell death. Here we discuss emerging evidence indicating how cancer cells adopt various strategies to override apoptosis, including amplifying the antiapoptotic machinery, downregulating the proapoptotic program, or both.


Outcome processing and the sense of agency.
People can distinguish outcomes they cause from those they do not; that is, they are quite able to sense self-agency in outcomes. A well-received idea is that the sense of agency is produced by a comparison between a predicted outcome and the actual outcome that occurs. While research has generally focused on understanding predictive representations and the comparison process, less work has been done on the actual outcomes and, in particular, how these are perceived or apprehended. Here, we studied this issue. In two experiments, we found outcomes are continuously, as opposed to partially, sampled throughout their span. Specifically, we found that prediction-inconsistent signals embedded within otherwise prediction-consistent outcomes were able to influence agency ratings, and this was true whether the contrary signals were embedded early or late in the outcome.


Structure-function relationships of a membrane pore forming toxin revealed by reversion mutagenesis.
Cyt2Aa1 is a haemolytic membrane pore forming toxin produced by Bacillus thuringiensis subsp. kyushuensis. To investigate membrane pore formation by this toxin, second-site revertants of an inactive mutant toxin Cyt2Aa1-I150A were generated by random mutagenesis using error-prone PCR. The decrease in side chain length caused by the replacement of isoleucine by alanine at position 150 in the alphaD-beta4 loop results in the loss of important van der Waals contacts that exist in the native protein between I150 and K199 and L203 on alphaE. 28 independent revertants of I150A were obtained and their relative toxicity can be explained by the position of the residue in the structure and the effect of the mutation on side-chain interactions. Analysis of these revertants revealed that residues on alphaA, alphaB, alphaC, alphaD and the loops between alphaA and alphaB, alphaD and beta5, beta6 and beta7 are important in pore formation. These residues are on the surface of the molecule suggesting that they may participate in membrane binding and toxin oligomerization. Changing the properties of the amino acid side-chains of these residues could affect the conformational changes required to transform the water-soluble toxin into the membrane insertion competent state.


Appetitive and aversive motivation in depression: The temporal dynamics of task-elicited asymmetries in alpha oscillations.
The capability model of alpha asymmetries posits that state emotional manipulations are a more powerful detector of depression-related motivational deficits than alpha activity at rest. The present study used a time-frequency approach to investigate the temporal dynamics of event-related changes in alpha power during passive viewing of emotional pictures in individuals with dysphoria (n = 23) and in individuals without dysphoria (n = 24). In the whole group, the processing of pleasant and unpleasant compared to neutral pictures was associated with a decrease in event-related alpha power (i.e., alpha desynchronization) at centro-parietal and parietal scalp sites in the 538-1400 ms post-stimulus. The group with dysphoria revealed a smaller alpha desynchronization than the group without dysphoria in response to pleasant, but not neutral and unpleasant, stimuli at frontal, fronto-central and centro-parietal sites. Interestingly, at central and centro-parietal scalp sites, the difference between groups in response to pleasant stimuli was lateralized to the right hemisphere, whereas no clear lateralization was observed at frontal and fronto-central scalp sites. These findings suggest that decreased cortical activity (i.e., reduced alpha desynchronization) in a network involving bilateral frontal and right-lateralized parietal regions may provide a specific measure of deficits in approach-related motivation in depression.


The effects of marking and capture on recapture frequencies of butterflies.
As a preliminary to a population study using markrelease-recapture techniques, specimens of the Satyrid buttfly Melanargia galathea (L.) were subjected to a number of marking and capture techniques. Although the adults are thought to display both aposematic and cryptic coloration, the use of marks of different sizes and colours had no significant effect on recapture frequencies. However, repeated disturbance due to capture was found to significantly reduce recapture frequency. The influence of the different techniques on recapture frequencies could not be detected reliably by excessively low recapture rates, or by comparisons to Poisson distributions. It is suggested that these comparisons are of limited value as measures of the suitability of a marking or handling scheme. Subsequent work showed that capture affected recapture rates of several other species. Moreover, these effects could not be readily predicted from knowledge of the biology of these species. The implications of these findings are discussed.


Sonographic diagnosis of placenta accreta. Presentation of six cases.
Placenta accreta is a rare complication of pregnancy that risks the life of pregnant women. We report six cases, five of which had ultrasound examination performed before delivery, and one whose diagnosis was made retrospectively.


The phylogenetic position of the oxymonad Saccinobaculus based on SSU rRNA.
The oxymonads are a group of structurally complex anaerobic flagellates about which we know very little. They are found in association with complex microbial communities in the guts of animals. There are five recognized families of oxymonads; molecular data have been acquired for four of these. Here, we describe the first molecular data from the last remaining group, represented by Saccinobaculus, an organism that is found exclusively in the hindgut of the wood-eating cockroach Cryptocercus. We sequenced small subunit ribosomal RNA (SSU rRNA) from total gut DNA to describe Saccinobaculus SSU rRNA diversity. We also sequenced SSU rRNA from manually isolated cells of the two most abundant and readily identifiable species: the type species Saccinobaculus ambloaxostylus and the taxonomically contentious Saccinobaculus doroaxostylus. We inferred phylogenetic trees including all five known oxymonad subgroups in order to elucidate the internal phylogeny of this poorly studied group, to resolve some outstanding issues of the taxonomy and identification of certain Saccinobaculus species, and to investigate the evolution of character states within it. Our analysis recovered strong support for the existence of the five subgroups of oxymonads, and consistently united the subgroups containing Monocercomonoides and Streblomastix, but was unable to resolve any further higher-order branching patterns.


The BOLD response in primary motor cortex and supplementary motor area during kinesthetic motor imagery based graded fMRI neurofeedback.
There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.


An experiential approach to cultural awareness in child welfare.
To promote the training of workers for more effective practice with ethnic minorities, the authors report on a program whose key feature is internship in ethnic minority agencies.


Structural priming during comprehension: A pattern from many pieces.
Syntactic/structural priming has been shown to take place during comprehension. However, early comprehension findings revealed discrepancies with those in production, such as little to no abstract priming, yet readily observable lexically-mediated priming. These observations spurred important questions about whether structural processing is more lexically dependent during comprehension, whether abstract priming occurs at all during comprehension, and whether the mechanisms of structural facilitation are shared across these two modalities. The past decade has fortunately yielded many influential structural priming studies in comprehension, including those that seek to bridge the gap between structural processing across production and comprehension. This review serves to summarize recent findings that provide compelling evidence that abstract structural priming and learning do take place in comprehension, and that these effects show parity with those found in production. Competing mechanistic explanations of structural priming are also reviewed and considered in light of findings in both modalities. Lastly, a summary is provided that outlines future lines of inquiry needed to establish a better understanding of structural representation, priming, and learning in comprehension, and more generally.


The electrophysiologic basis for the antiarrhythmic and anticonvulsant effects of n-3 polyunsaturated fatty acids: heart and brain.
The n-3 polyunsaturated fatty acids (PUFA) have been shown to be antiarrhythmic in animals and probably in humans. PUFA stabilize the electrical activity of isolated cardiac myocytes by modulating sarcolemmal ion channels, so that a stronger electrical stimulus is required to elicit an action potential and the refractory period is markedly prolonged. Inhibition of voltage-dependent sodium currents, which initiate action potentials in excitable tissues, and of the L-type calcium currents, which initiate release of sarcoplasmic calcium stores, thus increasing cytosolic free calcium concentrations and activating the contractile proteins in myocytes, appears at present to be the probable major antiarrhythmic mechanisms of PUFA. Because the ion channels in neurons have channel proteins essentially homologous to those in the heart, the n-3 fatty acids would appear to be likely to affect the electrical activity in the brain in a manner similar to their effects in the heart, and accumulating evidence supports this notion. Evidence of important beneficial neurological effects of dietary n-3 PUFA are emerging with more likely to be discovered.


Increased peripheral helper T cells type 17 subset correlates with the severity of psoriasis vulgaris.
Recently, a new subgroup of T cells, named peripheral helper T (Tph) cells, has been implicated in autoimmune pathogenesis. An imbalance of Tph cell subsets influences the severity of immune-related diseases. However, the characteristics and roles of Tph cell subsets in psoriasis remain unknown. Programmed cell death 1-positive, chemokine C-X-C receptor (CXCR) 5-negative Tph cells can be divided into 3 subgroups based on differential expression of chemokine CXCR3 and chemokine C-C receptor (CCR) 6. CXCR3+CCR6- Tph cells are classified as Tph1, CXCR3-CCR6- Tph cells are classified as Tph2, and CXCR3-CCR6+ Tph cells are classified as Tph17. In this study, conditions of circulating Tph cell subsets and CD4+CXCR5+ follicular helper T (Tfh) cells in 27 patients with psoriasis and 13 healthy individuals were detected by flow cytometry. The level of plasma chemokine C-X-C ligand (CXCL) 13 was measured by enzyme-linked immunosorbent assay. The correlations between the above indexes and disease severity were explored. In the peripheral blood of patients with psoriasis, Tph17 cells had an activated, proliferative phenotype; the quantity of the cells correlated with disease severity. Plasma CXCL13 levels were elevated in psoriasis and associated with disease severity and the frequency of Tph17 cells. CD4+CXCR5+ Tfh cells were increased in patients and positively correlated with disease severity, the frequency of Tph17 cells, and plasma CXCL13 levels. Our results suggest that Tph17 cells and the CXCL13/CXCR5 axis may be involved in the pathogenesis of psoriasis and represent new immunotherapeutic targets for treating psoriasis.


