Enhancing Characteristic Gene Selection and Tumor Classification by the Robust Laplacian Supervised Discriminative Sparse PCA.
Characteristic gene selection and tumor classification of gene expression data play major roles in genomic research. Due to the characteristics of a small sample size and high dimensionality of gene expression data, it is a common practice to perform dimensionality reduction prior to the use of machine learning-based methods to analyze the expression data. In this context, classical principal component analysis (PCA) and its improved versions have been widely used. Recently, methods based on supervised discriminative sparse PCA have been developed to improve the performance of data dimensionality reduction. However, such methods still have limitations: most of them have not taken into consideration the improvement of robustness to outliers and noise, label information, sparsity, as well as capturing intrinsic geometrical structures in one objective function. To address this drawback, in this study, we propose a novel PCA-based method, known as the robust Laplacian supervised discriminative sparse PCA, termed RLSDSPCA, which enforces the L2,1 norm on the error function and incorporates the graph Laplacian into supervised discriminative sparse PCA. To evaluate the efficacy of the proposed RLSDSPCA, we applied it to the problems of characteristic gene selection and tumor classification problems using gene expression data. The results demonstrate that the proposed RLSDSPCA method, when used in combination with other related methods, can effectively identify new pathogenic genes associated with diseases. In addition, RLSDSPCA has also achieved the best performance compared with the state-of-the-art methods on tumor classification in terms of major performance metrics. The codes and data sets used in the study are freely available at http://csbio.njust.edu.cn/bioinf/rlsdspca/.


Signet Rings Around the World.
Esophageal and gastric adenocarcinoma of signet ring subtype is aggressive and portends a poor prognosis. This subtype of an already aggressive cancer metastasizes widely and can progress quickly. Hart and colleagues outline an unusual and specific metastasis following resection of signet ring esophageal adenocarcinoma. More frequent surveillance for resected patients may help identify metastases early.


Research Progress of Cordyceps sinensis and Its Fermented Mycelium Products on Ameliorating Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition.
Renal fibrosis is a hallmark and common outcome of various chronic kidney diseases (CKDs) and manifests pathologically as accumulation and deposition of extracellular matrix (ECM) in the kidney. Epithelial-to-mesenchymal transition (EMT) has been shown to be an important mechanism involved in renal fibrosis. Cordyceps sinensis, a traditional Chinese medicine, has long been used for the treatment of renal fibrosis. As research on the mycelium of C. sinensis progressed, a variety of medicines developed from fermented mycelium were used to treat CKD. However, their efficacies and mechanisms have not been fully summarized. In this review, five medicines developed from fermented mycelium of C. sinensis are presented. The pharmacodynamic effects of C. sinensis on different animal models of renal fibrosis are summarized. The in vitro studies and related mechanisms of C. sinensis on renal cells are detailed. Finally, the application and efficacy of these five commercial medicines that meet national standards in different types of CKD are summarized. From this review, it can be concluded that C. sinensis can alleviate various causes of renal fibrosis to some extent, and its mechanism is related to TGF-β1 dependent signaling, inhibition of inflammation, and improvement of renal function. Further research on rigorously designed, large-sample, clinically randomized controlled trial studies and detailed mechanisms should be conducted.


Crystal structure of the multidrug resistance regulator RamR complexed with bile acids.
During infection, Salmonella senses and responds to harsh environments within the host. Persistence in a bile-rich environment is important for Salmonella to infect the small intestine or gallbladder and the multidrug efflux system AcrAB-TolC is required for bile resistance. The genes encoding this system are mainly regulated by the ramRA locus, which is composed of the divergently transcribed ramA and ramR genes. The acrAB and tolC genes are transcriptionally activated by RamA, whose encoding gene is itself transcriptionally repressed by RamR. RamR recognizes multiple drugs; however, the identity of the environmental signals to which it responds is unclear. Here, we describe the crystal structures of RamR in complexes with bile components, including cholic acid and chenodeoxycholic acid, determined at resolutions of 2.0 and 1.8 Å, respectively. Both cholic and chenodeoxycholic acids form four hydrogen bonds with Tyr59, Thr85, Ser137 and Asp152 of RamR, instead of π-π interactions with Phe155, a residue that is important for the recognition of multiple compounds including berberine, crystal violet, dequalinium, ethidium bromide and rhodamine 6 G. Binding of these compounds to RamR reduces its DNA-binding affinity, resulting in the increased transcription of ramA and acrAB-tolC. Our results reveal that Salmonella senses bile acid components through RamR and then upregulates the expression of RamA, which can lead to induction of acrAB-tolC expression with resulting tolerance to bile-rich environments.


Evaluation of twenty human adenoviral types and one infectivity-enhanced adenovirus for the therapy of soft tissue sarcoma.
The clinical course of sarcoma warrants the development of new therapeutic options, such as gene therapy. However, the lack of coxsackievirus-adenovirus receptor (CAR) on sarcoma cells limits the efficacy of adenovirus type 5 (Ad5)-based gene therapy. In this study we evaluated 20 different adenoviral types and 1 Ad5 vector with RGD-containing fiber for their internalization efficiency in sarcoma cells. We demonstrated that adenovirus types 35, 3, 7, 11, 9, and 22 and Ad5lucRGD virions (ranked in descending order) have significantly higher internalization efficiency in the tested sarcoma cells when compared with Ad5. On the basis of these results we developed a conditionally replication-competent adenoviral vector, Ad5Delta24.Ki.COX, and compared its oncolytic efficacy with that of Ad5/35Delta24.Ki.COX, an Ad5-based vector with the Ad35 fiber shaft and knob domains. Because both vectors differed only in the fiber, we were able to assess whether the adenoviral type with the most efficient internalization resulted also in enhanced treatment efficacy. We evaluated the antineoplastic activity of the oncolytic adenoviral vectors alone or in combination with the expression of measles virus fusogenic membrane glycoproteins and/or ifosfamide. The findings of our xenograft model were as follows: animals that received Ad5/35-based therapy had significantly smaller tumors than animals treated with the homologous Ad5-based vectors. In addition, we demonstrated that the combination of virotherapy, intratumoral expression of fusogenic membrane glycoproteins, and ifosfamide was clearly superior compared with treatment with individual components alone or as combinations of two components. In conclusion, Ad35-based vectors are promising for the treatment of sarcoma.


