Preoperative functional assessment of auditory cortex in adult cochlear implant users.
To explore functional neuroanatomical responses to auditory stimulation before and after implantation. A prospective study of three cochlear implant candidates (pure-tone averages of 90 dB HL or greater bilaterally and hearing in noise test [HINT] performances of <40%) in which regional cerebral blood flow (rCBF) was assessed using single photon emission computed tomography (SPECT). Candidates watched a 15-minute videotaped story under four conditions: audio presented monaurally in the right and left ears (aided), audio presented binaurally (aided), and visual-only presentation of the story. Five minutes into each story, 20 to 25 mCi of technetium 99m (99mTc) hexamethyl-propyleneamine-oxime (HMPAO) (Ceratec; Nycomed Amersham, Princeton, NJ, U.SA) was injected over a 30-second period to ensure that subjects were unaware of tracer administration. Subjects were scanned for 20 minutes using a PRISM 3000 gamma camera (Picker International, Cleveland, OH, U.S.A.). Data were normalized and co-registered, and subtraction images were compiled. Subtraction images contrasted activation patterns generated under the visual-only control condition to the auditory activation states acquired monaurally and binaurally. Right and left ear monaural stimulation in normal hearing subjects resulted in significant bilateral activation of Brodmann areas 41, 42, 21, 22, and 38. Although substantial intersubject response variability was noted, subjects generally failed to bilaterally activate these areas under monaural hearing aid presentations; however, bilateral activation of areas 41 and 22 was noted under binaural presentations. Despite relatively similar hearing losses in each ear, significant differences in preoperative auditory cortex activation were observed between ears. These data suggest that functional brain imaging provides a useful tool for exploring the responsiveness of the auditory cortex in cochlear implant candidates.


Resolution of two ADP-ribosylation factor 1 GTPase-activating proteins from rat liver.
ADP-ribosylation factor 1 (ARF1) is a 21 kDa GTP-binding protein that regulates multiple steps in membrane traffic. Here, two ARF1 GTPase-activating proteins (GAPs) from rat liver were resolved. The GAPs were antigenically distinct. One reacted with a polyclonal antibody raised against the GAP catalytic peptide previously purified by Makler et al. [Makler, Cukierman, Rotman, Admon and Cassel (1995) J. Biol. Chem. 270, 5232-5237], and here is referred to as GAP1. The other GAP (GAP2) did not react with the antibody. These GAPs differed in phospholipid dependencies. GAP1 was activated 3-7-fold by the acid phospholipids phosphatidylinositol 4, 5-bisphosphate (PIP2), phosphatidic acid (PA) and phosphatidylserine (PS). In contrast, GAP2 was stimulated 20-40-fold by PIP2. PA and PS had no effect by themselves but PA increased GAP2 activity in the presence of PIP2. The GAPs were otherwise similar in activity. In the presence of phosphoinositides, the Km of GAP1 for ARF1-GTP was estimated to be 8.1+/-1.6 microM and the dissociation constant for ARF1-guanosine 5',3-O-(thio)triphosphate (GTP[S]) was 7.4+/-2.2 microM. GAP2 was similar with a Km for ARF1-GTP of 5.4+/-1.2 microM and a dissociation constant for ARF1-GTP[S] of 4.8+/-0.3 microM. Similarly, no differences were found in substrate preferences. Both GAP1 and GAP2 used ARF1 and ARF5 as substrates but not ARF6 or ARF-like protein-2. The potential role of multiple ARF GAPs in the independent regulation of ARF at specific steps in membrane traffic is discussed.


Effect οf Genotype and Growing Year on the Nutritional, Phytochemical, and Antioxidant Properties of Industrial Hemp (Cannabis sativa L.) Seeds.
Cannabis sativa L. seeds have been an important source of protein, oil, and dietary fiber for human and animals. Currently, there is a growing interest in the commercial products of these seeds, which are recognized as a legitimate source of medicaments, cosmeceuticals, and nutraceuticals. The objective of this study was to investigate the nutritional, phytochemical composition, and antioxidant properties of seeds from seven hemp cultivars grown in Greece for three consecutive years. All the measured parameters strongly varied under the influence of growing year and genotype. In particular, protein, oil, and carbohydrates' content of hemp seeds as well as fatty acids' composition were mainly affected by genotype, whereas the growing year had a major effect on phytochemical components and antioxidant activity, which was determined by the 2,2'-azino-bis (3-ethylbenzthiazoline sulfonate) (ABTS) and ferric-reducing antioxidant power (FRAP) assays. Moreover, a predominant effect of the year was observed for phenolic profiles as determined by high-performance liquid chromatography and total carotenoids' content. This study suggests that hemp seeds could be a promising food crop as a result of their high nutritive traits and antioxidant potential. A comparison of the studied cultivars, showed that Finola seeds had the highest oil and protein contents and, thus, appeared to be the most promising cultivar for cultivation in Greece.


[Double fertilization in flowering plants: 1898-2008].
A short review of the results of investigations in the field of plant embryology in vivo and in vitro which are directly connected with the discovery of double fertilization in flowering plants by S.G. Navashin is presented. These results have been obtained by using the methods of electron and fluorescence microscopy, cytophotometry, cultures of isolated ovules, sperms, eggs, and embryo sac central cells. The question on an origin of the female gametophyte of flowering plants, double fertilization, and endosperm are discussed. It is emphasized that the progress in this field is connected mostly with the study of molecular processes which control the development and functioning of a female gametophyte and sporophyte at the early stages of ontogenesis.


Effects of composition on catalytic activities of molybdenum doped platinum nanoparticles.
The physical and chemical properties of bimetallic nanoparticles can be optimized by tuning the particle composition. In this study, we identified CO adsorption and dissociation energetics on five Pt-Mo nanoparticles at different concentrations, the lowest energy Pt7, Pt6Mo, Pt5Mo2, Pt4Mo3, and Mo7 clusters. We have shown that the CO adsorption and dissociation energies and preferred CO adsorption sites are largely dependent on the composition of the nanoparticles. As the Mo concentration increases, the strength of the C-O internal bond in the adsorption complex decreases, as indicated by a decrease in the C-O stretching frequency. Also, more Mo sites in the nanoparticle become available for CO adsorption, and the preferred CO adsorption site switches from Pt to Mo. For these reasons, dissociation of CO is energetically favorable on Pt4Mo3 and Mo7. On both compositions, we have shown that the dissociation paths begin with CO adsorbed on a Mo site in a multifold configuration, in particular in a tilted configuration. These findings provide insight on the effects of the composition on the chemical and catalytical properties of Pt-Mo nanoparticles, thereby guiding future experiments on the synthesis of nanoparticles, especially those that may be suitable for various desired applications containing CO.


The Complex Effects of PKM2 and PKM2:IP3R Disruption on Intracellular Ca2+ Handling and Cellular Functions.
Pyruvate kinase M (PKM) 2 was described to interact with the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and suppress its activity. To further investigate the physiological importance of the PKM2:IP3R interaction, we developed and characterized HeLa PKM2 knockout (KO) cells. In the HeLa PKM2 KO cells, the release of Ca2+ to the cytosol appears to be more sensitive to low agonist concentrations than in HeLa wild-type (WT) cells. However, upon an identical IP3-induced Ca2+ release, Ca2+ uptake in the mitochondria is decreased in HeLa PKM2 KO cells, which may be explained by the smaller number of contact sites between the ER and the mitochondria. Furthermore, in HeLa PKM2 KO cells, mitochondria are more numerous, though they are smaller and less branched and have a hyperpolarized membrane potential. TAT-D5SD, a cell-permeable peptide representing a sequence derived from IP3R1 that can disrupt the PKM2:IP3R interaction, induces Ca2+ release into the cytosol and Ca2+ uptake into mitochondria in both HeLa WT and PKM2 KO cells. Moreover, TAT-D5SD induced apoptosis in HeLa WT and PKM2 KO cells but not in HeLa cells completely devoid of IP3Rs. These results indicate that PKM2 separately regulates cytosolic and mitochondrial Ca2+ handling and that the cytotoxic effect of TAT-D5SD depends on IP3R activity but not on PKM2. However, the tyrosine kinase Lck, which also interacts with the D5SD sequence, is expressed neither in HeLa WT nor PKM2 KO cells, and we can also exclude a role for PKM1, which is upregulated in HeLa PKM2 KO cells, indicating that the TAT-D5SD peptide has a more complex mode of action than anticipated.


Neural oscillation, network, eloquent cortex and epileptogenic zone revealed by magnetoencephalography and awake craniotomy.
Magnetoencephalography (MEG) is a method of functional neuroimaging. The concomitant use of MEG and electrocorticography has been found to be useful in elucidating neural oscillation and network, and to localize epileptogenic zone and functional cortex. We describe our early experience using MEG in neurosurgical patients, emphasizing on its impact on patient management as well as the enrichment of our knowledge in neurosciences. A total of 10 subjects were included; five patients had intraaxial tumors, one with an extraaxial tumor and brain compression, two with arteriovenous malformations, one with cerebral peduncle hemorrhage and one with sensorimotor cortical dysplasia. All patients underwent evoked and spontaneous MEG recordings. MEG data was processed at band-pass filtering frequency of between 0.1 and 300 Hz with a sampling rate of 1 kHz. MEG source localization was performed using either overdetermined equivalent current dipoles or underdetermined inversed solution. Neuromag collection of events software was used to study brain network and epileptogenic zone. The studied data were analyzed for neural oscillation in three patients; brain network and clinical manifestation in five patients; and for the location of epileptogenic zone and eloquent cortex in two patients. We elucidated neural oscillation in three patients. One demonstrated oscillatory phenomenon on stimulation of the motor-cortex during awake surgery, and two had improvement in neural oscillatory parameters after surgery. Brain networks corresponding to clinico-anatomical relationships were depicted in five patients, and two networks were illustrated here. Finally, we demonstrated epilepsy cases in which MEG data was found to be useful in localizing the epileptogenic zones and functional cortices. The application of MEG while enhancing our knowledge in neurosciences also has a useful role in epilepsy and awake surgery.


