Computational Inference, Validation, and Analysis of 5'UTR-Leader Sequences of Alleles of Immunoglobulin Heavy Chain Variable Genes.
Upstream and downstream sequences of immunoglobulin genes may affect the expression of such genes. However, these sequences are rarely studied or characterized in most studies of immunoglobulin repertoires. Inference from large, rearranged immunoglobulin transcriptome data sets offers an opportunity to define the upstream regions (5'-untranslated regions and leader sequences). We have now established a new data pre-processing procedure to eliminate artifacts caused by a 5'-RACE library generation process, reanalyzed a previously studied data set defining human immunoglobulin heavy chain genes, and identified novel upstream regions, as well as previously identified upstream regions that may have been identified in error. Upstream sequences were also identified for a set of previously uncharacterized germline gene alleles. Several novel upstream region variants were validated, for instance by their segregation to a single haplotype in heterozygotic subjects. SNPs representing several sequence variants were identified from population data. Finally, based on the outcomes of the analysis, we define a set of testable hypotheses with respect to the placement of particular alleles in complex IGHV locus haplotypes, and discuss the evolutionary relatedness of particular heavy chain variable genes based on sequences of their upstream regions.


[Features of vascular reactivity, sodium metabolism and its humoral regulation in healthy subjects with a family history of hypertension].
The examination of 140 normal individuals with a family history of essential hypertension (FHEH) showed a number of differences in their cardiovascular and renin-aldosterone responses as compared to 170 normal subjects of the control group. Two years later the results were analyzed once again with regard to blood pressure changes. It turned out that subjects with a FHEH and an unfavourable pattern of blood pressure changes over two years exhibited elevated response of cutaneous vessels to angiotensin and noradrenaline, a higher threshold of gustatory sensitivity to salt and an increased BP response to psychoemotional stress already during the first examination. It is concluded that the most informative markers of the prehypertension state among the genetically determined features characteristic of healthy individuals with a FHEH are changes in sodium metabolism and regulation which are responsible for the development of vascular hyperactivity.


Health system tests CRM data base. Community Health Network uses direct mail to boost physicians.
A six-month pilot patient retention project for Community Health Network (CHN), Indianapolis, ran from July 2002 to January 2003. It was a direct mail campaign on behalf of some members of the group practices owned by CHN, designed to test the use of the system's CRM database. Patients of the physicians received personal, dynamically-generated cards reminding them to schedule appointments and tests. Each mailing cost $1.76, including production and mailing.


Management of depression in the elderly.
Depressive illness in late life may present to doctors in the community or on general hospital wards. Management often involves physical treatments, but social and psychological approaches may also be important. This article considers acute treatment, continuation treatment (to prevent relapse) and the treatment of resistant depressive illnesses.


Training residents to care for the mentally ill.
Recent changes in Royal College training requirements have highlighted the need for residency programs to be able to offer challenging and worthwhile experiences to their trainees in caring for the chronically mentally ill. This training should bring them into contact with patients at each stage of their illness and recovery and expose them to the different settings in which treatment or management takes place. Postgraduate programs face many problems in organizing this teaching that arise from the nature and course of long-term psychiatric illnesses, the organization of residency training programs, attitudes and preconceptions of residents and teachers and competing time demands. The authors review these problems, identify specific goals for the training and suggest strategies for achieving these goals. Expectations of postgraduate programs, clinical placements, supervisors and residents themselves are outlined.


Idiopathic Inflammatory Myopathy with Delayed Finger Opening Resembling Grip Myotonia.
Grip myotonia can be a clue for the diagnosis of myotonic disorders. However, several clinical conditions cause delayed finger opening mimicking grip myotonia. We herein report a 44-year-old man with idiopathic inflammatory myopathy who presented with delayed finger opening resembling grip myotonia. The delayed finger opening differed from grip myotonia given the absence of the warm-up phenomenon and percussion myotonia, relative sparing of the thumb extension, and pronounced weakness of the extensor digitorum. Focusing on the extension of the thumb and other fingers may aid in the differentiation between delayed finger opening and true grip myotonia.


Comparison of multiecho postprocessing schemes for SWI with use of linear and nonlinear mask functions.
SWI is an MR technique conventionally implemented with single-echo gradient-echo data. The purpose of this study was to compare single-echo SWI processing and 2 multiecho SWI processing schemes: postaverage, where an SWI image is created for each echo and then averaged to create a single volume; and frequency-based, where a SWI image is generated from an average frequency image. Linear and nonlinear mask functions were investigated for all 3 processing schemes. Comprehensive optimizations were performed. Single and multigradient-echo data were acquired at 3T in 10 volunteers. Contrast-to-noise ratio was measured in various structures. Visibilities of the same structures were ranked in different SWI images by trained raters. When image evaluation was based on measurements of contrast-to-noise ratio, the nonlinear mask and frequency-based scheme were superior. However, when image evaluation was based on ranks of qualitative visibility, the linear mask and postaverage scheme were superior. Although the nonlinear mask and frequency-based scheme allow increased contrast of paramagnetic perturbers such as the globus pallidus, periventricular veins, red nucleus, and subthalamic nucleus, they do not necessarily increase the information content of the image; rather, they result in a harsh contrast that is visually unpleasing to radiologists and wherein more subtle structure is relatively less apparent. Linearly masked postaverage SWI is the recommended implementation of multiecho SWI for radiologic use; however, nonlinearly masked frequency-based SWI may have use in computer-based segmentation or registration.


Widespread positive selection in the photosynthetic Rubisco enzyme.
Rubisco enzyme catalyzes the first step in net photosynthetic CO2 assimilation and photorespiratory carbon oxidation and is responsible for almost all carbon fixation on Earth. The large subunit of Rubisco is encoded by the chloroplast rbcL gene, which is widely used for reconstruction of plant phylogenies due to its conservative nature. Plant systematicists have mainly used rbcL paying little attention to its function, and the question whether it evolves under Darwinian selection has received little attention. The purpose of our study was to evaluate how common is positive selection in Rubisco among the phototrophs and where in the Rubisco structure does positive selection occur. We searched for positive selection in rbcL sequences from over 3000 species representing all lineages of green plants and some lineages of other phototrophs, such as brown and red algae, diatoms, euglenids and cyanobacteria. Our molecular phylogenetic analysis found the presence of positive selection in rbcL of most analyzed land plants, but not in algae and cyanobacteria. The mapping of the positively selected residues on the Rubisco tertiary structure revealed that they are located in regions important for dimer-dimer, intradimer, large subunit-small subunit and Rubisco-Rubisco activase interactions, and that some of the positively selected residues are close to the active site. Our results demonstrate that despite its conservative nature, Rubisco evolves under positive selection in most lineages of land plants, and after billions of years of evolution Darwinian selection still fine-tunes its performance. Widespread positive selection in rbcL has to be taken into account when this gene is used for phylogenetic reconstructions.


Atypical antipsychotics and anorexia nervosa: a review.
There is currently mixed opinion regarding the value of using atypical antipsychotics to treat anorexia nervosa (AN). To evaluate the literature on the use of atypical antipsychotics in AN. A review of all studies and clinical guidelines published before September 2009 involving use of an atypical antipsychotic in patients with AN. Analysis is by narrative synthesis. Forty-three publications or study protocols were found, including four randomized-controlled trials, five open-label trials and 26 case reports. The most studied drugs were olanzapine, quetiapine and risperidone. Atypical antipsychotics appear safe and there is some evidence of positive effects on depression, anxiety and core eating disordered psychopathology in patients with anorexia nervosa. Currently there is insufficient evidence to confirm atypical antipsychotics enhance weight gain in this setting. Further high quality evidence is needed in this area in order to provide practical guidance to clinicians. However, the main challenge is to persuade adequate numbers of AN patients to participate in research trials.


Endovascular Device Choice and Tools for Recanalization of Medium Vessel Occlusions: Insights From the MeVO FRONTIERS International Survey.
Background: Endovascular treatment (EVT) for stroke due to medium vessel occlusion (MeVO) can be technically challenging. Devices and tools are rapidly evolving. We aimed to gain insight into preferences and global perspectives on the usage of endovascular tools in treating MeVOs. Methods: We conducted an international survey with seven scenarios of patients presenting A3, M2/3, M3, M3/4, or P2/3 occlusions. Respondents were asked for their preferred first-line endovascular approach, and whether they felt that the appropriate endovascular tools were available to them. Answers were analyzed by occlusion location and geographical region of practice, using multinomial/binary logistic regression. Results: A total of 263 neurointerventionists provided 1836 responses. The first-line preferences of physicians were evenly distributed among stent-retrievers, combined approaches, and aspiration only (33.2, 29.8, and 26.8%, respectively). A3 occlusions were more often treated with stent-retrievers (RR 1.21, 95% CI: 1.07-1.36), while intra-arterial thrombolysis was more often preferred in M3 (RR 2.47, 95% CI: 1.53-3.98) and M3/4 occlusions (RR 7.71, 95% CI: 4.16-14.28) compared to M2/3 occlusions. Respondents who thought appropriate tools are currently not available more often chose stent retrievers alone (RR 2.07; 95% CI: 1.01-4.24) or intra-arterial thrombolysis (RR 3.35, 95% CI: 1.26-8.42). Physicians who stated that they do not have access to optimal tools opted more often not to treat at all (RR 3.41, 95% CI: 1.11-10.49). Stent-retrievers alone were chosen more often and contact aspiration alone less often as a first-line approach in Europe (RR 2.12, 95% CI: 1.38-3.24; and RR 0.49, 95% CI 0.34-0.70, respectively) compared to the United States and Canada. Conclusions: In EVT for MeVO strokes, neurointerventionalists choose a targeted vessel specific first-line approach depending on the occlusion location, region of practice, and availability of the appropriate tools.