Applying NV center-based quantum sensing to study intracellular free radical response upon viral infections.
Although viruses are known to modify the free radical concentration in infected cells, the exact location and concentrations of such changes remain unknown. Although this information is important to understand the virus pathogenesis and design better anti-viral drugs or vaccines, obtaining it with the conventional free radical/ROS detection techniques is impossible. Here, we elucidate the utility of diamond magnetometry for studying the free radical response of baby hamster kidney-21 cells upon Semliki Forest virus infection. Specifically, we optically probe the alterations in free radical concentration near infectious viruses via measuring the spin-lattice relaxation (T1) of NV defect ensembles embedded in intracellular nanodiamonds. We performed measurements both at random locations as well as close to the virus entry by conjugating viruses to nanodiamond sensors. We observed alterations of T1, which represent the intracellular free radical concentration during the viral replication process. Moreover, relaxometry is also used to monitor real-time free radical variation during the early infectious process.


The heterogeneous well-being effects of intergenerational mobility perceptions.
Individuals make comparisons with their parents which determine their intergenerational mobility perceptions, yet very little is known about the areas used for intergenerational comparison and whether these matter for individuals' well-being. In 2021 we commissioned a nationally representative survey in Georgia in which we explicitly asked 1159 individuals an open-ended question on the most important areas in their intergenerational comparisons. More than 170 types of answers were provided by respondents and many of these responses went beyond the standard indicators of intergenerational mobility. We show that the areas of intergenerational comparison significantly differ between those who perceive themselves as being downwardly and upwardly mobile or immobile using the measure of mobility previously validated in cross-national research. Using, among other statistical approaches, treatment effects estimators, we demonstrate that some areas of intergenerational comparison, particularly in terms of income attainment, are significantly and consistently associated with internationally validated measures of well-being.


Diversity in Older Adults' Use of the Internet: Identifying Subgroups Through Latent Class Analysis.
As for all individuals, the Internet is important in the everyday life of older adults. Research on older adults' use of the Internet has merely focused on users versus nonusers and consequences of Internet use and nonuse. Older adults are a heterogeneous group, which may implicate that their use of the Internet is diverse as well. Older adults can use the Internet for different activities, and this usage can be of influence on benefits the Internet can have for them. The aim of this paper was to describe the diversity or heterogeneity in the activities for which older adults use the Internet and determine whether diversity is related to social or health-related variables. We used data of a national representative Internet panel in the Netherlands. Panel members aged 65 years and older and who have access to and use the Internet were selected (N=1418). We conducted a latent class analysis based on the Internet activities that panel members reported to spend time on. Second, we described the identified clusters with descriptive statistics and compared the clusters using analysis of variance (ANOVA) and chi-square tests. Four clusters were distinguished. Cluster 1 was labeled as the "practical users" (36.88%, n=523). These respondents mainly used the Internet for practical and financial purposes such as searching for information, comparing products, and banking. Respondents in Cluster 2, the "minimizers" (32.23%, n=457), reported lowest frequency on most Internet activities, are older (mean age 73 years), and spent the smallest time on the Internet. Cluster 3 was labeled as the "maximizers" (17.77%, n=252); these respondents used the Internet for various activities, spent most time on the Internet, and were relatively younger (mean age below 70 years). Respondents in Cluster 4, the "social users," mainly used the Internet for social and leisure-related activities such as gaming and social network sites. The identified clusters significantly differed in age (P<.001, ω2=0.07), time spent on the Internet (P<.001, ω2=0.12), and frequency of downloading apps (P<.001, ω2=0.14), with medium to large effect sizes. Social and health-related variables were significantly different between the clusters, except social and emotional loneliness. However, effect sizes were small. The minimizers scored significantly lower on psychological well-being, instrumental activities of daily living (iADL), and experienced health compared with the practical users and maximizers. Older adults are a diverse group in terms of their activities on the Internet. This underlines the importance to look beyond use versus nonuse when studying older adults' Internet use. The clusters we have identified in this study can help tailor the development and deployment of eHealth intervention to specific segments of the older population.


Targeting of focal adhesion kinase by flavonoids and small-interfering RNAs reduces tumor cell migration ability.
Focal adhesion kinase (FAK), a member of a growing family of structurally distinct protein tyrosine kinases (PTK), has been linked to specific phosphorylation events, and the elevation of FAK activity in human carcinoma cells is associated with increased invasive potential. In the present study, therefore, we developed two experiments to test the hypothesis that FAK is a determinant of, and plays an important role in, regulating tumor cell migration. In the first, the biological functions of FAK were examined using flavonoid inhibition. MiaPaCa-2 cells, treated with luteolin (Lu) and quercetin (Qu), were used to dampen FAK phosphorylation and protein expression by parallel suppression of cell migration ability. The second experiment involved suppression of FAK expression using small-interfering RNAs (siRNA) specific to FAK. While not affecting cellular proliferation or apoptosis, the siRNA targeting FAK almost completely inhibited FAK protein expression in MiaPaCa-2 cells and potently blocked the cell migration mediated by FAK. Our results show that FAK functions as a key regulator of cell migration, and that FAK activity can be suppressed by specific FAK siRNA, and by luteolin and quercetin. It appears reasonable to conclude, therefore, that suppression of FAK protein has a significant impact on tumor cell invasiveness.


A climatic stability approach to prioritizing global conservation investments.
Climate change is impacting species and ecosystems globally. Many existing templates to identify the most important areas to conserve terrestrial biodiversity at the global scale neglect the future impacts of climate change. Unstable climatic conditions are predicted to undermine conservation investments in the future. This paper presents an approach to developing a resource allocation algorithm for conservation investment that incorporates the ecological stability of ecoregions under climate change. We discover that allocating funds in this way changes the optimal schedule of global investments both spatially and temporally. This allocation reduces the biodiversity loss of terrestrial endemic species from protected areas due to climate change by 22% for the period of 2002-2052, when compared to allocations that do not consider climate change. To maximize the resilience of global biodiversity to climate change we recommend that funding be increased in ecoregions located in the tropics and/or mid-elevation habitats, where climatic conditions are predicted to remain relatively stable. Accounting for the ecological stability of ecoregions provides a realistic approach to incorporating climate change into global conservation planning, with potential to save more species from extinction in the long term.