Advancements in Home-Based Devices for Detecting Obstructive Sleep Apnea: A Comprehensive Study.
Obstructive Sleep Apnea (OSA) is a respiratory disorder characterized by frequent breathing pauses during sleep. The apnea-hypopnea index is a measure used to assess the severity of sleep apnea and the hourly rate of respiratory events. Despite numerous commercial devices available for apnea diagnosis and early detection, accessibility remains challenging for the general population, leading to lengthy wait times in sleep clinics. Consequently, research on monitoring and predicting OSA has surged. This comprehensive paper reviews devices, emphasizing distinctions among representative apnea devices and technologies for home detection of OSA. The collected articles are analyzed to present a clear discussion. Each article is evaluated according to diagnostic elements, the implemented automation level, and the derived level of evidence and quality rating. The findings indicate that the critical variables for monitoring sleep behavior include oxygen saturation (oximetry), body position, respiratory effort, and respiratory flow. Also, the prevalent trend is the development of level IV devices, measuring one or two signals and supported by prediction software. Noteworthy methods showcasing optimal results involve neural networks, deep learning, and regression modeling, achieving an accuracy of approximately 99%.


[Development of the Italian versions of the FREE Scale and the CSI. Theoretical considerations and preliminary analysis.]
The Flexible Regulation of Emotional Expression (FREE) Scale assesses the ability to enhance and suppress displayed emotions among a range of hypothetical contexts. The Context Sensitivity Index (CSI) measures the ability to perceive cues to contextual demands across different situations. This study aimed to present the first step of the adaptation and validation to the Italian context of the FREE and the CSI scales. A sample of 120 Italian students took part in this first step. Six focus groups were conducted to explore the Context sensitivity, Emotional Flexibility, and Flexible Regulation of Emotional Expression constructs in the Italian context. Verbatim transcripts were analyzed with T-LAB software and two kinds of analyses were performed. Results of the Thematic Analysis of Elementary Contexts showed four clusters: "emotional flexibility", "emotion management", "emotion regulation", and "context sensitivity". Results of Factorial Analysis of Correspondences indicated three factors with the first two factors explaining about 80% of the variance. Factor 1, which opposed "emotional flexibility" and "context sensitivity" at its negative pole; "emotion management" and "emotion regulation" at its positive pole, was named "Cognitive and emotive functions of mind". Factor 2, which opposed "context sensitivity" and "emotion regulation" on the positive pole, "emotional flexibility" and "emotion management" on the negative pole, was named "Elaboration-adaptation as aim of the subject". Preliminary results obtained through a qualitative approach supported the validity of the flexible regulation of emotional expression and the context sensitivity constructs in the Italian context. These results will be tested with a quantitative approach in the next steps of this research.


Adolescent cocaine exposure causes enduring macroscale changes in mouse brain structure.
Cocaine dependence is associated with abnormalities in brain structure in humans. However, it is unclear whether these differences in brain structure predispose an individual to drug use or are a result of cocaine's action on the brain. This study investigates the impact of chronic cocaine exposure on brain structure and drug-related behavior in mice. Specifically, mice received daily cocaine or saline injections for 20 d during two developmental time periods: adolescence (27-46 d old) and young adulthood (60-79 d old). Following 30 d of abstinence, either fixed brain T2 weighted magnetic resonance images were acquired on a 7 T scanner at 32 μm isotropic voxel dimensions or mice were assessed for sensitization to the locomotor stimulant effects of cocaine. Three automated techniques (deformation-based morphometry, striatum shape analysis, and cortical thickness assessment) were used to identify population differences in brain structure in cocaine-exposed versus saline-exposed mice. We found that cocaine induced changes in brain structure, and these were most pronounced in mice exposed to cocaine during adolescence. Many of these changes occurred in brain regions previously implicated in addiction including the nucleus accumbens, striatum, insular cortex, orbitofrontal cortex, and medial forebrain bundle. Furthermore, exposure to the same cocaine regimen caused sensitization to the locomotor stimulant effects of cocaine, and these effects were again more pronounced in mice exposed to cocaine during adolescence. These results suggest that altered brain structure following 1 month of abstinence may contribute to these persistent drug-related behaviors, and identify cocaine exposure as the cause of these morphological changes.


Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy.
Liver macronodules, ranging from benign to low-grade or high-grade dysplastic nodules (LGDNs/HGDNs) and hepatocellular carcinoma (HCC), may develop during chronic liver diseases (CLDs). Current guidelines were recently updated and the noninvasive criteria for the diagnosis of small HCC are based on a single typical radiological pattern and nonconclusive coincidental findings with two techniques. This study aimed to assess the accuracy and disagreements of noninvasive multiphasic examinations for the diagnosis of HCC and dysplastic nodules (DNs) and the role of biopsy. Seventy-four consecutive patients with CLD with ultrasound-detected 1-2-cm nodules underwent, within 1 month, multiphasic computed tomography (CT), magnetic resonance imaging (MRI), and biopsy of the nodule. Median age was 60 years; 33 patients (45%) had hepatitis C virus, 20 (27%) had hepatitis B virus, and 13 (18%) patients had no cirrhosis. Biopsy revealed 47 HCCs, 6 HGDNs, 1 LGDNs, 1 cholangiocarcinoma, and 1 epithelioid hemangioendothelioma. There were no tumors in the other 18 patients. All patients (31 of 31; 100%) who had conclusive coincidental findings (i.e., arterial enhancement and washout) on both examinations had HCC or HGDN (sensitivity, 57%; specificity, 100%). All patients (51 of 51; 100%) who had conclusive findings on at least one of the two examinations had HCC or HGDN (sensitivity, 96%; specificity, 100%). There was a disagreement regarding imaging findings between CT and MRI in 21 of 74 (28%) patients and no washout on both examinations in 23 of 74 patients (31%). In these 44 patients, liver biopsy provided an initial accurate diagnosis. The noninvasive diagnosis of HCC or HGDN can be obtained if arterial enhancement and washout are found in a single dynamic imaging examination. These findings are frequently discordant on both CT and MRI, supporting the place of biopsy for the diagnosis of small HCCs.


Social media data for biodiversity conservation.
Systematic conservation planning is considered best practice for identifying priority areas, but applications remain limited where biodiversity data are insufficient. In a recent article, Chowdhury et al. tap into citizen scientists via Facebook to address this gap in Bangladesh. Here, I discuss the importance of their demonstrated pipeline, from data acquisition to conservation prioritisation.


Intersubunit cross-linking by cis-dichlorodiammineplatinum(II) stabilizes an alpha 2-macroglobulin "nascent" state: evidence that thiol ester bond cleavage correlates with receptor recognition site exposure.
Treatment of human alpha 2-macroglobulin (alpha 2M) with proteinase results in cleavage of the alpha 2M subunits and subsequently in a conformational change in the inhibitor. This change irreversibly traps the proteinase and is accompanied by the generation of four thiol groups as well as exposure of receptor recognition sites. cis-Dichlorodiammineplatinum(II) (cis-DDP) causes extensive intersubunit cross-linking of alpha 2M. Incubation of alpha 2M or cis-DDP-treated alpha 2M with trypsin results in complete subunit cleavage; however, trypsin treatment of cis-DDP-alpha 2M does not result in a conformational change as determined by nondenaturing polyacrylamide gel electrophoresis (PAGE), receptor recognition site exposure, or appearance of thiol groups from the inhibitor. These results are in marked contrast to previous studies which demonstrated that incubation of cis-DDP-treated alpha 2M with CH3NH2 resulted in thiol ester bond cleavage and receptor recognition site exposure. cis-DDP-treated alpha 2M bound only 0.13 mol of 125I-trypsin/mol of cis-DDP-alpha 2M. Incubation of trypsin-treated cis-DDP-alpha 2M with diethyldithiocarbamate (DDC), a potent chelator of platinum compounds, results in the removal of the intersubunit cross-links and completion of the alpha 2M conformational change as determined by nondenaturing PAGE. Complete receptor recognition site exposure and the appearance of 3.3 thiol groups/mol of alpha 2M also occur following this treatment. These results demonstrate that cross-linking of alpha 2M by cis-DDP prevents a conformational change in the inhibitor which is necessary for thiol ester bond activation and cleavage.(ABSTRACT TRUNCATED AT 250 WORDS)


Diabetes Technology Update: Use of Insulin Pumps and Continuous Glucose Monitoring in the Hospital.
The use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems has gained wide acceptance in diabetes care. These devices have been demonstrated to be clinically valuable, improving glycemic control and reducing risks of hypoglycemia in ambulatory patients with type 1 diabetes and type 2 diabetes. Approximately 30-40% of patients with type 1 diabetes and an increasing number of insulin-requiring patients with type 2 diabetes are using pump and sensor technology. As the popularity of these devices increases, it becomes very likely that hospital health care providers will face the need to manage the inpatient care of patients under insulin pump therapy and CGM. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized. Health care institutions must have clear policies and procedures to allow the patient to continue to receive CSII treatment to maximize safety and to comply with existing regulations related to self-management of medication. Randomized controlled trials are needed to determine whether CSII therapy and CGM systems in the hospital are associated with improved clinical outcomes compared with intermittent monitoring and conventional insulin treatment or with a favorable cost-benefit ratio.


Two new rearranged clerodane diterpenes from Thai Tinospora baenzigeri.
A new rearranged clerodane-type diterpene (1), tinobaenzigeride, and a new rearranged clerodane glucoside (2) were isolated from the stems of Tinospora baenzigeri, along with four known compounds (3‒6). Their structures were elucidated by spectroscopic data analysis. In addition, the structure and configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 1 are a rare example of rearranged clerodanes, since it contains a fully oxygenated tetrahydrofuran moiety. The isolated compounds were evaluated for their cytotoxicity against Hep-G2 and MCF-7 cancer cells, none of them did show any significant activity at 25 μM.


Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus--a DTI study in major depressive disorder.
Depression is commonly conceptualized as corticolimbic dysregulation. Due to insufficient studies in normal aged populations especially subcortical sources of disconnection are unclear in contrast to potentially general parietal white matter (WM) deficits. This may be due to important influences of variable patient characteristics, most importantly episode severity. Especially thalamic disconnections have been functionally revealed, however, their structural correlates have not been distinctly investigated for its highly diverse subnuclei. We compared 20 major depressive disorder (MDD) patients with mixed Hamilton depression rating scale (HAMD) severity to matched controls in fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Robust acquisition of 4 repetitions restricted to twelve directions, also to match the same parameters used by Eckert et al. (2011) who described a preferential architecture of centromedian (CM) and mediodorsal (MD) thalamic connections. Second to whole brain analysis, we tested for group differences within the preferred structural network of these two nuclei using a tract of interest (TOI) approach. Significant FA deficits in a whole brain analysis were only found in right parietal WM (p<0.05, corrected). Effects of severity were found for increasing thalamic FA. Post hoc analysis revealed this effect to be restricted to CM specific tracts. In contrast, we found MD to dorsolateral prefrontal cortex (DLPFC) tracts to be decreased in FA. Unspecific decreases between MD and CM towards amygdala were paralleled by primary amygdala FA reductions. Specificity of the TOI approach and heterogenous sample. Robust parietal FA reductions, controlled for age effects were found in MDD. Further we revealed subcortical disease state dependency of FA in thalamic tracts, specific to predescribed preferential connections.