Right-Ear Advantage for Unaided and Aided Speech Perception in Noise in Older Adults.
To investigate whether the magnitude of the right-ear advantage (REA) for speech perception in noise decreased in aided conditions as compared with unaided conditions in older adults bilaterally fitted with hearing aids. A secondary aim was to determine the effect of audibility on the right- and left-ear processing for speech stimuli in both aided and unaided conditions. Forty-two older adult, bilateral hearing-aid users were selected. Pure-tone audiometry and the hearing-in-noise test (HINT) were carried out and real-ear insertion gain (REIG) was measured in all participants. All HINT stimuli were delivered via loudspeakers in the free field in both aided and unaided conditions. Right-ear scores for HINT were significantly better than the left ear in both unaided and aided conditions. No significant differences in the magnitude of the REA between the unaided HINT and aided HINT scores were found. Regression models showed that audibility explained 47% and 53% of the variance in unaided HINT scores in the right and left ears, respectively. For the aided HINT scores, age and audibility explained 46% of the variability for the left-ear scores, while for the right ear, the only remaining significant variable in the model was REIG, which explained 12% of the right-ear HINT scores. Right-ear processing is significantly more efficient for speech stimuli in both unaided and aided conditions in older adults. Audibility affected unaided speech perception in right and left ears similarly however this was not the case in the aided condition. Audibility was associated with aided speech perception in noise in the left ear only.


Communicative Competence of Oral Deaf Children While Explaining Game Rules.
Classrooms are characterized by interactions in a range of genres. The concise language required by expository interactions can be challenging for children who have atypical language, including children who are deaf and hard of hearing (DHH). This study compared the way three groups of upper primary school students (aged 8-13 years) taught a peer to play a new unfamiliar board game: (a) DHH "experts" teaching a "novice" hearing peer; (b) hearing experts teaching a DHH novice; and (c) a hearing expert teaching a hearing novice. All DHH students were enrolled in mainstream schools and used spoken language as the main mode of communication. All three groups were able to convey game rules and purpose, and navigate clarifications. Differences emerged in the accuracy of the use of referents when instructing their peers how to play the game. The specific content vocabulary and the need to emphasize new concise information also challenged the DHH children. This study highlights the importance of including expository tasks in language support and intervention for children who are DHH.


Escherichia coli B2 strains prevalent in inflammatory bowel disease patients have distinct metabolic capabilities that enable colonization of intestinal mucosa.
Escherichia coli is considered a leading bacterial trigger of inflammatory bowel disease (IBD). E. coli isolates from IBD patients primarily belong to phylogroup B2. Previous studies have focused on broad comparative genomic analysis of E. coli B2 isolates, and identified virulence factors that allow B2 strains to reside within human intestinal mucosa. Metabolic capabilities of E. coli strains have been shown to be related to their colonization site, but remain unexplored in IBD-associated strains. In this study, we utilized pan-genome analysis and genome-scale models (GEMs) of metabolism to study metabolic capabilities of IBD-associated E. coli B2 strains. The study yielded three results: i) Pan-genome analysis of 110 E. coli strains (including 53 isolates from IBD studies) revealed discriminating metabolic genes between B2 strains and other strains; ii) Both comparative genomic analysis and GEMs suggested that B2 strains have an advantage in degrading and utilizing sugars derived from mucus glycan, and iii) GEMs revealed distinct metabolic features in B2 strains that potentially allow them to utilize energy more efficiently. For example, B2 strains lack the enzymes to degrade amadori products, but instead rely on neighboring bacteria to convert these substrates into a more readily usable and potentially less sought after product. Taken together, these results suggest that the metabolic capabilities of B2 strains vary significantly from those of other strains, enabling B2 strains to colonize intestinal mucosa.The results from this study motivate a broad experimental assessment of the nutritional effects on E. coli B2 pathophysiology in IBD patients.


Effects on ROM and joint position sense of the neck of two different interventions.
[Purpose] The purpose of this study was to evaluate whether neuromuscular joint facilitation (NJF) training is superior to NJF distal resistance training at improving the ROM and proprioceptive acuity of the neck. [Subjects] 10 healthy subjects (8 males, 2 females) participated in this study. [Methods] The participants were allocated to three groups: 10 in the control group, 10 in the NJF distal resistance training group, and 10 in the NJF training group. A miniature wireless motion recorder was used to record the maximum cervical range of motion and joint position error (JPE) before and after the interventions. The three interventions were tested on different days. [Results] No difference of ROM was observed among the three groups. A significant pre- to post-intervention decrease in JPE in extension was identified in the NJF group. No other significant differences were observed among the three groups. [Conclusion] The NJF training conferred remarkable benefits on the cervical JPE of healthy people. This result suggests that the best way to improve proprioceptive acuity is intervention together with proximal resistance training, such as NJF training.


Early designs of the myograph.
A surge in quantitative muscle physiology began with the mid-nineteenth century introduction of a new instrument capable of measuring contraction events with millisecond resolution. This strictly mechanical device, called a "myograph" by its designer Hermann von Helmholtz, was based on existing technology but included several important innovations that made it suitable for recording accurately the high speed events of muscle contraction. A variety of different myograph designs, each with its own advantages and disadvantages, ultimately came into existence and populated muscle physiology laboratories into the twentieth century.


Identification and localization of the Tgl protein, which is required for Myxococcus xanthus social motility.
Tgl protein is required for the production of the type IV pili found at a pole of the Myxococcus xanthus cell. These pili are essential for social motility. Evidence is presented that Tgl is a membrane protein, based on experiments with polyclonal antibody specific for Tgl that was raised against the fusion proteins beta-galactosidase-Tgl and TrpE-Tgl. Immunoaffiity-purified antibody reacted with a protein in M. xanthus having an apparent molecular mass of 27.5 kDa as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, while the sequence of the tgl gene translates into a polypeptide of 27 kDa. Although these numbers are close, it is likely that the primary tgl translation product is processed and modified in M. xanthus. The N terminus has a signal peptidase II recognition sequence, cleavage of which is expected to remove 19 amino acid residues. When the tgl gene is expressed in Escherichia coli, the protein product consistently migrates faster in the gel than mature Tgl expressed in M. xanthus, suggesting a second modification by addition which slows migration of the protein from M. xanthus. Tgl, as detected by its specific antibody, sediments with the membrane fraction of cells. It can be extracted with detergents but not with salt or by the addition of chelators for divalent cations. In an equilibrium gradient, Tgl bands at the buoyant density of membranes and with the NADH-oxidase activity. Intact cells failed to bind anti-Tgl antibody, and less than 2% of the total Tgl is released in soluble form from the periplasm. Yet, cells that had been osmotically shocked and treated with paraformaldehyde were able to react with the specific antibody--a reaction absent from cells with a deletion of the tgl transcription unit. Assuming that osmotic shock disrupts the outer membrane, the fractionation and localization data imply that Tgl is attached to the inner or outer membranes, from which it is exposed to the intermembranous space. Tgl is necessary for synthesis of pili in M. xanthus and is the only pilus protein that can be donated by other cells (stimulation). Tgl contains six tandem copies of the tetratrico peptide repeat structural motif. Its membrane localization, capacity for stimulation, and content of tetratrico structural repeats together suggest that Tgl may be necessary for the assembly of pilin subunits into filaments.


Formation of contacts between mast cells and sympathetic neurons in vitro.
Functional interactions between mast cells and peripheral nerves may occur at sites of association seen in vivo. To study the interactions, we developed a tissue culture model of murine sympathetic neurons co-cultured with rat basophilic leukaemia (RBL-2H3) cells (homologues of mucosal mast cells) or rat peritoneal mast cells. In co-cultures of up to 3 days, light microscopy identified neurite contacts with peritoneal mast cells or RBL-2H3 cells, but not with glial cells or fibroblasts. Electron microscopy confirmed membrane-membrane contact between neurites and RBL-2H3 cells. Time-lapse analysis of interactions between neurons and RBL-2H3 cells showed that 60-100% of the cells in a given field acquired neurite contact within 17 h. In matching control studies, there was no increase in the frequency of neurite contact with cells of the rat plasmacytoma line (YB2/0): these were not selected as targets, and contacts were broken if formed. Time-lapse records of the derivation of neurites from their path suggested a neurotropic effect of mast cells, with neurite contact ensuing when the intervening distance was less than 36 +/- 4 microns. Once formed, contacts were invariably maintained throughout the period of examination (up to 72 h), in contrast to YB2/O or fibroblast contacts. We conclude that neurons selectively form and maintain connections with cells representative of rat connective tissue-type and mucosal mast cells in vitro. Similar interactions in vivo could promote nerve/mast cell contacts, which may allow bidirectional communication between the nervous and immune systems.


An Inexpensive High-Temporal Resolution Electronic Sun Journal for Monitoring Personal Day to Day Sun Exposure Patterns.
Exposure to natural sunlight, specifically solar ultraviolet (UV) radiation contributes to lifetime risks of skin cancer, eye disease, and diseases associated with vitamin D insufficiency. Improved knowledge of personal sun exposure patterns can inform public health policy; and help target high-risk population groups. Subsequently, an extensive number of studies have been conducted to measure personal solar UV exposure in a variety of settings. Many of these studies, however, use digital or paper-based journals (self-reported volunteer recall), or employ cost prohibitive electronic UV dosimeters (that limit the size of sample populations), to estimate periods of exposure. A cost effective personal electronic sun journal (ESJ) built from readily available infrared photodiodes is presented in this research. The ESJ can be used to complement traditional UV dosimeters that measure total biologically effective exposure by providing a time-stamped sun exposure record. The ESJ can be easily attached to clothing and data logged to personal devices (including fitness monitors or smartphones). The ESJ improves upon self-reported exposure recording and is a cost effective high-temporal resolution option for monitoring personal sun exposure behavior in large population studies.