Agelasine D suppresses RANKL-induced osteoclastogenesis via down-regulation of c-Fos, NFATc1 and NF-κB.
In the present study, we investigated the effect of agelasine D (AD) on osteoclastogenesis. Treatment of bone marrow macrophages (BMMs) with receptor activator of nuclear factor κB ligand (RANKL) resulted in a differentiation of BMMs into osteoclasts as evidenced by generation of tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated cells and formation of pits in calcium phosphate-coated plates. However, RANKL-induced osteoclastogenesis was significantly suppressed by AD treatment. We also confirmed the increased mRNA and protein expression of osteoclastic markers, such as TRAP, cathepsin K and matrix metalloproteinase-9, during RANKL-induced osteoclast differentiation and this was down-regulated by AD treatment. Moreover, AD treatment significantly suppressed RANKL-induced mRNA expression of DC-STAMP and OC-STAMP and cell fusion of TRAP-positive mononuclear osteoclast precursors. In addition, AD suppressed RANKL-induced expression of transcription factors, c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important transcription factors involved in differentiation of BMMs into osteoclasts. Furthermore, RANKL-induced phosphorylation of extracellular signal-related kinase (ERK) and activation of NF-κB were also inhibited by AD treatment. Collectively, these results suggest that AD inhibits RANKL-induced osteoclastogenesis by down-regulation of multiple signaling pathways involving c-Fos, NFATc1, NF-κB and ERK. Our results also suggest that AD might be a potential therapeutic agent for prevention and treatment of osteoporosis.


Personality and perception of tinnitus.
Tinnitus has high prevalence and a wide range of etiologies and of impacts on sufferers. Our objective was to develop understanding of the role of personality in the perception of tinnitus in the general population. As a theoretical basis for this, we combined elements of a general model of signal detection with the ideas of ignition (development) and promotion (neural transmission) of tinnitus, and considered plausible roles for personality factors within this conceptual framework. We interviewed a birth cohort of 970 people aged 32 yr sampled from the general population. On the basis of questioning, we divided them into three groups, those without tinnitus, those with occasional tinnitus (including those with transient tinnitus of very brief duration), and those who experienced tinnitus most of the time. We also established how annoying or distressing the tinnitus was, and assessed personality using the Multidimensional Personality Questionnaire. Tinnitus was experienced rarely by 38.2% and half the time or more by 6.8% of those studied. Men and women did not differ in the amount of tinnitus reported, but women were more likely to find it annoying. People from lower socioeconomic backgrounds were more likely to report tinnitus. People with tinnitus were more socially withdrawn, reactive to stress, alienated, and less Self-Controlled. People who were more annoyed by tinnitus were more socially withdrawn, and men were more stress reactive and alienated. Our interpretation of the findings is that personality influences the persistence of tinnitus by influencing the tendency to be aware of it. Consideration of personality factors may improve the ability to tailor tinnitus therapies, and the concept of awareness may benefit treatment outcomes by showing tinnitus sufferers a means of internalizing the locus of control over their symptoms.


Unit-cell scale mapping of ferroelectricity and tetragonality in epitaxial ultrathin ferroelectric films.
Typically, polarization and strain in ferroelectric materials are coupled, leading to the generally accepted direct relation between polarization and unit-cell tetragonality. Here, by means of high-resolution transmission electron microscopy we map, on the unit-cell scale, the degree of tetragonality and the displacements of cations away from the centrosymmetry positions in an ultrathin epitaxial PbZr(0.2)Ti(0.8)O(3) film on a SrRuO(3) electrode layer deposited on a SrTiO(3) substrate. The lattice is highly tetragonal at the centre of the film, whereas it shows reduced tetragonality close to the interfaces. Most strikingly, we find that the maximum off-centre displacements for the central area of the film do not scale with the tetragonality. This challenges the fundamental belief in a strong polarization-tetragonality coupling in PbTiO(3)-based ferroelectrics, at such thicknesses. Furthermore, a systematic reduction of the atomic displacements is measured at the interfaces, suggesting that interface-induced suppression of the ferroelectric polarization plays a critical role in the size effect of nanoscale ferroelectrics.


Influence of extremely low frequency magnetic fields on chromosomes and the mitotic cycle in Vicia faba L., the broad bean.
Vicia faba seedlings were subjected to one of the following magnetic fields continuously for 3 days: 0 Hz (DC) at 5 mT, 50 Hz at 1.5 mT, 60 Hz at 1.5 mT, and 75 Hz at 1.5 mT. The lengths of all the phases of mitosis differed from the controls in all treatments using alternating magnetic fields and for prophase and metaphase in the DC condition. In particular, all treatments increased the length of prophase significantly in meristematic root-tip cells compared with the controls. The implications of these results for chromosome coiling are discussed. The length of prophase, however, did not vary significantly between any of the treatments. Furthermore, none of the exposed seedlings had a greater frequency of chromosome breakages above that of the control plants.


Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo.
Signal transducer and activator of transcription 3 (Stat3) is constitutively activated in a variety of cancers and it is a common feature of prostate cancer. Thus, Stat3 represents a promising molecular target for tumor therapy. We applied a DNA vector-based Stat3-specific RNA interference approach to block Stat3 signaling and to evaluate the biological consequences of Stat3 down-modulation on tumor growth using a mouse model. To investigate the therapeutic potential of blocking Stat3 in cancer cells, three small interfering RNAs (siRNA; Stat3-1, Stat3-2, and Stat3-3) specific for different target sites on Stat3 mRNA were designed and used with a DNA vector-based RNA interference approach expressing short hairpin RNAs to knockdown Stat3 expression in human prostate cancer cells in vitro as well as in vivo. Of the three equivalently expressed siRNAs, only Stat3-3 and Stat3-2, which target the region coding for the SH2 domain and the coiled-coil domain, respectively, strongly suppressed the expression of Stat3 in PC3 and LNCaP cells. The Stat3-1 siRNA, which targeted the DNA-binding domain, exerted no effect on Stat3 expression, indicating that the gene silencing efficiency of siRNA may be dependent on the local structure of Stat3 mRNA. The Stat3 siRNAs down-regulated the expression of Bcl-2 (an anti-apoptotic protein), and cyclin D1 and c-Myc (cell growth activators) in prostate cancer cells. Inhibition of Stat3 and its related genes was accompanied by growth suppression and induction of apoptosis in cancer cells in vitro and in tumors implanted in nude mice. These data indicate that Stat3 signaling is a promising molecular target for prostate cancer therapy and that vector-based Stat3 siRNA may be useful as a therapeutic agent for treatment of prostate cancer.


