Thyroid Cytology: The Japanese System and Experience at Yamashita Thyroid Hospital.
In Japan, fine-needle aspiration (FNA) cytology is the most important diagnostic modality for triaging patients with thyroid nodules. A clinician (endocrinologist, endocrine surgeon, or head and neck surgeon) generally performs FNA cytology at the outpatient clinic, and ultrasound (US)-guided FNA is widespread because US is extremely common and most clinicians are familiar with it. Although almost all FNA thyroid samples are examined by certified cytopathologists and pathologists, some clinicians assess cytological specimens themselves. In Japan, there are two clinical guidelines regarding the management of thyroid nodules. One is the General Rules for the Description of Thyroid Cancer (GRDTC) published by the Japanese Society of Thyroid Surgery (JSTS) in 2005, and the other is the national reporting system for thyroid FNA cytology published by the Japan Thyroid Association in 2013 (Japanese system). Although the Bethesda System for Reporting Thyroid Cytopathology (Bethesda system) is rarely used in Japan, both the GRDTC and Japanese system tried to incorporate the Bethesda system so that the cytological diagnoses would be compatible with each other. The essential point of the Japanese system is stratification of follicular neoplasm (FN) into three subgroups based on cytological features in order to reduce unnecessary diagnostic thyroidectomy, and this system has been successful in stratifying the risk of malignancy in FN patients at several high-volume thyroid surgery centers. In Japan, the measurement of thyroglobulin and/or calcitonin in FNA needle washings is often used as an adjunct for diagnosis of possible cervical lymph node metastasis when FNA cytology is performed.


Antigen-driven focal inflammatory death of malaria liver stages.
Multiple immunizations using live irradiated sporozoites, the infectious plasmodial stage delivered into the host skin during a mosquito bite, can elicit sterile immunity to malaria. CD8(+) T cells seem to play an essential role in this protective immunity, since their depletion consistently abolishes sterilizing protection in several experimental models. So far, only a few parasite antigens are known to induce CD8(+) T cell-dependent protection, but none of them can reach the levels of protection afforded by live attenuated parasites. Systematic attempts to identify novel antigens associated with this efficient cellular protection were so far unsuccessful. In addition, the precise mechanisms involved in the recognition and elimination of parasitized hepatocytes in vivo by CD8(+) T cells still remain obscure. Recently, it has been shown that specific effector CD8(+) T cells, after recognition of parasitized hepatocytes, recruit specific and non-specific activated CD8(+) T cells to the site of infection, resulting in the formation of cellular clusters around and in the further elimination of intracellular parasites. The significance of this finding is discussed in the perspective of a general mechanism of antigen-dependent focalized inflammation and its consequences for the elimination of malaria liver stages.


Surfactant Protein A and B Gene Polymorphisms and Risk of Respiratory Distress Syndrome in Late-Preterm Neonates.
Newborns delivered late-preterm (between 340/7 and 366/7 weeks of gestation) are at increased risk of respiratory distress syndrome (RDS). Polymorphisms within the surfactant protein (SP) A and B gene have been shown to predispose to RDS in preterm neonates. The aim of this study was to investigate whether specific SP-A and/or SP-B genetic variants are also associated with RDS in infants born late-preterm. This prospective cross-sectional study included 56 late-preterm infants with and 60 without RDS. Specific SP-A1/SP-A2 haplotypes and SP-B Ile131Thr polymorphic alleles were determined in blood specimens using polymerase-chain-reaction and DNA sequencing. The SP-A1 6A4 and the SP-A2 1A5 haplotypes were significantly overrepresented in newborns with RDS compared to controls (OR 2.86, 95%CI 1.20-6.83 and OR 4.68, 95%CI 1.28-17.1, respectively). The distribution of the SP-B Ile131Thr genotypes was similar between the two late-preterm groups. Overall, the SP-A1 6A4 or/and SP-A2 1A5 haplotype was present in 20 newborns with RDS (35.7%), resulting in a 4.2-fold (1.60-11.0) higher probability of RDS in carriers. Multivariable regression analysis revealed that the effect of SP-A1 6A4 and SP-A2 1A5 haplotypes was preserved when adjusting for known risk or protective factors, such as male gender, smaller gestational age, smaller weight, complications of pregnancy, and administration of antenatal corticosteroids. Specific SP-A genetic variants may influence the susceptibility to RDS in late-preterm infants, independently of the effect of other perinatal factors.


Tarsal tunnel syndrome: a study of the clinical and neurophysiological results of decompression.
The neurophysiological and clinical outcomes of surgical decompression of 22 cases of tarsal tunnel syndrome are analysed. Recent work by Pfeiffer & Cracchiolo has suggested a successful outcome in only 44% of cases. We have reviewed the outcome of surgery both clinically and with the use of nerve conduction studies. Pre- and post-operative motor conduction delays in the plantar nerves are compared with clinical results found both in the clinic and later by a postal questionnaire. Despite careful clinical and neurophysiological assessment prior to a full surgical release, only 42% of patients had a satisfactory outcome. A larger reduction in plantar nerve conduction delay post-operatively corresponded well to an improvement in symptoms. However, we were unable to predict which cases would respond to decompression using clinical or electrophysiological methods. We question the use of nerve conduction studies in the diagnosis of tarsal tunnel syndrome, and also the role of surgery in the management of this condition.


Implications of Probiotics on the Maternal-Neonatal Interface: Gut Microbiota, Immunomodulation, and Autoimmunity.
Probiotics are being investigated for the treatment of autoimmune disease by re-balancing dysbiosis induced changes in the immune system. Pregnancy is a health concern surrounding autoimmune disease, both for the mother and her child. Probiotics for maternity are emerging on the market and have gained significant momentum in the literature. Thus far, evidence supports that probiotics alter the structure of the normal microbiota and the microbiota changes significantly during pregnancy. The interaction between probiotics-induced changes and normal changes during pregnancy is poorly understood. Furthermore, there is emerging evidence that the maternal gut microbiota influences the microbiota of offspring, leading to questions on how maternal probiotics may influence the health of neonates. Underpinning the development and balance of the immune system, the microbiota, especially that of the gut, is significantly important, and dysbiosis is an agent of immune dysregulation and autoimmunity. However, few studies exist on the implications of maternal probiotics for the outcome of pregnancy in autoimmune disease. Is it helpful or harmful for mother with autoimmune disease to take probiotics, and would this be protective or pathogenic for her child? Controversy surrounds whether probiotics administered maternally or during infancy are healthful for allergic disease, and their use for autoimmunity is relatively unexplored. This review aims to discuss the use of maternal probiotics in health and autoimmune disease and to investigate their immunomodulatory properties.


Complete Genome Sequence of a Chlorobenzene Degrader, Pandoraea pnomenusa MCB032.
Chlorobenzenes are ubiquitously distributed, highly persistent, and toxic environmental contaminants. Pandoraea pnomenusa MCB032 was isolated as a new dominant chlorobenzene-utilizing strain from a functionally stable bioreactor during the treatment of chlorobenzenes when strain Burkholderia sp. JS150 disappeared. In study, we report the complete genome sequence of strain MCB032 which consists of a circular chromosome and three plasmids, which are ~ 6 Mb in length with 5450 open reading frames-12 encoding rRNAs and 77 encoding tRNAs. We further identified 17 putative genes encoding the enzymes involved in the methyl-accepting chemotaxis proteins in sensing chemical gradients during chemotaxis. The annotated complete genome sequence of this strain will provide genetic insights into the degradation of chlorinated aromatic compounds. The information will empower the elucidation of chlorobenzene affinity hierarchy and species succession in the bioreactor.


Site-specific time heterogeneity of the substitution process and its impact on phylogenetic inference.
Model violations constitute the major limitation in inferring accurate phylogenies. Characterizing properties of the data that are not being correctly handled by current models is therefore of prime importance. One of the properties of protein evolution is the variation of the relative rate of substitutions across sites and over time, the latter is the phenomenon called heterotachy. Its effect on phylogenetic inference has recently obtained considerable attention, which led to the development of new models of sequence evolution. However, thus far focus has been on the quantitative heterogeneity of the evolutionary process, thereby overlooking more qualitative variations. We studied the importance of variation of the site-specific amino-acid substitution process over time and its possible impact on phylogenetic inference. We used the CAT model to define an infinite mixture of substitution processes characterized by equilibrium frequencies over the twenty amino acids, a useful proxy for qualitatively estimating the evolutionary process. Using two large datasets, we show that qualitative changes in site-specific substitution properties over time occurred significantly. To test whether this unaccounted qualitative variation can lead to an erroneous phylogenetic tree, we analyzed a concatenation of mitochondrial proteins in which Cnidaria and Porifera were erroneously grouped. The progressive removal of the sites with the most heterogeneous CAT profiles across clades led to the recovery of the monophyly of Eumetazoa (Cnidaria+Bilateria), suggesting that this heterogeneity can negatively influence phylogenetic inference. The time-heterogeneity of the amino-acid replacement process is therefore an important evolutionary aspect that should be incorporated in future models of sequence change.