A decision tree-based approach for determining low bone mineral density in inflammatory bowel disease using WEKA software.
Decision tree classification is a standard machine learning technique that has been used for a wide range of applications. Patients with inflammatory bowel disease (IBD) are at increased risk of developing low bone mineral density (BMD). This study aimed at developing a new approach to select truly affected IBD patients who are indicated for densitometry, hence, subjecting fewer patients for bone densitometry and reducing expenses. Simple decision trees have been developed by means of WEKA (Waikato Environment for Knowledge Analysis) package of machine learning algorithms to predict factors influencing the bone density among IBD patients. The BMD status was the outcome variable whereas age, sex, duration of disease, smoking status, corticosteroid use, oral contraceptive use, calcium or vitamin D supplementation, menstruation, milk abstinence, BMI, and levels of calcium, phosphorous, alkaline phosphatase, and 25-OH vitamin D were all attributes. Testing showed the decision trees to have sensitivities of 65.7-82.8%, specificities of 95.2-96.3%, accuracies of 86.2-89.8%, and Matthews correlation coefficients of 0.68-0.79. Smoking status was the most significant node (root) for ulcerative colitis and IBD-associated trees whereas calcium status was the root of Crohn's disease patients' decision tree. BD specialists could use such decision trees to reduce substantially the number of patients referred for bone densitometry and potentially save resources.


Racial-ethnic Differences in Actigraphy, Questionnaire, and Polysomnography Indicators of Healthy Sleep: The Multi-Ethnic Study of Atherosclerosis.
A paradigm shift in sleep science argues for a systematic, multidimensional approach to investigate sleep's association with disease and mortality and to address sleep disparities. We utilized the comprehensive sleep assessment of the Multi-Ethnic Study of Atherosclerosis (2010- 2013), a cohort of U.S. White, Black, Chinese, and Hispanic adults and older adults (n=1,736; mean age=68.3), to draw 13 sleep dimensions and create composite Sleep Health Scores to quantify multidimensional sleep health disparities. After age and sex adjustment in linear regression, compared to White participants, Black participants showed the greatest global sleep disparity, then Hispanic and Chinese participants. We estimated relative 'risk' of obtaining favorable sleep compared to White adults at the component level by race/ethnicity (lower is worse). The largest disparities were in objectively-measured sleep timing regularity (RRBlack [95% CI]: 0.37 [0.29,0.47], RRHispanic: 0.64 [0.52,0.78], RRChinese: 0.70 [0.54,0.90]) and duration regularity (RRBlack: 0.55 [0.47,0.65], RRHispanic: 0.76 [0.66,0.88], RRChinese: 0.74 [0.61,0.90]), after sex and age adjustment. Disparities in duration and continuity were also apparent, and Black adults were additionally disadvantaged in %N3 (slow wave sleep), sleepiness, and sleep timing (24-hour placement). Sleep timing regularity, duration regularity, duration, and continuity may comprise a multidimensional cluster of targets to reduce racial-ethnic sleep disparities.


Highly deoxynivalenol contaminated oats and immune function in horses.
The aim of the present study was to investigate the impact of deoxynivalenol (DON) on cellular and humoral immune parameters in horses. A feeding trial using naturally contaminated oats with high (20.2 mg/kg) and low (0.49 mg/kg) levels of DON was conducted. Two groups of five mares were fed 2 kg oats daily with high or low DON levels for two weeks, using a crossover design with a three-week wash-out period. No adverse effects on general health were observed. Only minor diet-related changes in differential blood counts and serum biochemistry were noted. Serum haptoglobin concentration was significantly elevated after feeding DON (p = 0.04). Lymphocyte subsets (CD4+ CD8+, CD2+, CD21+, MHCII+) and lymphocyte proliferation data (concanavalin A, phytohemagglutinin, pokeweed mitogen) were not different between feeding-groups. It can be concluded that daily DON intakes as high as 6.9 to 9.5 mg/100 kg BW appear to have no major impact on the measured immune response of horses, indicating that this species has a high tolerance for DON.


Intraflagellar transport (IFT) protein IFT25 is a phosphoprotein component of IFT complex B and physically interacts with IFT27 in Chlamydomonas.
Intraflagellar transport (IFT) is the bidirectional movement of IFT particles between the cell body and the distal tip of a flagellum. Organized into complexes A and B, IFT particles are composed of at least 18 proteins. The function of IFT proteins in flagellar assembly has been extensively investigated. However, much less is known about the molecular mechanism of how IFT is regulated. We herein report the identification of a novel IFT particle protein, IFT25, in Chlamydomonas. Dephosphorylation assay revealed that IFT25 is a phosphoprotein. Biochemical analysis of temperature sensitive IFT mutants indicated that IFT25 is an IFT complex B subunit. In vitro binding assay confirmed that IFT25 binds to IFT27, a Rab-like small GTPase component of the IFT complex B. Immunofluorescence staining showed that IFT25 has a punctuate flagellar distribution as expected for an IFT protein, but displays a unique distribution pattern at the flagellar base. IFT25 co-localizes with IFT27 at the distal-most portion of basal bodies, probably the transition zones, and concentrates in the basal body region by partially overlapping with other IFT complex B subunits, such as IFT46. Sucrose density gradient centrifugation analysis demonstrated that, in flagella, the majority of IFT27 and IFT25 including both phosphorylated and non-phosphorylated forms are cosedimented with other complex B subunits in the 16S fractions. In contrast, in cell body, only a fraction of IFT25 and IFT27 is integrated into the preassembled complex B, and IFT25 detected in complex B is preferentially phosphorylated. IFT25 is a phosphoprotein component of IFT particle complex B. IFT25 directly interacts with IFT27, and these two proteins likely form a subcomplex in vivo. We postulate that the association and disassociation between the subcomplex of IFT25 and IFT27 and complex B might be involved in the regulation of IFT.


Temporal Consistency and Movement Effort of Repetitive Reaching During Continuation in Children and Adults.
The ability to match one's movements to an external beat and maintain that rhythm in the absence of the beat suggests sophisticated, well-developed neural control. Children (aged 5-10 years) were compared with adults (aged 18-30 years) during a repetitive reaching task to determine development of this control. Children as young as 5 years exhibited this control. The mean rate of reaching did not differ between groups nor did it differ during the two phases, suggesting an overall ability to internalize and continuously repeat a given pace. Children aged 5-8 years were significantly more variable than children aged 9-10 years and adults, likely attributable to variability in central control processes. We found a possible transition period of temporal control. Children aged 9-10 years begin to exhibit more adult-like levels of variability with respect to temporal consistency and movement effort.


Simultaneous application of single-shot Ramanography and particle image velocimetry.
A simultaneous two-dimensional determination of the concentration field and the velocity field in a turbulent mixing process is demonstrated for the first time to the best of our knowledge by using planar Raman scattering (Ramanography) and particle image velocimetry. An example of application of these techniques is tested by considering the mixing characteristic of a two-component nozzle for the injection of liquid ethanol into pure water.


A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints.
Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.


Reconstruction of medial patellofemoral ligament for chronic patellar instability.
Disruption of the capsule, medial patellar retinaculum, and/or vastus medialis obliqus has been associated with recurrent patellar instability. Biomechanical studies have shown that the medial patellofemoral ligament (MPFL) is the main restraint against lateral patella displacement and reconstruction of the MPFL has become an accepted surgical technique to restore patellofemoral stability in patients having recurrent patellar dislocation. We report a prospective series of patients of chronic patellar instability treated by reconstruction of medial patellofemoral ligament. Twelve patients (15 knees) with recurrent dislocation of patella, were operated between January 2006 and December 2008. All patients had generalised ligament laxity with none had severe grade of patella alta or trochlear dysplasia. The MPFL was reconstructed with doubled semitendinosus tendon. Patients were followed up with subjective criteria, patellar inclination angle, and Kujala score. The mean duration of followup after the operative procedures was an average of 42 months (range 24-60 months) 10 knees showed excellent results, 3 knees gave good results, and 2 knees had a fair result. The average patellar inclination angle decreased from 34.3° to 18.6°. The average preoperative Kujala functional score was 44.8 and the average postoperative score was 91.9. MPFL reconstruction using the semitendinosus tendon gives good results in patients with chronic patellar instability without predisposing factors like severe patella alta and high-grade trochlear dysplasia, and for revision cases.


Spin-dependent electrified protein interfaces for probing the CISS effect.
Bio-spinterfaces present numerous opportunities to study spintronics across the biomolecules attached to (ferro)magnetic electrodes. While it offers various exciting phenomena to investigate, it is simultaneously challenging to make stable bio-spinterfaces as biomolecules are sensitive to many factors that it encounters during thin-film growth to device fabrication. The chirality-induced spin-selectivity effect is an exciting discovery, demonstrating an understanding that a specific electron's spin (either up or down) passes through a chiral molecule. The present work utilizes Ustilago maydis Rvb2 protein, an ATP-dependent DNA helicase (also known as Reptin), to fabricate bio-spintronic devices to investigate spin-selective electron transport through the protein. Ferromagnetic materials are well-known for exhibiting spin-polarization, which many chiral and biomolecules can mimic. We report herein spin-selective electron transmission through Rvb2 that exhibits 30% spin polarization at a low bias (+0.5 V) in a device configuration, Ni/Rvb2 protein/indium tin oxide measured under two different magnetic configurations. Our findings demonstrate that biomolecules can be put in circuit components without any expensive vacuum deposition for the top contact. The present study holds a remarkable potential to advance spin-selective electron transport in other biomolecules, such as proteins and peptides, for biomedical applications.


Global asymptotic stability of delayed cellular neural networks.
A new criterion for the global asymptotic stability of the equilibrium point of cellular neural networks with multiple time delays is presented. The obtained result possesses the structure of a linear matrix inequality and can be solved efficiently using the recently developed interior-point algorithm. A numerical example is used to show the effectiveness of the obtained result.