Immunohistochemical study of the Nrf2 pathway in colorectal cancer: Nrf2 expression is closely correlated to Keap1 in the tumor and Bach1 in the normal tissue.
Oxidative stress is a contributing factor in the carcinogenesis of colorectal cancer. The Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] pathway is one of the major cellular defense mechanisms against oxidative stress. This study investigated the expression of the Nrf2 pathway in colorectal cancer. Formalin-fixed paraffin-embedded tissue arrays consisting of the tumor, adjacent normal, and distant normal tissues from the resected specimens of 83 colorectal cancer patients were subjected to immunohistochemical (IHC) staining with antibodies against Nrf2, kelch-like ECH-associated protein 1 (Keap1), p21, P62, Parkinson protein 7 (Park7), prohibitin, BTB and CNC homology 1 (Bach1), CD34 and 8-hydroxy-2'-deoxyguanosine (8-OHdG). The mean IHC density of each IHC staining was digitally analyzed. The results showed that molecules of the Nrf2 pathway were actively expressed, with different expression profiles among the tumor and normal tissues. The oxidative stress, represented by the mean IHC staining density of 8-OHdG, did not differ but was correlated with the expressions of different Nrf2 pathway molecules to a varied extent in tumor and normal tissues of colorectal cancer. Keap1 [estimate, 0.49; 95% confidence interval (CI), 0.19-0.79] and Bach1 (estimate, 0.24; 95% CI, 0.11-0.38) were significant predictors for the expression of 8-OHdG and had the closest proximity to Nrf2 in the cluster dendrogram of the tumor and distant normal tissues, respectively. Advanced stage (estimate, 14.9; 95% CI, 2.99-26.8) and current smoker (estimate, 15.6; 95% CI, 1.92-29.3) were significant predictors with high estimates for Bach1 in the adjacent and distant normal tissues, respectively. In colorectal cancer, the molecules of the Nrf2 pathway have different expression profiles and a difference in their importance, especially Keap1 and Bach1, related to Nrf2 and oxidative stress among tumor and normal tissues.


New chemistry of transition metal oxyhydrides.
In this review we describe recent advances in transition metal oxyhydride chemistry obtained by topochemical routes, such as low temperature reduction with metal hydrides, or high-pressure solid-state reactions. Besides the crystal chemistry, magnetic and transport properties of the bulk powder and epitaxial thin film samples, the remarkable lability of the hydride anion is particularly highlighted as a new strategy to discover unprecedented mixed anion materials.


Taking risk prediction to the next level. Advances in biomarker research for atherosclerosis.
Advances in risk prediction are necessary to stem the tide of the increasing incidence of global cardiovascular disease. Newly discovered biomarkers are needed for primary and secondary prevention and will undoubtedly play a major role in drug development programs and monitoring of treatment efficacy. The combination of improved -omics technologies and the investigation of relatively untapped sources of biomarkers will likely result in risk algorithms that will add value on top of the traditional risk factors. New sources of biomarkers are being explored with encouraging results. These include microvesicles, microRNAs, circulating cells and atherosclerotic plaques. We will review these sources for their potential for new biomarkers. Furthermore, the major impact of advances in genetics on risk prediction and biomarker development programs will be discussed.


Paraoxonase 1 activity, concentration and genotype in cardiovascular disease.
To provide up-to-date information on the most recent advances in the epidemiology, biochemistry and molecular biology of the antiatherosclerotic enzyme paraoxonase 1. Case-control and prospective studies published during the period covered by this review have indicated that paraoxonase 1 'status' (i.e. activity and/or concentration) was a more important coronary heart disease risk factor than the paraoxonase 1 genetic polymorphisms. New findings on the role of paraoxonase 1 in homocysteine metabolism are reviewed, as are advances in the nutritional and pharmacological regulation of paraoxonase 1. The recent controversy over whether paraoxonase 1 or platelet-activating factor acetylhydrolase is responsible for the antioxidant activity of high-density lipoprotein is also addressed. In the light of recent findings, we believe that genetic epidemiological studies of the paraoxonase 1 polymorphisms in relation to coronary heart disease should no longer be undertaken unless they are very large and prospective in nature. More research should be undertaken to discover the biochemical mechanisms underlying the mode of action of paraoxonase 1 and the factors which modulate its activity and/or concentration. Bharti Mackness is funded by the International HDL Research Awards Programme. All authors receive research funding from the British Heart Foundation and Diabetes UK.


[The role of bicalutamide in the treatment of prostate cancer].
Bicalutamide is an effective, non-steroidal antiandrogen, suitable for oral, once daily administration. Bicalutamide 50 mg plus LHRHa is at least as effective as flutamide plus LHRHa in terms of survival and time to progression. Monotherapy with bicalutamide 150 mg once daily has similar survival rates compared with castration in advanced non-metastatic disease. Current clinical trials are evaluating the efficacy of bicalutamide as monotherapy in the setting of adjuvant therapy in early stage disease. Sexual interest appears to be better preserved with bicalutamide than with castration. Breast pain and gynecomastia are the most common side effects. Bicalutamide is not associated with interstitial pneumonitis and difficulty with light/dark adaptation seen with nilutamide, and in 50 mg/day dosage causes a lower incidence of diarrhea than flutamide 750 mg/day. Changes in hepatic function are usually transient and resolve or improve during therapy or after bicalutamide treatment is withdrawn.


Deciphering protein-protein interactions during the biogenesis of cytochrome c oxidase from Paracoccus denitrificans.
Biogenesis of the mitochondrial cytochrome c oxidase (COX) is a complex process due to its numerous subunits encoded by two genomes, as well as the localization of redox centers deep within the membrane. Here, we have assessed the biogenesis of the homologous aa₃-type oxidase of the soil bacterium Paracoccus denitrificans. First, protein partners were analyzed using various membrane solubilization strategies to show interactions between COX and CtaG, a chaperone implicated in CuB site metallation. Using an unbiased MS approach after immunological pull-down from untreated or cross-linked membranes, we then extend our view towards a hypothetical 'biogenesis complex' by identifying two further metal-inserting chaperones, Surf1c and Sco, together with enzymes catalyzing heme a synthesis. Our study also tentatively supports previous speculation regarding the existence of a predominantly co-translational mechanism for cofactor insertion during COX biogenesis.


[Performance improvement project for the introduction of safety devices: interdisciplinary approach and participation of professionals].
Develop a performance improvement project to introduce safety needle tube holder for venous blood collection after evaluation of the professionals. Reach: Costa Ponent Primary Care Direction and the Hospital Viladecans Hospital from Institute Català de la Salut. Create interdisciplinary group. Design in two phases. First, material selection and assessment of safety devices. Second, implementation and evaluation of the proposed performance improvements. The material was selected using standardized criteria on safety devices, suitability to clinical practice and technical compatibility The assessment was qualitative questionnaire by adapting the Centers for Disease Control and Prevention. We evaluated three types of needles, two of them were evaluated by 54 primary care professionals and one for 12 professionals from the hospital. Good acceptance regarding their interaction with technology and patient safety. It was considered effective safety device. The overall rating was satisfactory. Underutilized the material by hospital professionals. There were no differences regarding sex, the hand size, experience, training you received, and type of needle. It prepared a proposal to come in progressively safety needle tube holder in primary care. The evaluation performed in the hospital it was considered insufficient. Interdisciplinary participation is essential to implement measures to safe care. The safety needle evaluated were effective with respect to security professionals and the patient. The involvement of different levels of the organization have developed a proposal for performance improvement adapted to the needs of our environment.