Does influent COD/N ratio affect nitrogen removal and N2O emission in a novel biochar-sludge amended soil wastewater infiltration system (SWIS)?
Nitrogen removal and N2O emission of a biochar-sludge amended soil wastewater infiltration system (SWIS) with/without intermittent aeration under different influent COD/N ratios was investigated. Nitrogen removal and N2O emission were affected by influent COD/N ratio. Under a COD/N ratio between 1:1 and 15:1, average chemical oxygen demand (COD), NH4 +-N and total nitrogen (TN) removal rates decreased with COD/N ratio increase in non-aerated SWISs amended with/without biochar-sludge; an increasing COD/N ratio hardly affected COD and NH4 +-N removal in a biochar-sludge amended SWIS with intermittent aeration; the N2O emission rate decreased with COD/N ratio increase in the studied SWISs. The biochar-sludge amended SWIS with intermittent aeration achieved high COD (92.2%), NH4 +-N (96.8%), and TN (92.7%) removal rates and a low N2O emission rate (10.6 mg/(m2 d)) under a COD/N ratio of 15:1, which was higher than those in non-aerated SWISs amended with/without biochar-sludge. Combining the biochar-sludge amended SWIS with intermittent aeration enhanced the number of nitrifying bacteria, denitrifying bacteria, nitrate reductase activities, nitrite reductase activities, and improved the abundance of nitrogen removal functional genes under a high influent COD/N ratio. The results suggested that the joint use of intermittent aeration and biochar-sludge in a SWIS could be an effective and appropriate strategy for improving nitrogen removal and reducing N2O emissions in treating high COD/N ratio wastewater.


The neurocognitive role of working memory load when Pavlovian motivational control affects instrumental learning.
Research suggests that a fast, capacity-limited working memory (WM) system and a slow, incremental reinforcement learning (RL) system jointly contribute to instrumental learning. Thus, situations that strain WM resources alter instrumental learning: under WM loads, learning becomes slow and incremental, the reliance on computationally efficient learning increases, and action selection becomes more random. It is also suggested that Pavlovian learning influences people's behavior during instrumental learning by providing hard-wired instinctive responses including approach to reward predictors and avoidance of punishment predictors. However, it remains unknown how constraints on WM resources affect instrumental learning under Pavlovian influence. Thus, we conducted a functional magnetic resonance imaging (fMRI) study (N = 49) in which participants completed an instrumental learning task with Pavlovian-instrumental conflict (the orthogonalized go/no-go task) both with and without extra WM load. Behavioral and computational modeling analyses revealed that WM load reduced the learning rate and increased random choice, without affecting Pavlovian bias. Model-based fMRI analysis revealed that WM load strengthened RPE signaling in the striatum. Moreover, under WM load, the striatum showed weakened connectivity with the ventromedial and dorsolateral prefrontal cortex when computing reward expectations. These results suggest that the limitation of cognitive resources by WM load promotes slow and incremental learning through the weakened cooperation between WM and RL; such limitation also makes action selection more random, but it does not directly affect the balance between instrumental and Pavlovian systems.


A single domestication for maize shown by multilocus microsatellite genotyping.
There exists extraordinary morphological and genetic diversity among the maize landraces that have been developed by pre-Columbian cultivators. To explain this high level of diversity in maize, several authors have proposed that maize landraces were the products of multiple independent domestications from their wild relative (teosinte). We present phylogenetic analyses based on 264 individual plants, each genotyped at 99 microsatellites, that challenge the multiple-origins hypothesis. Instead, our results indicate that all maize arose from a single domestication in southern Mexico about 9,000 years ago. Our analyses also indicate that the oldest surviving maize types are those of the Mexican highlands with maize spreading from this region over the Americas along two major paths. Our phylogenetic work is consistent with a model based on the archaeological record suggesting that maize diversified in the highlands of Mexico before spreading to the lowlands. We also found only modest evidence for postdomestication gene flow from teosinte into maize.


Understanding Familial Risk for Depression: A 25-Year Perspective.
Major depressive disorder (MDD) is among the most prevalent, debilitating, and costly of all illnesses worldwide. Investigators have made considerable progress in elucidating psychological and biological correlates of MDD; however, far less is known about factors that are implicated in risk for depression. Given the high risk for MDD associated with a family history of depression, investigators have worked to understand both the effects of parental depression on offspring and the mechanisms that might underlie familial risk for MDD. In this article, we describe the evolution of investigators' understanding of the psychobiological functioning of children of depressed parents, and we present recent findings concerning cognitive and neural aspects of risk for MDD using our high-risk sample as a context and foundation for this discussion. We integrate these data in a conceptualization of mechanisms underlying risk for depression, focusing on the constructs of emotion dysregulation and stress reactivity. Recognizing the 25-year anniversary of the Association for Psychological Science, we place this presentation in the context of the past 25 years of research on depression. We conclude by discussing the significance of emotion dysregulation and stress reactivity for studying risk for depression, for developing approaches to prevent MDD, and for moving theory and research in this field forward.


Deep Vision for Breast Cancer Classification and Segmentation.
(1) Background: Female breast cancer diagnoses odds have increased from 11:1 in 1975 to 8:1 today. Mammography false positive rates (FPR) are associated with overdiagnoses and overtreatment, while false negative rates (FNR) increase morbidity and mortality. (2) Methods: Deep vision supervised learning classifies 299 × 299 pixel de-noised mammography images as negative or non-negative using models built on 55,890 pre-processed training images and applied to 15,364 unseen test images. A small image representation from the fitted training model is returned to evaluate the portion of the loss function gradient with respect to the image that maximizes the classification probability. This gradient is then re-mapped back to the original images, highlighting the areas of the original image that are most influential for classification (perhaps masses or boundary areas). (3) Results: initial classification results were 97% accurate, 99% specific, and 83% sensitive. Gradient techniques for unsupervised region of interest mapping identified areas most associated with the classification results clearly on positive mammograms and might be used to support clinician analysis. (4) Conclusions: deep vision techniques hold promise for addressing the overdiagnoses and treatment, underdiagnoses, and automated region of interest identification on mammography.


Quantitative detection of Streptococcus pneumoniae cells harbouring single or multiple copies of the gene encoding the green fluorescent protein.
A modified gfp gene from Aequorea victoria, encoding a variant of the green fluorescent protein (GFP), was subcloned into the mobilizable plasmid pMV158. gfp was placed under the control of the inducible P(M) promoter of the Streptococcus pneumoniae gene malM, cloned in plasmid pLS70. The P(M) promoter is regulated by the product of the pneumococcal malR gene, which is inactivated by growing the cells in maltose-containing media. By homologous recombination, the P(M)-gfp construction was integrated into the host chromosome in a single copy. In both conditions (single and multiple copies), the pneumococcal cells were able to express GFP in an inducible or constitutive form, depending on whether the S. pneumoniae strain harboured a wild-type or a mutant malR gene. Quantification of the levels of GFP expressed by cultures supplemented with sucrose or maltose as carbon sources was feasible by fluorescence spectroscopy. Phase-contrast and fluorescence microscopy allowed pneumococcal cells expressing GFP in mixed cultures to be distinguished from those not carrying the gfp gene.


In Situ, Real-Time Visualization of Electrochemistry Using Magnetic Resonance Imaging.
The drive to develop better electrochemical energy storage devices requires the development of not only new materials, but also better understanding of the underpinning chemical and dynamical processes within such devices during operation, for which new analytical techniques are required. Currently, there are few techniques that can probe local composition and transport in the electrolyte during battery operation. In this paper, we report a novel application of magnetic resonance imaging (MRI) for probing electrochemical processes in a model electrochemical cell. Using MRI, the transport and zinc and oxygen electrochemistry in an alkaline electrolyte, typical of that found in zinc-air batteries, are investigated. Magnetic resonance relaxation maps of the electrolyte are used to visualize the chemical composition and electrochemical processes occurring during discharge in this model metal-air battery. Such experiments will be useful in the development of new energy storage/conversion devices, as well as other electrochemical technologies.


Why do males in Scotland die younger than those in England? Evidence from three prospective cohort studies.
To examine explanations for the higher rates of male mortality in two Scottish cohorts compared with a cohort in south-east England for which similar data were collected. We compared three cohort studies which recruited participants in the late 1960s and early 1970s. A total of 13,884 men aged 45-64 years at recruitment in the Whitehall occupational cohort (south-east England), 3,956 men in the Collaborative occupational cohort and 6,813 men in the Renfrew & Paisley population-based study (both central Scotland) were included in analyses of all-cause and cause-specific mortality. All-cause mortality was 25% (age-adjusted hazard ratio 1.25, 95% confidence interval (CI)1.21 to 1.30) and 41% (hazard ratio 1.41 (95% CI 1.36 to 1.45) higher in the Collaborative and Renfrew & Paisley cohorts respectively compared to the Whitehall cohort. The higher mortality rates were substantially attenuated by social class (to 8% and 17% higher respectively), and were effectively eliminated upon the further addition of the other baseline risk factors, such as smoking habit, lung function and pre-existing self-reported morbidity. Despite this, coronary heart disease mortality remained 11% and 16% higher, stroke mortality 45% and 37% higher, mortality from accidents and suicide 51% and 70% higher, and alcohol-related mortality 46% and 73% higher in the Collaborative and Renfrew & Paisley cohorts respectively compared with the Whitehall cohort in the fully adjusted model. The higher all-cause, respiratory, and lung cancer male mortality in the Scottish cohorts was almost entirely explained by social class differences and higher prevalence of known risk factors, but reasons for the excess mortality from stroke, alcohol-related causes, accidents and suicide remained unknown.