Support for incentive-sensitization theory in adolescent ad libitum smokers using ecological momentary assessment.
The incentive-sensitization theory (IST) has emerged as a potentially useful theory in explaining substance addiction. IST postulates that the prolonged use of a substance can alter neural systems that are often involved in incentive motivation and reward processes, leading to an increased "sensitization" to the substance and associated stimuli. However, this increased sensitization is thought to mediate only the individual's craving of the substance (e.g., their "wanting"), not their enjoyment of the substance (e.g., their "liking"), a process that may involve unconscious implicit changes in cognitive networks linked to specific substances. Consequently, IST may better explain the real-world dissonance reported for individuals who want to accomplish long-term substance cessation but fail to do so, a phenomenon that is common in adolescent smokers. Thus, the present study aimed to examine the principles of IST in a sample of 154 adolescent ad libitum smokers (Mage = 16.57, SDage = 1.12, 61.14% male) utilizing ecological momentary assessment. Data were analyzed utilizing a multilevel structural equation model examining changes in positive affect (PA), negative affect (NA), and stress from Time 1 (T1) and Time 2 (T2) as a function of smoking and tested the influence of implicit cognition (specifically, implicit attitudes about smoking [Implicit Association Test (IAT)]) on these associations. Consistent with the principles of IST, results found a modest significant negative association between smoking status at T1 and PA at T2 (B = -0.11, p = .047). This association was further moderated by IAT (B = -0.19, p = .029) and was particularly potentiated at high levels of IAT (B = -0.44, p < .001), compared to low (B = -0.05, p = .663) or mean levels of IAT (B = -0.25, p = .004). Findings from this study provide additional support to the principles underlying IST and indicate that, in adolescents, smoking may result in thwarted PA indicative of a transition from "liking" toward "wanting," and this is especially pronounced among those with stronger implicit smoking cognitions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


[Gender-dependent effects of histone deacetylase inhibitor sodium valproate on early olfactory learning in 129Sv mice].
In the brain, histone acetylation underlies both learning and the maintenance of long-term sustained effects of early experience which is further epigenetically inherited. However, the role of acetylation in learning previously has only been studied in adult animals: high level of learning could be dependent on high levels of histone H3 acetylation in the brain. The role of acetylation in the mechanisms of early learning has not been studied. In the present work, we were interested whether histone deacetylase inhibitor sodium valproate which increases the level of histone H3 acetylation will affect early olfactory discrimination learning in 8-day-old pups of 129Sv mice that are characterized by low efficiency of learning with imitation of maternal grooming. Multiple valproate injections from 3rd to 6th postnatal day had a gender-dependent effect: learning was selectively improved in male but not in female pups. In the female pups, learning improvement was observed after multiple injections of saline. Possible epigenetic mechanisms underlying these sex differences are discussed.


Trying Times and Trying Out Solutions: Intimate Partner Violence Screening and Support for Women Veterans During COVID-19.
Initial reports indicate widespread increases in intimate partner violence (IPV) rates during the coronavirus disease 2019 (COVID-19) pandemic. Women veterans are at particular risk for experiencing IPV, and the COVID-19 pandemic and resulting stay-at-home orders may be exacerbating this risk. IPV screening and intervention are an integral part of the care provided to women veterans in the Veteran's Health Administration (VHA). Current changes in healthcare delivery during COVID-19 may present challenges to the VHA's standard methods of initiating IPV screening and intervention with women veterans. We discuss the potential challenges VHA healthcare providers may be encountering when conducting routine IPV screening during the COVID-19 pandemic and when providing resources and support to women veterans experiencing IPV. We describe solutions to these challenges, including existing efforts led by the VHA IPV Assistance Program (IPVAP) as well as additional potential solutions. New ideas and partnerships will be critical for helping the VHA continue to assist women veterans experiencing IPV as the COVID-19 pandemic evolves. Though our focus is on women veterans and the VHA, the challenges and solutions we discuss are likely applicable to other populations experiencing IPV and other health care systems screening for IPV.


Immunotherapy and gene therapy as novel treatments for cancer.
The immune system interacts closely with tumors during the disease development and progression to metastasis. The complex communication between the immune system and the tumor cells can prevent or promote tumor growth. New therapeutic approaches harnessing protective immunological mechanisms have recently shown very promising results. This is performed by blocking inhibitory signals or by activating immunological effector cells directly. Immune checkpoint blockade with monoclonal antibodies directed against the inhibitory immune receptors CTLA-4 and PD-1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is an anti-CTLA-4 antibody which demonstrated good results when administered to patients with melanoma. Gene therapy has also shown promising results in clinical trials. Particularly, Herpes simplex virus (HSV)-mediated delivery of the HSV thymidine kinase (TK) gene to tumor cells in combination with ganciclovir (GCV) may provide an effective suicide gene therapy for destruction of glioblastomas, prostate tumors and other neoplasias by recruiting tumor-infiltrating lymphocytes into the tumor. The development of new treatment strategies or combination of available innovative therapies to improve cell cytotoxic T lymphocytes trafficking into the tumor mass and the production of inhibitory molecules blocking tumor tissue immune-tolerance are crucial to improve the efficacy of cancer therapy.


Changes in seagrass species composition in northwestern Gulf of Mexico estuaries: effects on associated seagrass fauna.
The objective of this study was to measure the communities associated with different seagrass species to predict how shifts in seagrass species composition may affect associated fauna. In the northwestern Gulf of Mexico, coverage of the historically dominant shoal grass (Halodule wrightii) is decreasing, while coverage of manatee grass (Syringodium filiforme) and turtle grass (Thalassia testudinum) is increasing. We conducted a survey of fishes, crabs, and shrimp in monospecific beds of shoal, manatee, and turtle grass habitats of South Texas, USA to assess how changes in sea grass species composition would affect associated fauna. We measured seagrass parameters including shoot density, above ground biomass, epiphyte type, and epiphyte abundance to investigate relationships between faunal abundance and these seagrass parameters. We observed significant differences in communities among three seagrass species, even though these organisms are highly motile and could easily travel among the different seagrasses. Results showed species specific relationships among several different characteristics of the seagrass community and individual species abundance. More work is needed to discern the drivers of the complex relationships between individual seagrass species and their associated fauna.


Molecular cloning and sequence analysis of the genome of chicken anaemia agent.
The replicative form (RF) DNA of chicken anaemia agent (CAA) was isolated and cloned into bacterial plasmids. After religation of the cloned CAA DNA and transfection into MDCC-MSB1 cells, the DNA could induce c.p.e. characteristic of that caused by CAA, and an antigen was produced which gave positive immunofluorescence when detected with an anti-CAA serum. Sanger sequencing of the 2298 bp genome revealed several open reading frames (ORFs); the major ORF encoded a polypeptide of 51.8K. In SDS-PAGE of CAA viral particles a 50K protein has been reported as the only detectable viral protein. The genomic region downstream of the major ORF had several predicted GC-rich inverted repeats, a poly(A) signal and four copies of an 18 bp repeat element. Database searches did not reveal any sequence with homology to the viral genomic DNA, nor to the amino acid sequence of any of the ORFs, apart from the N-terminal 40 amino acids of the major ORF which showed a limited similarity to the structure of protamines.


Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies.
Tamoxifen contributes to decreased recurrence and mortality of patients with hormone receptor-positive breast cancer. As this drug is metabolized by phase I and phase II enzymes, the interindividual variations of their enzymatic activity are thought to be associated with individual responses to tamoxifen. Among these enzymes, CYP2D6 is considered to be a rate-limiting enzyme in the generation of endoxifen, a principal active metabolite of tamoxifen, and the genetic polymorphisms of CYP2D6 have been extensively investigated in association with the plasma endoxifen concentrations and clinical outcome of tamoxifen therapy. In addition to CYP2D6, other genetic factors including polymorphisms in various drug-metabolizing enzymes and drug transporters have been implicated to their relations to clinical outcome of tamoxifen therapy, but their effects would be small. Although the results of association studies are controversial, accumulation of the evidence has revealed us the important and critical issues in the tamoxifen pharmacogenomics study, namely the quality of genotyping, the coverage of genetic variations, the criteria for sample collection and the source of DNAs, which are considered to be common problematic issues in pharmacogenomics studies. This review points out common critical issues in pharmacogenomics studies through the lessons we have learned from tamoxifen pharmacogenomics, as well as summarizes the results of pharmacogenomics studies for tamoxifen treatment.


Post mortem survey of peripheral dental caries in 510 Swedish horses.
Peripheral caries (PC) of equine teeth is a poorly described disorder that can cause serious clinical problems if it progresses. To assess the prevalence, sites and severity of PC in a population of Swedish horses. A post mortem study of 510 equine skulls was performed in 2 Swedish equine abattoirs. PC only affected the cheek teeth (CT) and was present in 6.1% (31/510) of skulls. It affected mainly the peripheral cementum, and 87% of PC in the 29 affected mature horses occurred in the 3 caudal CT (Triadan 09-11). Concurrent infundibular caries involving most maxillary CT (mean 9.7/skull) was present in 32% of skulls affected with PC. Trotting horses (mean age 8.1 years) believed to be on a high concentrate and silage diet were preferentially affected with PC in this population. Food was usually tightly adherent to the PC lesions and this feature may have promoted the progression of the disease. Significantly increased levels of diastemata were present in PC-affected horses, and periodontal disease was present in areas adjacent to some PC lesions. PC is a relatively common disorder of horses under certain management conditions that can progress to cause serious dental disorders, especially if concurrent, widespread infundibular caries is present. Equine clinicians should be aware of this significant dental disorder and research into its aetiopathogenesis, possible prevention and treatment are required.


Bowel preparation in "real-life" small bowel capsule endoscopy: a two-center experience.
Video capsule endoscopy (VCE) is an established diagnostic tool for the investigation of small bowel (SB) pathology. Bowel preparation prior to VCE may improve visualization, transit time, and diagnostic yield. We aimed to evaluate the "real-life" experience comparing two different preparation protocols in patients undergoing SB VCE. We performed a retrospective analysis of prospectively collected data from SB VCE procedures, performed in two tertiary care medical centers in Israel. VCE procedures performed at "Sheba Medical Center" used a 2-L polyethylene glycol (PEG) bowel preparation (n=360) while VCEs performed at "Rambam Health Care campus" used a clear liquid diet plus 12-h fast protocol (n=500). A dichotomous preparation scale (adequate, inadequate) was used to classify cleansing quality. Data collection included patient and procedural details. The proportion of VCE procedures with adequate bowel preparation and the overall positive SB findings in the two different bowel preparation protocols were evaluated. SB completion rates were higher in the PEG protocol (96% vs. 83%, P<0.001) and SB passage time was significantly faster in the PEG protocol (mean 217±73 vs. 238±77 min, P<0.001). Bowel preparation quality was similar between groups (8% vs. 7% inadequate preparation, P=0.591). Overall positive SB findings were similar between the two groups (57% clear liquid fasting only vs. 51% PEG protocol, P=0.119). In this large cohort, a 2-L PEG protocol had similar preparation quality and diagnostic yield compared with clear liquid fasting.