Evolution of host specialization in the Adelgidae (Insecta: Hemiptera) inferred from molecular phylogenetics.
The Adelgidae form a small group of insects in the Aphidoidea. They are cyclically parthenogenetic with host alternating, multiple-generation complex life cycles and are restricted to certain host genera in the Pinaceae. Species that host alternate always have Picea as the primary host where sexual reproduction and gall formation occur, and another genus in the Pinaceae as the secondary host where a series of parthenogenetic generations are produced. Other species that do not host alternate complete their entire life cycle on one host and only reproduce parthenogenetically. We studied relationships within Adelgidae using DNA sequences from the mitochondrial COI, COII, and cytb genes, and the nuclear EF1alpha gene. Analysis of the combined data resulted in a well-resolved phylogeny in which the major adelgid clades correspond neatly to their association with secondary host genera. Specialization on each secondary host genus occurred only once and was followed by diversification on the host genus. Molecular dating of divergence times in the Adelgidae suggest that diversification among host genera occurred in the Late Cretaceous and Early Tertiary when the Pinaceae genera were diverging. It is not clear, however, whether the Adelgidae and Pinaceae co-diversified because the relationships among the Pinaceae genera are not fully resolved. We discuss implications for adelgid taxonomy, life cycle evolution, and evolution of the interaction between adelgids and their host plants.


Serous detachment of the macula associated with advanced glaucomatous cupping.
Enhanced depth imaging of the optic nerve of a patient with a serous detachment and profound cupping of the optic nerve secondary to angle-closure glaucoma revealed a large dehiscence of the lamina cribrosa. Adjacent to the defect in the lamina were cystoid spaces within the nerve appearing to contain fluid. The most temporal of these could be seen to extend through the optic nerve and up into the macula. This visualized pathway suggests that mechanical dehiscence of the lamina may allow fluid, possibly derived from cerebrospinal fluid, to track up into the macula.


Use of genetic knockouts to modulate disease expression in a murine model of lupus, MRL/lpr mice.
MRL-MPJ Fas(lpr) (MRL/lpr) mice are a prototypic murine model for lupus characterized by an accelerated autoimmune syndrome. Disease begins as early as 8-wk-of-age in these animals with polyclonal B cell activation and elevated levels of serum IgM. By 12 to 16-wk-of-age MRL/lpr mice begin to produce a variety of autoantibodies including anti-dsDNA and anti-ss-DNA antibodies. From 16 to 24 wk, MRL/lpr mice develop proliferative immune complex mediated glomerulonephritis, vasculitis, arthritis, and massive lymphadenopathy that results in renal failure and death in 50% of the mice by 24-wk-of-age. This review will discuss several different genetic knockout experimental approaches used to study disease expression in MRL/lpr mice including various approaches in our laboratory aimed at autoantibody (Ab) production and inflammatory mediators.


Talbot-Lau X-ray phase contrast for tiling-based acquisitions without reference scanning.
Grating-based Talbot-Lau interferometers are a popular choice for phase-contrast X-ray acquisitions. Here, an air reference scan has to be acquired prior to an object scan. This particularly complicates acquisition of large objects: large objects are tiled into multiple scans due to the small field of view of current gratings. However, phase reference drifts occurring between these scans may require to repeatedly move the object in and out of the X-ray beam to update the reference information. We developed an image processing technique that completely removes the need for phase reference scans in tiled acquisitions. We estimate the reference from object scans using a tailored iterated robust regression, using a novel efficient optimizer. Our evaluation indicates that the estimated reference is not only close to the acquired reference but also improves the final image quality. We hypothesize that this is because we mitigate errors that are introduced when actually acquiring the reference phase. Phase-contrast imaging of larger objects may benefit from computational estimation of phase reference data due to reduced scanning complexity and improved image quality.


Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts.
Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.


Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial.
Reduced growth hormone (GH) concentrations are observed in men with human immunodeficiency virus (HIV) lipodystrophy. To investigate the effects of growth hormone-releasing hormone (GHRH), a GH secretagogue, in treatment of HIV lipodystrophy. Randomized, double-blind, placebo-controlled trial conducted at a research center in the United States between October 2002 and June 2003 and enrolling 31 HIV-infected men aged 18 to 60 years with evidence of lipodystrophy. Participants were assigned to receive GHRH (1 mg subcutaneously twice daily) or placebo for 12 weeks. The primary outcome was change in concentrations of insulin-like growth factor 1 (IGF-1) to detect overall change in GH levels in response to GHRH. Secondary end points included body composition by dual-energy x-ray absorptiometry and computed tomography, lipodystrophy ratings, and levels of glucose, insulin, and lipids. Mean (SD) IGF-1 concentrations increased significantly in the GHRH group vs the placebo group (104 [110] ng/mL vs 6 [44] ng/mL, P =.004). Lean body mass significantly increased in the GHRH group vs the placebo group (0.9 [1.3] kg vs -0.3 [1.7] kg, P =.04), trunk fat significantly decreased (-0.4 [0.7] kg vs 0.2 [0.6] kg, P =.03), and the ratio of trunk to lower extremity fat improved significantly (-0.22 [0.32] vs 0.14 [0.29], P =.005). Abdominal visceral fat was reduced (-19.2 [36.6] cm2 vs 2.3 [24.3] cm2, P =.07) and the ratio of abdominal visceral fat to abdominal subcutaneous fat improved significantly more in the GHRH group (-0.19 [0.28] vs 0.07 [0.27], P =.02). Both physician and patient rating of lipodystrophy in the arms, legs, and abdomen also improved significantly. Levels of glucose, insulin, and lipids did not change significantly. GHRH was well tolerated and effectively increased levels of IGF-1 in HIV-infected men with lipodystrophy. Total and regional body composition improved in response to GHRH, with increased lean mass and reduced truncal and visceral fat. Use of GHRH may potentially be a beneficial treatment strategy for this population.