Laser-induced fluorescence measurements of translational temperature and relative cycle number by use of optically pumped trace-sodium vapor.
Sodium fluorescence induced by a narrow-bandwidth tunable laser has been used to measure temperature, pressure, axial velocity, and species concentrations in wind tunnels, rocket engine exhausts, and the upper atmosphere. Optical pumping of the ground states of the sodium, however, can radically alter the shape of the laser-induced fluorescence excitation spectrum, complicating such measurements. Here a straightforward extension of rate equations originally proposed to account for the features of the pumped spectrum is used to make temperature measurements from spectra taken in pumped vapor. Also determined from the spectrum is the relative fluorescence cycle number, which has application to measurement of diffusion rate and transverse flow velocity. The accuracy of both the temperature and the cycle-number measurements is comparable with that of temperature measurements made in the absence of pumping.


Phylotranscriptomic analysis of the origin and early diversification of land plants.
Reconstructing the origin and evolution of land plants and their algal relatives is a fundamental problem in plant phylogenetics, and is essential for understanding how critical adaptations arose, including the embryo, vascular tissue, seeds, and flowers. Despite advances in molecular systematics, some hypotheses of relationships remain weakly resolved. Inferring deep phylogenies with bouts of rapid diversification can be problematic; however, genome-scale data should significantly increase the number of informative characters for analyses. Recent phylogenomic reconstructions focused on the major divergences of plants have resulted in promising but inconsistent results. One limitation is sparse taxon sampling, likely resulting from the difficulty and cost of data generation. To address this limitation, transcriptome data for 92 streptophyte taxa were generated and analyzed along with 11 published plant genome sequences. Phylogenetic reconstructions were conducted using up to 852 nuclear genes and 1,701,170 aligned sites. Sixty-nine analyses were performed to test the robustness of phylogenetic inferences to permutations of the data matrix or to phylogenetic method, including supermatrix, supertree, and coalescent-based approaches, maximum-likelihood and Bayesian methods, partitioned and unpartitioned analyses, and amino acid versus DNA alignments. Among other results, we find robust support for a sister-group relationship between land plants and one group of streptophyte green algae, the Zygnematophyceae. Strong and robust support for a clade comprising liverworts and mosses is inconsistent with a widely accepted view of early land plant evolution, and suggests that phylogenetic hypotheses used to understand the evolution of fundamental plant traits should be reevaluated.


OSA: a fast and accurate alignment tool for RNA-Seq.
Accurately mapping RNA-Seq reads to the reference genome is a critical step for performing downstream analysis such as transcript assembly, isoform detection and quantification. Many tools have been developed; however, given the huge size of the next generation sequencing datasets and the complexity of the transcriptome, RNA-Seq read mapping remains a challenge with the ever-increasing amount of data. We develop Omicsoft sequence aligner (OSA), a fast and accurate alignment tool for RNA-Seq data. Benchmarked with existing methods, OSA improves mapping speed 4-10-fold with better sensitivity and less false positives. OSA can be downloaded from http://omicsoft.com/osa. It is free to academic users. OSA has been tested extensively on Linux, Mac OS X and Windows platforms.


Comparing responses of four ungulate species to playbacks of baboon alarm calls.
A growing body of evidence suggests that a wide range of animals can recognize and respond appropriately to calls produced by other species. Social learning has been implicated as a possible mechanism by which heterospecific call recognition might develop. To examine whether familiarity and/or shared vulnerability with the calling species might influence the ability of sympatric species to distinguish heterospecific alarm calls, we tested whether four ungulate species (impala: Aepyceros melampus; tsessebe: Damaliscus lunatus; zebra: Equus burchelli; wildebeest: Connochaetes taurinus) could distinguish baboon (Papio hamadryas ursinus) alarm calls from other loud baboon calls produced during intra-specific aggressive interactions ('contest' calls). Overall, subjects' responses were stronger following playback of alarm calls than contest calls. Of the species tested, impala showed the strongest responses and the greatest difference in composite response scores, suggesting they were best able to differentiate call types. Compared with the other ungulate species, impala are the most frequent associates of baboons. Moreover, like baboons, they are susceptible to both lion and leopard attacks, whereas leopards rarely take the larger ungulates. Although it seems possible that high rates of association and/or shared vulnerability may influence impala's greater ability to distinguish among baboon call types, our results point to a stronger influence of familiarity. Ours is the first study to compare such abilities among several community members with variable natural histories, and we discuss future experiments that would more systematically examine development of these skills in young ungulates.


Noble-metal-free ternary CN-ZCS-NiS nanocomposites for enhanced solar photocatalytic H2-production activity.
Photocatalytic hydrogen production from water using a noble-metal-free catalyst has aroused tremendous and interdisciplinary attention. In this work, we report a series of original noble-metal-free ternary nanocomposites of C3N4-Zn0.5Cd0.5S heterojunctions loaded with NiS by a precipitation hydrothermal method. They were characterized by XRD, TEM, SEM-EDS, UV-vis, XPS, PL spectra, and transient photocurrent response measurements. The facts proved that they were efficient and stable photocatalysts to enhance the hydrogen production activity prepared by the precipitation hydrothermal method. Among these photocatalysts, C3N4-Zn0.5Cd0.5S-1% NiS showed excellent photocatalytic performance with a H2-production rate of 53.190 mmol g-1 h-1 which is 405 times higher than the pure CN. The high catalytic activity was attributed to the synergistic effect of the NiS cocatalyst and the nanoheterojunctions between ZCS nanoparticles and 2D CN nanosheets, which were propitious to accelerate charge transfer, promote the separation of photogenerated electron-hole pairs and expedite the surface H2-evolution kinetics.


The smut fungus Ustilago esculenta has a bipolar mating system with three idiomorphs larger than 500 kb.
Zizania latifolia Turcz., which is mainly distributed in Asia, has had a long cultivation history as a cereal and vegetable crop. On infection with the smut fungus Ustilago esculenta, Z. latifolia becomes an edible vegetable, water bamboo. Two main cultivars, with a green shell and red shell, are cultivated for commercial production in Taiwan. Previous studies indicated that cultivars of Z. latifolia may be related to the infected U. esculenta isolates. However, related research is limited. The infection process of the corn smut fungus Ustilago maydis is coupled with sexual development and under control of the mating type locus. Thus, we aimed to use the knowledge of U. maydis to reveal the mating system of U. esculenta. We collected water bamboo samples and isolated 145 U. esculenta strains from Taiwan's major production areas. By using PCR and idiomorph screening among meiotic offspring and field isolates, we identified three idiomorphs of the mating type locus and found no sequence recombination between them. Whole-genome sequencing (Illumina and PacBio) suggested that the mating system of U. esculenta was bipolar. Mating type locus 1 (MAT-1) was 552,895 bp and contained 44% repeated sequences. Sequence comparison revealed that U. esculenta MAT-1 shared high gene synteny with Sporisorium reilianum and many repeats with Ustilago hordei MAT-1. These results can be utilized to further explore the genomic diversity of U. esculenta isolates and their application for water bamboo breeding.


[Y chromosome and male infertility: what is a normal Y chromosome?].
The human Y chromosome contains a number of genes and gene families that are essential for germ cell development and maintenance. Many of these genes are located in highly repetitive elements that are subject to rearrangements. Deletion of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approximately 10-15% of men with severe forms of spermatogenic failure. Several partial AZFc deletions have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as an inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, also results in the absence of several AZFc genes and it may be a genetic risk factor for spermatogenic failure. However, the link between these partial deletions and fertility is unclear. The gr/gr deletion is not a single deletion but a combination of deletions that vary in size and complexity and result in the absence of different genes. There are also regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletions appear to be fixed and may have little influence on spermatogenesis. Most of these data (gene content and Y chromosome structure) have been deduced from the reference Y chromosome sequence deposited in NCBI. However, recently there have been attempts to define these types of structural rearrangements in the general population. These have highlighted the considerable degree of structural diversity that exist. Trying to correlate these changes with the phenotypic variability is a major challenge and it is likely that there will not be a single reference (or normal) Y chromosome sequence but many.


Middle and inferior temporal gyrus gray matter volume abnormalities in first-episode schizophrenia: an MRI study.
Magnetic resonance imaging (MRI) studies of schizophrenia reveal temporal lobe structural brain abnormalities in the superior temporal gyrus and the amygdala-hippocampal complex. However, the middle and inferior temporal gyri have received little investigation, especially in first-episode schizophrenia. High-spatial-resolution MRI was used to measure gray matter volume in the inferior, middle, and superior temporal gyri in 20 patients with first-episode schizophrenia, 20 patients with first-episode affective psychosis, and 23 healthy comparison subjects. Gray matter volume in the middle temporal gyrus was smaller bilaterally in patients with first-episode schizophrenia than in comparison subjects and in patients with first-episode affective psychosis. Posterior gray matter volume in the inferior temporal gyrus was smaller bilaterally in both patient groups than in comparison subjects. Among the superior, middle, and inferior temporal gyri, the left posterior superior temporal gyrus gray matter in the schizophrenia group had the smallest volume, the greatest percentage difference, and the largest effect size in comparisons with healthy comparison subjects and with affective psychosis patients. Smaller gray matter volumes in the left and right middle temporal gyri and left posterior superior temporal gyrus were present in schizophrenia but not in affective psychosis at first hospitalization. In contrast, smaller bilateral posterior inferior temporal gyrus gray matter volume is present in both schizophrenia and affective psychosis at first hospitalization. These findings suggest that smaller gray matter volumes in the dorsal temporal lobe (superior and middle temporal gyri) may be specific to schizophrenia, whereas smaller posterior inferior temporal gyrus gray matter volumes may be related to pathology common to both schizophrenia and affective psychosis.