Generation of a Xenopus laevis F1 albino J strain by genome editing and oocyte host-transfer.
Completion of the Xenopus laevis genome sequence from inbred J strain animals has facilitated the generation of germline mutant X. laevis using targeted genome editing. In the last few years, numerous reports have demonstrated that TALENs are able to induce mutations in F0 Xenopus embryos, but none has demonstrated germline transmission of such mutations in X. laevis. In this report we used the oocyte host-transfer method to generate mutations in both tyrosinase homeologs and found highly-penetrant germline mutations; in contrast, embryonic injections yielded few germline mutations. We also compared the distribution of mutations in several F0 somatic tissues and germ cells and found that the majority of mutations in each tissue were different. These results establish that X. laevis J strain animals are very useful for generating germline mutations and that the oocyte host-transfer method is an efficient technique for generating mutations in both homeologs.


[Metabolic syndrome and physical activity].
Because the metabolic syndrome (MS) poses a growing public health problem, it is crucial to identify related modifiable risk factors. The MS is a multifaceted syndrome, however, physical activity (PA) is thought to be one of the protective factors in MS occurrence. The purpose of this study is to analyse recent literature on the association between PA and MS. Studies seem to agree in the protective effect of PA in MS occurrence, but associations are only seen in moderate or high PA levels. Differences observed in studies are probably related to different study methods. According to recent literature adequate PA levels can help to lower the risk of developing MS; PA can decrease body weight, visceral fat accumulation, improve insulin sensitivity, decrease plasma level of triglycerides, increase plasma levels of HDL cholesterol and decrease blood pressure.


Drivers of the time-varying heat-cold-mortality association in Spain: A longitudinal observational study.
A number of studies have reported reductions in mortality risk due to heat and cold over time. However, questions remain about the drivers of these adaptation processes to ambient temperatures. We aimed to analyse the demographic and socioeconomic drivers of the downward trends in vulnerability to heat- and cold-related mortality observed in Spain during recent decades (1980-2018). We collected data on all-cause mortality, temperature and relevant contextual indicators for 48 provinces in mainland Spain and the Balearic Islands between Jan 1, 1980, and Dec 31, 2018. Fourteen contextual indicators were analysed representing ageing, isolation, urbanicity, heating, air conditioning (AC), house antiquity and ownership, education, life expectancy, macroeconomics, socioeconomics, and health investment. The statistical analysis was separately performed for the range of months mostly causing heat- (June-September) and cold- (October-May) related mortality. We first applied a quasi-Poisson generalised linear regression in combination with distributed lag non-linear models (DLNM) to estimate province-specific temperature-mortality associations for different periods, and then we fitted univariable and multivariable multilevel spatiotemporal meta-regression models to evaluate the effect modification of the contextual characteristics on heat- and cold-related mortality risks over time. The average annual mean temperature has risen at an average rate of 0·36 °C per decade in Spain over 1980-2012, although the increase in temperature has been more pronounced in summer (0·40 °C per decade in June-September) than during the rest of the year (0·33 °C per decade). This warming has been observed, however, in parallel with a progressive reduction in the mortality risk associated to both hot and cold temperatures. We found independent associations for AC with heat-related mortality, and heating with cold-related mortality. AC was responsible for about 28·6% (31·5%) of the decrease in deaths due to heat (extreme heat) between 1989 and 1993 and 2009-2013, and heating for about 38·3% (50·8%) of the reductions in deaths due to cold (extreme cold) temperatures. Ageing (ie, proportion of population over 64 years) attenuated the decrease in cold-related mortality. AC and heating are effective societal adaptive measures to heat and cold temperatures. This evidence holds important implications for climate change health adaptation policies, and for the projections of climate change impacts on human health.


User Perceptions of ¡Protéjase!: An Intervention Designed to Increase Protective Equipment Use Among Mexican Immigrant and Mexican American Farmworkers.
Farmworkers' exposures to pesticides are reduced when they wear personal protective equipment (PPE), and mobile health (mHealth) platforms can potentially deliver information to farmworkers to help promote PPE use. However, little is known about the feasibility of using mHealth platforms to promote farmworkers' use of PPE. The objective of the study was to describe the development and feasibility-testing of Protect Yourself! (¡Protéjase!), an intervention designed to increase PPE use. As the vast majority of farmworkers in the United States are from Mexico, we examined the intervention in a primarily Mexican-origin farmworker population. ¡Protéjase was developed in several steps. First, we performed ethnographic observations to understand what prevents PPE use. Next, we developed program components that met the challenges uncovered in the ethnographic observations, seeking direct feedback from farmworkers on each component. Feasibility was assessed using surveys and focus groups. Material was provided in Spanish or English at the preference of the participant. Finally, we pilot tested each component of the intervention, including: (1) PPE that was provided to each worker for their personal use during the intervention trial, and (2) delivery of an application-based tool that promoted the use of PPE through daily individualized messaging. 55 farmworkers enrolled in the study, but only 41 of 55 (75%) completed the entire pilot intervention trial. Results focus on the evaluation of the intervention, and include only those who completed the entire trial. Among farmworkers who completed the entire intervention trial, all but two farmworkers were born in Mexico and were Spanish speaking. Still, all study participants self-identified as Mexican or Mexican-American. When asked what changes were needed in the intervention's messaging or delivery to increase user satisfaction, 22 out of 41 participants (54%) felt that no changes were needed. However, 16 of 41 participants (39%) suggested small changes to messaging (eg, refer to long pants as pants only) to improve their understanding of the messages. Finally, a small number (3 of 41 participants, 7%) felt that messages were difficult to read, primarily due to low literacy. The ¡Protéjase! mHealth program demonstrated very good feasibility, satisfaction, and acceptance; potential improvements (eg, small modifications in messaging to increase farmworkers' use) were noted. Overall, the PPE provided to workers as well as the mHealth platform were both perceived as useful for promoting PPE use.


Saliva: a challenging human fluid to diagnose brain disorders with a focus on Alzheimer's disease.
Biomarkers are molecules of biological processes that help in both the diagnosis of human diseases and in follow-up assessments of therapeutic responses. Biomarkers can be measured in many human fluids, such as blood, cerebrospinal fluid, urine, and saliva. The -omics methods (genomics, RNomics, proteomics, and metabolomics) are useful at measuring thousands of markers in a small volume. Saliva is a human fluid that is easily accessible, without any ethical concerns. Yet, saliva remains unexplored in regard to many human disease biomarkers. In this review, we will give an overview on saliva and how it can be influenced by exogenous factors. As we focus on the potential use of saliva as a diagnostic tool in brain disorders (especially Alzheimer's disease), we will cover how saliva is linked to the brain. We will discuss that saliva is a heterogeneous human fluid, yet useful for the discovery of biomarkers in human disorders. However, a procedure and consensus that is controlled, validated, and standardized for the collection and processing of saliva is required, followed by a highly sensitive diagnostic approach.


Feasibility of Extended Dissection of Lateral Pelvic Lymph Nodes During Laparoscopic Total Mesorectal Excision in Patients with Locally Advanced Lower Rectal Cancer: A Single-Center Pilot Study After Neoadjuvant Chemotherapy.
BACKGROUND The feasibility of additional dissection of the lateral pelvic lymph nodes (LPLNs) in patients undergoing total mesorectal excision (TME) combined with neoadjuvant chemotherapy (NAC) for locally advanced rectal cancer (LARC) is controversial. The use of laparoscopic surgery is also debated. In the present study, we evaluated the utility of laparoscopic dissection of LPLNs during TME for patients with LARC and metastatic LPLNs after NAC, based on our experience with 19 cases. MATERIAL AND METHODS Twenty-five patients with LARC with swollen LPLNs who underwent laparoscopic TME and LPLN dissection were enrolled in this pilot study. The patients were divided into 2 groups: those patients with NAC (n=19) and without NAC (n=6). Our NAC regimen involved 4 to 6 courses of FOLFOX plus panitumumab, cetuximab, or bevacizumab. RESULTS The operative duration was significantly longer in the NAC group than in the non-NAC group (648 vs. 558 minutes, respectively; P=0.022). The rate of major complications, defined as grade ≥3 according to the Clavien-Dindo classification, was similar between the 2 groups (15.8% vs. 33.3%, respectively; P=0.4016). No conversion to conventional laparotomy occurred in either group. In the NAC group, a histopathological complete response was obtained in 2 patients (10.5%), and a nearly complete response (Tis N0 M0) was observed in one patient (5.3%). Although the operation time was prolonged in the NAC group, the other perioperative factors showed no differences between the 2 groups. CONCLUSIONS Laparoscopic LPLN dissection is feasible in patients with LARC and clinically swollen LPLNs, even after NAC.