Polycrystalline metasurface perfect absorbers fabricated using microsphere photolithography.
Microsphere photolithography (MPL) is a practical, cost-effective nanofabrication technique. It uses self-assembled microspheres in contact with the photoresist as microlenses. The microspheres focus incident light to a sub-diffraction limited array of photonic jets in the photoresist. This Letter explores the MPL technique to pattern metal-insulator-metal metasurfaces with near-perfect absorption at mid-wave infrared (MWIR) frequencies. Experimental results are compared to electromagnetic simulations of both the exposure process and the metasurface response. The microsphere self-assembly technique results in a polycrystalline metasurface; however, the metal-insulator-metal structure is shown to be defect tolerant. While the MPL approach imposes geometric constraints on the metasurface design, once understood, the technique can be used to create functional devices. In particular, the ability to tune the resonant wavelength with the exposure dose raises the potential of hierarchical structures.


Controlled continuous flow delivery system for investigating taste-aroma interactions.
A multichannel flavor delivery system, Dynataste, was developed. Controlled amounts of isoamyl acetate (100 ppm) and sucrose (0-3%) solution was administered to experienced and naïve assessors who used time intensity techniques to record perceived 'fruit' flavor intensity. In-nose volatile delivery was monitored using atmospheric pressure chemical ionization-mass spectrometry. Results indicated that sucrose is a key driver of fruit flavor intensity but that the magnitude of the effect varies between individuals. The combined temporal analysis of chemical stimuli in vivo and sensory data indicate evidence of interactions at a perceptual level. Comparison of experienced and naïve assessors revealed cross-modal interactions in each group, although a subgroup of experienced assessors was unaffected by changes in sucrose concentration. This raises the question of the selected use of experienced panels in cross modal investigations.


IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth.
BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.


Buoyancy under control: underwater locomotor performance in a deep diving seabird suggests respiratory strategies for reducing foraging effort.
Because they have air stored in many body compartments, diving seabirds are expected to exhibit efficient behavioural strategies for reducing costs related to buoyancy control. We study the underwater locomotor activity of a deep-diving species from the Cormorant family (Kerguelen shag) and report locomotor adjustments to the change of buoyancy with depth. Using accelerometers, we show that during both the descent and ascent phases of dives, shags modelled their acceleration and stroking activity on the natural variation of buoyancy with depth. For example, during the descent phase, birds increased swim speed with depth. But in parallel, and with a decay constant similar to the one in the equation explaining the decrease of buoyancy with depth, they decreased foot-stroke frequency exponentially, a behaviour that enables birds to reduce oxygen consumption. During ascent, birds also reduced locomotor cost by ascending passively. We considered the depth at which they started gliding as a proxy to their depth of neutral buoyancy. This depth increased with maximum dive depth. As an explanation for this, we propose that shags adjust their buoyancy to depth by varying the amount of respiratory air they dive with. Calculations based on known values of stored body oxygen volumes and on deep-diving metabolic rates in avian divers suggest that the variations of volume of respiratory oxygen associated with a respiration mediated buoyancy control only influence aerobic dive duration moderately. Therefore, we propose that an advantage in cormorants--as in other families of diving seabirds--of respiratory air volume adjustment upon diving could be related less to increasing time of submergence, through an increased volume of body oxygen stores, than to reducing the locomotor costs of buoyancy control.


Probiotic Administration Increases Amino Acid Absorption from Plant Protein: a Placebo-Controlled, Randomized, Double-Blind, Multicenter, Crossover Study.
The fate of dietary protein in the gut is determined by microbial and host digestion and utilization. Fermentation of proteins generates bioactive molecules that have wide-ranging health effects on the host. The type of protein can affect amino acid absorption, with animal proteins generally being more efficiently absorbed compared with plant proteins. In contrast to animal proteins, most plant proteins, such as pea protein, are incomplete proteins. Pea protein is low in methionine and contains lower amounts of branched-chain amino acids (BCAAs), which play a crucial role in muscle health. We hypothesized that probiotic supplementation results in favorable changes in the gut microbiota, aiding the absorption of amino acids from plant proteins by the host. Fifteen physically active men (24.2 ± 5.0 years; 85.3 ± 12.9 kg; 178.0 ± 7.6 cm; 16.7 ± 5.8% body fat) co-ingested 20 g of pea protein with either AminoAlta™, a multi-strain probiotic (5 billion CFU L. paracasei LP-DG® (CNCM I-1572) plus 5 billion CFU L. paracasei LPC-S01 (DSM 26760), SOFAR S.p.A., Italy) or a placebo for 2 weeks in a randomized, double-blind, crossover design, separated by a 4-week washout period. Blood samples were taken at baseline and at 30-, 60-, 120-, and 180-min post-ingestion and analyzed for amino acid content. Probiotic administration significantly increased methionine, histidine, valine, leucine, isoleucine, tyrosine, total BCAA, and total EAA maximum concentrations (Cmax) and AUC without significantly changing the time to reach maximum concentrations. Probiotic supplementation can be an important nutritional strategy to improve post-prandial changes in blood amino acids and to overcome compositional shortcomings of plant proteins. ClinicalTrials.gov Identifier: ISRCTN38903788.


Endothelin-1 regulates adiponectin gene expression and secretion in 3T3-L1 adipocytes via distinct signaling pathways.
Adiponectin, which is specifically and highly expressed in adipose tissue, has pleiotropic insulin-sensitizing effects. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide mainly produced by endothelial cells. We previously showed that ET-1 can induce insulin resistance in vitro and in vivo and proposed that it might regulate adiponectin expression and secretion, thus affecting the homeostasis of whole-body energy metabolism. In the present study, we explored the regulatory effects of ET-1 on adiponectin expression and secretion and the underlying mechanisms in 3T3-L1 adipocytes using Northern blotting and ELISA. ET-1 was found to cause a significant time- and dose-dependent decrease in adiponectin expression, and this effect was inhibited by the ET type A receptor (ETAR) antagonist BQ-610 but not by the ETBR antagonist BQ-788. To explore the underlying mechanism, we examined the involvement of the cAMP-dependent protein kinase A-, phospholipase A2-, protein kinase C-, and MAPK-mediated pathways using inhibitors and found that only PD98059 and U0126, inhibitors that blocked MAPK/ERK kinase's ability to activate the ERKs, prevented ET-1-induced down-regulation of adiponectin. Furthermore, acute ET-1 treatment significantly stimulated adiponectin secretion by 3T3-L1 adipocytes, and this effect was inhibited by the ETAR antagonist BQ-610, the inositol-1,4,5-triphosphate receptor blocker 2-APB, and phospholipase C inhibitor U73122, showing that the release of adiponectin stimulated by ET-1 was mediated through the ETAR and the inositol-1,4,5-triphosphate pathway. In conclusion, ET-1 regulates adiponectin expression and secretion by two different signaling pathways in 3T3-L1 adipocytes. These findings suggested that the cardiovascular system affects adipocyte physiology by regulating the expression of adipocytokines and, consequently, energy homeostasis via vasoactive factors, such as ET-1.