Perceived and actual wildfire danger: an economic and spatial analysis study in Colorado (USA).
Over the last 20 years, costs for wildfire initial attack in the U.S. have increased significantly. The increased cost relates to wildfire suppression practices, as well as the growing number of homes in the wildland urban interface. Requiring wildland urban interface residents to pay an annual tax for their wildfire risk could lower costs to the general taxpayer. Willingness-to-pay for wildfire prevention, in relation to both perceived and actual wildfire danger, was the focus of this study. Surveyed Colorado wildland urban interface residents were found to have a high awareness of wildfire risk and were willing-to-pay over $400 annually to reduce this risk. Respondents' beliefs about wildfire frequency were comparable to the wildfire regimes of their areas' pre-European settlement.


Neuroanatomical correlates of behavioural disorders in dementia.
Neurodegenerative diseases are associated with profound changes in social and emotional function. The emergence of increasingly sophisticated methods for measuring brain volume has facilitated correlation of local changes in tissue content with cognitive and behavioural changes in neurodegenerative disease. The current study examined neuroanatomical correlates of behavioural abnormalities, as measured by the Neuropsychiatric Inventory, in 148 patients with dementia using voxel-based morphometry. Of 12 behaviours examined, 4 correlated with tissue loss: apathy, disinhibition, eating disorders and aberrant motor behaviour. Increasing severity across these four behaviours was associated with tissue loss in the ventral portion of the right anterior cingulate cortex (vACC) and adjacent ventromedial superior frontal gyrus (vmSFG), the right ventromedial prefrontal cortex (VMPC) more posteriorly, the right lateral middle frontal gyrus, the right caudate head, the right orbitofrontal cortex and the right anterior insula. In addition, apathy was independently associated with tissue loss in the right vmSFG, disinhibition with tissue loss in the right subgenual cingulate gyrus in the VMPC, and aberrant motor behaviour with tissue loss in the right dorsal ACC and left premotor cortex. These data strongly support the involvement of the right hemisphere in mediating social and emotional behaviour and highlight the importance of distinct regions on the medial wall of the right frontal lobe in regulating different behaviours. Furthermore, the findings underscore the utility of studying patients with dementia for understanding the neuroanatomical basis of social and emotional functions.


Tribbles coordinates mitosis and morphogenesis in Drosophila by regulating string/CDC25 proteolysis.
Morphogenesis and cell differentiation in multicellular organisms often require accurate control of cell divisions. We show that a novel cell cycle regulator, tribbles, is critical for this control during Drosophila development. During oogenesis, the level of tribbles affects the number of germ cell divisions as well as oocyte determination. The mesoderm anlage enters mitosis prematurely in tribbles mutant embryos, leading to gastrulation defects. We show that Tribbles acts by specifically inducing degradation of the CDC25 mitotic activators String and Twine via the proteosome pathway. By regulating CDC25, Tribbles serves to coordinate entry into mitosis with morphogenesis and cell fate determination.


Perching and resting-A paradigm for UAV maneuvering with modularized landing gears.
Perching helps small unmanned aerial vehicles (UAVs) extend their time of operation by saving battery power. However, most strategies for UAV perching require complex maneuvering and rely on specific structures, such as rough walls for attaching or tree branches for grasping. Many strategies to perching neglect the UAV's mission such that saving battery power interrupts the mission. We suggest enabling UAVs with the capability of making and stabilizing contacts with the environment, which will allow the UAV to consume less energy while retaining its altitude, in addition to the perching capability that has been proposed before. This new capability is termed "resting." For this, we propose a modularized and actuated landing gear framework that allows stabilizing the UAV on a wide range of different structures by perching and resting. Modularization allows our framework to adapt to specific structures for resting through rapid prototyping with additive manufacturing. Actuation allows switching between different modes of perching and resting during flight and additionally enables perching by grasping. Our results show that this framework can be used to perform UAV perching and resting on a set of common structures, such as street lights and edges or corners of buildings. We show that the design is effective in reducing power consumption, promotes increased pose stability, and preserves large vision ranges while perching or resting at heights. In addition, we discuss the potential applications facilitated by our design, as well as the potential issues to be addressed for deployment in practice.


Genome-wide analysis reveals divergent patterns of gene expression during zygotic and somatic embryo maturation of Theobroma cacao L., the chocolate tree.
Theobroma cacao L. is a tropical fruit tree, the seeds of which are used to create chocolate. In vitro somatic embryogenesis (SE) of cacao is a propagation system useful for rapid mass-multiplication to accelerate breeding programs and to provide plants directly to farmers. Two major limitations of cacao SE remain: the efficiency of embryo production is highly genotype dependent and the lack of full cotyledon development results in low embryo to plant conversion rates. With the goal to better understand SE development and to improve the efficiency of SE conversion we examined gene expression differences between zygotic and somatic embryos using a whole genome microarray. The expression of 28,752 genes was determined at 4 developmental time points during zygotic embryogenesis (ZE) and 2 time points during cacao somatic embryogenesis (SE). Within the ZE time course, 10,288 differentially expressed genes were enriched for functions related to responses to abiotic and biotic stimulus, metabolic and cellular processes. A comparison ZE and SE expression profiles identified 10,175 differentially expressed genes. Many TF genes, putatively involved in ethylene metabolism and response, were more strongly expressed in SEs as compared to ZEs. Expression levels of genes involved in fatty acid metabolism, flavonoid biosynthesis and seed storage protein genes were also differentially expressed in the two types of embryos. Large numbers of genes were differentially regulated during various stages of both ZE and SE development in cacao. The relatively higher expression of ethylene and flavonoid related genes during SE suggests that the developing tissues may be experiencing high levels of stress during SE maturation caused by the in vitro environment. The expression of genes involved in the synthesis of auxin, polyunsaturated fatty acids and secondary metabolites was higher in SEs relative to ZEs despite lack of lipid and metabolite accumulation. These differences in gene transcript levels associated with critical processes during seed development are consistent with the fact that somatic embryos do not fully develop the large storage cotyledons found in zygotic embryos. These results provide insight towards design of improved protocols for cacao somatic embryogenesis.


The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development.


The thoracoplastic approach to chest wall reconstruction: preliminary results of a multidisciplinary approach to minimize morbidity.
Chest wall reconstruction remains challenging because of the variable nature of the defect. Muscle-sparing approaches have been described but are not widely applied today. The authors reviewed an institutional experience with chest wall reconstruction and describe the thoracoplastic approach, which aims to optimize flap selection. A retrospective review was conducted identifying all patients undergoing chest wall reconstruction performed by the senior author. Demographic information and operative characteristics were detailed and factors were analyzed for association with postoperative outcomes. Outcomes were also compared for conventional versus thoracoplastic groups. Forty-five patients underwent chest wall reconstruction at an average age of 54.2 ± 16.3 years. Sarcomas were most common (51 percent), followed by breast (16 percent) and lung (11 percent). The average number of ribs resected was 3.2 ± 1.4, with an average defect size of 212 ± 185 cm2. The most commonly used flaps included the latissimus dorsi and pectoralis major (72 percent). Mesh was incorporated in 58 percent of repairs and operative time was 6.2 ± 2.5 hours. The incidence of surgical complications was 23 percent, most commonly wound infection and nonhealing wound (20 percent). The thoracoplastic approach, used in 14 patients, demonstrated no differences in outcomes with follow-up of 14 months. Operative time was nearly identical, and the thoracoplastic group required significantly less blood products when transfused. Latissimus dorsi and pectoralis major flaps were used more frequently in the thoracoplastic group, although this did not reach significance (78.6 percent versus 69.2 percent). The thoracoplastic approach appears to be safe and effective when compared with conventional methods. Although definitive conclusions cannot be drawn, the authors' early experience is promising. The authors believe applying these principles improves aesthetic and functional outcomes and preserves the oncologic safety profile.