Isolation and characterization of beneficial bacteria associated with citrus roots in Florida.
Cultivable diversity of bacteria associated with citrus was investigated as part of a larger study to understand the roles of beneficial bacteria and utilize them to increase the productive capacity and sustainability of agro-ecosystems. Citrus roots from Huanglongbing (HLB) diseased symptomatic and asymptomatic citrus were used in this study. A total of 227 and 125 morphologically distinct colonies were isolated and characterized from HLB asymptomatic and symptomatic trees, respectively. We observed that the frequency of bacterial isolates possessing various plant beneficial properties was significantly higher in the asymptomatic samples. A total of 39 bacterial isolates showing a minimum of five beneficial traits related to mineral nutrition [phosphate (P) solubilization, siderophore production, nitrogen (N) fixation], development [indole acetic acid (IAA) synthesis], health [production of antibiotic and lytic enzymes (chitinase)], induction of systemic resistance [salicylic acid (SA) production], stress relief [production of 1-amino-cyclopropane-1-carboxylate deaminase] and production of quorum sensing [N-acyl homoserine lactones] signals were characterized. A bioassay using ethidium monoazide (EMA)-qPCR was developed to select bacteria antagonistic to Candidatus Liberibacter asiaticus. Using the modified EMA-qPCR assay, we found six bacterial isolates showing maximum similarity to Paenibacillus validus, Lysinibacillus fusiformis, Bacillus licheniformis, Pseudomonas putida, Microbacterium oleivorans, and Serratia plymutica could significantly reduce the population of viable Ca. L. asiaticus in HLB symptomatic leaf samples. In conclusion, we have isolated and characterized multiple beneficial bacterial strains from citrus roots which have the potential to enhance plant growth and suppress diseases.


Sustained high glucose intake accelerates type 1 diabetes in NOD mice.
Epidemiological studies have suggested that dietary factors, especially high consumption of high glycaemic index carbohydrates and sugars, may trigger or exacerbate the progression of type 1 diabetes. We aimed to provide experimental evidence to confirm this relevance and to explore the underlying mechanisms. NOD mice were given sustained high-glucose drinking or glucose-free water and observed for the incidence of type 1 diabetes and islet inflammation. RNAseq was performed to detect the transcriptome changes of the NOD islet beta cell line NIT-1 after high glucose treatment, and mass spectrometry was performed to detect the proteome changes of NIT-1-cells-derived sEVs. Sustained high glucose drinking significantly aggravates islet inflammation and accelerates the onset of type 1 diabetes in NOD mice. Mechanistically, high glucose treatment induces aberrant ER stress and up-regulates the expression of autoantigens in islet beta cell. Moreover, high glucose treatment alters the proteome of beta-cells-derived sEVs, and significantly enhances the ability of sEVs to promote DC maturation and stimulate immune inflammatory response. This study provides evidence for negative effect of high glucose intake as a dietary factor on the pathogenesis of type 1 diabetes in genetically predisposed individuals. Therefore, avoiding high sugar intake may be an effective disease prevention strategy for children or adults susceptible to type 1 diabetes.


Flexible Ti3C2Tx/PEDOT:PSS films with outstanding volumetric capacitance for asymmetric supercapacitors.
MXenes are two-dimensional transition metal carbides/nitrides, and they have shown exciting application prospects for electrochemical energy storage in the future owing to their hydrophilicity, metallic conductivity and surface redox reactions, which are crucial for high-capacitance and high-rate electrode materials. However, the strong tendency of adjacent MXene flakes to aggregate or self-restack under the van der Waals force limits the electrochemical performance of MXene-based electrodes for practical applications. In this study, we developed a simple and effective method to prepare Ti3C2Tx/PEDOT:PSS hybrid films via filtering the Ti3C2Tx/Clevios PH1000 compound inks, followed by H2SO4 treatment. H2SO4 treatment could remove part of the insulating PSS from the Ti3C2Tx/PEDOT:PSS hybrid film, resulting in significant conductivity enhancement of the composite. Furthermore, the conductive PEDOT not only acted as a pillar between Ti3C2Tx sheets to expose more electroactive surfaces and reduce ion diffusion pathways but also played a role as a conductive bridge to form multidimensional electronic transport channels for accelerating the electrochemical reaction process. As a result, the as-prepared H2SO4-treated Ti3C2Tx/PEDOT:PSS (Ti3C2Tx/P-100-H) hybrid film exhibited 4.5-fold increase in the specific surface area and high volumetric capacitance of 1065 F cm-3 at 2 mV s-1 with superior rate performance in 1 M H2SO4 electrolyte. Especially, we assembled an asymmetric supercapacitor (ASC) with excellent flexibility based on a Ti3C2Tx/P-100-H hybrid negative electrode and rGO film positive electrode, which delivered high energy density of 23 mW h cm-3 and high power density of 7659 mW cm-3. Moreover, a simple luminous band was designed and powered by our two ASCs in series. The outstanding volumetric electrochemical performance and energy density of the ASC based on the flexible Ti3C2Tx/P-100-H hybrid film electrode demonstrated its promising potential as a strong power source for small portable and wearable electronic devices.


Tissue damage after single high-dose intraoperative irradiation of the canine liver: evaluation in time by means of radionuclide imaging and light microscopy.
To establish the tolerance of liver tissue to single high-dose intraoperative irradiation, the histopathological changes in the canine liver after single high-dose intraoperative irradiation were investigated by means of radionuclide imaging and light microscopy. Intraoperative irradiation at doses of 0, 10, 20, 25 or 30 Gy was applied to a part of the liver of 25 beagles. Radionuclide imaging using (99m)Tc-sulfur colloid was performed at several times during follow-up. Elective humane killing was done 3 months and 1, 2, 3 and 5 years after irradiation. Light microscopy was used to identify histopathological alterations. There was no morbidity or mortality during a maximal follow-up of 5 years. In 40% of the animals, a region of diminished uptake was observed at the irradiation site. The regions of diminished uptake of the radiopharmaceutical agent became smaller with time. Light microscopic examination revealed severe parenchymal fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area 1 to 2 years after irradiation. At 3 and 5 years, vascular changes with endothelial proliferation and focal arteriolar hyalinosis were observed. This study demonstrates that intraoperative irradiation of a part of the liver in the canine model can be applied safely. Light microscopy confirmed that histological damage was not always accompanied by diminished uptake of the radiopharmaceutical agent at the irradiation site.


Posttraumatic stress disorder (PTSD) symptom profiles among people who have experienced abuse: Findings from the NESARC-III study.
Greater recognition of diversity in psychological responses to traumatic events has led to increased exploration of posttrauma symptom typologies and risk factors for more "complex" presentations. We sought to identify unique PTSD symptom profiles associated with the experience of physical and sexual abuse and to determine whether exposure in childhood, type of abuse, frequency of abuse and familial support were associated with profiles indicating increased symptom complexity. We analyzed data from 6,769 American adults (M = 43.93 years, SD = 15.35, 70.9% female) from the National Epidemiologic Survey on Alcohol and Related Conditions-III who reported histories of physical or sexual abuse. Latent Class Analysis was used to identify distinct profiles of the twenty PTSD symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Abuse in childhood, type of abuse, frequency of childhood abuse, emotional support in childhood and a range of demographic variables were compared across classes. Five classes were educed: High All (19.6%), Threat (14.4%), Dysphoric (13.7%), Moderate Threat (29.4%) and Low Symptom (22.9%). Contrary to our hypotheses, trauma exposure in childhood did not predict class membership while type of abuse did. The High All and Dysphoric classes had greater frequency of childhood abuse, lower support in childhood, and a history of sexual abuse when compared to their less complex, predominantly fear-based counterparts (Threat and Moderate Threat classes, respectively). These constellations of DSM-5 PTSD symptoms may be a proxy for increased "complexity" and may indicate a need for alternative or additional therapeutic interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


A generalized Michaelis-Menten equation for the analysis of growth.
The functional form W = (W0Kc + Wf t(c)) /(Kc + t(c)), where W is body size at age t, W0 and Wf are the zero- and infinite-time values of W, respectively, and K and c are constants, is derived. This new generalized Michaelis-Menten-type equation provides a flexible model for animal growth capable of describing sigmoidal and diminishing returns behavior. The parameters of the nonlinear model are open to biological interpretation and can be used to calculate reliable estimates of growth traits, such as maximum or average postnatal growth rates. To evaluate the new model, the derived equation and standard growth functions such as the Gompertz and Richards were used to fit 83 growth data sets of different animal species (fish, mice, hamsters, rats, guinea pigs, rabbits, cats, dogs, broilers, turkeys, sheep, goats, pigs, horses, and cattle) with a large range in body size. A comparative study was carried out based on mathematical, statistical, and biological characteristics of the models. The statistical goodness-of-fit achieved with the new model was similar to that of Richards, and both were slightly superior to the Gompertz. The new model differed from the others with respect to some of the estimated growth traits, but there were highly significant correlation coefficients between estimates obtained with the different models, and the ranking of animals based on growth parameters computed with the new function agreed with the rankings computed by the other models. Therefore, the new model, with its variable inflection point, was able to adequately describe growth in a wide variety of animals, to fit a range of data showing sigmoidal growth patterns, and to provide satisfactory estimates of traits for quantifying the growth characteristics of each type of animal.


Dysregulation of the endogenous cannabinoid system in adult rats prenatally treated with the cannabinoid agonist WIN 55,212-2.
Cannabis is widely abused by women at reproductive age and during pregnancy. Animal studies showed a particular vulnerability of the developing brain to prenatal chronic cannabinoid administration. We determined whether prenatal exposure to WIN 55,212-2, a potent cannabinoid receptor agonist, affected (1) density, affinity and/or function of cannabinoid CB(1) receptors, (2) endogenous levels of the endocannabinoid anandamide, (3) activities of the major anandamide synthesising and hydrolysing enzymes, N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), respectively, in brain areas of adult male offspring rats. Furthermore, the effect of prenatal WIN 55,212-2 on spontaneous motility was analyzed. Pregnant rats were treated daily with WIN 55,212-2 (0.5 mg/kg, gestation day 5-20) or vehicle. [(3)H]CP 55,940 and WIN 55,212-2-stimulated [(35)S] GTPgammaS binding were carried out in cerebellum, cerebral cortex, hippocampus, striatum and limbic areas of male adult offspring. Levels of anandamide, FAAH and NAPE-PLD activity were also determined. EC(50) values for WIN 55,212-2-stimulated [(35)S]GTPgammaS binding were significantly different in hippocampus (-26%) and striatum (+27%) in WIN 55,212-2-treated rats. Cannabinoid CB(1) receptor density and affinity were not affected in any analyzed region. In the striatum, increased anandamide levels were associated with reduced FAAH and enhanced NAPE-PLD activities. Opposite changes in anandamide levels and enzymatic activities were detected in limbic areas of WIN 55,212-2-treated rats. Ambulatory activity between WIN 55,212-2- and vehicle-treated adult offspring did not vary. Our results show that prenatal exposure to cannabinoid agonist induces a long-term alteration of endocannabinoid system in brain areas involved in learning-memory, motor activity and emotional behavior.