Relationship of hypovitaminosis D and secondary hyperparathyroidism with bone mineral density among UK resident Indo-Asians.
There is a high prevalence of vitamin D deficiency in UK resident Indo-Asians and this may be complicated by secondary hyperparathyroidism. To investigate the relationship between these conditions and bone mineral density (BMD) in Indo-Asian rheumatology patients. 110 Indo-Asian patients presenting to a general rheumatology clinic were selected for the study, of whom 77 were vitamin D deficient (HD), and 33 also had associated secondary hyperparathyroidism (HD-SHPT). BMD measurements at the femoral neck (FN), lumbar spine (LS), distal radius (DR), and radius 33% were obtained. T and Z scores were used in the evaluation of the dual energy x ray absorptiometry findings. The Mann-Whitney U test and chi(2) tests were used in the statistical analysis. The patients with HD-SHPT had significantly lower serum 25-OH-vitamin D, higher serum alkaline phosphatase, and lower calcium levels than the HD group. Both T and Z scores failed to show any significant difference between the groups in the LS, but patients with HD-SHPT compared with those with HD had significantly lower FN T scores (-1.05 (1.47) v 0.28 (1.22), p=0.003), FN Z scores (-0.45 (1.27) v 0.26 (0.96), p=0.001), DR T scores (-1.83 (1.82) v -0.44 (1.77), p<0.001), DR Z scores (-1.25 (1.44) v -0.08 (1.6), p=0.001), radius 33% T scores (-1.65 (1.66) v -0.79 (1.21), p=0.008), and radius 33% Z scores (-1.07 (1.28) v -0.44 (1.1), p=0.017). Hypovitaminosis D complicated by secondary hyperparathyroidism is associated with significantly decreased bone mineral density.


Dexamethasone induced preadipocyte recruitment and expression of CCAAT/enhancing binding protein alpha and peroxisome proliferator activated receptor-gamma proteins in porcine stromal-vascular (S-V) cell cultures obtained before and after the onset of fetal adipogenesis.
The present study examined the influence of dexamethasone (DEX) treatment on preadipocyte recruitment and expression of transcription factor proteins in adipose tissue stromal-vascular (S-V) cell cultures from 50 and 75 day old pig fetuses and young pigs. C/EBPalpha, C/EBPdelta, and PPARgamma immunoreactive cells had evenly reactive nuclei and unreactive nucleoli. DEX recruited many more preadipocytes in 75 day than in 50 day fetal S-V cultures. However, DEX did not increase the number of differentiated preadipocytes (lipid+, C/EBPalpha+) in 50 day S-V cultures and only slightly increased this number in 75 day fetal S-V cultures. In fetal cultures, extensive, precocious increases in C/EBPalpha expression (number of reactive cells) by day three were followed by extensive decreases in expression. However, PPARgamma expression was not expressed precociously since preadipocyte lipid accretion and PPARgamma immunoreactivity were strongly linked in fetal and pig S-V cultures. Nevertheless, all cells with lipid in fetal S-V cultures were C/EBPalpha and PPARgamma reactive. DEX increases preadipocyte differentiation in pig S-V cultures and in this study DEX increased PPARgamma expression to a much greater degree in pig than in fetal S-V cultures. These studies suggest that restricted adipogenesis in the pig fetus is attributable to limited DEX induced PPARgamma expression.


Influenza infection and risk of acute myocardial infarction in England and Wales: a CALIBER self-controlled case series study.
An association between infections and vascular events has been observed, but the specific effect of influenza and influenza-like illnesses on triggering acute myocardial infarction (AMI) is unclear. Episodes of first AMI from 1 January 2003 through 31 July 2009 were identified using linked anonymized electronic medical records from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. Self-controlled case series analysis was used to investigate AMI risks after consultation for acute respiratory infection. Infections were stratified by influenza virus circulation, diagnostic code, and vaccination status to assess whether influenza was more likely than other infections to trigger AMI. Of 22,024 patients with acute coronary syndrome, 11,208 met the criterion of having had their first AMI at the age of ≥ 40 years, and 3927 had also consulted for acute respiratory infection. AMI risks were significantly raised during days 1-3 after acute respiratory infection (incidence ratio, 4.19 [95% confidence interval, 3.18-5.53], with the effect tapering over time. The effect was greatest in those aged ≥ 80 years (P = .023). Infections occurring when influenza was circulating and those coded as influenza-like illness were associated with consistently higher incidence ratios for AMI (P = .012). Influenza and other acute respiratory infections can act as a trigger for AMI. This effect may be stronger for influenza than for other infections. NCT01106196.


Arabidopsis thaliana cor15b, an apparent homologue of cor15a, is strongly responsive to cold and ABA, but not drought.
We previously described a cold-regulated (cor) gene from Arabidopsis thaliana, cor15a (formerly cor15), that encodes a 15 kDa polypeptide that is targeted to chloroplasts (C. Lin and M. Thomashow, Plant Physiol 99 (1992): 519-525). Here we describe an apparent homologue of cor15a, cor15b. cor15b is located immediately downstream from cor15a (within 1 kb) and has the same relative 5' to 3' orientation as cor15a. The predicted coding regions for the two genes are 82% identical at the nucleic acid sequence level. Transcripts for cor15b, like those of cor15a, increase dramatically in response to low temperature and exogenous application of ABA. However, only cor15a transcripts accumulate to high levels in response to drought. The cor15a/cor15b gene pair is the third case in which A. thaliana cold-regulated genes have been found to exist as tandem gene pairs with the members of each pair being differentially regulated.


Epidemiologic impact of blood culture practices and antibiotic consumption on pneumococcal bacteraemia in children.
This study examined the roles of two different diagnostic approaches to children with fever of unknown origin in determining the patterns of pneumococcal bacteraemia in two Spanish regions by comparing their main epidemiologic characteristics. Whereas a blood culture is routinely obtained in this setting in Navarre, this is not generally the case in Majorca. Additionally, the potential role of antibiotic consumption in each region was also analysed. Cumulative incidences in children under the age of 14 years were 26.6 per 100,000 child-years in Navarre (121.1 in children <2 years of age) and 7.3 per 100,000 child-years in Majorca (33.3 in children <2 years of age). In contrast, the incidences per 1,000 blood cultures were similar in both regions. The relative risks of occult bacteraemia, bacteraemic pneumonia and meningitis among the children of Navarre compared to Majorcan children were 11.8, 2.6 and 0.8, respectively. The risk for less virulent (vaccine serotypes plus 6A, 19A and 23A) and for more virulent serotypes (1 and 7) was 4.9 and 3.1 times higher in Navarre, respectively. The number of 7-valent pneumococcal conjugate vaccine (PCV7) doses administered between 2003 and 2004 were also higher in Navarre. Conversely, antibiotic resistance and paediatric prescriptions for broad-spectrum antibiotics were greater in Majorca. Although the most salient differences between both regions, including the effectiveness of pneumococcal conjugate vaccine in Navarre, appeared to be confounded by the higher frequency of blood cultures taken there, certain differences in serotype composition may be explained by the higher antibiotic consumption in Majorca.


[Parents' attitudes towards childhood fever. A cross-sectional survey in the Lyon metropolitan area (202 cases)].
The patient overload in pediatric healthcare facilities is caused in part by parents bringing their children in for consultations for fever. We conducted a survey in the Lyon metropolitan area to improve our understanding of parents' attitudes towards their children's fever. To assess the frequency and characteristics of healthcare utilization and evaluate parents' knowledge and attitudes before consulting. A random sample of families with at least one child under 6 years of age and living in the Lyon metropolitan area was surveyed by telephone, according to a closed questionnaire that was answered by the person usually responsible for the child's health. 202 families were questioned: 58.9% defined fever as a temperature over 38 degrees C, and 82% used rectal thermometers to measure temperature. Among 144 parents of children with an episode of fever within the previous 12 months, 73% called a physician during the episode, 44% of them immediately. Working-class parents called more frequently (90%) than parents who were professionals or managers (74%). Most parents (94%) administered medication to the child several times before calling the physician. Paracetamol and ibuprofen were mentioned most often. 93% of fever episodes led to consultations. Our results show that 59% of the sample defined fever as a temperature equal to 38 degrees C and that fever episodes lead commonly and quickly to physician visits, but that parents do use physical methods and drugs to reduce fever before calling a physician.


Pituitary adenylate cyclase-activating polypeptide type 1 receptor signaling evokes long-lasting nociceptive behaviors through the activation of spinal astrocytes in mice.
Intrathecal (i.t.) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) induces long-lasting nociceptive behaviors for more than 60 min in mice, while the involvement of PACAP type1 receptor (PAC1-R) has not been clarified yet. The present study investigated signaling mechanisms of the PACAP-induced prolonged nociceptive behaviors. Single i.t. injection of a selective PAC1-R agonist, maxadilan (Max), mimicked nociceptive behaviors in a dose-dependent manner similar to PACAP. Pre- or post-treatment of a selective PAC1-R antagonist, max.d.4, significantly inhibited the nociceptive behaviors by PACAP or Max. Coadministration of a protein kinase A inhibitor, Rp-8-Br-cAMPS, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor, PD98059 or a c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly inhibited the nociceptive behaviors by Max. Immunohistochemistry and immunoblotting analysis revealed that spinal administration of Max-induced ERK phosphorylation and JNK phosphorylation, and also augmented an astrocyte marker, glial fibrillary acidic protein in mouse spinal cord. Furthermore, an astroglial toxin, l-α-aminoadipate, significantly attenuated the development of the nociceptive behaviors and ERK phosphorylation by Max. These results suggest that the activation of spinal PAC1-R induces long-lasting nociception through the interaction of neurons and astrocytes.