Study of tonotopic brain changes with functional MRI and FDG-PET in a patient with unilateral objective cochlear tinnitus.
We studied possible brain changes with functional MRI (fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) in a patient with a rare, high-intensity "objective tinnitus" (high-level SOAEs) in the left ear of 10 years duration, with no associated hearing loss. This is the first case of objective cochlear tinnitus to be investigated with functional neuroimaging. The objective cochlear tinnitus was measured by Spontaneous Otoacoustic Emissions (SOAE) equipment (frequency 9689 Hz, intensity 57 dB SPL) and is clearly audible to anyone standing near the patient. Functional modifications in primary auditory areas and other brain regions were evaluated using 3T and 7T fMRI and FDG-PET. In the fMRI evaluations, a saturation of the auditory cortex at the tinnitus frequency was observed, but the global cortical tonotopic organization remained intact when compared to the results of fMRI of healthy subjects. The FDG-PET showed no evidence of an increase or decrease of activity in the auditory cortices or in the limbic system as compared to normal subjects. In this patient with high-intensity objective cochlear tinnitus, fMRI and FDG-PET showed no significant brain reorganization in auditory areas and/or in the limbic system, as reported in the literature in patients with chronic subjective tinnitus.


dsSynthetic: synthetic data generation for the DataSHIELD federated analysis system.
Platforms such as DataSHIELD allow users to analyse sensitive data remotely, without having full access to the detailed data items (federated analysis). While this feature helps to overcome difficulties with data sharing, it can make it challenging to write code without full visibility of the data. One solution is to generate realistic, non-disclosive synthetic data that can be transferred to the analyst so they can perfect their code without the access limitation. When this process is complete, they can run the code on the real data. We have created a package in DataSHIELD (dsSynthetic) which allows generation of realistic synthetic data, building on existing packages. In our paper and accompanying tutorial we demonstrate how the use of synthetic data generated with our package can help DataSHIELD users with tasks such as writing analysis scripts and harmonising data to common scales and measures.


Deficits in Limb Praxis in Patients With Obsessive-Compulsive Disorder.
There is recent evidence of deficits in praxis in patients with primary dystonia. Obsessive-compulsive disorder (OCD) has been linked to disorders of higher-order motor function, such as dystonia. However, no clear mechanism underlying such a relationship has been found. This pilot study aimed to identify whether patients with OCD might also show deficits in praxis. Patients with OCD were compared with healthy volunteers on a meaningless gesture imitation task. Patients showed significantly lower scores in this task. Further studies are needed to elucidate the nature of patients' deficits in praxis. This might reveal similar mechanisms underlying OCD and some types of movement disorders.


Central modifications of reflex parameters may underlie the fastest arm movements.
Descending and reflex pathways usually converge on common interneurons and motoneurons. This implies that active movements may result from changes in reflex parameters produced by control signals conveyed by descending systems. Specifically, according to the lambda-model, a fast change in limb position is produced by a rapid change in the threshold of the stretch reflex. Consequently, external perturbations may be ineffective in eliciting additional reflex modifications of electromyographic (EMG) patterns unless the perturbations are relatively strong. In this way, the model accounts for the relatively weak effects of perturbations on the initial agonist EMG burst (Ag1) usually observed in fast movements. On the other hand, the same model permits robust reflex modifications of the timing and shape of the Ag1 in response to strong perturbations even in the fastest movements. To test the model, we verified the suggestion that the onset time of the Ag1, even in the fastest movements, depends on proprioceptive feedback in a manner consistent with a stretch reflex. In control trials, subjects (n = 6) made fast unopposed elbow flexion movements of approximately 60 degrees (peak velocity 500-700 degrees/s) in response to an auditory signal. In random test trials, a brief (50 ms) torque of 8-15 Nm either assisting or opposing the movement was applied 50 ms after this signal. Subjects had no visual feedback and were instructed not to correct arm deflections in case of perturbations. In all subjects, the onset time of the Ag1 depended on the direction of perturbation: it was 25-60 ms less in opposing compared with assisting load conditions. Assisting torques caused, at a short latency of 37 ms, an additional antagonist EMG burst preceding the Ag1. The direction-dependent effects of the perturbation persisted when cutaneous feedback was suppressed. It was concluded that the direction-dependent changes in the onset time and duration of the Ag1 as well as the antagonist activation preceding the Ag1 resulted from stretch reflex activity elicited by the perturbations rather than from a change in the control strategy or cutaneous reflexes. The results support the hypothesis on the hierarchical scheme of sensorimotor integration in which EMG patterns and movement emerge from the modification of the thresholds and other parameters of proprioceptive reflexes by control systems.


Stiffness of the C-terminal disordered linker affects the geometry of the active site in endoglucanase Cel8A.
Cellulosomes are complex multi-enzyme machineries which efficiently degrade plant cell-wall polysaccharides. The multiple domains of the cellulosome proteins are often tethered together by intrinsically disordered regions. The properties and functions of these disordered linkers are not well understood. In this work, we study endoglucanase Cel8A, which is a relevant enzymatic component of the cellulosomes of Clostridium thermocellum. We use both all-atom and coarse-grained simulations to investigate how the conformations of the catalytic domain of Cel8A are affected by the disordered linker at its C terminus. We find that when the endoglucanase is bound to its substrate, the effective stiffness of the linker can influence the distances between groups of amino-acid residues throughout the entire enzymatic domain. In particular, variations in the linker stiffness can lead to small changes in the geometry of the active-site cleft. We suggest that such geometrical changes may have an effect on the catalytic activity of the enzyme.


A Systematic Study Reveals that Xylella fastidiosa Strains from Pecan Are Part of X. fastidiosa subsp. multiplex.
Xylella fastidiosa causes disease in a number of economically important crops, ornamental plants, and shade trees, including grapevine, citrus, oleander, and sycamore. In pecan, X. fastidiosa causes pecan bacterial leaf scorch (PBLS), which leads to defoliation and reduces nut yield. No economically effective treatments are available for PBLS. In order to improve PBLS management practices, it is necessary to determine the subspecies of X. fastidiosa strains that infect pecan so that potential sources of inoculum may be identified. Multiprimer polymerase chain reaction (PCR) and phylogenetic analyses using nucleotide sequence data from the 16S-23S rRNA intergenic transcribed spacer (ITS) region and pglA consistently identified strains of X. fastidiosa isolated from pecan as X. fastidiosa subsp. multiplex. Enterobacterial repetitive intergenic consensus PCR and repetitive extragenic palindromic (REP)-PCR analyses were congruent with phylogenetic analyses. REP-PCR analyses indicated genetic variation within strains of X. fastidiosa from pecan. From these same analyses, X. fastidiosa strains from sycamore, grapevine, and oleander from Louisiana were identified as subsp. multiplex, subsp. fastidiosa, and subsp. sandyi, respectively. This study provides additional information about the host ranges of X. fastidiosa subspecies.


Assessment of Accelerometers for Measuring Upper-Extremity Physical Activity.
The overarching goal of this study was to examine the use of triaxial accelerometers in measuring upper-extremity motions to monitor upper-extremity-exercise compliance. There were multiple questions investigated, but the primary objective was to investigate the correlation between visually observed arm motions and triaxial accelerometer activity counts to establish fundamental activity counts for the upper extremity. Cross-sectional, basic research. Clinical laboratory. Thirty healthy individuals age 26 ± 6 y, body mass 24 ± 3 kg, and height 1.68 ± 0.09 m volunteered. Participants performed 3 series of tasks: activities of daily living (ADLs), rehabilitation exercises, and passive shoulder range of motion at 5 specific velocities on an isokinetic dynamometer while wearing an accelerometer on each wrist. Participants performed exercises with their dominant arm to examine differences between sides. A researcher visually counted all arm motions to correlate counts with physical activity counts provided by the accelerometer. Physical activity counts derived from the accelerometer and visually observed activity counts recorded from a single investigator. There was a strong positive correlation (r = .93, P < .01) between accelerometer physical activity counts and visual activity counts for all ADLs. Accelerometers activity counts demonstrated side-to-side difference for all ADLs (P < .001) and 5 of the 7 rehabilitation activities (P < .003). All velocities tested on the isokinetic dynamometer were shown to be significantly different from each other (P < .001). There is a linear relationship between arm motions counted visually and the physical activity counts generated by an accelerometer, indicating that arm motions could be potentially accounted for if monitoring arm usage. The accelerometers can detect differences in relatively slow arm-movement velocities, which is critical if attempting to evaluate exercise compliance during early phases of shoulder rehabilitation. These results provide fundamental information that indicates that triaxial accelerometers have the potential to objectively monitor and measure arm activities during rehabilitation and ADLs.


The predictive power of stock market's expectations volatility: A financial synchronization phenomenon.
We explore the use of implied volatility indices as a tool for estimate changes in the synchronization of stock markets. Specifically, we assess the implied stock market's volatility indices' predictive power on synchronizing global equity indices returns. We built the correlation network of 26 stock indices and implemented in-sample and out-of-sample tests to evaluate the predictive power of VIX, VSTOXX, and VXJ implied volatility indices. To measure markets' synchronization, we use the Minimum Spanning Tree length and the length of the Planar Maximally Filtered Graph. Our results indicate a high predictive power of all the volatility indices, both individually and together, though the VIX predominates over the evaluated options. We find that an increase in the markets' volatility expectations, captured by the implied volatility indices, is a good Granger predictor of an increase in the synchronization of returns in the following month. Estimating, monitoring, and predicting returns' synchronization is essential for investment decision-making, especially for diversification strategies and regulating financial systems.