Density-based clustering with topographic maps.
A new unsupervised competitive learning rule is introduced, called the kernel-based Maximum Entropy learning Rule (kMER), for equiprobabilistic topographic map formation. The application envisaged is density-based clustering. An empirical study is conducted to compare the clustering performance of kMER with that of a number of other unsupervised competitive learning rules.


Effect of a Glyphosate-Containing Herbicide on Escherichia coli and Salmonella Ser. Typhimurium in an In Vitro Rumen Simulation System.
Glyphosate (N-(phosphonomethyl)glycine) is the most-used herbicide worldwide. Many studies in the past have shown that residues of the herbicide can be found in many cultivated plants, including those used as livestock feed. Sensitivity to glyphosate varies with bacteria, particularly those residing in the intestine, where microbiota is exposed to glyphosate residues. Therefore, less susceptible pathogenic isolates could have a distinct advantage compared to more sensitive commensal isolates, probably leading to dysbiosis. To determine whether the ruminal growth and survival of pathogenic Escherichia coli or Salmonella serovar Typhimurium are higher when glyphosate residues are present in the feed, an in vitro fermentation trial with a "Rumen Simulation System" (RUSITEC) and a glyphosate-containing commercial formulation was performed. Colony forming units of E. coli and Salmonella ser. Typhimurium decreased steadily in all fermenters, regardless of the herbicide application. Minimum inhibitory concentrations of the studied Salmonella and E. coli strains did not change, and antibiotic susceptibility varied only slightly but independent of the glyphosate application. Overall, application of the glyphosate-containing formulation in a worst-case concentration of 10 mg/L neither increased the abundance for the tested E. coli and Salmonella strain in the in vitro fermentation system, nor promoted resistance to glyphosate or antibiotics.


Dendritic Self-assembled Structures from Therapeutic Charged Pentapeptides.
CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.


Study of hydroxy propyl guar derivative for its gelling property and it's use in the formulation of tenoxicam gels.
Gels of tenoxicam 1% w/w were formulated using 2% w/w hydroxy propyl guar derivative and 3% w/w sodium carboxy methyl cellulose as gelling agents. A detailed rheological investigation was carried out to study the influence of preservative, drug and preservative, solvent system and the preservative, drug, solvent system and the preservative on the pseudoplastic behaviour of polymers. Hydroxy propyl guar derivative in 2% w/w strength resulted in gels with a higher pseudoplastic index value of 3.383 in contrast to an index value of 1.797 for a 3% w/w sodium carboxy methyl cellulose gels of a similar composition. The gels were stored at different temperatures and variations in pH values were recorded. Hydroxy propyl guar derivative based gels revealed variations in pH values over a narrow range in contrast to sodium carboxy methyl cellulose gels. The gels were subjected to short term stability studies by storing gels at refrigerated temperature, lab temperature, at 37 degrees C and at 45 degrees C. Gels based on hydroxy propyl guar derivative revealed better drug keeping qualities in contrast to sodium carboxy methyl cellulose stabilized gels. Release studies of tenoxicam from formulations across hairless albino mice skin revealed a zero order drug release pattern from both the formulations.


Extended-bandwidth frequency sweeps of a distributed feedback laser using combined injection current and temperature modulation.
This article details the generation of an extended-bandwidth frequency sweep using a single, communication grade distributed feedback (DFB) laser. The frequency sweep is generated using a two-step technique. In the first step, injection current modulation is employed as a means of varying the output frequency of a DFB laser over a bandwidth of 99.26 GHz. A digital optical phase lock loop is used to lock the frequency sweep speed during current modulation, resulting in a linear frequency chirp. In the second step, the temperature of the DFB laser is modulated, resulting in a shifted starting laser output frequency. A laser frequency chirp is again generated beginning at this shifted starting frequency, resulting in a frequency-shifted spectrum relative to the first recorded data. This process is then repeated across a range of starting temperatures, resulting in a series of partially overlapping, frequency-shifted spectra. These spectra are then aligned using cross-correlation and combined using averaging to form a single, broadband spectrum with a total bandwidth of 510.9 GHz. In order to investigate the utility of this technique, experimental testing was performed in which the approach was used as the swept-frequency source of a coherent optical frequency domain reflectometry system. This system was used to interrogate an optical fiber containing a 20 point, 1-mm pitch length fiber Bragg grating, corresponding to a period of 100 GHz. Using this technique, both the periodicity of the grating in the frequency domain and the individual reflector elements of the structure in the time domain were resolved, demonstrating the technique's potential as a method of extending the sweeping bandwidth of semiconductor lasers for frequency-based sensing applications.


Maurice Hugh Frederick Wilkins CBE: 15 December 1916 - 5 October 2004.
Maurice Hugh Frederick Wilkins was the 'Third man of the double helix; according to the publishers who were allowed to foist this title on his late-written autobiography. Certainly it is for his role in the discover of the duplex secondary structure of DNA that he will be remembered. It might be argued that he was the first man, rather than the third, for it was his successful revival of X-ray diffraction studies of DNA and his earliest result in 1950, a pattern of a well-oriented and polycrystalline DNA of unprecedented quality, that allowed him to conclude almost immediately that the basic framework of the genetical material was simple and symmetrical, and that the symmetrical structure took the form of a helix. This same pattern, displayed at a conference in Naples six months later, was the major inspiration for the involvement of J. D. Watson (ForMemRS 1981) in modelling DNA structure in collaboration with F. H. C. Crick (FRS 1959). Crick was a personal friend of Maurice's and was more involved with studies of proteins until the progress of Maurice's research programme and Watson's enthusiastic presence in Cambridge convinced him to put nucleic acids first. The carefully crafted citation for the 1960 Lasker Award, which these three men shared in 1960, put Maurice's name first and accurately referred to '...the painstaking x-ray diffraction studies of Wilkins that provided a most important clue that was pursued in a ingenious fashion and to a logical conclusion by Crick and Watson...'. Maurice's diffraction studies of DNA were not only the alpha but also the omega of the double helix because it left to him to remedy a major flaw in the original (1953) Watson-Crick conjecture. Maurice Wilkin's early acceptance of DNA as the genetic material and his recognition that it had structures that could and should be tackled by X-ray diffraction analyses, not necessarily under his exclusive control, was important in ensuring that the essence of DNA's structure was discovered as early as it was. His success in resolving patiently and successfully all the technical problems, great and small, that arose unpredictably in the course of his work on DNA and RNA was substantial. He was less successful in defending himself against the slings and arrows that unjustly assail those involved in momentous exercises. His pacific acceptance of these misfortunes was typical of a life that had priorities beyond the laboratory and required him to do as one would be done by.


Rotational Diffusion of Soft Vesicles Filled by Chiral Active Particles.
We investigate the dynamics of two-dimensional soft vesicles filled with chiral active particles by employing the overdamped Langevin dynamics simulation. The unidirectional rotation is observed for soft vesicles, and the rotational angular velocity of vesicles depends mainly on the area fraction (ρ) and angular velocity (ω) of chiral active particles. There exists an optimal parameter for ω at which the rotational angular velocity of vesicle takes its maximal value. Meanwhile, at low concentration the continuity of curvature is destroyed seriously by chiral active particles, especially for large ω, and at high concentration the chiral active particles cover the vesicle almost uniformly. In addition, the center-of-mass mean square displacement for vesicles is accompanied by oscillations at short timescales, and the oscillation period of diffusion for vesicles is consistent with the rotation period of chiral active particles. The diffusion coefficient of vesicle decreases monotonously with increasing the angular velocity ω of chiral active particles. Our investigation can provide a few designs for nanofabricated devices that can be driven in a unidirectional rotation by chiral active particles or could be used as drug-delivery agent.


Identification of benzothiazoles as novel PCSK9 inhibitors.
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a clinically validated target on the treatment of cardiovascular disease (CVD). PCSK9 can regulate the hepatocyte surface low density lipoprotein receptor (LDLR) level by binding to LDLR and leading to their degradation in the lysosome. The clinical use of two monoclonal antibodies (alirocumab and evolocumab, approved in 2015) and one small interfering RNA (inclisiran, approved in 2020) which can inhibit PCSK9 function proved that they are very effective in lowering low density lipoprotein cholesterol (LDL-C). However, the high treatment costs and parenteral administration of these drugs prohibited widespread use and reduced their long-term advantage. Comparatively, small molecule drugs have many incomparable advantages of macromolecules, such as lower treatment cost, more drug administration options, superior pharmacokinetic properties, less adverse immunogenic responses and better affordable production. In this paper, we identified a series of benzothiazoles small molecule PCSK9 inhibitors through extensive screening. The structure and activity relationship (SAR) was summarized to facilitate further optimization. Moreover, the primary mechanism of action of the most potent compound was also investigated.


[Epidemiology and risk factors of ischemic stroke in the Middle Ob region].
Based on the methods of the Brain Stroke Register, a study was made of epidemiology and risk factors (RF) of ischemic brain stroke (IBS) in one of the cities of the Middle Ob region, numbering 220 thousand population. Based on 615 cases of IBS, a noticeable rise of the disease incidence was revealed in a group of subjects aged 40-49 years as was a high level of the morbidity and mortality among persons over 60 years. Studies into RF discovered a high portion of arterial hypertension (75.1%), atherosclerosis (44.3%), aggravated heredity (28.6%), coronary heart disease (27.9%), alcohol abuse (17.9%). In 90.8% of cases, IBS developed in the presence of unfavorable fluctuations in atmospheric pressure, relative humidity, temperature, and the rate of air movement.