Artificial intelligence as a tool to aid in the differentiation of equine ophthalmic diseases with an emphasis on equine uveitis.
Due to recent developments in artificial intelligence, deep learning, and smart-device-technology, diagnostic software may be developed which can be executed offline as an app on smartphones using their high-resolution cameras and increasing processing power to directly analyse photos taken on the device. A software tool was developed to aid in the diagnosis of equine ophthalmic diseases, especially uveitis. Prospective comparison of software and clinical diagnoses. A deep learning approach for image classification was used to train software by analysing photographs of equine eyes to make a statement on whether the horse was displaying signs of uveitis or other ophthalmic diseases. Four basis networks of different sizes (MobileNetV2, InceptionV3, VGG16, VGG19) with modified top-layers were evaluated. Convolutional Neural Networks (CNN) were trained on 2346 pictures of equine eyes, which were augmented to 9384 images. 261 separate unmodified images were used to evaluate the performance of the trained network. Cross validation showed accuracy of 99.82% on training data and 96.66% on validation data when distinguishing between three categories (uveitis, other ophthalmic diseases, healthy). One source of selection bias for the artificial intelligence presumably was the increased pupil size, which was mainly present in horses with ophthalmic diseases due to the use of mydriatics, and was not homogeneously dispersed in all categories of the dataset. Our system for detection of equine uveitis is unique and novel and can differentiate between uveitis and other equine ophthalmic diseases. Its development also serves as a proof-of-concept for image-based detection of ophthalmic diseases in general and as a basis for its further use and expansion.


The 4-year evolution of a social and behavioral pharmacy course.
To evaluate the impact of 3 sequential course revisions on student performance in and perceived value of a social science-based course. The initial revision emphasized study of the primary literature and traditional assessments of student learning. Subsequent course revisions emphasized active learning and reflective assessment methodologies. The syllabi, grade distributions, and course evaluations were collected at baseline and after each revision and compared. Student performance in and their perceived value of the course declined after the initial course revision, but significantly improved after subsequent revisions with performance measures returning to baseline. Positioning social science-based courses as a bridge to practice while using active-learning techniques to deliver content had a positive impact on students' perceived value of this Social and Behavioral Pharmacy course without compromising performance measures.


Climate change reduces nectar secretion in two common Mediterranean plants.
Global warming can lead to considerable impacts on natural plant communities, potentially inducing changes in plant physiology and the quantity and quality of floral rewards, especially nectar. Changes in nectar production can in turn strongly affect plant-pollinator interaction networks-pollinators may potentially benefit under moderate warming conditions, but suffer as resources reduce in availability as elevated temperatures become more extreme. Here, we studied the effect of elevated temperatures on nectar secretion of two Mediterranean Lamiaceae species-Ballota acetabulosa and Teucrium divaricatum. We measured nectar production (viz. volume per flower, sugar concentration per flower and sugar content per flower and per plant), number of open and empty flowers per plant, as well as biomass per flower under a range of temperatures selected ad hoc in a fully controlled climate chamber and under natural conditions outdoors. The average temperature in the climate chamber was increased every 3 days in 3 °C increments from 17.5 to 38.5 °C. Both study species showed a unimodal response of nectar production (volume per flower, sugar content per flower and per plant) to temperature. Optimal temperature for sugar content per flower was 25-26 °C for B. acetabulosa and 29-33 °C for T. divaricatum. According to our results, moderate climate warming predicted for the next few decades could benefit nectar secretion in T. divaricatum as long as the plants are not water stressed, but have a moderate negative effect on B. acetabulosa. Nevertheless, strong warming as predicted by climate change models for the end of the 21st century is expected to reduce nectar secretion in both species and can thus significantly reduce available resources for both wild bees and honeybees in Mediterranean systems.


UDP-N-acetylglucosamine-glycoprotein N-acetylglucosaminyltransferase in regenerating rat liver.
The assay condition for N-acetylglucosaminyltransferase activities in rat liver microsomal fraction was developed. The enzyme activities towards endogenous acceptors within 48 h after partial hepatectomy were lower than in controls, exceeding the control level by 96 h, and then higher than in controls up to 240 h after the operation. The changes in N-acetylglucosaminyltransferase activities towards exogenous acceptor (UDP-2-acetamido-2-deoxy-D-glucose: glycoprotein 2-acetamido-2-deoxy-D-glucosyltransferase, EC 22.214.171.124) were consistent with those in the enzyme activities towards endogenous acceptors at 144 h, but not at 48 h, after the operation. The contents of protein and the levels of protein-bound hexosamine in the liver microsomes were decreased at early period of liver regeneration. These results suggest that the acceptor capacity of liver microsomal proteins is diminished during first 48 h of the regeneration. This may be responsible for the decreased transfer of the amino sugar to nascent glycoproteins. However, the enzyme activity was enhanced at 144 h and the level of endogenous acceptors may increase.


A review of recent developments of metal-organic frameworks as combined biomedical platforms over the past decade.
Metal-organic frameworks (MOFs), also called porous coordination polymers, represent a class of crystalline porous materials made up of organic ligands and metal ions/metal clusters. Herein, an overview of the preparation of different metal-organic frameworks and the recent advances in MOF-based stimuli-responsive drug delivery systems (DDSs) with the drug release mechanisms including pH-, temperature-, ion-, magnetic-, pressure-, adenosine-triphosphate (ATP)-, H2S-, redox-, responsive, and photoresponsive MOF were rarely introduced. The combination therapy containing of two or more treatments can be enhanced treatment effectiveness through overcoming limitations of monotherapy. Photothermal therapy (PTT) combined with chemotherapy (CT), chemotherapy in combination with PTT or other combinations were explained to overcome drug resistance and side effects in normal cells as well as enhancing the therapeutic response. Integrated platforms containing of photothermal/drug-delivering functions with magnetic resonance imaging (MRI) properties exhibited great advantages in cancer therapy.


Toward catecholamine responsiveness in cardiogenic shock: insights from the CRASH score.
To model a prognostic score in patients with cardiogenic shock that incorporates catecholamine responsiveness and hemodynamics. Assessment of the best accuracy of the score (CRASH score: Catecholamine Refractoriness and Assistance guide based on cardiogenic Shock Hemodynamics) to predict in-hospital mortality and/or extracorporeal life support, based on a retrospective study performed in a medical-surgical intensive care unit. We included 66 patients with cardiogenic shock from various etiologies. We modeled the CRASH score to be a simple score with the best accuracy to predict in-hospital mortality and/or extracorporeal life support. The CRASH score was defined as the cardiac power index (CPI) divided by the square root of 1 + inotropic score (IS, sum of different catecholamines pondered with their variable efficiency): CRASH score = CPI/square root (IS + 1). A CRASH score <0.0375 predicted death and/or extracorporeal life support with a sensitivity of 68% and a specificity of 92%. The area under the ROC curve was 0.851, achieving an overall accuracy of 0.833. The CRASH score had improved accuracy when compared with Simplified Acute Physiology, Sleeper, and CardSHOCK scores (p<0.05 for all). With a threshold of 0.300 we found even higher specificity (95%) at the price of decreased sensibility (52%) and accuracy. In patients with cardiogenic shock, the CRASH score (= CPI/square root (IS + 1)) <0.0375 allowed patients at high risk of adverse outcome to be identified.


Effect of cooking temperature on alkaline phosphatase in the production of raw-milk Pecorino cheese.
Alkaline phosphatase (ALP) is a native raw-milk enzyme used in many countries as the standard assay for rapidly validating the milk pasteurization process. Due to the increased restrictions on the production or import of cheeses produced from unpasteurized milk, ALP activity (<10 mU/g) in cheese was measured as a simple and reliable method to check proper milk pasteurization in cheese for both safety inspection and trading controls. In Sicily, the artisanal cheesemaking of the Protected Denomination of Origin (PDO) semi-hard cheeses made with raw sheep milk, includes the cooking of the curd, after whey separation, in a wooden vat under hot Scotta whey (≥80°C), for 3 to 4 h, and finally is left to cool at ambient temperature. Thus, the temperatures adopted during cheesemaking may inactivate the ALP enzyme. To this purpose, the aim of this study was to demonstrate how different temperatures of Scotta whey (35°C [T35], 60°C [T60], 70°C [T70], 80°C [T80], 90°C [T90], and 100°C [T100]) used during the second cooking of Pecorino cheeses after molding for 3 h, influence the ALP activity in fresh and 3-mo aged cheese, both at core and outside. The results highlight that the rate of reduction of ALP was greater with increasing temperature of the second cooking, in particular for T 80°C curd, indicating that the use of Scotta whey >80°C could be a breakpoint able to reduce the ALP activity to values <10 mU/g. Different effects between the core and the outside portions of the experimental cheeses were found, with a decrease in ALP activity more on the outside than in the core portions, in both fresh and 3-mo aged cheeses, for T80, T90, and T100 treatments. Care must be taken in using ALP to control the use of pasteurized milk in the production of PDO cheeses without considering the cheesemaking processes, such as the second cooking, which could be equal to pasteurization, and an adequate interaction of time and temperature can reduce the ALP activity to values comparable with cheeses produced with pasteurized milk.


Diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A clinical and genetic study.
Two Iraqi sisters and a female cousin developed diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and deafness (D), (the 'DIDMOAD' syndrome) before the age of 12 years. One girl exhibited all the features of this disease complex only 3 months after an unusually late onset of recognizable symptoms at 11 years 9 months. Another girl died suddenly and unexpectedly. This family study illustrates the recessive inheritance pattern of the syndrome.