Resource Use in Small Island States: Material Flows in Iceland and Trinidad and Tobago, 1961-2008.
Iceland and Trinidad and Tobago are small open, high-income island economies with very specific resource-use patterns. This article presents a material flow analysis (MFA) for the two countries covering a time period of nearly five decades. Both countries have a narrow domestic resource base, their economy being largely based on the exploitation of one or two key resources for export production. In the case of Trinidad and Tobago, the physical economy is dominated by oil and natural gas extraction and petrochemical industries, whereas Iceland's economy for centuries has been based on fisheries. More recently, abundant hydropower and geothermal heat were the basis for the establishment of large export-oriented metal processing industries, which fully depend on imported raw materials and make use of domestic renewable electricity. Both countries are highly dependent on these natural resources and vulnerable to overexploitation and price developments. We show how the export-oriented industries lead to high and growing levels of per capita material and energy use and carbon dioxide emissions resulting from large amounts of processing wastes and energy consumption in production processes. The example of small open economies with an industrial production system focused on few, but abundant, key resources and of comparatively low complexity provides interesting insights of how resource endowment paired with availability or absence of infrastructure and specific institutional arrangements drives domestic resource-use patterns. This also contributes to a better understanding and interpretation of MFA indicators, such as domestic material consumption.


Systemic sulfonamides as a cause of bilateral, anterior uveitis.
Between September 1976 and May 1989, 12 cases of uveitis attributed to the systemic use of sulfonamide derivatives were reported to the National Registry of Drug-Induced Ocular Side Effects and the US Food and Drug Administration. We evaluated these reports in addition to one case previously reported in the literature and one patient seen at the Uveitis Clinic, Oregon Health Sciences University, Portland. The patients' median age was 34 years. Twelve of 14 patients were treated with trimethoprim-sulfamethoxazole. All patients for whom the location of the eye disease was specified presented with an iritis. Six reports included a description of ocular symmetry, with all patients having bilateral inflammation. Of the nine patients for whom data on the duration of drug use was available, seven experienced adverse effects within 8 days of beginning trimethoprim-sulfamethoxazole therapy and four showed effects within 24 hours. Three patients had histories of rechallenge with trimethoprim-sulfamethoxazole, and in each case acute iritis recurred within 24 hours of reinstitution of therapy. Five patients had additional evidence of an adverse reaction manifested as Stevens-Johnson syndrome, erythema multiforme, diffuse macular or vesicular rashes, stomatitis, glossitis, conjunctival and scleral injection, and granulomatous hepatitis. The consistent presentation including bilateral, anterior inflammation and the recurrence with rechallenge strongly indicate a cause-effect relationship. Although uveitis secondary to sulfonamides is a rarely diagnosed clinical event, recognition of the distinct presentation of this entity is important in the differential diagnosis of uveitis.


Prevalence of human papillomavirus and Epstein-Barr virus DNA in penile cancer cases from Brazil.
Penile cancer is a potentially mutilating disease. Although its occurrence is relatively rare worldwide, penile cancer rates can be high in developing countries. A few studies have been conducted on the involvement of human papillomavirus (HPV) in penile carcinoma, which have found HPV present in 30-70% of penile malignant lesions, with a higher prevalence of HPV 16 and 18. It has been assumed that cofactors, such as Epstein-Barr virus (EBV) infections, may play a role in the progression of penile neoplasia. The aim of this study was to determine HPV and EBV prevalence in 135 penile malignant lesions from Brazilian men through the use of MY09/11 polymerase chain reaction (PCR), type-specific PCR and restriction fragment length polymorphism analysis. HPV prevalence among the men tested was 60.7%. Of the men who tested positive, 27 presented with HPV 16 (29.7%), five with HPV 18 (5.5%), 21 with HPV 45 (23.1%) and nine with HPV 6 (9.9%). Seven mixed infections were detected (9.2%), while 11 cases remained untyped (13.4%). Regarding EBV positivity, 46.7% of the samples contained EBV DNA with EBV-1 as the most prevalent type (74.6%). More than 23% of the men were co-infected with both HPV and EBV, while 35% presented exclusively with HPV DNA and 20% presented only with EBV DNA. Penile carcinoma aetiology has not been fully elucidated and the role of HPV and EBV infections individually or synergistically is still controversial. Hence, more studies are needed to determine their possible role in carcinogenesis.


Kinetic and Structural Characterization of the Interaction of 6-Methylidene Penem 2 with the β-Lactamase from Mycobacterium tuberculosis.
Mycobacterium tuberculosis is intrinsically resistant to most β-lactam antibiotics because of the constitutive expression of the blaC-encoded β-lactamase. This enzyme has extremely high activity against penicillins and cephalosporins, but weaker activity against carbapenems. The enzyme can be inhibited by clavulanate, avibactam, and boronic acids. In this study, we investigated the ability of 6-methylidene β-lactams to inhibit BlaC. One such compound, penem 2, inhibited BlaC more than 70 times more efficiently than clavulanate. The compound forms a covalent complex with BlaC as shown by mass spectrometry. Crystallization of the complex revealed that the bound inhibitor was covalently attached via the Ser70 active site residue and that the covalently, acylated form of the inhibitor had undergone additional chemistry yielding a 4,7-thiazepine ring in place of the β-lactam and a thiazapyroline ring generated as a result of β-lactam ring opening. The stereochemistry of the product of the 7-endo-trig cyclization was the opposite of that observed previously for class A and D β-lactamases. Addition of penem 2 greatly synergized the antibacterial properties of both ampicillin and meropenem against a growing culture of M. tuberculosis. Strikingly, penem 2 alone showed significant growth inhibition, suggesting that in addition to its capability of efficiently inhibiting BlaC, it also inhibited the peptidoglycan cross-linking transpeptidases.


Epidemiology of Pierre-Robin sequence in Europe: A population-based EUROCAT study.
Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies. We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%). This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS.


Aging increases oxidative stress and renal expression of oxidant and antioxidant enzymes that are associated with an increased trend in systolic blood pressure.
The aim of this study was to investigate whether the effects of aging on oxidative stress markers and expression of major oxidant and antioxidant enzymes associate with impairment of renal function and increases in blood pressure. To explore this, we determined age-associated changes in lipid peroxidation (urinary malondialdehyde), plasma and urinary hydrogen peroxide (H(2)O(2)) levels, as well as renal H(2)O(2) production, and the expression of oxidant and antioxidant enzymes in young (13 weeks) and old (52 weeks) male Wistar Kyoto (WKY) rats. Urinary lipid peroxidation levels and H(2)O(2) production by the renal cortex and medulla of old rats were higher than their young counterparts. This was accompanied by overexpression of NADPH oxidase components Nox4 and p22(phox) in the renal cortex of old rats. Similarly, expression of superoxide dismutase (SOD) isoforms 2 and 3 and catalase were increased in the renal cortex from old rats. Renal function parameters (creatinine clearance and fractional excretion of sodium), diastolic blood pressure and heart rate were not affected by aging, although slight increases in systolic blood pressure were observed during this 52-week period. It is concluded that overexpression of renal Nox4 and p22(phox) and the increases in renal H(2)O(2) levels in aged WKY does not associate with renal functional impairment or marked increases in blood pressure. It is hypothesized that lack of oxidative stress-associated effects in aged WKY rats may result from increases in antioxidant defenses that counteract the damaging effects of H(2)O(2).


Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission.
The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged <60 years, and 944 aged ≥60 years) enrolled in Cancer and Leukemia Group B treatment protocols and the cytogenetics companion protocol 8461 between 1983 and 2004. At 10 years, 267 (16.6%) of patients aged <60 years and 23 (2.4%) of those aged ≥60 years were alive and disease-free. This disease-free AML group consisted predominantly of patients with core-binding factor AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) and those with a normal karyotype. Occurrences of AML beyond 10 years were infrequent and associated with cytogenetic findings different from those at diagnosis. These data provide evidence that the frequency of long-term cure of AML is low among younger and especially older patients in the absence of Allo-HCT in CR1. In older patients not appropriate for Allo-HCT, these data provide further justification for early use of alternative treatments outside of intensive chemotherapy.


Independent and parallel visual processing of ensemble statistics: Evidence from dual tasks.
The visual system can represent multiple objects in a compressed form of ensemble summary statistics (such as object numerosity, mean, and feature variance/range). Yet the relationships between the different types of visual statistics remain relatively unclear. Here, we tested whether two summaries (mean and numerosity, or mean and range) are calculated independently from each other and in parallel. Our participants performed dual tasks requiring a report about two summaries in each trial, and single tasks requiring a report about one of the summaries. We estimated trial-by-trial correlations between the precision of reports as well as correlations across observers. Both analyses showed the absence of correlations between different types of ensemble statistics, suggesting their independence. We also found no decrement (except that related to the order of report explained by memory retrieval) in performance in dual compared to single tasks, which suggests that two statistics of one ensemble can be processed in parallel.