Studies on time: a proposal on how to get out of circularity.
The analysis of time is vitiated very often by circularity: several disciplines, such as psychology, linguistics, and neurosciences, analyze time by using concepts or terms which already contain in themselves, or are based, on the experience and notion of time (as when, for example, time is defined as "duration", or when our ability to estimate durations is explained by resorting to the notion of an internal clock). Some detailed examples of circularity in the analysis of time are given here and examined. A way out of circularity is then given: it is represented by the proposal of attentional semantics (AS) of considering words and their meanings in terms of the aim they serve, and the means and processes developed and implemented in order to achieve that aim. According to AS, the main aim of words is that of indicating to, and eliciting in, the listener or reader a specific conscious experience: namely, the conscious experience referred to by their meanings. Words achieve their main aim by conveying the condensed instructions on the attentional operations one has to perform if one wants to consciously experience what is expressed through and by them. By describing the conscious experiences elicited by words in terms of the attentional operations that are responsible for the production of such conscious experiences, AS offers an a-linguistic counterpart to language, and therefore an effective way out of circularity. Following in footsteps of Mach (Contributions to the analysis of the sensations, 1890), but slightly revising his hypothesis, AS defines time-sensation as the perception of the effort made, or alternatively the nervous energy expended, by the organ of attention when performing a "temporal activity" (for instance, estimating duration), that is, when one's own attention is focused in a continuous and incremental way on the conscious product of the ("non-temporal") activity performed by means of another portion of one's attention.


CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
CTL-associated antigen 4 (CTLA4) blockade releases inhibitory controls on T cell activation and proliferation, inducing antitumor immunity in both preclinical and early clinical trials. We examined the mechanisms of action of anti-CTLA4 and a GM-CSF-transduced tumor cell vaccine (Gvax) and their impact on the balance of effector T cells (Teffs) and Tregs in an in vivo model of B16/BL6 melanoma. Tumor challenge increased the frequency of Tregs in lymph nodes, and untreated tumors became infiltrated by CD4+Foxp3- and CD4+Foxp3+ T cells but few CD8+ T cells. Anti-CTLA4 did not deplete Tregs or permanently impair their function but acted in a cell-intrinsic manner on both Tregs and Teffs, allowing them to expand, most likely in response to self antigen. While Gvax primed the tumor-reactive Teff compartment, inducing activation, tumor infiltration, and a delay in tumor growth, the combination with CTLA4 blockade induced greater infiltration and a striking change in the intratumor balance of Tregs and Teffs that directly correlated with tumor rejection. The data suggest that Tregs control both CD4+ and CD8+ T cell activity within the tumor, highlight the importance of the intratumor ratio of effectors to regulators, and demonstrate inversion of the ratio and correlation with tumor rejection during Gvax/anti-CTLA4 immunotherapy.


[Determination of 3,4-dioxyphenyl-L-alanine by spectrophotometric and chromatographic methods in enzymatic synthesis using microbial cells].
A possibility of using the ninhydrin reaction for 3,4-dihydroxyphenyl-L-alanine (DOPA) determining during the synthesis from pyrocatechol and ammonium pyruvate was verified by using free and immobilized cells of Citrobacter freundii, st. 62. Spectrophotometric assay was performed at the adsorption maximum for the DOPA-ninhydrin complex at 390 nm. DOPA can be reliably quantified in the presence of all components at 20-fold and greater dilution of the reaction mixture. A high-sensitive quantitative assay of the reaction mixture was developed based on phase-reversed HPLC. A quantitative correlation was observed between spectrophotometric and chromatographic assays. The assays were employed to study in detail the initial period and equilibrium of DOPA synthesis and its characteristic features, which made it possible to construct a kinetic model of the process.


What are the information needs and concerns of individuals with Polycystic Kidney Disease? Results of an online survey using Facebook and social listening analysis.
Polycystic Kidney Disease (PKD) is a hereditary disorder that has no cure and can result in end stage kidney failure. Searching for health information online and via social media is a common phenomenon in many medical conditions. However, no recent studies have documented the information needs, online behaviours, and concerns of people with PKD. The aim of this study was to explore the information needs of individuals with PKD and their carers by documenting (i) the information needs (ii) online information health seeking behaviours (iii) the perceived challenges of living with PKD and (iv) dietary concerns. A 17-item survey was constructed by undertaking a social listening analysis. This survey was then distributed via PKD related social media groups on Facebook. Seven groups distributed the survey with permission from the group owners. Open free text survey questions were analysed thematically using content analysis. A total of 536 respondents completed the online survey (70.9 % female, 77 % aged 35-70, 70.2 % diagnosed more than 10 years ago). The major information need expressed by participants with PKD was for dietary information. Information regarding medications, medical management and symptom control were also desired. The overarching themes arising from the free text responses to the major challenge of living with PKD included 'learning to navigate dietary ambiguities'; 'managing social, psychological and emotional needs'; and 'accepting an uncertain future'. In addition to a strong desire for practical and specific dietary information, participants expressed a need for more online information pertaining to management of fatigue, pain, complications and how to manage mental health. Online peer support was also highly regarded and desired. This study provides contemporary insights into the type of information desired by people with PKD. The results indicated that there was a strong desire for unambiguous information and guidance from health professionals to facilitate self-management, alleviate concerns, and address the complexities of living with Polycystic Kidney Disease. While diet is an important and frequently expressed need, there also remains a large demand for information on how to support psychological needs, and on medical management in order to support treatment decision making. Future work is required to develop specific, actionable and evidence-based resources for patients that are available online and through health professionals. Increased access to renal dietitians, peer support and additional training for health professionals could also improve patient-centered care and support self-management.


Parkinson's disease: genetics and beyond.
Parkinson's disease (PD) is characterized clinically by resting tremor, rigidity, bradykinesia and postural instability due to progressive and selective loss of dopamine neurons in the ventral substantia nigra, with the presence of ubiquitinated protein deposits called Lewy bodies in the neurons. The pathoetiology of cell death in PD is incompletely understood and evidence implicates impaired mitochondrial complex I function, altered intracellular redox state, activation of proapoptotic factors and dysfunction of ubiquitinproteasome pathway. Now it is believed that genetic aberration, an environmental toxin or combination of both leads to a cascade of events culminating in the destruction of myelinated brainstem catecholaminergic neurons. Also the role of production of significant levels of abnormal proteins, which may misfold, aggregate and interfere with intracellular processes causing cytotoxicity has recently been hypothesized. In this article, the diverse pieces of evidence that have linked the various factors responsible for the pathophysiology of PD are reviewed with special emphasis to various candidate genes and proteins. Furthermore, the present therapeutic strategies and futuristic approaches for the pharmacotherapy of PD are critically discussed.


Surface-immobilized pyridine-functionalized gamma-cyclodextrin: alkanethiol co-adsorption-induced reorientation.
Monolayers of di-6A,6B-deoxy-6-(4-pyridylmethyl)amino-gamma-cyclodextrin (gamma-CD-(py)2) have been formed on polycrystalline platinum electrodes and investigated using electrochemical and surface-enhanced Raman spectroscopy (SERS). The behavior of self-assembled monolayers of (gamma-CD-(py)2) alone, (gamma-CD-(py)2) backfilled with 1-nonanethiol, and 1-nonanethiol are reported. The potential dependence of the capacitance indicates that the film capacitance is higher for the backfilled CD layers than for 1-nonanethiol layers, most likely due to ion flux through the CD cavity. SERS spectra of the backfilled layer exhibit features associated with both pyridine-functionalized CD and alkane moieties. Investigations using [Fe(CN)6]4- as a solution-phase probe indicate that the backfilled CD-alkane thiol layer exhibits enhanced blocking properties compared to gamma-CD-(py)2 films alone. Complete blocking was achieved by a combination of backfilling and insertion of a high-affinity guest 1-adamantylamine into the cavity. Significantly, an electroactive guest with high affinity for gamma-CD, [Co(biptpy)2]2+, does not exhibit a redox response at the gamma-CD-(py)2 layer but molecular recognition is turned on by backfilling the CD layer with 1-nonanethiol molecules. This switching on of the electrochemical activity suggests that the CD hosts are initially inaccessible but reorientate upon backfilling, exposing the CD opening to solution and permitting a supramolecular host-guest complex to form. The binding of [Co(biptpy)2]2+ to gamma-CD in the backfilled monolayer depends on the bulk concentration of guest and is modeled by the Langmuir isotherm, yielding an association constant for the Co2+ state of 1.45 +/- 0.46 x 105 M-1 and a limiting surface coverage 1.49 +/- 0.25 x 10-11 mol cm-2. The surface coverage of the divalent state is higher than the trivalent state, reflecting the dynamic nature of the inclusion.


Prostate imaging features that indicate benign or malignant pathology on biopsy.
Accurate diagnosis of clinically significant prostate cancer is essential in identifying patients who should be offered treatment with curative intent. Modifications to the Gleason grading system in recent years show that accurate grading and reporting at needle biopsy can improve identification of clinically significant prostate cancers. Extracapsular extension of prostate cancer has been demonstrated to be an adverse prognostic factor with greater risk of metastatic spread than organ-confined disease. Tumor volume may be an independent prognostic factor and should be considered in conjunction with other factors. Multi-parametric magnetic resonance imaging (MP-MRI) has become an increasingly important tool in the diagnosis and characterization of prostate cancer. MP-MRI allows T2-weighted (T2W) anatomical imaging to be combined with functional and physiological assessment. Diffusion-weighted imaging (DWI) has shown greater sensitivity, specificity and negative predictive value compared to prostate specific antigen (PSA) testing and T2W imaging alone and has a more positive correlation with Gleason score and tumour volume. Dynamic gadolinium contrast-enhanced (DCE) imaging can exhibit difficulties in distinguishing prostatitis from malignancy in the peripheral zone, and between benign prostatic hyperplasia (BPH) and malignancies in the transition zone (TZ). Computer aided diagnosis utilizes software to aid radiologists in detecting and diagnosing abnormalities from diagnostic imaging. New techniques of quantitative MRI, such as VERDICT MRI use tissue-specific factors to delineate different cellular and microstructural phenotypes, characterizing tissue properties with greater detail. Proton MR spectroscopic imaging (MRSI) is a more technically challenging imaging modality than DCE and DWI MRI. Over the last decade, choline and prostate-specific membrane antigen (PSMA) positron emission tomography (PET) have developed as better tools for staging than conventional imaging. While hyperpolarized MRI shows promise in improving the imaging and differentiation of benign and malignant lesions there is further work required. Accurate reading and interpretation of diagnostic investigations is key to accurate identification of abnormal areas requiring biopsy, sparing those in whom benign or indolent disease can be managed by non-invasive means. Embracing and advancing existing technologies is essential in furthering this process.


Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis.
The results from small clinical studies suggest that therapy with adult bone marrow (BM)-derived cells (BMCs) reduces infarct size and improves left ventricular function and perfusion. However, the effects of BMC transplantation in patients with ischemic heart disease remains unclear. We searched MEDLINE, EMBASE, Science Citation Index, CINAHL (Cumulative Index to Nursing and Allied Health), and the Cochrane Central Register of Controlled Trials (CENTRAL) (through July 2006) for randomized controlled trials and cohort studies of BMC transplantation to treat ischemic heart disease. We conducted a random-effects meta-analysis across eligible studies measuring the same outcomes. Eighteen studies (N = 999 patients) were eligible. The adult BMCs included BM mononuclear cells, BM mesenchymal stem cells, and BM-derived circulating progenitor cells. Compared with controls, BMC transplantation improved left ventricular ejection fraction (pooled difference, 3.66%; 95% confidence interval [CI], 1.93% to 5.40%; P<.001); reduced infarct scar size (-5.49%; 95% CI, -9.10% to -1.88%; P = .003); and reduced left ventricular end-systolic volume (-4.80 mL; 95% CI, -8.20 to -1.41 mL; P = .006). The available evidence suggests that BMC transplantation is associated with modest improvements in physiologic and anatomic parameters in patients with both acute myocardial infarction and chronic ischemic heart disease, above and beyond conventional therapy. Therapy with BMCs seems safe. These results support conducting large randomized trials to evaluate the impact of BMC therapy vs the standard of care on patient-important outcomes.


Adult limb and breast amputees' experience and descriptions of phantom phenomena-A qualitative study.
Background Phantom phenomena - pain or other sensations appearing to come from amputated body parts - are frequent consequences of amputation and can cause considerable suffering. Also, stump pain, located in the residual limb, is in the literature often related to the phantom phenomena. The condition is not specific to amputated limbs and has, to a lesser extent, been reported to be present after radical surgery in other body parts such as breast, rectum and teeth. Multi-causal theories are used when trying to understand these phenomena, which are recognized as the result of complex interaction among various parts of the central nervous system confirmed in studies using functional brain imaging techniques. Functional brain imaging has yielded important results, but without certainty being related to phantom pain as a subjective clinical experience. There is a wide range of treatment methods for the condition but no documented treatment of choice. Aims In this study a qualitative, explorative and prospective design was selected, in the aim to understand the patients' personal experience of phantom phenomena. The research questions focused at how patients affected by phantom pain and or phantom sensations describe, understand, and live with these phenomena in their daily life. This study expanded 'phantom phenomena' to also encompass phantom breast phenomenon. Since the latter phenomenon is not as well investigated as the phantom limb, there is clinical concern that this is an underestimated problem for women who have had breasts removed. Methods The present study forms the first part of a larger, longitudinal study. Only results associated with data from the first interviews with patients, one month after an amputation, are presented here. At this occasion, 28 patients who had undergone limb amputation (20) or mastectomy (8) were interviewed. The focused, semi-structured interviews were recorded, transcribed, and then analyzed using discourse-narrative analysis. Results The interviewees had no conceptual problems in talking about the phenomena or distinguishing between various types of discomfort and discomfort episodes. Their experience originated from a vivid, functioning body that had lost one of its parts. Further, the interviewees reported the importance of rehabilitation and advances in prosthetic technology. Loss of mobility struck older amputees as loss of social functioning, which distressed them more than it did younger amputees. Phantom sensations, kinetic and kinesthetic perceptions, constituted a greater problem than phantom pain experienced from the amputated body parts. The descriptions by patients who had had mastectomies differed from those by patients who had lost limbs in that the phantom breast could be difficult to describe and position spatially. The clinical implication of this study is that when phantom phenomena are described as everyday experience, they become a psychosocial reality that supplements the definition of phantom phenomena in scientific literature and clinical documentation. Conclusions There is a need for clinical dialogues with patients, which besides, providing necessary information about the phenomena to the patients creates possibilities for health professionals to carefully listen to the patients' own descriptions of which functional losses or life changes patients fear the most. There is a need for more qualitative studies in order to capture the extreme complexity of the pain-control system will be highlighted.


Fine-tuning of auditory cortex during speech production.
The cortex suppresses sensory information when it is the result of a self-produced motor act, including the motor act of speaking. The specificity of the auditory cortical suppression to self-produced speech, a prediction derived from the posited operation of a precise forward model system, has not been established. We examined the auditory N100 component of the event-related brain potential elicited during speech production. While subjects uttered a vowel, they heard real-time feedback of their unaltered voice, their pitch-shifted voice, or an alien voice substituted for their own. The subjects' own unaltered voice feedback elicited a dampened auditory N100 response relative to the N100 elicited by altered or alien auditory feedback. This is consistent with the operation of a precise forward model modulating the auditory cortical response to self-generated speech and allowing immediate distinction of self and externally generated auditory stimuli.


Assessing equitable access to urban green space: the role of engineered water infrastructure.
Urban green space and water features provide numerous social, environmental, and economic benefits, yet disparities often exist in their distribution and accessibility. This study examines the link between issues of environmental justice and urban water management to evaluate potential improvements in green space and surface water access through the revitalization of existing engineered water infrastructures, namely stormwater ponds. First, relative access to green space and water features were compared for residents of Tampa, Florida, and an inner-city community of Tampa (East Tampa). Although disparities were not found in overall accessibility between Tampa and East Tampa, inequalities were apparent when quality, diversity, and size of green spaces were considered. East Tampa residents had significantly less access to larger, more desirable spaces and water features. Second, this research explored approaches for improving accessibility to green space and natural water using three integrated stormwater management development scenarios. These scenarios highlighted the ability of enhanced water infrastructures to increase access equality at a variety of spatial scales. Ultimately, the "greening" of gray urban water infrastructures is advocated as a way to address environmental justice issues while also reconnecting residents with issues of urban water management.


[Surgical treatment of a patient with stage v multinodular toxic goiter, severe thyrotoxicosis, strangulation syndrome and severe comorbidities].
The authors describe thyroidectomy in a patient with multinodular toxic goiter stage V, severe thyrotoxicosis complicated by thyro-cardiac disease, strangulation syndrome and severe comorbidities. Nodular euthyroid goiter was first diagnosed in 1992, and resection of the right thyroid lobe was performed. Progressive enlargement of thyroid gland and thyrotoxicosis occurred after coronavirus infection in February, 2020. Along with progression of thyrotoxicosis and strangulation of cervical organs, the patient suffered from portal vein thrombosis, pulmonary embolism. Myeloproliferative disease with essential thrombocythemia was also diagnosed. Volume of the right and left thyroid lobes was 69 and 101.3 cm3, respectively. X-ray examination of the esophagus revealed narrowing at C6 level up to 5-8 mm. Surgery time was 2 hours, dimension of removed right thyroid lobe - 10.0×7.5×6.5 cm, left thyroid lobe - 11.0×6.5×5.5 cm, total weight - 348 g. The patient was discharged in 6 days after surgery.


Availability of the Molecular Switch XylR Controls Phenotypic Heterogeneity and Lag Duration during Escherichia coli Adaptation from Glucose to Xylose.
The glucose-xylose metabolic transition is of growing interest as a model to explore cellular adaption since these molecules are the main substrates resulting from the deconstruction of lignocellulosic biomass. Here, we investigated the role of the XylR transcription factor in the length of the lag phases when the bacterium Escherichia coli needs to adapt from glucose- to xylose-based growth. First, a variety of lag times were observed when different strains of E. coli were switched from glucose to xylose. These lag times were shown to be controlled by XylR availability in the cells with no further effect on the growth rate on xylose. XylR titration provoked long lag times demonstrated to result from phenotypic heterogeneity during the switch from glucose to xylose, with a subpopulation unable to resume exponential growth, whereas the other subpopulation grew exponentially on xylose. A stochastic model was then constructed based on the assumption that XylR availability influences the probability of individual cells to switch to xylose growth. The model was used to understand how XylR behaves as a molecular switch determining the bistability set-up. This work shows that the length of lag phases in E. coli is controllable and reinforces the role of stochastic mechanism in cellular adaptation, paving the way for new strategies for the better use of sustainable carbon sources in bioeconomy.IMPORTANCE For decades, it was thought that the lags observed when microorganisms switch from one substrate to another are inherent to the time required to adapt the molecular machinery to the new substrate. Here, the lag duration was found to be the time necessary for a subpopulation of adapted cells to emerge and become the main population. By identifying the molecular mechanism controlling the subpopulation emergence, we were able to extend or reduce the duration of the lags. This work is of special importance since it demonstrates the unexpected complexity of monoclonal populations during growth on mixed substrates and provides novel mechanistic insights with regard to bacterial cellular adaptation.


Resident Participation in Fixation of Intertrochanteric Hip Fractures: Analysis of the NSQIP Database.
Future generations of orthopaedic surgeons must continue to be trained in the surgical management of hip fractures. This study assesses the effect of resident participation on outcomes for the treatment of intertrochanteric hip fractures. The National Surgical Quality Improvement Program (NSQIP) database (2010 to 2013) was queried for intertrochanteric hip fractures (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 820.21) treated with either extramedullary (Current Procedural Terminology [CPT] code 27244) or intramedullary (CPT code 27245) fixation. Demographic variables, including resident participation, as well as primary (death and serious morbidity) and secondary outcome variables were extracted for analysis. Univariate, propensity score-matched, and multivariate logistic regression analyses were performed to evaluate outcome variables. Data on resident participation were available for 1,764 cases (21.0%). Univariate analyses for all intertrochanteric hip fractures demonstrated no significant difference in 30-day mortality (6.3% versus 7.8%; p = 0.264) or serious morbidity (44.9% versus 43.2%; p = 0.506) between the groups with and without resident participation. Multivariate and propensity score-matched analyses gave similar results. Resident involvement was associated with prolonged operating-room time, length of stay, and time to discharge when a prolonged case was defined as one above the 90th percentile for time parameters. Resident participation was not associated with an increase in morbidity or mortality but was associated with an increase in time-related secondary outcome measures. While attending surgeon supervision is necessary, residents can and should be involved in the care of these patients without concern that resident involvement negatively impacts perioperative morbidity and mortality. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


DNA methylation in breast cancer.
Like all cancers, breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. This review will briefly discuss basic aspects of DNA methylation, recent advances in DNA methyltransferases, the role of altered chromatin organization and the concept of gene transcriptional regulation built on methylated CpGs. In particular, we discuss epigenetic regulation of certain critical tumor suppressor and growth regulatory genes implicated in breast cancer, and its relevance to breast cancer diagnosis, prognosis, progression and therapy.