Novel One-Dimensional Hollow Carbon Nanotubes/Selenium Composite for High-Performance Al-Se Batteries.
Herein, we successfully prepared one-dimensional nanowire with carbon-coated selenium (Se@CW) by using a simple wet chemical method and obtained a one-dimensional hollow Se@C nanotube (Se@CT) after the subsequent calcination treatment. We have formed a new Al-Se secondary battery by using Se@CT as the cathode and metal aluminum as the anode in the AlCl3/[EMIm]Cl electrolyte. It is believed that the oxidation intermediate of Se in Al-Se batteries may not only have Se22+, but there may be other oxidation intermediates, such as Se4+, Se2+, and Se82+. Therefore, Se@CT exhibits excellent charge-discharge performance in Al-Se batteries. Its initial discharge capacity reaches 447.2 mA h g-1 at 200 mA g-1, and the operating voltage is above 1.6 V. Its energy density approaches 708.8 W h k g-1, the capacity is still 162.9 mA h g-1 after 200 cycles at 500 mA g-1, and the corresponding capacity retention rate is up to 83.5%. In addition, its electrochemical performance is far superior to that of Se@CMK-3 in Al-Se batteries and the electrochemical properties of carbon materials, oxides, and sulfide electrode materials in some aluminum-ion batteries, which will open up a new direction for the development of new secondary aluminum-based batteries.


Ground squirrel splenic macrophages bind lipopolysaccharide over a wide range of temperatures at all phases of their annual hibernation cycle.
This study evaluates binding of bacterial lipopolysaccharide (LPS) by splenic macrophages from golden-mantled ground squirrels (Spermophilus lateralis, GMGS), a hibernating mammal, at a variety of in vitro incubation temperatures to determine whether this aspect of immune function is effective at low body temperatures. LPS-binding by ground squirrel macrophages was compared to that of rat splenic macrophages. Macrophages were collected from squirrels at discreet stages in their annual cycle and incubated with fluorescein-labeled LPS (LPS-FITC). The percentage of GMGS that bound LPS-FITC did not change as a function of hibernation season or as a function of incubation temperature. The total amount of LPS-FITC bound per cell was similarly unaffected by season or temperature, however, macrophages from torpid squirrels bound more LPS-FITC than cells from normothermic squirrels. Macrophages of golden-mantled ground squirrels bind LPS at a wide range of temperatures throughout their annual cycle; an ability shared between hibernators and non-hibernators alike.


Stopping decisions: information order effects on nonfocal evaluations.
We investigated how the order in which information is presented affects when a person decides to stop performing a task. A stopping decision is a decision to stop performing a task on the basis of a sequence of cues. Previous order-effects models do not account for how these contexts limit available working memory for making such decisions. Participants decided how long to perform a task known as the Work Hazard Game that began by rewarding points but later cost points if work continued after an unannounced "emergency." An additive sequence of cues indicated the probability of an emergency. Study I involved a three-group design with cue sequences that indicated the same risk at each decision point but whose final cue presented a high, medium, or low probability. Study 2 had a 2 x 2 design with high or low final cues and an easy or a challenging task. In Study I, participants stopped sooner when the most recent cue presented a high rather than low probability (p = .09), despite the same emergency risk. In Study 2, participants stopped sooner when the most recent cue presented a high rather than low probability for the challenging task but not for the easy task (p = .08). Stopping decisions appear sensitive to the most recent cue observed while experiencing task load. Participants responded to the same risks differently only on the basis of a change in presentation. Findings may be relevant for research and training for hazardous jobs, such as subsurface coal mining, fishing, and trucking.


Methyl 2-{[2-(4,4,5,5-tetra-methyl-1,3-dioxyl-4,5-dihydro-imidazol-2-yl)phen-yl]-oxy}acetate.
In the title compound, C(16)H(21)N(2)O(5), the benzene ring is nearly perpendicular to the imidazole ring, making a torsion angle of 88.6 (8)°·The crystal structure is stabilized by non-classical C-H⋯O and C-H⋯π inter-actions, which build up a three-dimensional network.


Glaucoma diagnostic ability of ganglion cell-inner plexiform layer thickness differs according to the location of visual field loss.
To determine whether the ganglion cell-inner plexiform layer (GCIPL) or circumpapillary retinal nerve fiber layer (cpRNFL) is better at distinguishing eyes with early glaucoma from normal eyes on the basis of the the initial location of the visual field (VF) damage. Retrospective, observational study. Eighty-four patients with early glaucoma and 43 normal subjects were enrolled. The patients with glaucoma were subdivided into 2 groups according to the location of VF damage: (1) an isolated parafoveal scotoma (PFS, N = 42) within 12 points of a central 10 degrees in 1 hemifield or (2) an isolated peripheral nasal step (PNS, N = 42) within the nasal periphery outside 10 degrees of fixation in 1 hemifield. All patients underwent macular and optic disc scanning using Cirrus high-definition optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). The GCIPL and cpRNFL thicknesses were compared between groups. Areas under the receiver operating characteristic curves (AUCs) were calculated. Comparison of diagnostic ability using AUCs. The average and minimum GCIPL of the PFS group were significantly thinner than those of the PNS group, whereas there was no significant difference in the average retinal nerve fiber layer (RNFL) thickness between the 2 groups. The AUCs of the average (0.962) and minimum GCIPL (0.973) thicknesses did not differ from that of the average RNFL thickness (0.972) for discriminating glaucomatous changes between normal and all glaucoma eyes (P =0.566 and 0.974, respectively). In the PFS group, the AUCs of the average (0.988) and minimum GCIPL (0.999) thicknesses were greater than that of the average RNFL thickness (0.961, P =0.307 and 0.125, respectively). However, the AUCs of the average (0.936) and minimum GCIPL (0.947) thicknesses were lower than that of the average RNFL thickness (0.984) in the PNS group (P =0.032 and 0.069, respectively). The GCIPL parameters were more valuable than the cpRNFL parameters for detecting glaucoma in eyes with parafoveal VF loss, and the cpRNFL parameters were better than the GCIPL parameters for detecting glaucoma in eyes with peripheral VF loss. Clinicians should know that the diagnostic capability of macular GCIPL parameters depends largely on the location of the VF loss.


Lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system for endometrial cancer: a multi-center study.
We investigated whether pelvic or para-aortic lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system in patients with endometrial cancer (EC). We reviewed 786 patients with EC from six tertiary medical centers between July 1996 and June 2008. All patients were classified according to the 1988 FIGO staging system: IA (n = 234); IB (n = 270); IC (n = 109); IIA (n = 35); IIB (n = 29); IIIA (n = 37); IIIB (n = 3); IIIC (n = 69), and the revised 2009 FIGO staging system was also applied to divide them: IA (=542); IB (=125); II (n = 29); IIIA (n = 18); IIIB (n = 3); IIIC1 (n = 43); IIIC2 (n = 26). Prognostic values between the 1988 and the revised 2009 FIGO staging systems were compared by multivariate Cox's proportional hazard analysis. The 1988 FIGO stage IC, IIB, IIIA + IIIB and IIIC, and the revised 2009 FIGO stage IB, II, IIIA + IIIB and IIIC2 diseases were prognostic factors for poor PFS, whereas the 1988 FIGO stage IIB and IIIC, and the revised 2009 FIGO stage II, IIIA + IIIB and IIIC2 diseases were unfavorable prognostic factors for OS. Although these results were similar to those in 595 patients who underwent pelvic or para-aortic lymphadenectomy, the revised 2009 FIGO stage IIIC1 disease was an additional prognostic factor for poor PFS and OS (adjusted HRs, 4.19 and 11.25; 95% CIs, 1.39-12.60 and 2.23-36.74). The revised 2009 FIGO staging system had a higher prognostic value than the 1988 FIGO staging system, and pelvic or para-aortic lymphadenectomy increased the prognostic value of the revised 2009 FIGO staging system for EC.


Methylene blue adsorption on graphene oxide/calcium alginate composites.
Graphene oxide has been used as an adsorbent in wastewater treatment. However, the dispersibility in aqueous solution and the biotoxicity to human cells of graphene oxide limits its practical application in environmental protection. In this research, a novel environmental friendly adsorbent, calcium alginate immobilized graphene oxide composites was prepared. The effects of pH, contact time, temperature and dosage on the adsorption properties of methylene blue onto calcium alginate immobilized graphene oxide composites were investigated. The equilibrium adsorption data were described by the Langmuir and Freundlich isotherms. The maximum adsorption capacity obtained from Langmuir isotherm equation was 181.81 mg/g. The pseudo-first order, pseudo-second order, and intraparticle diffusion equation were used to evaluate the kinetic data. Thermodynamic analysis of equilibriums indicated that the adsorption reaction of methylene blue onto calcium alginate immobilized graphene oxide composites was exothermic and spontaneous in nature.


Application of termite nest for adsorption of Cr(VI).
This work proposes the use of tree termite nest as an adsorbent for the reduction/removal of Cr(VI) present in aqueous solution. In laboratory experiments, adsorption of Cr(VI) was sensitive to pH in the range investigated (2-5), with maximum adsorption capacity achieved at pH 2 (3.70 ± 0.04 mg g(-1), representing 93.2% removal of Cr). The termite nest was characterized by off-line pyrolysis GC/MS (py-GC/MS), infrared spectroscopy (FTIR), and electron paramagnetic resonance spectroscopy (EPR). Pyrolysis of the adsorbent produced a complex mixture of aromatic compounds, including the guaiacyl and syringilic derivatives that are characteristic of lignocellulosic materials. Infrared spectroscopy revealed deprotonation of the carboxylic acid group of the biomass with increasing pH, which was associated with a decrease in the capacity for adsorption of Cr(VI). The EPR g-factor for the termite nest samples varied between 2.0037 and 2.0038, indicating the presence of organic free radicals that were responsible for the redox reaction. A second line with g-factor values of 1.9790, only observed for the samples after contact with Cr(VI) solutions at different pH values, was assigned to Cr(III)-Cr(III) exchange coupled pairs, which explained the capacity of the adsorbent to retain a large portion of the Cr(III) ions produced after reduction of Cr(VI) to Cr(III). Fixed-bed column experiments showed that the termite nest had a maximum adsorption capacity of 18.60 mg Cr g(-1), an adsorption efficiency varying between 60.8 and 97.4%, and a desorption efficiency varying between 54.5 and 91.4%, for three successive cycles. The adsorbent presented excellent performance in the removal of chromium under acidic conditions, with the advantage that it could be regenerated and reused.