Does the use of chloramphenicol in animals jeopardise the treatment of human infections?
It has been suggested that the therapeutic use of oral chloramphenicol in animals is liable to select resistance to antibiotics and that the resistance may jeopardise the treatment of infections in man. At present this risk appears minimal; resistance to chloramphenicol in animal bacteria may well be selected by the increasing use of semi-synthetic penicillins because of linkage between genes coding for production of beta-lactamase and resistance to chloramphenicol. Among salmonellae, the strains causing enteric fever have no animal reservoir and the few food poisoning incidents in man that require therapy can be treated with antibacterial agents such as trimethoprim. Chloramphenicol is not now the antibiotic of choice for any human infection except perhaps a few caused by Haemophilus influenzae. Resistance to antibiotics in 'human' cultures has largely been selected by the use of antibiotics in human medicine. Control of salmonellosis is essentially a public health, not a therapeutic problem.


Existence of three regulatory regions each containing a highly conserved motif in the promoter of plastid-encoded RNA polymerase gene (rpoB).
The plastid gene rpoB encodes a plastid-specific, DNA-dependent RNA polymerase. A study of a barley mutant, albostrians, indicated that rpoB itself is transcribed by a nuclear-encoded RNA polymerase. However, the molecular nature of the nuclear-encoded RNA polymerase and mechanisms of the transcriptional regulation of rpoB expression have not been elucidated. Using an in vivo transient assay system for gene expression in plastids, the 5'-flanking region of rpoB from Arabidopsis thaliana in plastids of cultured BY-2 tobacco cells was analyzed. A series of deletion analyses of the 5'-flanking region indicated that there were two positive and one negative regulatory regions for rpoB expression. Comparison of the 5'-flanking sequences of rpoB among several plant species revealed the existence of three conserved motifs in these regions.


Bisphosphonate-induced hypocalcemia associated with vitamin D deficiency in a patient with advanced cancer.
A case is presented of symptomatic hypocalcemia following treatment with bisphosphonates. This patient also had deficiency of 25 hydroxyvitamin D that was unrecognized. The use of bisphosphonates in cancer is increasing, not only in the treatment of hypercalcemia, but also for bone pain and to decrease the risk of skeletal morbidity in metastatic breast cancer, multiple myeloma, and Paget's disease in normocalcemic patients. The patient was probably vitamin D deficient because of a combination of poor oral intake, inadequate sunlight exposure, and the development of renal failure. However despite receiving both parenteral and oral calcium therapy, the serum calcium remained low until the replacement of vitamin D. With increasing use of bisphosphonate therapy in malignant disease, we believe that an assessment of vitamin D status, calcium intake, renal function, phosphate, magnesium, and albumin should be undertaken prior to initiating therapy in most palliative care patients.


Enhancing the radiological classification system from the distal femur to the proximal tibia.
This study aims to identify anatomical variants of the proximal tibia shaft and to develop a novel classification system for proximal tibia. Between October 2019 and April 2020, a total of 200 patients with standard knee anteroposterior radiographs were included in this study. We measured the inner diameter of the tibia 16 cm distally from the tibial plateau and 3 cm distally from the tibial spine. The ratio between these two measurements was applied as the novel index ratio. A total number of 197 patients (100 males and 97 females) with a median age of 68 years (range, 21 to 89 years) were included in the final analysis. According to the 25th and 75th percentiles, three groups were clustered for each sex. A higher distribution of the type B pattern was found in female and male patients. However, type A with a narrow inner diaphyseal diameter was less common in female patients. The median intraobserver reliability for rater 1 was 0.998. The inter-observer reliability was high (intraclass correlation coefficient: 0.998). There was a moderate correlation between the anteroposterior (AP) diameter and height (r=0.568) and a low correlation between the AP diameter and weight (r=0.376). The novel index shows no significant correlation between the index ratio and height (r=0.082), weight (r=0.014) or body mass index (r=-0.038). The novel classification presents three different types of tibia for each sex: type C has a wider inner diaphyseal diameter compared to type A with a narrow inner diaphyseal diameter. Type B has the widest distribution among the subjects.


Analysis of 4-methylpyrazole in plasma and urine by gas chromatography with nitrogen-selective detection.
A simple, sensitive, and specific gas chromatographic method for the quantitation of 4-methylpyrazole in plasma and urine is described. Samples containing 4-methylpyrazole, with 3-methylpyrazole as the internal standard, are extracted into ether and the concentrated ethereal extracts are chromatographed on a Carbowax 20M column using nitrogen-selective detection. Standard curves are linear and reproducible over the range of 25-1000 ng/mL for plasma and 0.5-5 micrograms/mL for urine. Recovery of 4-methylpyrazole is complete from plasma and urine, and the overall between-day coefficient of variation is within 6.0%. No interference is observed from the extractive constituents of plasma and urine. The assay method is suitable for an examination of 4-methylpyrazole disposition in animals and humans.


Gravitational Two-Loop Counterterm Is Asymptotically Safe.
Weinberg's asymptotic safety scenario provides an elegant mechanism to construct a quantum theory of gravity within the framework of quantum field theory based on a non-Gaussian fixed point of the renormalization group flow. In this work we report novel evidence for the validity of this scenario, using functional renormalization group techniques to determine the renormalization group flow of the Einstein-Hilbert action supplemented by the two-loop counterterm found by Goroff and Sagnotti. The resulting system of beta functions comprises three scale-dependent coupling constants and exhibits a non-Gaussian fixed point which constitutes the natural extension of the one found at the level of the Einstein-Hilbert action. The fixed point exhibits two ultraviolet attractive and one repulsive direction supporting a low-dimensional UV-critical hypersurface. Our result vanquishes the long-standing criticism that asymptotic safety will not survive once a "proper perturbative counterterm" is included in the projection space.