IRE1α Activation in Bone Marrow-Derived Dendritic Cells Modulates Innate Recognition of Melanoma Cells and Favors CD8+ T Cell Priming.
The IRE1α/XBP1s signaling pathway is an arm of the unfolded protein response (UPR) that safeguards the fidelity of the cellular proteome during endoplasmic reticulum (ER) stress, and that has also emerged as a key regulator of dendritic cell (DC) homeostasis. However, in the context of DC activation, the regulation of the IRE1α/XBP1s axis is not fully understood. In this work, we report that cell lysates generated from melanoma cell lines markedly induce XBP1s and certain members of the UPR such as the chaperone BiP in bone marrow derived DCs (BMDCs). Activation of IRE1α endonuclease upon innate recognition of melanoma cell lysates was required for amplification of proinflammatory cytokine production and was necessary for efficient cross-presentation of melanoma-associated antigens without modulating the MHC-II antigen presentation machinery. Altogether, this work provides evidence indicating that ex-vivo activation of the IRE1α/XBP1 pathway in BMDCs enhances CD8+ T cell specific responses against tumor antigens.


Echinococcus infections in the Baltic region.
In the Baltic countries, the two zoonotic diseases, alveolar echinococcosis (AE) caused by Echinococcus multilocularis, and cystic echinococcosis (CE) caused by Echinococcus granulosus, are of increasing public health concern. Observations from Estonia, Latvia and Lithuania indicate that the distribution of both parasites is wider in the Baltics than previously expected. In this paper, we review and discuss the available data, regarding both parasitoses in animals and humans, from the Baltic countries and selected adjacent regions. The data are not easily comparable but reveal a worrisome situation as the number of human AE and CE cases is increasing. Despite improvements in diagnostics and treatment, AE has a high morbidity and mortality in the Baltic region. For the control of both zoonoses, monitoring transmission patterns and timely diagnosis in humans as well as the development of local control programs present major challenges.


Recurrence of differentiated thyroid cancer in the elderly.
Data from the Surveillance Epidemiology and End Results Medicare-linked database were used to estimate the incidence of and risk factors associated with recurrent thyroid cancer, and to assess the impact of recurrence on mortality following diagnosis, controlling for mortality as a competing risk. We identified 2883 patients over 65 years of age diagnosed with a single, primary well-differentiated thyroid cancer between 1995 and 2007. A recurrence was considered if the patient had evidence of I-131 therapy, imaging for metastatic thyroid carcinoma, or complete thyroidectomy beyond 6 months of diagnosis. Competing risk regressions were performed using Cox proportional hazards models with 1- and 2-year landmarks. Recurrence was observed in 1117 (39%) of the 2883 patients in the cohort. Age, stage, and treatment status were significant risk factors for developing recurrent disease (P<0.0001). Patients with recurrent disease had a higher risk of all-cause mortality within 10 years of diagnosis than patients with no recurrence at 1- and 2-year landmarks. Patients with follicular histology and a recurrence were less likely to die from cancer (hazard ratio 0.54; P=0.03) than patients with no recurrence. The rate of recurrence of well-differentiated thyroid carcinomas in this sample of elderly patients was 39%. Extent of disease and older age negatively impacted the risk of recurrence from differentiated thyroid cancer. In these data, patients with follicular histology and a recurrence were less likely to die, suggesting that mortality and recurrence are competing risks. These data should be taken into account with individualized treatment strategies for elderly patients with recurrent malignant thyroid disease.


Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats.
Many phase I and II microsomal enzyme inducers share common mechanisms of transcriptional activation and thus share a similar battery of genes that are coordinately regulated. Many phase II metabolites are thought to be transported out of cells by multidrug resistance proteins 1, 2, and 3 (Mrp1, 2, and 3). The purpose of this study was to determine the organ distribution of these three transporters in rat, and whether they are coordinately regulated with phase I and II drug-metabolizing enzymes. Therefore, Mrp1, 2, and 3 mRNAs were quantified using branched DNA signal amplification in multiple tissues and in tissues from rats that were treated with 18 chemicals thought to induce drug-metabolizing enzymes by six different transcription activation mechanisms [aryl-hydrocarbon receptor ligands, constitutive androstane receptor (CAR) activators, pregnane-X-receptor ligands, peroxisome proliferator activator receptor ligands, electrophile response element (EpRE) activators, and CYP2E1 inducers]. It was found that Mrp1 was expressed at a high level in kidney, lung, intestine, and brain, with low expression in liver. Mrp2 was highly expressed in liver and duodenum, and Mrp3 was highly expressed throughout the intestine but very low in liver. Microsomal enzyme inducers did not markedly increase the expression of Mrp1 or Mrp2. However, Mrp3 expression was significantly increased by each of the CAR activators and an EpRE activator in liver. Mrp3 was not similarly induced in kidney and large intestine, demonstrating that the coordinate inducibility of Mrp3 is specific to the liver. We conclude that rat hepatic Mrp3 is induced by CAR activators, thus enhancing the vectoral excretion of some phase II metabolites from the liver to the blood.


Social problems of infertile women in India.
Female partners of 200 consecutively seen infertile couples attending our infertility clinic were interviewed on a structured, precoded form for the social problems faced by the childless women. One or more social problems were present in 34% couples, of whom 53% faced abandonment. Sixteen percent of the women had a strained relationship with their husbands. Social problems increased with duration of marriage and infertility, while these decreased with increase in age, education, and income of the husband. Similarly, the problems decreased with women's education and income. Only seven couples had requested AID.


Methyltransferase-like (METTL) homologues participate in Nicotiana benthamiana antiviral responses.
Methyltransferase (MTase) enzymes catalyze the addition of a methyl group to a variety of biological substrates. MTase-like (METTL) proteins are Class I MTases whose enzymatic activities contribute to the epigenetic and epitranscriptomic regulation of multiple cellular processes. N6-adenosine methylation (m6A) is a common chemical modification of eukaryotic and viral RNA whose abundance is jointly regulated by MTases and METTLs, demethylases, and m6A binding proteins. m6A affects various cellular processes including RNA degradation, post-transcriptional processing, and antiviral immunity. Here, we used Nicotiana benthamiana and plum pox virus (PPV), an RNA virus of the Potyviridae family, to investigated the roles of MTases in plant-virus interaction. RNA sequencing analysis identified MTase transcripts that are differentially expressed during PPV infection; among these, accumulation of a METTL gene was significantly downregulated. Two N. benthamiana METTL transcripts (NbMETTL1 and NbMETTL2) were cloned and further characterized. Sequence and structural analyses of the two encoded proteins identified a conserved S-adenosyl methionine (SAM) binding domain, showing they are SAM-dependent MTases phylogenetically related to human METTL16 and Arabidopsis thaliana FIONA1. Overexpression of NbMETTL1 and NbMETTL2 caused a decrease of PPV accumulation. In sum, our results indicate that METTL homologues participate in plant antiviral responses.


Familiarity perception call elicited under restricted sensory cues in peer-social interactions of the domestic chick.
Social cognitive mechanisms are central to understanding developmental abnormalities, such as autistic spectrum disorder. Peer relations besides parent-infant or pair-bonding interactions are pivotal social relationships that are especially well developed in humans. Cognition of familiarity forms the basis of peer socialization. Domestic chick (Gallus gallus) studies have contributed to our understanding of the developmental process in sensory-motor cognition but many processes remain unknown. In this report, we used chicks, as they are precocial birds, and we could therefore focus on peer interaction without having to consider parenting. The subject chick behavior towards familiar and unfamiliar reference peers was video-recorded, where the subject and the reference were separated by either an opaque or transparent wall. Spectrogram and behavior correlation analyses based on principal component analysis, revealed that chicks elicited an intermediate contact call and a morphologically different distress call, more frequently towards familiar versus unfamiliar chicks in acoustic only conditions. When both visual and acoustic cues were present, subject chicks exhibited approaching and floor pecking behavior, while eliciting joyful (pleasant) calls, irrespective of whether reference peers were familiar or unfamiliar. Our result showed that chicks recognized familiarity using acoustic cues and expressed cognition through modified distress calls. These finding suggests that peer affiliation may be established by acoustic recognition, independent of visual face recognition, and that eventually, both forms of recognition are integrated, with modulation of acoustic recognition.


Validating an artificial organelle: Studies of lipid droplet-specific proteins on adiposome platform.
New strategies are urgently needed to characterize the functions of the lipid droplet (LD). Here, adiposome, an artificial LD mimetic platform, was validated by comparative in vitro bioassays. Scatchard analysis found that the binding of perilipin 2 (PLIN2) to the adiposome surface was saturable. Phosphatidylinositol (PtdIns) was found to inhibit PLIN2 binding while it did not impede perilipin 3 (PLIN3). Structural analysis combined with mutagenesis revealed that the 73rd glutamic acid of PLIN2 is significant for the effect of PtdIns on the PLIN2 binding. Furthermore, adiposome was also found to be an ideal platform for in situ enzymatic activity measurement of adipose triglyceride lipase (ATGL). The significant serine mutants of ATGL were found to cause the loss of lipase activity. Our study demonstrates the adiposome as a powerful, manipulatable model system that mimics the function of LD for binding and enzymatic activity studies of LD proteins in vitro.