Prevalence of hepatitis E virus antibodies in Canadian swine herds and identification of a novel variant of swine hepatitis E virus.
Swine hepatitis E virus is a newly identified potentially zoonotic virus from pigs of particular concern for possible direct transmission to a human xenotransplant recipient by organ transplantation. In the present study, prevalence of serum antibodies to hepatitis E virus was examined in Canadian swine herds. A total of 998 serum samples collected from 6-month-old healthy slaughter hogs were examined by enzyme immunoassay and Western blot analysis for antibodies to the recombinant open reading frame 3 (ORF3) protein of hepatitis E virus expressed in Escherichia coli. These samples represented more than 80 different swine production units from five major swine-producing provinces across Canada. From this study, 594 samples (59.4%) were found to be positive for hepatitis E virus antibody. The seroprevalence was higher in Quebec (88.8%) and Ontario (80.1%) than in Alberta and Saskatchewan (38.3%). By PCR using a pair of oligonucleotide primers deduced from the ORF2 sequence of human hepatitis E virus, a specific hepatitis E virus sequence was recovered from feces of pigs. The nucleotide sequence identity between the U.S. swine hepatitis E virus and the Canadian isolate (SK3) was only 85.8%, suggesting that genotypic variations may exist in swine hepatitis E virus in North America. Among 165 serum samples collected from humans in Saskatchewan, 2.4% were found to be positive for antibodies to the hepatitis E virus ORF3 protein. Our data indicate that hepatitis E virus is highly prevalent in commercial swine populations in Canada and support the suggestion that the swine hepatitis E virus may be an important zoonotic agent for humans.


Aesthetic and biomechanical precision in complex cases.
The success of dental restorations should not only be measured by immediate outcomes, such as patient comfort and appearance, but also by long-term survival and stability of the definitive restorations. Long-term success is dependant on the level of precision at which treatment is carried out. The three main areas in which this precision should be focused are precision of fit, occiusal precision, and aesthetic precision.


Macaque models of human infectious disease.
Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease.


An Investigation on Mitochondrial DNA Deletions and Telomere Shortening during Multiple Passages of Adult Stem Cells.
Limited resources for adult stem cells necessitate their in vitro culture prior to clinical use. Investigating mitochondrial DNA (mtDNA) and telomere shortening has proved to be important indications of stem cell validity. This study was designed to investigate these indicators in multiple passages of three adult stem cell lines which were produced in our stem cell laboratory. In this study, Dental Pulp Stem Cells (DPSCs), Periapical Follicle Stem Cells (PAFSCs) and Human Foreskin Fibroblast (HFF) cell lines were expanded for 20 passages. After 1, 5, 10, 15 and 20 passages, expanded cells were harvested and DNA was extracted for further studies. Common mtDNA mutation was detected by multiplex PCR and telomere shortening was tested by Southern blot analysis. The common deletion was not detected in any of the stem cells or cell lines after several passages. In addition, Southern blot analysis indicated that the mean difference of telomere length between first and last passage was 0.25 kb in DPSC, 0.1 kb in PAFSC and 0.32 kb in HFF which indicates that the mean telomere length in various passages of the samples showed insignificant changes. Absence of mtDNA mutations in adult stem cell lines indicates good mitochondrial function even after 20 passages. In addition, absence of telomere shortening indicates stem cells validity after multiple passages. It is hoped this information could pave the way for using in vitro expansion of adult stem cells for future clinical applications.


Geographic variations in utilization rates in Veterans Affairs hospitals and clinics.
In the United States, geographic variation in hospital use is common. It is uncertain whether there are similar geographic variations in the health care system of the Department of Veterans Affairs (VA), which differs from the private sector because it predominantly serves men with annual incomes below $20,000, has a central system of administration, and uses salaried physicians. Thus, it might be less likely to have geographic variations. We used VA data bases to obtain information on patients treated for eight diseases (chronic obstructive pulmonary disease, pneumonia, congestive heart failure, angina, diabetes, chronic renal failure, bipolar disorder, and major depression). We analyzed their use of hospital and outpatient services by assessing the risk-adjusted numbers of hospital days (the average number of days a patient spent in the hospital per 12 months of follow-up, regardless of the number of hospital stays), hospital-discharge rates, and clinic-visit rates from 1991 through 1995 for the entire system and within the 22 geographically based health care networks. We found substantial geographic variation in hospital use for all eight cohorts of patients and all the years studied. Variations in the numbers of hospital days per person-year among the networks were greatest among patients with chronic obstructive pulmonary disease (ranging from a factor of 2.7 to a factor of 3.1) during a given year and smallest among patients with angina (ranging from a factor of 1.5 to a factor of 2.1). Levels of hospital use were highest in the Northeast and lowest in the West. The variation in the rates of clinic visits for principal medical care among the networks ranged from a factor of approximately 1.6 to a factor of 4.0; variations in the rates were greatest among patients with chronic renal failure and smallest among patients with chronic obstructive pulmonary disease. There was no clear geographic pattern in the rates of outpatient-clinic use. There are significant geographic variations in the use of hospital and outpatient services in the VA health care system. Because VA physicians are unable to increase their income by changing their patterns of practice, our findings suggest that their practice styles are similar to those of other physicians in their geographic regions.


Multiple partners, risky partners and HIV risk among low-income urban women.
A sample of 671 predominantly single, young black women living in 10 low-income housing developments in five cities completed an anonymous questionnaire assessing factors related to their risk of contracting the human immunodeficiency virus, including their sexual behavior and condom use, and their partners' risk-related behaviors. In the two months before the 1994 survey, 17% of the women had sex with multiple partners and 22% had an exclusive partner who either had had other sexual partners in the past year or had a history of injection drug use; 40% had an exclusive partner who they believed had not engaged in these risky behaviors. During the same interval, 26% of women who had multiple partners received treatment for a sexually transmitted disease, compared with 9-11% of those who had an exclusive relationship. Condom use at last intercourse and communications about condom use were less frequent among women with an exclusive, risky partner than among those with multiple partners; attitudinal barriers to condom use did not vary, however, by the characteristics of women's relationships.


Menstrual bleeding, hormones, and the menopausal transition.
The perimenopause represents a time of great variability in reproductive hormone dynamics and menstrual cycle characteristics, but age-related changes begin prior to this. These changes include a gradual increase in follicle stimulating hormone (FSH) levels, a gradual shortening of mean cycle length, and a decline in the number of ovarian follicles. The onset of perimenopause is thought to occur with the first break in menstrual cycle regularity. With the onset of cycle irregularities, hormone concentrations exhibit large increases in variability and unpredictability, rather than following a gradual trend with the approach of menopause, the final menstrual period. Abrupt spikes in gonadotropins and considerable fluctuations in estradiol and inhibin levels have been observed. Variability is the norm in the perimenopause, with hormonal fluctuations contributing to the visible signs of menstrual cycle and bleeding irregularities. To date there is no single endocrine indicator to serve as an adequate marker of menopausal status. This paper provides a review of research to date on patterns of reproductive hormones and menstrual bleeding during the menopausal transition. An understanding of such patterns can contribute to a better ability to distinguish "normal" transitional events from more serious pathology.


Open science, reproducibility, and transparency in ecology.
Reproducibility is a key tenet of the scientific process that dictates the reliability and generality of results and methods. The complexities of ecological observations and data present novel challenges in satisfying needs for reproducibility and also transparency. Ecological systems are dynamic and heterogeneous, interacting with numerous factors that sculpt natural history and that investigators cannot completely control. Observations may be highly dependent on spatial and temporal context, making them very difficult to reproduce, but computational reproducibility can still be achieved. Computational reproducibility often refers to the ability to produce equivalent analytical outcomes from the same data set using the same code and software as the original study. When coded workflows are shared, authors and editors provide transparency for readers and allow other researchers to build directly and efficiently on primary work. These qualities may be especially important in ecological applications that have important or controversial implications for science, management, and policy. Expectations for computational reproducibility and transparency are shifting rapidly in the sciences. In this work, we highlight many of the unique challenges for ecology along with practical guidelines for reproducibility and transparency, as ecologists continue to participate in the stewardship of critical environmental information and ensure that research methods demonstrate integrity.


Multi-omics data integration reveals metabolome as the top predictor of the cervicovaginal microenvironment.
Emerging evidence suggests that host-microbe interaction in the cervicovaginal microenvironment contributes to cervical carcinogenesis, yet dissecting these complex interactions is challenging. Herein, we performed an integrated analysis of multiple "omics" datasets to develop predictive models of the cervicovaginal microenvironment and identify characteristic features of vaginal microbiome, genital inflammation and disease status. Microbiomes, vaginal pH, immunoproteomes and metabolomes were measured in cervicovaginal specimens collected from a cohort (n = 72) of Arizonan women with or without cervical neoplasm. Multi-omics integration methods, including neural networks (mmvec) and Random Forest supervised learning, were utilized to explore potential interactions and develop predictive models. Our integrated analyses revealed that immune and cancer biomarker concentrations were reliably predicted by Random Forest regressors trained on microbial and metabolic features, suggesting close correspondence between the vaginal microbiome, metabolome, and genital inflammation involved in cervical carcinogenesis. Furthermore, we show that features of the microbiome and host microenvironment, including metabolites, microbial taxa, and immune biomarkers are predictive of genital inflammation status, but only weakly to moderately predictive of cervical neoplastic disease status. Different feature classes were important for prediction of different phenotypes. Lipids (e.g. sphingolipids and long-chain unsaturated fatty acids) were strong predictors of genital inflammation, whereas predictions of vaginal microbiota and vaginal pH relied mostly on alterations in amino acid metabolism. Finally, we identified key immune biomarkers associated with the vaginal microbiota composition and vaginal pH (MIF), as well as genital inflammation (IL-6, IL-10, MIP-1α).


FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance.
The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis. Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo-preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control. We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients. Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis. Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT-PCR, most often in FTC, while single stage RT-PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT-PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities. Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell-derived thyroid neoplasms.


A cell-associated oligo-1,6-alpha-glucosidase from an extremely thermophilic anaerobic bacterium, Thermoanaerobium Tok6-B1.
Cell-associated oligo-1,6-alpha-glucosidase (EC 22.214.171.124) was isolated from Thermoanaerobium Tok6-B1 grown on starch-containing medium. Activity was purified 11.4-fold by salt precipitation, gel filtration, hydroxyapatite and anion-exchange chromatography. Molecular mass was determined as 30,000 by SDS/polyacrylamide-gel electrophoresis and 33,000 by analytical gel filtration. The probable order of specificity was p-nitrophenyl-alpha D-glucose greater than-isomaltose greater than-isomaltotriose greater than-panose greater than-nigerose and no activity was shown against malto-oligosaccharides, melezitose, melibiose, raffinose, cellobiose, sophorose, gentiobiose, lactose, pullulan, dextran or amylose. The optima for activity and stability were between pH 5.6 and 7.0 and the half-life at pH 6.5 was 1000 min at 70 degrees C and 20 min at 76 degrees C. Activity was stabilized by substrate, Mg2+, Mn2+ and Ca2+, but was destabilized by Zn2+ and EDTA. N-Ethylmaleimide, glucose and 1-O-methyl-alpha D-glucose were inhibitory but 1-O-methyl-beta D-glucose stimulated activity. The activation energy (Ea) was 109 kJ/mol.


The Survivor Unmet Needs Survey (SUNS) for haematological cancer survivors: a cross-sectional study assessing the relevance and psychometric properties.
Relevant and psychometrically sound needs assessment tools are necessary for accurate assessment of haematological cancer survivors unmet needs. No previous study has developed nor psychometrically evaluated a comprehensive needs assessment tool for use with population-based samples of haematological cancer survivors. This study aimed to assess the validity and reliability of the Survivor Unmet Needs Survey (SUNS) with haematological cancer survivors. The relevance, content and face validity of the SUNS to haematological cancer survivors was assessed using qualitative interviews. Psychometric evaluation was conducted using data collected from haematological cancer survivors, aged 18-80 years at recruitment and recruited from four Australian cancer registries. Construct, convergent and discriminant validity; internal reliability and floor and ceiling effects were assessed. A second survey was completed by a sub-sample of survivors recruited from two of the four registries to assess test-retest reliability. Results from 17 qualitative interviews confirmed the relevance, face and content validity of the original items of the SUNS for use with haematological cancer survivors. Overall, 1,957 eligible haematological cancer survivors were contacted by the cancer registries. Of these 1,280 were sent a survey, and 715 returned a survey (37% of eligible survivors contacted and 56% of survivors sent a survey). A total of 529 survivors completed all 89 items of the SUNS and were included in the exploratory factor analysis. Exploratory factor analysis supported the original five-factor structure of the SUNS. Evidence for convergent validity was established, with all five domains of the SUNS illustrating a moderate positive correlation with all three subscales of the Depression Anxiety and Stress Scale (DASS-21). All Cronbach's alpha values were above 0.9 and all corrected item-total correlations were acceptable (>0.2). Criteria for discriminant validity was not met, with only 10 of the 15 (67%) a-priori hypotheses supported. Test-retest reliability was acceptable for 40 of the 89 items (45%) and for three of the five domains. Significant floor effects were evident for all five domains. The SUNS demonstrates evidence for multiple features of validity and reliability as a measure of unmet needs for haematological cancer survivors. However, evidence supporting some psychometric properties was limited.


A comparative study of policosanol Versus acipimox in patients with type II hypercholesterolemia.
An 8-week, randomized, double-blind study comparing the efficacy and tolerability of policosanol and acipimox was conducted in patients with type II hypercholesterolemia. Prior to entry into active treatment, all patients followed a standard cholesterol-lowering diet for 12 weeks. Sixty-three patients were randomized to receive either policosanol (10 mg/day) or acipimox (750 mg/day) tablets for 8 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly reduced total cholesterol (p < 0.0001) (15.8%), low-density lipoprotein (LDL)-cholesterol (21%) and the ratios of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (15.8%) and cholesterol to HDL-cholesterol (11.5%). Acipimox significantly lowered both cholesterol and LDL cholesterol by 7.5%. The percent changes of total cholesterol, LDL-cholesterol and both ratios were larger in the policosanol group than in the acipimox group. Both drugs were well tolerated. Acipimox significantly increased (p > 0.001) aspartate amino transferase levels but only four patients showed increases above the normal limit. Policosanol significantly reduced creatinine values (p > 0.05) but no patients had values out of the normal range. Four patients withdrew from the study (two from each group) but none withdrew because of adverse effects. No adverse effects were reported in the policosanol group, while five patients on acipimox reported adverse effects (hot flushes, nausea, vomiting, headache, hypochondrial pain and leg edema). These results indicate that policosanol (10 mg/day) was more effective and well tolerated than was acipimox (750 mg/day) in this study population.


Red blood cell transfusion in the critically ill patient.
Red blood cell (RBC) transfusion is a common intervention in intensive care unit (ICU) patients. Anemia is frequent in this population and is associated with poor outcomes, especially in patients with ischemic heart disease. Although blood transfusions are generally given to improve tissue oxygenation, they do not systematically increase oxygen consumption and effects on oxygen delivery are not always very impressive. Blood transfusion may be lifesaving in some circumstances, but many studies have reported increased morbidity and mortality in transfused patients. This review focuses on some important aspects of RBC transfusion in the ICU, including physiologic considerations, a brief description of serious infectious and noninfectious hazards of transfusion, and the effects of RBC storage lesions. Emphasis is placed on the importance of personalizing blood transfusion according to physiological endpoints rather than arbitrary thresholds.


[Comparative study of 0.5% racemic bupivacaine versus enantiomeric mixture (S75-R25) of 0.5% bupivacaine in brachial plexus block for orthopedic surgery.].
Several studies were performed with bupivacaine isomers in the attempt to find a safer drug than racemic bupivacaine. This study aimed at evaluating the efficacy of 0.5% bupivacaine enantiomeric mixture (MEE50%) as compared to 0.5% racemic bupivacaine in brachial plexus block for upper limb orthopedic surgery. Participated of this randomized double-blind study 40 patients aged 18 to 90 years, physical status ASA I and II, submitted to upper limb orthopedic surgeries, who were divided in two groups: Group R received 0.5% racemic bupivacaine; and Group L received 0.5% enantiomeric mixture (S75-R25) of bupivacaine both with 1:200,000 epinephrine, in a volume of 0.6 mL.kg-1 (3 mg.kg-1), limited to 40 mL. Motor and/or sensory characteristics of each nerve involved (musculocutaneous, radial, median, ulnar and medial cutaneous nerve of forearm), as well as the incidence of side effects were evaluated. There were no statistical differences in demographics. Hemodynamic parameters were similar between groups but systolic pressure was higher for Group R. There were no statistically significant differences in time to reach the greatest intensity of sensory and motor blocks. With one exception, the onset of motor block within the muscles innervated by the ulnar nerve was longer for Group L (10.75 versus 14.25 minutes). There were adequate sensory and motor blocks in both groups, with few side effects, suggesting that the 0.5% enantiomeric mixture (S75-R25) of bupivacaine with epinephrine is safe and effective for brachial plexus block of upper limb orthopedic surgeries.


Oregon's Coordinated Care Organizations and Their Effect on Prenatal Care Utilization Among Medicaid Enrollees.
Introduction Previous studies indicate that inadequate prenatal care is more common among women covered by Medicaid compared with private insurance. Increasing the proportion of pregnant women who receive early and adequate prenatal care is a Healthy People 2020 goal. We examined the impact of the implementation of Oregon's accountable care organizations, Coordinated Care Organizations (CCOs), for Medicaid enrollees, on prenatal care utilization among Oregon women of reproductive age enrolled in Medicaid. Methods Using Medicaid eligibility data linked to unique birth records for 2011-2013, we used a pre-posttest treatment-control design that compared prenatal care utilization for women on Medicaid before and after CCO implementation to women never enrolled in Medicaid. Additional stratified analyses were conducted to explore differences in the effect of CCO implementation based on rurality, race, and ethnicity. Results After CCO implementation, mothers on Medicaid had a 13% increase in the odds of receiving first trimester care (OR 1.13, CI 1.04, 1.23). Non-Hispanic (OR 1.20, CI 1.09, 1.32), White (OR 1.20, CI 1.08, 1.33) and Asian (OR 2.03, CI 1.26, 3.27) women on Medicaid were more likely to receive initial prenatal care in the first trimester after CCO implementation and only Medicaid women in urban areas were more likely (OR 1.14, CI 1.05, 1.25) to initiate prenatal care in the first trimester. Conclusion Following Oregon's implementation of an innovative Medicaid coordinated care model, we found that women on Medicaid experienced a significant increase in receiving timely prenatal care.