Ultrafast nonlinear optical response of Dirac fermions in graphene.
The speed of solid-state electronic devices, determined by the temporal dynamics of charge carriers, could potentially reach unprecedented petahertz frequencies through direct manipulation by optical fields, consisting in a million-fold increase from state-of-the-art technology. In graphene, charge carrier manipulation is facilitated by exceptionally strong coupling to optical fields, from which stems an important back-action of photoexcited carriers. Here we investigate the instantaneous response of graphene to ultrafast optical fields, elucidating the role of hot carriers on sub-100 fs timescales. The measured nonlinear response and its dependence on interaction time and field polarization reveal the back-action of hot carriers over timescales commensurate with the optical field. An intuitive picture is given for the carrier trajectories in response to the optical-field polarization state. We note that the peculiar interplay between optical fields and charge carriers in graphene may also apply to surface states in topological insulators with similar Dirac cone dispersion relations.


Classification of Individual Finger Movements Using Intracortical Recordings in Human Motor Cortex.
Intracortical microelectrode arrays have enabled people with tetraplegia to use a brain-computer interface for reaching and grasping. In order to restore dexterous movements, it will be necessary to control individual fingers. To predict which finger a participant with hand paralysis was attempting to move using intracortical data recorded from the motor cortex. A 31-yr-old man with a C5/6 ASIA B spinal cord injury was implanted with 2 88-channel microelectrode arrays in left motor cortex. Across 3 d, the participant observed a virtual hand flex in each finger while neural firing rates were recorded. A 6-class linear discriminant analysis (LDA) classifier, with 10 × 10-fold cross-validation, was used to predict which finger movement was being performed (flexion/extension of all 5 digits and adduction/abduction of the thumb). The mean overall classification accuracy was 67% (range: 65%-76%, chance: 17%), which occurred at an average of 560 ms (range: 420-780 ms) after movement onset. Individually, thumb flexion and thumb adduction were classified with the highest accuracies at 92% and 93%, respectively. The index, middle, ring, and little achieved an accuracy of 65%, 59%, 43%, and 56%, respectively, and, when incorrectly classified, were typically marked as an adjacent finger. The classification accuracies were reflected in a low-dimensional projection of the neural data into LDA space, where the thumb-related movements were most separable from the finger movements. Classification of intention to move individual fingers was accurately predicted by intracortical recordings from a human participant with the thumb being particularly independent.


[The modulation of mitochondrial pore sensitivity of isolated myocardial preparations to the action of phenylarsenoxide].
In the experiments with coperfused isolated ring strips from a. carotis (A) and trabecule (T) from the right auricle of guinea pigs it has been shown the modification of a sensitivity of mitochondrial pore (MP) to the action of its activators. Exogenous NO-donor-sodium nitroprusside and hypoxic precondition (HP) caused a protective action on myocardium and arterial vessels isolated preparations of the old animals due to reducing of a myocardium MP sensitivity. While the contractile response to control electric stimulation T and A of the trained animals was almost twice lower in comparison to the group untraining ones, which can be evidence of the resources depleted of myocardium and vessels preparations caused by hypoxic training of the old animals.


Case reports in autism: issues in diagnosis and treatment.
Autism is a relatively common developmental disorder characterized by pervasive impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Two case reports are presented to illustrate important aspects of diagnosis and treatment. Early clinical diagnosis is essential so that appropriate intervention can be implemented. A multidisciplinary approach to treatment is recommended due to the impact of autism on many aspects of behavior and development.


Psychological capital of petrochemical corporate employees during COVID-19 social isolation: a longitudinal analysis.
The COVID-19 pandemic is a major public health emergency and a significant stressor to most people. The objective of this study was to examine the mental health status and social support level of participants from 2019 to 2020. The study aimed to investigate the changes in people's psychological capital state due to the COVID-19 pandemic. A longitudinal study was performed to study the psychosocial predictors of mental health among a sample of 2,999 Chinese employees in 2019, and the follow-up survey was conducted one year later. Regression coefficients were visualized in a heatmap. Path analysis was performed base on the structural equation model (SEM) to measure the associations between study variables. The status of mental health, resilience, and optimism changed significantly during the pandemic (P < 0.05). The level of employee's social support in 2019 could significantly and positively predicted the level of employee's psychological capital in 2020, and the level of employee mental health in 2019 significantly and negatively predicted the level of employee psychological capital in 2020. The mental health of employees played an intermediary role between social support and psychological capital. These results highlight that the COVID-19 pandemic has a strong impact on the psychological capital of company employees. While demanding performance, corporations should ensure timely intervention in the mental health of their employees.


Endemic zoonoses in the tropics: a public health problem hiding in plain sight.
Zoonotic diseases are a significant burden on animal and human health, particularly in developing countries. Despite recognition of this fact, endemic zoonoses often remain undiagnosed in people, instead being mistaken for febrile diseases such as malaria. Here, as part of Veterinary Record's ongoing series of articles on One Health, a multidisciplinary team of researchers from Scotland, Tanzania and New Zealand argues that a One Health approach is needed to effectively combat these diseases.


Ability of Three Endodontic Sealers to Fill the Root Canal System in Association with Gutta-Percha.
The present study compared the ability of the endodontic sealers AH Plus, Pulp Canal Sealer and EndoREZ to fill the root canal system in association with gutta-percha. Ninety mandibular premolars were accessed, prepared and divided into three groups of 30 teeth each, according to the sealer used to fill the canals: AH Plus, Pulp Canal Sealer and EndoREZ. All the teeth were filled using the continuous wave of condensation technique. The specimens were then decalcified, dehydrated, rendered transparent, and analyzed by three independent evaluators with 8x magnification. Chi-squared test (χ(2), p < 0.05) was used to compare the groups in relation to the totally filled, the partially filled and the non filled ramifications. The same test was used to compare the directions of filled ramifications and the number of ramifications among the three thirds of the roots. EndoREZ filled a significantly higher number of ramifications than AH Plus and Pulp Canal Sealer (χ(2), p < 0.05). All the groups showed higher number of totally filled ramifications than partially filled and unfilled ramifications. The ramifications were more frequently detected in the apical third, followed by medium and coronal thirds, respectively (χ(2), p < 0.05). The ramifications were more frequently detected towards lingual direction (χ(2), p < 0.05). EndoREZ presented higher ability to fill the root canal system in association with gutta-percha when compared to AH Plus and Pulp Canal Sealer. The ramifications were more frequently detected in the apical third, running in a lingual direction.


Cerebrospinal fluid gradients of acetylcholinesterase and butyrylcholinesterase activity in healthy aging.
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in 13 sequential 2 ml aliquots of cerebrospinal fluid (CSF) obtained by lumbar puncture from 7 young and 7 elderly healthy normal subjects. The slopes of the rostrocaudal gradients of AChE and BChE were calculated and compared to those of total protein concentration and the major dopaminergic metabolite homovanillic acid (HVA), for which a pronounced rostrocaudal gradient (with highest concentrations of HVA in more rostral CSF) is consistent with HVA originating primarily from the brain. AChE activity was higher in more caudal fractions of young, but not elderly subjects and there was a significant difference between the mean AChE gradient slopes in the young and old groups. These results suggest that the spinal cord makes an important contribution to AChE activity in lumbar CSF. Furthermore, the absence of a negative AChE gradient in elderly subjects may be the result of a greater rate of entry of cerebral AChE into CSF, possibly as a consequence of an increased ventricular surface area and shorter diffusion distances in atrophic elderly brains. In contrast to AChE, BChE activity and total protein concentrations were higher in more caudal CSF fractions of not only young but also old subjects. In addition, there was a significant correlation between the gradient slopes of BChE activity and total protein concentrations, suggesting that the majority of BChE activity in lumbar CSF derives from the same source as the majority of total protein, namely plasma. The diffuse (i.e. brain and spinal cord) origin of AChE in lumbar CSF would explain the relatively modest changes in lumbar CSF AChE activity in diseases involving certain central cholinergic systems, most notably Alzheimer's disease.


Lung tissue bioengineering for chronic obstructive pulmonary disease: overcoming the need for lung transplantation from human donors.
Introduction: Chronic obstructive pulmonary disease (COPD) affects more than 380 million people, causing more than 3 million deaths annually worldwide. Despite this enormous burden, currently available therapies are largely limited to symptom control. Lung transplant is considered for end-stage disease but is severely limited by the availability of human organs. Furthermore, the pre-transplant course is a complex orchestration of locating and harvesting suitable lungs, and the post-transplant course is complicated by rejection and infection. Lung tissue bioengineering has the potential to relieve the organ shortage and improve the post-transplant course by generating patient-specific lungs for transplant. Additionally, emerging progenitor cell therapies may facilitate in vivo regeneration of pulmonary tissue, obviating the need for transplant. Areas Covered: We review several lung tissue bioengineering approaches including the recellularization of decellularized scaffolds, 3D bioprinting, genetically-engineered xenotransplantation, blastocyst complementation, and direct therapy with progenitor cells. Articles were identified by searching relevant terms (see Key Words) in the PubMed database and selected for inclusion based on novelty and uniqueness of their approach. Expert Opinion: Lung tissue bioengineering research is in the early stages. Of the methods reviewed, only direct cell therapy has been investigated in humans. We anticipate a minimum of 5-10 years before human therapy will be feasible.