Radioimmunoreactivity and receptor binding activity of specific epididymal proteins of the rat and other species.
Radioimmunoassay (RIA) and radioreceptor assay (RRA) for the 32K Rat Epididymal Protein (REP) have been developed. Washed intact rat epididymal spermatozoa were used as receptors in the RRA. The effects of epididymal and seminal fluids of other species in these assays were studied. The results showed that there is species specificity in the immunoreactivity and receptor binding activity of sperm coating proteins.


Non-invasive spectroscopic and imaging systems for prediction of beef quality in a meat processing pilot plant.
This study evaluated a range of diffuse reflectance spectroscopic (Vis-NIR spectrophotometers) and imaging (Hyperspectral imaging cameras) instruments for predicting pH, IMF and shear force values of beef in a meat processing pilot plant. A total of 364 beef striploin samples were evaluated and prediction models were developed using PLSR. Models for pH and IMF (except Vis snapshot camera) showed good fit with high Rcv2 (0.29-0.92) and low SECV values. Good prediction accuracy with high Rp2 (0.44-0.90), RPD and low SEP values was also observed. While low values of Rp2 for shear force was observed, the expected curvilinear relationship between predicted values of shear force and predicted values of pH was observed suggesting that spectroscopic measurements were able detect biophysical factors associated to these two attributes. Overall, it can be concluded that diffuse reflectance spectroscopy combined with chemometrics has a great potential to be used as an on/in-line quality monitoring system for the meat processing industry.


Video-assisted thoracic surgery lobectomy for pulmonary sequestration.
Pulmonary sequestration is a rare developmental abnormality, and the patients usually present with recurrent pneumonia. We report a case of video-assisted thoracic surgery lobectomy in a 32-year-old woman with an intrapulmonary sequestration in the left lower lobe.


Developing and validating a parser-based suicidality detection model in text-based mental health services.
Advances in text-mining can potentially aid online text-based mental health services in detecting suicidality. However, false positive remains a challenge. Data of a free 24/7 online text-based counseling service in Hong Kong were used to develop a novel parser-based algorithm (PBSD) to detect suicidal ideation while minimizing false alarms. Sessions containing keywords related to suicidality were extracted (N = 1267). PBSD first applies a sentence parser to work out the grammatical structure of each sentence, including subject, object, dependent and modifier. Then a set of syntax rules were applied to judge if a flagged sentence is a true or false positive. Half of the sessions were randomly selected to train PBSD, the remaining were used as the test set. A standard keywords matching model was adopted as the baseline comparison. Accuracy and recall were reported to demonstrate models' performance. Of the 1267 sessions, 585 (46.2 %) were false alarms. The false alarms were categorized into four types: negation-induced false alarms (NIFA; 14 %), subject-induced false alarms (SIFA; 19 %), tense-induced false alarms (TIFA; 30 %), and other types of false alarms (OTFA; 37 %). PBSD significantly outperforms the baseline keywords matching model on accuracy (0.68 vs 0.53, 28.3 %). It successfully amended 36.8 % (105/297) lexicon matching-caused false alarms. The reduction on recall was marginal (1 vs 0.96, 4 %). The proposed model significantly improves the use of lexicon-based method by reducing false alarms and improving the accuracy of suicidality detection. It can potentially reduce unnecessary panic and distraction caused by false alarms among frontline service-providers.


Crosstalk between axon guidance signaling and bone remodeling.
The maintenance of skeletal integrity is tightly regulated by two cell types, bone forming osteoblasts and bone resorbing osteoclasts. Although the role of the nervous system in regulating osteoblasts and osteoclasts was identified over a decade ago, the molecular mechanism of skeletal-neural interactions in bone homeostasis has only been studied recently. In particular, the complex roles of axon guidance molecules, such as semaphorins and ephrins, in the bone have been studied extensively. In this review, we highlight the latest advances in determining the functions of semaphorins and ephrins in the establishment and maintenance of the skeletal system, with a focus on the functional interaction between the skeletal and nervous systems.


Six NAC transcription factors involved in response to TYLCV infection in resistant and susceptible tomato cultivars.
NAC transcription factors (TFs) belong to plant-specific TFs, which have been identified in many plant species. The NAC TFs act as the nodes of a regulatory network in plant's response to abiotic and biotic stresses. Till now, response of tomato NAC TFs involved in Tomato yellow leaf curl virus (TYLCV) infection is unknown. In the present study, six NAC TFs were identified to respond to TYLCV infection in tomato. We observed that transcripts of four NAC genes (SlNAC20, SlNAC24, SlNAC47, and SlNAC61) were induced after TYLCV infection in resistant tomato cultivar. Virus-induced gene silencing analysis (VIGS) indicated that SlNAC61 played positive roles in response to TYLCV infection. Tomato NAC TFs were not only involved in defense regulation but in development and stress progress. These NAC TFs interacted with other proteins, including protein phosphatase and mitogen-activated protein kinase. Some defense response TFs, such as WRKY, TGA, MYB, NAC, could interact with NAC proteins by binding cis-elements in promoter regions of NAC TFs. These identified tomato NAC TFs cooperated with other TFs and proteins, indicating the complex response mechanism of described NAC TFs involved in TYLCV infection. The results will offer new evidence to further understand the NAC TFs involved in response to TYLCV infection in tomato.


Exploring Posttraumatic Stress Symptoms and Posttraumatic Growth among Children Living beyond Cancer and Their Parents Using an Actor-Partner Interdependence Model.
There is a growing focus on describing both negative and positive outcomes in the wake of childhood cancer. The purpose of this study was to describe and explore the relationships between posttraumatic stress symptoms (PTSS) and posttraumatic growth (PTG) among children living beyond cancer and one of their parents. As part of a larger online survey, 113 children (Mage at time of study = 15.82 (SD = 4.81); Mage at diagnosis = 5.86 (SD = 4.66)) and one of their parents completed questionnaires assessing PTSS and PTG. Descriptive statistics were used to describe the sample and levels of PTSS and PTG. Data were z-transformed and analyzed using bivariate correlations and t-tests. An actor-partner interdependence model (APIM) was used to test whether children's and their parents' PTSS was associated with their own PTG (actor effect) and the others' PTG (partner effect). PTSS was low and PTG was moderate in this sample relative to scale ranges. There were no significant differences between the children's and their parents' PTSS (p = 0.535) or PTG (p = 0.534). Results from the APIM showed no significant actor effects (p = 0.185). A significant overall partner effect (p = 0.020) emerged. Lower PTSS for children was associated with greater PTG for their parents (b = -0.29, p = 0.018), but parent's PTSS was not associated with children's PTG (p = 0.434). This sample reported similar levels of PTSS and PTG to that which has been reported in the literature. Children and their parents' scores on PTSS and PTG measures were not significantly different from one another. Children's PTSS was negatively associated with their parents PTG, illuminating the ways in which PTSS and PTG may be related in the context of childhood cancer. Exploring family-based strategies to reduce PTSS and enhance PTG may be warranted, though further studies are required.


tRNA creation by hairpin duplication.
Many studies have suggested that the modern cloverleaf structure of tRNA may have arisen through duplication of a primordial hairpin, but the timing of this duplication event has been unclear. Here we measure the level of sequence identity between the two halves of each of a large sample of tRNAs and compare this level to that of chimeric tRNAs constructed either within or between groups defined by phylogeny and/or specificity. We find that actual tRNAs have significantly more matches between the two halves than do random sequences that can form the tRNA structure, but there is no difference in the average level of matching between the two halves of an individual tRNA and the average level of matching between the two halves of the chimeric tRNAs in any of the sets we constructed. These results support the hypothesis that the modern tRNA cloverleaf arose from a single hairpin duplication prior to the divergence of modern tRNA specificities and the three domains of life.


Internal hernia caused by bridge formation between the medial and lateral segments of the liver: a case report.
Despite numerous reports on ischemic bowel obstruction caused by internal hernia, no case presentation has been reported of an internal hernia caused by a bridge formed between the medial and lateral zones of the liver. Herein, we report the first case of ischemic bowel obstruction caused by a hepatic bridge. A 24-year-old man complaining of abdominal pain was referred to our hospital and admitted. Computed tomography showed formation of a closed loop of small bowel with a hernia orifice near the hilar region, and poor contrast of the prolapsed small bowel. We suspected ischemic bowel obstruction caused by an internal hernia with a fissure of the greater omentum as the hernia orifice, and performed emergency surgery. Laparoscopic observation revealed that the medial and lateral segments of the liver formed a bridge on the dorsal side at the liver portal, and that the small intestine was ischemic in the gap created between the bridge and the medial and lateral liver segments. A Meckel's diverticulum was also invaginated in the gap. The bridge was dissected out and the hernia orifice was opened to release the bowel obstruction. The small bowel was preserved and the Meckel's diverticulum was resected. The patient's postoperative course was uneventful. We experienced a case of ischemic bowel obstruction caused by hepatic bridge formation, which was successfully treated by laparoscopic surgery.