Electron transport-dependent taxis in Rhodobacter sphaeroides.
Rhodobacter sphaeroides showed chemotaxis to the terminal electron acceptors oxygen and dimethyl sulfoxide, and the responses to these effectors were shown to be influenced by the relative activities of the different electron transport pathways. R. sphaeroides cells tethered by their flagella showed a step-down response to a decrease in the oxygen or dimethyl sulfoxide concentration when using them as terminal acceptors. Bacteria using photosynthetic electron transport, however, showed a step-down response to oxygen addition. Addition of the proton ionophore carbonyl cyanide 4-trifluoromethoxyphenylhydrazone did not cause a transient behavioral response, although it decreased the electrochemical proton gradient (delta p) and increased the rate of electron transport. However, removal of the ionophore, which caused an increase in delta p and a decrease in the electron transport rate, resulted in a step-down response. Together, these data suggest that behavioral responses of R. sphaeroides to electron transport effectors are caused by changes in the rate of electron transport rather than changes in delta p.


FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer.
Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were downregulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the antitumor activity of IR in vivo Therefore, FLIP downregulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. Mol Cancer Ther; 15(10); 2432-41. ©2016 AACR.


Tracking All Members of a Honey Bee Colony Over Their Lifetime Using Learned Models of Correspondence.
Computational approaches to the analysis of collective behavior in social insects increasingly rely on motion paths as an intermediate data layer from which one can infer individual behaviors or social interactions. Honey bees are a popular model for learning and memory. Previous experience has been shown to affect and modulate future social interactions. So far, no lifetime history observations have been reported for all bees of a colony. In a previous work we introduced a recording setup customized to track up to 4,000 marked bees over several weeks. Due to detection and decoding errors of the bee markers, linking the correct correspondences through time is non-trivial. In this contribution we present an in-depth description of the underlying multi-step algorithm which produces motion paths, and also improves the marker decoding accuracy significantly. The proposed solution employs two classifiers to predict the correspondence of two consecutive detections in the first step, and two tracklets in the second. We automatically tracked ~2,000 marked honey bees over 10 weeks with inexpensive recording hardware using markers without any error correction bits. We found that the proposed two-step tracking reduced incorrect ID decodings from initially ~13% to around 2% post-tracking. Alongside this paper, we publish the first trajectory dataset for all bees in a colony, extracted from ~3 million images covering 3 days. We invite researchers to join the collective scientific effort to investigate this intriguing animal system. All components of our system are open-source.


Tracking calcium dynamics from individual neurons in behaving animals.
Measuring the activity of neuronal populations with calcium imaging can capture emergent functional properties of neuronal circuits with single cell resolution. However, the motion of freely behaving animals, together with the intermittent detectability of calcium sensors, can hinder automatic monitoring of neuronal activity and their subsequent functional characterization. We report the development and open-source implementation of a multi-step cellular tracking algorithm (Elastic Motion Correction and Concatenation or EMC2) that compensates for the intermittent disappearance of moving neurons by integrating local deformation information from detectable neurons. We demonstrate the accuracy and versatility of our algorithm using calcium imaging data from two-photon volumetric microscopy in visual cortex of awake mice, and from confocal microscopy in behaving Hydra, which experiences major body deformation during its contractions. We quantify the performance of our algorithm using ground truth manual tracking of neurons, along with synthetic time-lapse sequences, covering a wide range of particle motions and detectability parameters. As a demonstration of the utility of the algorithm, we monitor for several days calcium activity of the same neurons in layer 2/3 of mouse visual cortex in vivo, finding significant turnover within the active neurons across days, with only few neurons that remained active across days. Also, combining automatic tracking of single neuron activity with statistical clustering, we characterize and map neuronal ensembles in behaving Hydra, finding three major non-overlapping ensembles of neurons (CB, RP1 and RP2) whose activity correlates with contractions and elongations. Our results show that the EMC2 algorithm can be used as a robust and versatile platform for neuronal tracking in behaving animals.


Associations between genetic variants in the IRGM gene and inflammatory bowel diseases in the Korean population.
Recent European ancestry genome-wide association studies have identified genetic variants of IRGM as significant susceptibility loci for Crohn's disease (CD). Therefore, we investigated whether genetic variants of IRGM confer genetic susceptibility to CD or ulcerative colitis (UC) and evaluated the genotype-phenotype associations in the Korean population. This study included 510 inflammatory bowel disease (IBD) patients (253 patients with CD and 257 with UC) and 520 healthy controls in Koreans. Initially, we performed direct sequencing analysis to identify unique IRGM single nucleotide polymorphisms (SNPs). Three selected haplotype-tagging SNPs and one risk locus (rs72553867, rs10065172, rs4958847, and rs12654043) within the IRGM were then geno-typed in patients and controls. IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62). We also found a relationship between SNP rs72553867 and CD susceptibility in the analysis of allelic frequency (P = 0.0117; OR = 0.67) and genotype frequency (dominant model, P = 0.002; OR = 0.55). In addition, we observed that the association of CD with rs10065172 became stronger in patients with younger age at diagnosis (≤ 20 years) or male gender. However, there was no significant association between the four SNPs and UC susceptibility. This is the first study to identify SNP rs10065172 and rs72553867 in IRGM as principal CD susceptibility loci in an Asian population.


Diagnostic value of symptoms and signs for identifying urinary tract infection in older adult outpatients: Systematic review and meta-analysis.
To critically appraise and evaluate the diagnostic value of symptoms and signs in identifying UTI in older adult outpatients, using evidence from observational studies. We searched Medline and Medline in process, Embase and Web of Science, from inception up to September 2017. We included studies assessing the diagnostic accuracy of symptoms and/or signs in predicting UTI in outpatients aged 65 years and above. Study quality was assessed using the QUADAS-2 tool. We identified 15 eligible studies of variable quality, with a total of 12,039 participants (range 65-4259), and assessed the diagnostic accuracy of 66 different symptoms and signs in predicting UTI. A number of symptoms and signs typically associated with UTI, such as nocturia, urgency and abnormal vital signs, were of limited use in older adult outpatients. Inability to perform a number of acts of daily living were predictors of UTI: For example, disability in feeding oneself, + ve LR: 11.8 (95% CI 5.51-25.2) and disability in washing one's hands and face, + ve LR: 6.84 (95% CI 4.08-11.5). The limited evidence of varying quality shows that a number of symptoms and signs traditionally associated with UTI may have limited diagnostic value in older adult outpatients.


Four-leaf-clover-shaped antenna for a THz photomixer.
To improve the output power of a photomixer used as a THz source, we propose a four-leaf-clover-shaped antenna structure composed of a highly resonant radiation element and a stable DC feed element. The resonance characteristics of the proposed structure were first investigated on a half-infinite substrate as a simplified radiation environment to reduce the computation time. Based on the antenna characteristics on that half-infinite substrate, the antenna structure was designed to have a maximum total efficiency and a maximum directivity on an extended hemispherical lens. The input resistance of this structure was six times that of a full-wavelength dipole, significantly improving the mismatch efficiency between a photomixer and the antenna. The terahertz output power from this structure is expected to be 2.7 times that of a full-wavelength dipole.


Quadrant root planing versus same-day full-mouth root planing.
The aim of this study was to determine whether same-day full-mouth scaling and root planing (FM-SRP) and quadrant scaling and root planing (Q-SRP) resulted in variations in the systemic humoral immune response dynamics (antibody titres and avidity) during active treatment and 3 and 6 months post-therapy. Forty patients with chronic periodontitis were recruited into this study. Subjects were randomised into two groups and received either scaling and root planing quadrant by quadrant at 2-weekly intervals (Q-SRP group) or same-day full-mouth scaling and root planing (FM-SRP group). Clinical measurements and serum samples were obtained at baseline and approximately 6 weeks after the last clinical intervention (R1) and 6 months after the initiation of therapy (R2). Furthermore, serum samples were obtained from each patient undergoing therapy (Q-SRP and FM-SRP) at 3 bi-weekly instances so as to determine the short-term effects of each session of scaling and root planing on the dynamics of the humoral immune response. Serum antibody titre was assayed by enzyme-linked immunosorbent assay (ELISA) and antibody avidity was measured by thiocyanate dissociation against five putative periodontal pathogens: Porphyromonas gingivalis; Actinobacillus actinomycetemcomitans; Prevotella intermedia; Treponema denticola and Bacteroides forsythus. Both therapies resulted in similar antibody titre reductions against the majority of the organisms tested and although there was a distinct trend for antibody avidity to increase following therapy, this was not found to be statistically significant, reflecting marked inter-individual variation. In addition, no evidence emerged from this study to support increased antibody titres following the active phases of both treatment approaches due to an inoculation effect. Nevertheless, significant short-term increases in antibody avidity to most test bacteria were noted for both treatment strategies. Both therapies were associated with a reduction in antibody titres and an increase in the binding ability or avidity of antibodies, but there was a marked inter-subject variability and statistical significance was reached for only some of the test bacteria. No significant differences in the humoral antibody dynamics were found between the two treatment approaches.