Oxidative DNA damage preventive activity and antioxidant potential of plants used in Unani system of medicine.
There is increasing recognition that many of today's diseases are due to the "oxidative stress" that results from an imbalance between the formation and neutralization of reactive molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can be removed with antioxidants. The main objective of the present study was to evaluate the antioxidant activity of plants routinely used in the Unani system of medicine. Several plants were screened for radical scavenging activity, and the ten that showed promising results were selected for further evaluation. Methanol (50%) extracts were prepared from ten Unani plants, namely Cleome icosandra, Rosa damascena, Cyperus scariosus, Gardenia gummifera, Abies pindrow, Valeriana wallichii, Holarrhena antidysenterica, Anacyclus pyrethrum, Asphodelus tenuifolius and Cyperus scariosus, and were used to determine their total phenolic, flavonoid and ascorbic acid contents, in vitro scavenging of DPPH(·), ABTS(·+), NO, (·)OH, O₂(·-) and ONOO(⁻), and capacity to prevent oxidative DNA damage. Cytotoxic activity was also determined against the U937 cell line. IC₅₀ values for scavenging DPPH(·), ABTS(·+), NO, (·)OH, O₂(·⁻) and ONOO(⁻) were in the ranges 0.007 ± 0.0001 - 2.006 ± 0.002 mg/ml, 2.54 ± 0.04 - 156.94 ± 5.28 μg/ml, 152.23 ± 3.51 - 286.59 ± 3.89 μg/ml, 18.23 ± 0.03 - 50.13 ± 0.04 μg/ml, 28.85 ± 0.23 - 537.87 ± 93 μg/ml and 0.532 ± 0.015 - 3.39 ± 0.032 mg/ml, respectively. The total phenolic, flavonoid and ascorbic acid contents were in the ranges 62.89 ± 0.43 - 166.13 ± 0.56 mg gallic acid equivalent (GAE)/g extract, 38.89 ± 0.52 - 172.23 ± 0.08 mg quercetin equivalent (QEE)/g extract and 0.14 ± 0.09 - 0.98 ± 0.21 mg AA/g extract. The activities of the different plant extracts against oxidative DNA damage were in the range 0.13-1.60 μg/ml. Of the ten selected plant extracts studied here, seven - C. icosandra, R. damascena, C. scariosus, G. gummifera, A. pindrow, V. wallichii and H. antidysenterica - showed moderate antioxidant activity. Finally, potentially significant oxidative DNA damage preventive activity and antioxidant activity were noted in three plant extracts: C. icosandra, R. damascena and C. scariosus. These three plant extracts showed no cytotoxic activity against U937 cells. The 50% methanolic extracts obtained from different plant parts contained significant amounts of polyphenols with superior antioxidant activity as evidenced by the scavenging of DPPH(·), ABTS(·+), NO, (·)OH, O₂(·⁻) and ONOO(⁻). C. icosandra, R. damascena and C. scariosus showed significant potential for preventing oxidative DNA damage and radical scavenging activity, and the G. gummifera, A. pindrow, V. wallichii, H. antidysenterica, A. pyrethrum, A. tenuifolius and O. mascula extracts showed moderate activity. The extracts of C. icosandra, R. damascena and C. scariosus showed no cytotoxicity against U937 cells. In conclusion, these routinely used Unani plants, especially C. icosandra, R. damascena and C. scariosus, which are reported to have significant activity against several human ailments, could be exploited as potential sources of natural antioxidants for plant-based pharmaceutical industries.


Paediatric morphoea: a holistic review. Part 1: epidemiology, aetiopathogenesis and clinical classification.
Morphoea, also known as localized scleroderma, is a debilitating fibrosing disorder of uncertain aetiology, affecting the skin and subcutaneous tissues. Paediatric-onset disease is not uncommon and is associated with frequent relapses. The disease has complex pathogenetic mechanisms and multiple clinical subtypes, and affects children of all ages. Recent research has focused on elucidating the disease pathophysiology and identifying measures of disease activity. We performed a literature search on PubMed, MEDLINE and Google Scholar, using keywords such as 'pediatric morphea', 'juvenile localised scleroderma' and 'juvenile systemic sclerosis'. Relevant studies, including randomized trials, reviews of standard current guidelines and original research articles, were selected, and results were analysed before being summarized. In the first of this two-part review, we provide a bird's-eye view of the current literature concerning the epidemiology, aetiopathogenesis and clinical classification of paediatric morphoea; in Part 2, we review the diagnosis, markers of disease activity, management and natural history.


Power calculations in genetic studies.
The power of a statistical test is the probability that it will yield a statistically significant result given that the null hypothesis is false. In other words, it represents the chance that the study will be successful in detecting a true effect and is dependent on a number of factors, including the magnitude of the effect, the sample size and study design, and the specified false-positive rate. Power calculations are primarily performed during the planning stages of a study, most typically in determining the sample size required. Consideration of statistical power can also sometimes shed light on the results of completed studies, particularly in the interpretation of negative results. In this article, we review the fundamentals of statistical power, discuss how power is calculated (using a genetic case/control study as an example), and consider the most pertinent factors that influence power in genetic studies. Finally, we focus on power in the context of modern whole-genome association studies, in which issues of coverage, multiple testing, and staged designs are paramount.


Preventing the emergence of multidrug-resistant microorganisms through antimicrobial use controls: the complexity of the problem.
Widespread use of antimicrobials in the inpatient and outpatient setting has been associated with the emergence of multidrug-resistant microorganisms. A variety of methods exist to improve the appropriateness of antimicrobial use in the inpatient setting, including guidelines, antimicrobial use evaluations, micribiology laboratory guidance, formulary development and antimicrobial restriction, use of antimicrobial order or automatic stop order forms, and antimicrobial audits. To decrease the selective pressure that leads to development of pathogen resistance and to reduce antimicrobial expenditures, infectious disease, infection control, pharmacy, and administrative staff need to improve clinician use of antimicrobials through development and implementation of antimicrobial use committees. Through the implementation of a comprehensive, multidisciplinary approach to antimicrobial use and development of clinician education programs, inappropriate antimicrobial use can be reduced, patient care can be improved, and substantial cost savings can be realized.


Characterization of TCF3 rearrangements in pediatric B-lymphoblastic leukemia/lymphoma by mate-pair sequencing (MPseq) identifies complex genomic rearrangements and a novel TCF3/TEF gene fusion.
The TCF3/PBX1 gene fusion is a recurrent genetic abnormality in pediatric B-lymphoblastic leukemia/lymphoma (B-ALL/LBL). While dual-color, dual-fusion fluorescence in situ hybridization (D-FISH) probes can detect TCF3/PBX1 fusions, further characterization of atypical TCF3 FISH patterns as indicated by additional or diminished TCF3 signals is currently limited. Herein we describe the use of a next-generation sequencing assay, mate-pair sequencing (MPseq), to characterize typical and cryptic TCF3/PBX1 fusions and to identify TCF3 translocation partners based on results obtained from our laboratory-developed TCF3/PBX1 D-FISH probe set. MPseq was performed on 21 cases of pediatric B-ALL/LBL with either TCF3/PBX1 fusion, or no TCF3/PBX1 fusion but with additional or diminished TCF3 signals obtained by our PBX1/TCF3 D-FISH probe set. In addition, MPseq was performed on one pediatric B-ALL/LBL case with an apparently normal karyotype and abnormal TCF3 break-apart probe results. Of 22 specimens successfully evaluated by MPseq, 13 cases (59%) demonstrated TCF3/PBX1 fusion, including three cases with previously undescribed insertional rearrangements. The remaining nine cases (41%) harbored various TCF3 partners, including six cases with TCF3/ZNF384, and one case each with TCF3/HLF, TCF3/FLI1 and TCF3/TEF. Our results illustrate the power of MPseq to characterize TCF3 rearrangements with increased precision and accuracy over traditional cytogenetic methodologies.


From Nanoscale to Microscale: Crossover in the Diffusion Dynamics within Two Pyrrolidinium-Based Ionic Liquids.
Knowledge of the ion motion in room temperature ionic liquids (RTILs) is critical for their applications in a number of fields, from lithium batteries to dye-sensitized solar cells. Experiments on a limited number of RTILs have shown that on macroscopic time scales the ions typically undergo conventional, Gaussian diffusion. On shorter time scales, however, non-Gaussian behavior has been observed, similar to supercooled fluids, concentrated colloidal suspensions, and more complex systems. Here we characterize the diffusive motion of ionic liquids based on the N-butyl-N-methylpyrrolidinium (PYR14) cation and bis(trifluoro methanesulfonyl)imide (TFSI) or bis(fluorosulfonyl)imide (FSI) anions. A combination of pulsed gradient spin-echo (PGSE) NMR experiments and molecular dynamics (MD) simulations demonstrates a crossover from subdiffusive behavior to conventional Gaussian diffusion at ∼10 ns. The deconvolution of molecular displacements into a continuous spectrum of diffusivities shows that the short-time behavior is related to the effects of molecular caging. For PYR14FSI, we identify the change of short-range ion-counterion associations as one possible mechanism triggering long-range displacements.


Early surgery compared to nonoperative management for mild degenerative cervical myelopathy: a cost-utility analysis.
Degenerative cervical myelopathy (DCM) is a form of acquired spinal cord compression and contributes to reduced quality of life secondary to neurological dysfunction and pain. There remains uncertainty regarding optimal management for individuals with mild myelopathy. Specifically, owing to lacking long-term natural history studies in this population, we do not know whether these individuals should be treated with initial surgery or observation. We sought to perform a cost-utility analysis to examine early surgery for mild degenerative cervical myelopathy from the healthcare payer perspective. We utilized data from the prospective observational cohorts included in the Cervical Spondylotic Myelopathy AO Spine International and North America studies to determine health related quality of life estimates and clinical myelopathy outcomes. We recruited all patients that underwent surgery for DCM enrolled in the Cervical Spondylotic Myelopathy AO Spine International and North America studies between December 2005 and January 2011. Clinical assessment measures were obtained using the Modified Japanese Orthopedic Association scale and health-related quality of life measures were obtained using the Short Form-6D utility score at baseline (preoperative), 6 months, 12 months and 24 months postsurgery. Cost measures inflated to January 2015 values were obtained using pooled estimates from the hospital payer perspective for surgical patients. We employed a Markov state transition model with Monte Carlo microsimulation using a lifetime horizon to obtain an incremental cost utility ratio associated with early surgery for mild myelopathy. Parameter uncertainty was assessed through deterministic means using one-way and two-way sensitivity analyses and probabilistically using parameter estimate distributions with microsimulation (10,000 trials). Costs and utilities were discounted at 3% per annum. Initial surgery for mild degenerative cervical myelopathy was associated with an incremental lifetime increase of 1.26 quality-adjusted life years (QALY) compared to observation. The associated cost incurred to the health-care payer over a lifetime horizon was $12,894.56, resulting in a lifetime incremental cost-utility ratio of $10,250.71/QALY. Utilizing a willingness to pay threshold in keeping with the World Health Organization definition of "very cost-effective" ($54,000 CDN), the probabilistic sensitivity analysis demonstrated that 100% of cases were cost-effective. Surgery compared to initial observation for mild degenerative cervical myelopathy was cost-effective from the Canadian healthcare payer perspective and was associated with lifetime gains in health-related quality of life.