Methylene blue inhibits NLRP3, NLRC4, AIM2, and non-canonical inflammasome activation.
Methylene blue (MB), which has antioxidant, anti-inflammatory, neuroprotective, and mitochondria protective effects, has been widely used as a dye and medication. However, the effect of MB on inflammasome activation has not yet been studied. Inflammasomes are multi-protein complexes that induce maturation of interleukins (ILs)-1β and -18 as well as caspase-1-mediated cell death, known as pyroptosis. Dysregulation of inflammasomes causes several diseases such as type 2 diabetes, Alzheimer's disease, and gout. In this study, we assess the effect of MB on inflammasome activation in macrophages. As the result, MB attenuated activation of canonical inflammasomes such as NLRP3, NLRC4, and AIM2 as well as non-canonical inflammasome activation. In addition, MB inhibited upstream signals such as inflammasome assembly, phagocytosis, and gene expression of inflammasome components via inhibition of NF-κB signaling. Furthermore, MB reduced the activity of caspase-1. The anti-inflammasome properties of MB were further confirmed in mice models. Thus, we suggest that MB is a broad-spectrum anti-inflammasome candidate molecule.


Molecular cloning and chemical synthesis of a novel antibacterial peptide derived from pig myeloid cells.
A group of myeloid precursors of defense peptides has recently been shown to have highly homologous N-terminal regions. Using a strategy based on this homology, a novel cDNA was cloned from pig bone marrow RNA and found to encode a 153-residue polypeptide. This comprises a highly conserved region encompassing a 29-residue signal peptide and a 101-residue prosequence, followed by a unique, 23-residue, cationic, C-terminal sequence. A peptide corresponding to this C-terminal sequence was chemically synthesized and shown to exert antimicrobial activity against both Gram positive and negative bacteria at concentrations of 2-16 microM. The activity of this potent and structurally novel antibacterial peptide appears to be mediated by its ability to damage bacterial membranes, as shown by the rapid permeabilization of the inner membrane of Escherichia coli.


In vitro and in vivo porphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid.
Several malignant tissues synthesize endogenous porphyrins after exposure to 5-aminolevulinic acid (5-ALA). The present experiments have been designed to elucidate whether the C6 glioma cell, a model cell for human malignant glioma, similarly synthesizes porphyrins when exposed to 5-ALA, and whether specific synthesis occurs when C6 cells are inoculated into rat brains to form a tumor. In this situation the blood-brain barrier may interfere with 5-ALA availability, and spreading of porphyrins with edema outside the tumor may occur. Flow cytometry is used to determine the course of cell volume and porphyrin fluorescence intensities in cultured C6 cells which are incubated in 1 mM 5-ALA. For the induction of experimental brain tumors, 10(4) untreated C6 cells are inoculated into the brains of rats. After 9 days animals receive 100 mg 5-ALA/kg body weight. Brains are removed after 3, 6, or 9 h and frozen coronal sections obtained for H/E staining or fluorescence spectography. Cultured C6 cells show a linear increase of protoporphyrin IX fluorescence after exposure to 5-ALA, which begins to plateau after 85 min. Marked fluorescence is also observed in solid and infiltrating experimental tumor. However, faint fluorescence also occurs in normal tissue, basal pia, choroid plexus, and, more obviously, in white-matter tracts bordering the tumor (maximal distance: 1.5 +/- 0.7 mm). The observations demonstrate that C6 cells synthesize protoporphyrin IX after exposure to 5-ALA in vitro and in vivo. However, when utilizing 5-ALA for fluorescence detection or photodynamic therapy of brain tumors, attention should be paid to the possibility of protoporphyrin IX occurring outside the tumor.


Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults.
Many adiposity traits have been related to health complications and premature death. These adiposity traits are intercorrelated but their underlying structure has not been extensively investigated. We report on the degree of commonality and specificity among multiple adiposity traits in normal-weight and moderately overweight adult males and females (mean body mass index (BMI)=22.9 kg m(-2), s.d.=2.4). A total of 75 healthy participants were assessed for a panel of adiposity traits including leg, arm, trunk, total fat masses and visceral adipose tissue (VAT) derived from dual energy X-ray absorptiometry (DXA), hepatic and muscle lipids from proton magnetic resonance spectroscopy, fat cell volume from an abdominal subcutaneous adipose tissue biopsy (n=36) and conventional anthropometry (BMI and waist girth). Spearman's correlations were calculated and were subjected to factor analysis. Arm, leg, trunk and total fat masses correlated positively (r=0.78-0.95) with each other. VAT correlated weakly with fat mass indicators (r=0.24-0.31). Intrahepatic lipids (IHL) correlated weakly with all fat mass traits (r=0.09-0.34), whereas correlations between DXA depots and intramyocellular lipids (IMCL) were inconsequential. The four DXA fat mass measures, VAT, IHL and IMCL depots segregated as four independent factors that accounted for 96% of the overall adiposity variance. BMI and waist girth were moderately correlated with the arm, leg, trunk and total fat and weakly with VAT, IHL and IMCL. Adiposity traits share a substantial degree of commonality, but there is considerable specificity across the adiposity variance space. For instance, VAT, IHL and IMCL are typically poorly correlated with each other and are poorly to weakly associated with the other adiposity traits. The same is true for BMI and waist girth, commonly used anthropometric indicators of adiposity. These results do not support the view that it will be possible to identify adequate anthropometric indicators of visceral, hepatic and muscle lipid content in normal-weight and moderately overweight individuals.


The relationship between calcium intake and pregnancy-induced hypertension: up-to-date evidence.
In 1980 we pointed to a relationship between calcium intake and pregnancy-induced hypertension. The original epidemiologic observations showed an inverse association between calcium intake and incidence of eclampsia after adjusting by several confounding factors. A series of recent randomized clinical trials have demonstrated a reduction in blood pressure with calcium supplementation in animals, in healthy and mildly hypertensive subjects, and in pregnant women. It is hypothesized that parathyroid hormone plays a role since it is affected by calcium intake and can partially regulate the concentration of free cytosolic ionized calcium, thus triggering smooth muscle contraction. Randomized clinical trials showing a reduction in the incidence of pregnancy-induced hypertension with calcium supplementation have not as yet been published. However, preliminary observations appear to support this hypothesis.


Large-Scale Flexible Surface-Enhanced Raman Scattering (SERS) Sensors with High Stability and Signal Homogeneity.
Flexible surface-enhanced Raman scattering (SERS) sensors have attracted great attention as a portable and low-cost device for chemical and bio-detection. However, flexible SERS sensors tend to suffer low signal spatial homogeneity due to the uneven distribution of active plasmonic nanostructures (hot spots) and quick degradation of their sensitivity due to low adhesion of hot spots and flexible substrates during fast sampling. Herein, a large-area (20 × 20 cm2) polyimide (PI)-based SERS sensor is exploited for trace detection with high signal homogeneity and stability. The SERS sensor is constructed from PI through in situ growth of silver and gold core-shell nanoparticles (Ag@Au NPs) based on chemical reduction and galvanic replacement processes. Benefiting from the abundant carboxyl groups on the surface-cleaved PI, densely and uniformly distributed Ag@Au NPs are successfully prepared on the film under ambient conditions. The high Raman enhancement factor (EF) (up to 1.07 × 107) and detection capability with low nanomolar (10-9 M) detection limits are obtained for this flexible SERS sensor. The uniform Raman signals in the random region show good signal homogeneity with a low variation of 8.7%. Moreover, the flexible SERS sensor exhibited superior efficiency and durability after storage for 30 days even after 500 cycles of mechanical stimuli (bending or torsion). The residue of pesticide thiram (tetramethylthiuram disulfide, TMTD) has been rapidly traced by direct sampling from the apple surface, and a sensitivity of 10 ng/cm2 for TMTD was achieved. These findings show that the PI-based SERS sensor is a very strong candidate for broad and simple utilization of flexible SERS for both laboratory and commercial applications in chemical and biomolecule detections.


A heavyweight early whale pushes the boundaries of vertebrate morphology.
The fossil record of cetaceans documents how terrestrial animals acquired extreme adaptations and transitioned to a fully aquatic lifestyle1,2. In whales, this is associated with a substantial increase in maximum body size. Although an elongate body was acquired early in cetacean evolution3, the maximum body mass of baleen whales reflects a recent diversification that culminated in the blue whale4. More generally, hitherto known gigantism among aquatic tetrapods evolved within pelagic, active swimmers. Here we describe Perucetus colossus-a basilosaurid whale from the middle Eocene epoch of Peru. It displays, to our knowledge, the highest degree of bone mass increase known to date, an adaptation associated with shallow diving5. The estimated skeletal mass of P. colossus exceeds that of any known mammal or aquatic vertebrate. We show that the bone structure specializations of aquatic mammals are reflected in the scaling of skeletal fraction (skeletal mass versus whole-body mass) across the entire disparity of amniotes. We use the skeletal fraction to estimate the body mass of P. colossus, which proves to be a contender for the title of heaviest animal on record. Cetacean peak body mass had already been reached around 30 million years before previously assumed, in a coastal context in which primary productivity was particularly high.


Prepucial skin flap for reconstruction of the scrotum in Fournier's gangrene.
A new procedure for reconstructing a scrotal defect caused by Fournier's gangrene is described. Complete and quick coverage of the exposed testicles is important aesthetically and functionally. A dorsally based prepucial flap is designed, flap viability is ensured by an abundant blood supply and venous drainage. This procedure for reconstruction of ventral hemiscrotum by using a flap of prepucial skin in non-circumcised persons has proved effective in selected cases.


Tympanometry and the stapedial reflex in the first five days of life.
Tympanometry was carried out on 45 full term neonates. It proved to be a straightforward procedure. The acoustic reflex was elicited using contralateral white noise stimulation at 70-85 dB and with a probe tone of 600 Hz. It was not detectable in the first hours of life, but was present in 100% of cases over 12 h of age. The initial absence of the reflex may be due to a transient conductive loss which resolves rapidly or, more likely, immaturity of the reflex itself at birth.