Terminal Diazirines Enable Reverse Polarization Transfer from 15 N2 Singlets.
Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The 15 N2 labeled diazirines are appealing motifs for hyperpolarization supporting relaxation protected states with long-lived lifetimes. The (-CH15 N2 ) diazirine groups investigated here are analogues to methyl groups, which provides the opportunity to transfer polarization stored on a relaxation protected (-CH15 N2 ) moiety to 1 H, thus combining the advantages of long lifetimes of 15 N polarization with superior sensitivity of 1 H detection. Despite the proximity of 1 H to 15 N nuclei in the diazirine moiety, 15 N T1 times of up to (4.6±0.4) min and singlet lifetimes Ts of up to (17.5±3.8) min are observed. Furthermore, we found terminal diazirines to support hyperpolarized 1 H2 singlet states in CH2 groups of chiral molecules. The singlet lifetime of 1 H singlets is up to (9.2±1.8) min, thus exceeding 1 H T1 relaxation time (at 8.45 T) by a factor of ≈100.


Adapting and Validating the Global Physical Activity Questionnaire (GPAQ) for Trivandrum, India, 2013.
A limitation of the Global Physical Activity Questionnaire (GPAQ) in assessing physical activity in India is that it does not capture the diversity of activities across cultures and by sex. The purpose of this study was to culturally adapt and validate the GPAQ by using an accelerometer in Thiruvananthapuram City, India. We developed a modified version of the GPAQ by adding a physical activity chart specific to the locale. We identified local physical activities through in-depth interviews, group discussions, and observation, and used Actigraph GT3X accelerometers to validate the modified GPAQ for a subsample of 47 women. Participants were drawn from a cross-sectional survey of 1,303 women aged 18 to 64 years, selected by multistage cluster sampling. Spearman rank correlation coefficients and intraclass correlation coefficients (ICC) were calculated to determine the correlation and level of agreement in moderate-to-vigorous physical activity (MVPA) on the basis of accelerometer measurement and the modified GPAQ. The correlation for MVPA between the modified GPAQ (overall) and the accelerometer (non-bouted MVPA) was 0.69 (95% confidence interval [CI], 0.39-0.85) with a moderately high ICC of 0.78 (95% CI, 0.56-0.90). The correlation for MVPA between the modified GPAQ and the accelerometer-based MVPA within bouts of at least 10 minutes was 0.60 (95% CI, 0.26-0.80) with an ICC of 0.55 (95% CI, 0.20-0.77) indicating a moderate level of agreement. The GPAQ can be used for assessing physical activity among women in India, and its adaptation and validation may be useful in other low-income or middle-income countries where activities are diverse in type and intensity.


Regulation of viral intermediate gene expression by the vaccinia virus B1 protein kinase.
The B1 gene of vaccinia virus encodes a serine/threonine protein kinase that is expressed early after infection. Under nonpermissive conditions, temperature-sensitive mutants (ts2 and ts25) that map to B1 fail to efficiently replicate viral DNA. Our goal was to extend studies on the function of B1 by determining if the kinase is required for intermediate or late gene expression, two events that ordinarily depend on viral DNA replication. First, we established that early viral gene expression occurred at the nonpermissive temperature. By using a transfection procedure that circumvents the viral DNA replication requirement, we found that reporter genes regulated by an intermediate promoter were transcribed only under conditions permissive for expression of active B1. To assay late gene expression, the T7 RNA polymerase gene was inserted into the genome of ts25 to form ts25/T7. A DNA replication-independent late gene transcription system was established by cotransfecting plasmids containing T7 promoter-driven late gene transcription factors and a late promoter reporter gene into ts25/T7-infected cells. Late genes, unlike intermediate genes, were expressed at the nonpermissive temperature. Last, we showed that overexpression of B1 stimulated intermediate but inhibited late gene expression in cells infected with wild-type virus.


The Tup1-Cyc8 protein complex can shift from a transcriptional co-repressor to a transcriptional co-activator.
Cyc8(Ssn6)-Tup1, a general co-repressor complex, is recruited to promoter DNA via interactions with DNA-binding regulatory proteins and inhibits the transcription of many different yeast genes. Previous studies have established that repression function of the complex is performed by one subunit of the complex, the Tup1 protein, and requires specific components of the RNA polymerase II holoenzyme such as Sin4 and Rgr1. In this study we test the transcriptional activity of the Cyc8 subunit using a lexA operator-containing reporter. We show that a LexA-Cyc8 hybrid stimulates transcription when expressed in a tup1Delta, a sin4Delta, or a rgr1Delta strain, suggesting that transcriptional activation is an intrinsic property of the Cyc8-Tup1 co-repressor. In support of this notion we demonstrate that Cyc8-Tup1 has a dual function on CIT2, a gene encoding a citrate synthase that is expressed upon mitochondrial dysfunction. First, we show that Cyc8-Tup1 is tethered to CIT2 promoter by interacting with the activation domain of Rtg3, a bHLH/L-Zip DNA-binding transactivator of CIT2. Next we demonstrate that Cyc8-Tup1 activates CIT2 transcription in response to mitochondrial dysfunction, and this stimulatory effect is mediated by Cyc8. In contrast, basal (noninduced) expression of this gene is inhibited by Tup1. These findings establish a positive role for the Cyc8-Tup1 complex in transcription and support a model by which specific metabolic signals may convert the Cyc8-Tup1 transcriptional co-repressor to a co-activator of certain promoters.


Role of antibody response in recovery from K-papovavirus infection in mice.
Intraperitoneal inoculation of mouse K papovavirus into infant (2 to 4 days old) Swiss albino mice produced a high-titered viremia which persisted until death due to pneumonitis on day 9 postinfection. Lungs and livers of these mice had virus-specific immunofluorescence and histological lesions. K-virus antibody was undetectable. Three- to four-week-old mice, although as susceptible to infection as infant mice, remained healthy and developed a much lower-titered viremia, a transient lung infection, and K-virus antibody on 4 to 5 days postinfection. Three- to four-week-old mice treated with cyclophosphamide developed a high-titered viremia with death 10 to 17 days postinfection and no detectable antibodies. A single intraperitoneal inoculation of K-virus antibody at 5 h or 1 day postinfection completely protected the infant Swiss albino mice. Partial protection was achieved when antibody was transferred on days 2, 3, and 4 postinoculation. Transfer of antibody to cytoxan-treated Swiss albino mice on days 3 and 6 postinfection completely portected them against K-virus-induced lesions and mortality. Transfer of normal adult BALB/c splenocytes to syngeneic infant mice before K-virus infection did not protect from death but increased survival time. Transfer of 4- to 12-day K-virus-primed adult splenocytes before infection gave a nearly 100% protection. When given before infection, the protection afforded by T-cell-enriched and B-cell-enriched adult primed splenocytes was 0 and 100%, respectively. Transfer of primed B cells on day 1 post-inoculation completely protected the infant mice. This protection decreased to 86, 57, and 56% when the primed B cells were transferred on days 2, 3, and 4 post-inoculation, respectively. These data suggest that the antibody response is of critical importance in the recovery of mice from K-virus infection. Antibody probably acts by aborting viremia, thereby preventing extensive seeding of lungs with virus.


Anti-GSTT1 antibodies and Null genotype correlate with histological changes of antibody mediated rejection in kidney transplantation.
The presence of anti-Glutathione S-transferase T1 (GSTT1) antibodies (abs) has been hypothesized as a pathogenic contributor in antibody-mediated rejection (AMR). We aimed to evaluate the relationship between genetic variants of GSTT1, anti-GSTT1 abs and AMR in a cohort of 87 kidney transplant (KTx) patients using Immucor's non-HLA Luminex assay. Patients were classified according to biopsy-proven AMR and HLA-DSA status: AMR with positive anti-HLA-DSAs (AMR/DSA+, n = 29), AMR but no detectable anti-HLA-DSAs (AMR/DSA-, n = 28) and control patients with stable allograft function and no evidence of rejection (n = 30). At an MFI cut-off of 3000, the overall prevalence of anti-GSTT1 abs was 18.3%. The proportion of patients with anti-GSTT1 abs was higher in the AMR/DSA- group (25%), compared to the control (13.3%) and AMR/DSA+ group (3.4%) (p = 0.06). Among patients with anti-GSTT1 abs, the MFI was higher in AMR/DSA- and GSTT1-Null patients. Of 81 patients who underwent GSTT1 genotyping, 19.8% were homozygotes for the null allele (GSTT1-Null). GSTT1-Null status in the transplant recipients was associated with the development of anti-GSTT1 abs (OR, 4.49; 95%CI, 1.2-16.7). In addition, GSTT1-Null genotype (OR 26.01; 95%CI, 1.63-404) and anti-GSTT1 ab positivity (OR 14.8; 95%CI, 1.1-190) were associated with AMR. Within AMR/DSA- patients, the presence of anti-GSTT1 abs didn't confer a higher risk of failure within the study observation period. The presence of anti-GSTT1 abs and GSTT1-Null genotype is associated with AMR, but do not appear to lead to accelerated graft injury in this cohort of early allograft injury changes, with a limited period of follow-up.


The presence of conspecific decoys enhances the attractiveness of an NaCl resource to the yellow-spined locust, Ceracris kiangsu.
Adults of the yellow-spined bamboo locust, Ceracris kiangsu Tsai (Orthoptera: Oedipodidae), aggregate and gnaw at human urine-contaminated materials, a phenomenon termed puddling. Several urine-borne chemicals, including NaCl, are known to stimulate adult C. kiangsu to consume filter paper. Because in nature C. kiangsu adults may use cues to locate puddling resources, we tested the influence of conspecific decoys (dried C. kiangsu) on foraging and consumption of 3% NaCl-treated filter paper. In a two-choice test experiment in the laboratory, female adults showed no preference for filter papers (not treated with NaCl) with or without decoys. In contrast, C. kiangsu females consumed significantly more NaCl-treated filter paper on which conspecific decoys were attached than those without decoys in both the laboratory and in a bamboo forest. When the bait was changed to 3% NaCl plus the insecticide bisultap, significantly more C. kiangsu were killed in the bamboo forest when decoys were present, however the results were not significant when the experiment was done in the laboratory. Hence, moving towards conspecifics seems to facilitate NaCl resource foraging in C. kiangsu, suggesting that the presence of conspecifics promotes feeding on puddling resources.