An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury.
Our previous studies have shown that treatment with an alpha4beta1 integrin blocking antibody after spinal cord injury (SCI) in rats decreases intraspinal inflammation and oxidative damage, improving neurological function. Here, we studied effects of a high affinity small molecule alpha4beta1 inhibitor, BIO5192. First, rats were treated intravenously with BIO5192 (10 mg/kg) or with vehicle (controls) to assess effects of integrin blockade for 24 h or 72 h after thoracic clip-compression SCI. BIO5192 treatment significantly decreased the MPO enzymatic activity (neutrophil infiltration) and ED-1 expression (macrophage density) by 40% and 38% at 24 h and by 52% and 25% at 72 h post injury, respectively. In cord homogenates, BIO5192 treatment decreased expression of the oxidative enzymes gp91(phox), inducible nitric oxide and cyclooxygenase-2 by approximately 40% at both times of analysis. Free radical concentration decreased by 30% and lipid peroxidation decreased by 34% and 46%, respectively, at 24 h and 72 h after SCI. Next, after blockade by BIO5192 for 72 h, neurological outcomes were analyzed for 1-6 weeks after SCI. Motor function significantly improved when assessed by an open-field test. Treated rats planter placed their hind paws and/or dorsal stepped, with weight support, whereas controls only swept their hindlimbs. BIO5192 treatment also decreased mechanical allodynia elicited from the trunk and hind paw by up to 35%. This improved function correlated with decreased lesion size and spared myelin-containing white matter. The neurological improvement offered by this neuroprotective strategy supports the potential for an anti-integrin treatment for SCI.


A comparison of variability between absolute and relative blood flow restriction pressures.
Recommendations are that blood flow restriction (BFR) be applied relative to arterial occlusion pressure (AOP) to provide a similar stimulus. Compare variability of the change in blood flow, shear rate and discomfort between recommended relative pressures and an absolute pressure. During one visit, brachial arterial blood flow was measured in 91 participants using pulse-wave Doppler ultrasonography. After 5-min seated rest, AOP was measured. Following another 5-min rest, blood flow and discomfort were assessed twice before cuff inflation as controls (C1 and C2), then again with a cuff inflated to each BFR pressure (all measures separated by 1-min). Change scores from C1 to all subsequent measures were calculated (i.e., C2-C1; 40% AOP-C1; 80% AOP-C1; 100 mmHg-C1). Variability of the changes were compared via pairwise modified Pitman-Morgan tests (α = 0.008). Variance (95% CI) of the change for blood flow (ml/min), shear rate (1/s), and discomfort (AU) had similar trends. C2-C1 differed from all conditions (all p < 0.001), 40% AOP-C1 differed from 80% AOP-C1 and 100 mmHg-C1 (all p < 0.001), which did not differ (both p ≥ 0.117). Blood flow: C2-C1 = 469.79 (357.90, 644.07), 40% AOP-C1 = 1263.18 (962.34, 1731.80), 80% AOP-C1 = 1752.90 (1335.42, 2403.18), 100 mmHg-C1 = 1603.18 (1221.36, 2197.92); shear rate: C2-C1 = 6248.24 (4760.10, 8566.15), 40% AOP-C1 = 14 625.30 (11 142.06, 20 050.95), 80% AOP-C1 = 22 064.02 (16 809.13, 30 249.27), 100 mmHg-C1 = 20 778.76 (15 829.98, 28 487.21); discomfort: C2-C1 = 0.07 (0.05, 0.08), 40% AOP-C1 = 2.03 (1.55, 2.78), 80% AOP-C1 = 4.26 (3.25, 5.84), 100 mmHg-C1 = 4.50 (3.43, 6.17). Contrary to previous suggestions, applying relative pressures does not necessarily guarantee a similar stimulus. It seems that higher pressures produce more variable changes even if the external pressure applied is made relative to each individual.


Potential blindness: an unusual complication of lateral canthopexy.
Lateral canthopexy is a commonly performed procedure in craniofacial and cosmetic surgery. In craniofacial surgery, lateral canthal fixation is performed in conjunction with a wide range of transcranial or subcranial procedures during the process of soft tissue re-suspension. A number of fixation materials have gained popular use. A case of craniofrontonasal dysplasia is reported in which a wire loop canthopexy fixation has become disengaged 3 months after a history of trauma and rotated to present a sharp surface against the sclera. Urgent surgical exploration prevented the apparently imminent complication of globe penetration with associated threat to vision.


Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies.
Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of glutamate receptors (GluRs) in excitatory neurotransmission implicates their involvement in epileptogenesis and genetic susceptibility to IGEs. A trinucleotide repeat polymorphism detected in the 3' untranslated region of the kainate-selective GluR6 receptor gene (GRIK2) on chromosome 6 makes it possible to perform linkage and association studies with this high-ranking candidate gene. The present study tested the hypothesis that allelic variants of GRIK2 contribute to the genetic susceptibility to the common IGEs. Linkage and association analyses were conducted in 63 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, or childhood absence epilepsy. Our linkage and association results suggest that allelic variants of GRIK2 are not involved in the expression of the common familial IGEs, and radiation hybrid mapping assigns GRIK2 to the chromosomal region 6q16.3-q21. This localization excludes GRIK2 as a candidate for the putative IGE susceptibility locus "EJM1" on the short arm of chromosome 6.


Obesity and the risk of disability in a 12-year cohort study: the role of psychological distress.
Recent cross-sectional findings suggest that co-occurring obesity and psychological problems amplify the risk of disability, but longitudinal evidence is lacking. We assessed this effect in a longitudinal cohort of adults. Twelve years of data (1994/1995-2006/2007) were obtained from the Canadian National Population Health Survey. This study followed 8,062 adults that were interviewed every 2 years. Disability status was derived from the Health Utility Index Mark 3. Covariates of interest were repeated psychological distress (Kessler K6 scale) and obesity (body mass index ≥30). Incidence of disability was estimated from Cox proportional hazards models, adjusting for sociodemographic and health variables. Hazard rate of disability in those with either obesity (n = 955) or distress (n = 1,044), or both (n = 138) were compared to those without (n = 5,925). Participants with both obesity and repeated distress had double the risk of disability compared to those with obesity or distress alone {adjusted hazard ratio of 2.8 [95% confidence interval (CI) 1.8, 4.5] compared to 1.4 (CI 1.1, 1.8) and 1.8 (CI 1.4, 2.3), respectively}. Recurrent psychological distress combined with obesity amplified the risk for disability normally associated with these conditions.


[Comparison of the efficacy of parenteral and enteral pertussis immunization in the rabbit (author's transl)].
The effects of immunization with inactivated B. pertussis were studied in the rabbit using enteral (oral and via suppositories) and parenteral immunization routes. The rise in agglutinating and complement-binding immunoglobulins in the rabbit serum was about equal following immunization by suppository and parenteral administration, but the demonstration of local immunity (immunoglobulins reacting with B. pertussis in salive) by immunofluorescence methods was observed only in the group immunized with enterally-administered B. pertussis.


A modified tie-over dressing for skin grafts.
This paper describes a simple modification of the conventional tie-over dressing used in skin grafting. A plastic bead is used to gather together the tie-over threads and an aluminium collar provides a rapid method of securing the tie.


Congenital adrenal hyperplasia in pregnancy.
The congenital adrenal hyperplasias (CAH) are a group of inherited enzymatic defects of adrenal steroid biosynthesis. Deficiencies of each enzyme required in the steroid biosynthesis pathway are known, and these deficiencies are all inherited as autosomal recessive disorders. During pregnancy, maternal and fetal problems are confined to women who have 21-hydroxylase deficiency (P450c21 deficiency), 11-hydroxylase deficiency (P450c11 deficiency), and 3 beta-hydroxysteroid dehydrogenase deficiency (3 beta HSD deficiency), because other adrenal enzyme deficiencies are not compatible with fertility. The interposition of the placenta on the hypothalamic-pituitary-adrenal axis and other endocrine changes during pregnancy impact considerably on the clinical evaluation of the congenital adrenal hyperplasias. Successful management of CAH in pregnancy requires a firm knowledge of normal adrenal anatomic and endocrine changes that occur during gestation. Women with severe forms of CAH have decreased fertility rates because of oligo-ovulation, and successful conception requires a combination of good therapeutic compliance, careful endocrine monitoring, and often ovulation induction. From a fetal and neonatal standpoint, accurate prenatal diagnosis of 21-hydroxylase deficiency and 11-hydroxylase deficiency is now possible, which allows for prenatal treatment in an attempt to minimize clinical problems in the neonates. Prevention of masculinization of affected female fetuses by corticosteroid suppression has been attempted in both 21-hydroxylase deficiency and 11beta-hydroxylase deficiency CAH, with variable degrees of success. This review provides an overview of the congenital adrenal hyperplasias and their management during pregnancy.


Subjective sexual experience in college women.
A random sample of 100 undergraduate women were interviewed about their subjective sexual experience. Sexual sensations during masturbation, oral sex, intercourse, and intercourse with concurrent clitoral massage were summarized and differentiated. Sensations labeled "orgasm" by a majority of the subjects were identified, and the suggestion was made that experiences other than that outlined by Masters and Johnson may be considered orgasmic by women in a more general population. Some support was found for Singer and Singer's typology of orgasm at a subjective level. Most subjects who experienced multiple orgasms found them no more satisfying than single ones. Clitoral and vaginal orgasms may be distinguished subjectively, but no clear preference for one or the other emerged from a consensus of the subjects. Orgasm rate was significantly related (p less than 0.001) to satisfaction during intercourse and oral sex, but not during masturbation. Some evidence was found supporting the role of social learning in developing sensitivity in the clitoris and vagina and possibly the breasts.


Immune-mediated loss of transgene expression from virally transduced brain cells is irreversible, mediated by IFNγ, perforin, and TNFα, and due to the elimination of transduced cells.
The adaptive immune response to viral vectors reduces vector-mediated transgene expression from the brain. It is unknown, however, whether this loss is caused by functional downregulation of transgene expression or death of transduced cells. Herein, we demonstrate that during the elimination of transgene expression, the brain becomes infiltrated with CD4(+) and CD8(+) T cells and that these T cells are necessary for transgene elimination. Further, the loss of transgene-expressing brain cells fails to occur in the absence of IFNγ, perforin, and TNFα receptor. Two methods to induce severe immune suppression in immunized animals also fail to restitute transgene expression, demonstrating the irreversibility of this process. The need for cytotoxic molecules and the irreversibility of the reduction in transgene expression suggested to us that elimination of transduced cells is responsible for the loss of transgene expression. A new experimental paradigm that discriminates between downregulation of transgene expression and the elimination of transduced cells demonstrates that transduced cells are lost from the brain upon the induction of a specific antiviral immune response. We conclude that the anti-adenoviral immune response reduces transgene expression in the brain through loss of transduced cells.


Early Biomarker Signatures in Surgical Sepsis.
Sepsis has complex, time-sensitive pathophysiology and important phenotypic subgroups. The objective of this study was to use machine learning analyses of blood and urine biomarker profiles to elucidate the pathophysiologic signatures of subgroups of surgical sepsis patients. This prospective cohort study included 243 surgical sepsis patients admitted to a quaternary care center between January 2015 and June 2017. We applied hierarchical clustering to clinical variables and 42 blood and urine biomarkers to identify phenotypic subgroups in a development cohort. Clinical characteristics and short-term and long-term outcomes were compared between clusters. A naïve Bayes classifier predicted cluster labels in a validation cohort. The development cohort contained one cluster characterized by early organ dysfunction (cluster I, n = 18) and one cluster characterized by recovery (cluster II, n = 139). Cluster I was associated with higher Acute Physiologic Assessment and Chronic Health Evaluation II (30 versus 16, P < 0.001) and SOFA scores (13 versus 5, P < 0.001), greater prevalence of chronic cardiovascular and renal disease (P < 0.001) and septic shock (78% versus 17%, P < 0.001). Cluster I had higher mortality within 14 d of sepsis onset (11% versus 1.5%, P = 0.001) and within 1 y (44% versus 20%, P = 0.032), and higher incidence of chronic critical illness (61% versus 30%, P = 0.001). The Bayes classifier achieved 95% accuracy and identified two clusters that were similar to development cohort clusters. Machine learning analyses of clinical and biomarker variables identified an early organ dysfunction sepsis phenotype characterized by inflammation, renal dysfunction, endotheliopathy, and immunosuppression, as well as poor short-term and long-term clinical outcomes.


Research Techniques Made Simple: Preclinical Development of Combination Antitumor Targeted Therapies in Dermatology.
The identification and application of targeted therapies that inhibit critical pathways in malignant cells have shown tremendous promise for improving clinical outcomes for patients with advanced cutaneous malignancies. However, tumor cell heterogeneity, development of drug resistance, and risks of off-target effects remain barriers to prolonged remission and definitive cure. Herein, we describe the potential that combinations of antitumor targeted agents may offer in overcoming these challenges and detail techniques whereby promising combination regimens can be identified and further evaluated preclinically. Cancer cell lines and primary patient-derived malignant cells can be utilized to perform dose-response screenings in vitro for individual targeted agents before moving toward the evaluation of potential synergistic combinations. Mathematical analyses, including the Chou-Talalay method, determine combination indices and Hill slopes that permit relative comparisons among various drug combinations by quantification of synergistic activities. Further preclinical in vivo evaluation of promising single versus combination regimens may be studied in relevant mouse models of cutaneous malignancy. Ultimately, the formulation of combination targeted therapy regimens may be more broadly effective and less toxic, helping to better inform clinical trial design and prioritization.


Factors contributing to the disturbance of coagulation and fibrinolysis in dengue virus infection.
Hemorrhage is one of the hallmarks of dengue hemorrhagic fever. However, the mechanisms that cause hemorrhage are unclear. In this review we focus on the possible factors that may be involved in the disturbance of coagulation and fibrinolysis during dengue virus (DENV) infection. Factors such as autoantibodies and cytokines induced by DENV infection as well as hemostatic molecules expressed on DENV-infected cells, and DENV viral proteins may all contribute to the defect of hemostasis during DENV infection. It is the combination of these viral and host factors that may tilt the balance of coagulation and fibrinolysis toward bleeding in dengue patients.


Soluble Amyloid Precursor Protein Alpha Interacts with alpha3-Na, K-ATPAse to Induce Axonal Outgrowth but Not Neuroprotection: Evidence for Distinct Mechanisms Underlying these Properties.
Amyloid precursor protein (APP) is cleaved not only to generate the amyloid peptide (Aß), involved in neurodegenerative processes, but can also be metabolized by alpha secretase to produce and release soluble N-terminal APP (sAPPα), which has many properties including the induction of axonal elongation and neuroprotection. The mechanisms underlying the properties of sAPPα are not known. Here, we used proteomic analysis of mouse cortico-hippocampal membranes to identify the neuronal specific alpha3 (α3)-subunit of the plasma membrane enzyme Na, K-ATPase (NKA) as a new binding partner of sAPPα. We showed that sAPPα recruits very rapidly clusters of α3-NKA at neuronal surface, and its binding triggers a cascade of events promoting sAPPα-induced axonal outgrowth. The binding of sAPPα with α3-NKA was not observed for sAPPα-induced Aß1-42 oligomers neuroprotection, neither the downstream events particularly the interaction of sAPPα with APP before endocytosis, ERK signaling, and the translocation of SET from the nucleus to the plasma membrane. These data suggest that the mechanisms of the axonal growth promoting and neuroprotective properties of sAPPα appear to be specific and independent. The signals at the cell surface specific to trigger these mechanisms require further study.


Female multiple matings and male harassment and their effects on fitness of arrhenotokous Thrips tabaci (Thysanoptera: Thripidae).
Although it is generally assumed that one or a few matings are sufficient to maximize female fitness and that mating is generally assumed to be costly to females, multiple matings of females have been reported across a wide and taxonomically diverse set of animals. Here, we investigated female mating frequency and male harassment rate in arrhenotokous Thrips tabaci. In addition, the cost to females of mating, multiple matings, and male harassment to females was evaluated. We found that T. tabaci females mated multiple times during their lifetime and were subjected to a high rate of male harassment at all the ages we tested. Mating was costly to females in terms of reducing longevity and delaying the initiation of egg laying, although mating did not affect the survivorship and longevity of males. Furthermore, continual exposure to males also resulted in a fitness cost to mated females in terms of delayed egg production and reduced fecundity. Virgin females of arrhenotokous thrips produce only male progeny whereas mated females of arrhenotokous thrips produce males from unfertilized eggs and females from fertilized eggs. However, multiple matings did not allow females to fertilize a larger proportion of their eggs to increase the female offspring ratio. Our study demonstrates the conflicts between the occurrence of multiple matings and the cost of sexual activities. This raises questions about the evolution of multiple matings and polyandry in this species. Furthermore, these findings suggest that such phenomena may occur in other animal species and influence the evolution of their mating systems.


A longitudinal observational retrospective study on risk factors and predictive model of PICC associated thrombosis in cancer patients.
To analyze the incidence of PICC associated venous thrombosis. To predict the risk factors of thrombosis. To validate the best predictive model in predicting PICC associated thrombosis. Consecutive oncology cases in 341 who initially naive intended to be inserted central catheter for chemotherapy, were recruited to our dedicated intravenous lab. All patients used the same gauge catheter, Primary endpoint was thrombosis formation, the secondary endpoint was infusion termination without thrombosis. Two patients were excluded. 339 patients were divided into thrombosis group in 59 (17.4%) and non-thrombosis Group in 280 (82.6%), retrospectively. Tumor, Sex, Age, Weight, Height, BMI, BSA, PS, WBC, BPC, PT, D-dimer, APTT, FIB, Smoking history, Location, Catheter length, Ratio and Number as independent variables were analyzed by Fisher's scoring, then Logistic risk regression, ROC analysis and nomogram was introduced. Total incidence was 17.4%. Venous mural thrombosis in 2 (3.4%), "fibrin sleeves" in 55 (93.2%), mixed thrombus in 2 (3.4%), symptomatic thrombosis in 2 (3.4%), asymptomatic thrombosis in 57 (96.6%), respectively. Height (χ² = 4.48, P = 0.03), D-dimer (χ² = 37.81, P < 0.001), Location (χ² = 7.56, P = 0.006), Number (χ² = 43.64, P < 0.001), Ratio (χ² = 4.38, P = 0.04), and PS (χ² = 58.78, P < 0.001), were statistical differences between the two groups analyzed by Fisher's scoring. Logistic risk regression revealed that Height (β = -0.05, HR = 0.95, 95%CI: 0.911-0.997, P = 0.038), PS (β = 1.07, HR = 2.91, 95%CI: 1.98-4.27, P < 0.001), D-dimer (β0.11, HR = 1.12, 95%CI: 1.045-1.200, P < 0.001), Number (β = 0.87, HR = 2.38, 95% CI: 1.619-3.512, P < 0.001) was independently associated with PICC associated thrombosis. The best prediction model, D-dimer + Number as a novel co-variable was validated in diagnosing PICC associated thrombosis before PICC. Our research revealed that variables PS, Number, D-dimer and Height were risk factors for PICC associated thrombosis, which were slightly associated with PICC related thrombosis, in which, PS was the relatively strongest independent risk factor of PICC related thrombosis.