Sterol carrier protein-2 mediated cholesterol esterification in transfected L-cell fibroblasts.
The relative function of the 15 and 13.2 kDa forms of SCP-2 in cholesterol trafficking and metabolism was assessed using L-cell fibroblasts permanently transfected with the cDNA encoding for either the mouse 15 kDa or 13.2 kDa SCP-2. Expression of the 15 kDa, but not the 13.2 kDa SCP-2 increased [3H]cholesteryl ester formation from medium derived cholesterol by 30% compared to control cells. In both SCP-2 expressing cell lines, sphingomyelinase treatment increased the initial rate of [3 H]cholesteryl ester formation from plasma membrane derived cholesterol more than 11-fold and elevated [3H]cholesteryl ester levels 1.5-fold compared to control cells. Expression of both proteins resulted in nearly a 1.5-fold increase in [3H]oleic acid esterification into cholesteryl esters, although [3H]oleic acid esterification into triacylglycerols was also increased in the 13.2 kDa SCP-2 expressing cells relative to control. In both transfected cell lines, the cholesteryl ester mass was increased nearly 2-fold compared to control cells, consistent with increased cholesteryl ester synthesis. Similarly, triacylglycerol levels were increased 1.3-fold in the 13.2 kDa SCP-2 expressing cells which is consistent with the increased [3H]oleic acid esterification into triacylglycerol. In the 15 kDa SCP-2 expressing cells, triacylglycerol levels were decreased 60%, but free cholesterol levels were increased 1.2-fold relative to control cells. Thus, only the 15 kDa expression product, containing the putative targeting sequence, specifically enhanced cholesteryl ester formation from either plasma membrane or medium-derived cholesterol. In contrast, the 13.2 kDa expression product, lacking the putative targeting sequence, stimulated an increase in [3H]oleic acid esterification into both cholesterol and triacylglycerol pools, suggesting a non-specific stimulation of fatty acid esterification.


IN SEARCH OF HOMOPLASTIC TENDENCIES: STATISTICAL INFERENCE OF TOPOLOGICAL PATTERNS IN HOMOPLASY.
The "tendency" for homoplasy to appear in closely related taxa has been widely discussed but rarely quantified. This paper proposes statistical tests that examine the topological distribution of homoplasy within characters in phylogenies. They test whether character changes are localized (confined to some subtree), or clustered (occur in proximity to each other), relative to two null models of character evolution. Null Model I assumes that the observed number of character changes are dispersed randomly among the internodes of the tree, whereas Model II weights the probability that an internode contains a change by the length of that internode-estimated by the total number of character changes along that internode. Localization is measured by the largest furthest-neighbor distance between changes, clustering by the mean nearest neighbor distance. Distances are measured either by the number of intervening branches or the number of intervening character changes. Analyses of four cladistic data sets from the literature reveal very few characters that exhibit significant levels of clustering or localization-no more than would be expected by chance. In every data set a majority of characters exhibited at least weak tendencies, but in only one data set was there a significant excess of such characters. The present findings do not provide compelling evidence for the existence of "tendencies" in homoplasy, at least among characters used to reconstruct phylogenies. They should be sought elsewhere, in cladistic analyses of larger scope, probably among a class of characters defined a priori on a structural or functional basis.


Gonadotropins and female sex steroid hormones in cyst fluid and serum from patients with ovarian tumors.
The objective of the present study was to determine the concentrations of LH, FSH, 17beta-estradiol and progesterone in ovarian cyst fluid and serum from patients with benign and malignant ovarian tumors and to assess the correlation of the gonadotropin and female sex steroid hormone concentrations with menopausal and tumor status. Ovarian cyst fluid and blood samples were prospectively collected from 103 patients with ovarian tumors. Seventy-four of the patients had benign ovarian tumors while 29 patients had malignant ovarian tumors. Malignant ovarian tumors showed significantly higher LH and FSH cyst fluid concentrations compared to concentrations from patients with benign tumors. Within the malignant subset, LH and FSH concentrations correlated with increasing FIGO stage and grade. Furthermore, LH and FSH cyst fluid concentrations showed strong correlations (r > 0.62) with serum concentrations in case of malignant tumors, especially in postmenopausal women, but not in case of benign tumors. The highest gonadotropin concentrations were observed in cyst fluid from malignant ovarian tumors. The most probable explanation for this is an increased vascular permeability within the cysts. Supportive evidence for such an increased vascular permeability is our previous finding of significantly higher VEGF concentrations in cyst fluid from malignant ovarian tumors. The possibility of ectopic production of LH and FSH by malignant ovarian tissue cannot completely be ruled out.


CRYSTMET: a database of the structures and powder patterns of metals and intermetallics.
CRYSTMET is a database of critically evaluated crystallographic data for metals (including alloys, intermetallics and minerals) and associated bibliographic, chemical and physical information. Also included are simulated powder diffraction patterns for all of the entries. The database currently contains almost 70,000 entries and covers the literature exhaustively from 1922 to the present. The database is available on CD-ROM with search/analysis software for use on personal computers. This software can be used with any database in the appropriate format; currently CRYSTMET and the ICSD databases are available. This paper describes the database content, the procedures used in its construction, the software made available to the user and a number of potential uses for the data.


Cluster-Glass Phase in Pyrochlore XY Antiferromagnets with Quenched Disorder.
We study the impact of quenched disorder (random exchange couplings or site dilution) on easy-plane pyrochlore antiferromagnets. In the clean system, order by disorder selects a magnetically ordered state from a classically degenerate manifold. In the presence of randomness, however, different orders can be chosen locally depending on details of the disorder configuration. Using a combination of analytical considerations and classical Monte Carlo simulations, we argue that any long-range-ordered magnetic state is destroyed beyond a critical level of randomness where the system breaks into magnetic domains due to random exchange anisotropies, becoming, therefore, a glass of spin clusters, in accordance with the available experimental data. These random anisotropies originate from off-diagonal exchange couplings in the microscopic Hamiltonian, establishing their relevance to other magnets with strong spin-orbit coupling.


Correlation of the disease-specific Canadian Cardiovascular Society (CCS) classification and health-related quality of life (15D) in coronary artery disease patients.
Generic health-related quality of life (HRQoL) and disease-specific instruments measure HRQoL from different aspects, although generic instruments often contain dimensions that reflect common symptoms. We evaluated how the change in 15D HRQoL and Canadian Cardiovascular Society (CCS) grading of angina severity correlate among coronary artery disease patients during 12-month follow-up. Altogether 1 271 patients scheduled for coronary angiography between June 2015 and February 2017 returned the 15D HRQoL and CCS questionnaires before angiography and after one-year follow-up as a part of routine clinical practice. Spearman correlations between one-year changes in the CCS and the 15D and its dimensions were evaluated. Changes in 15D were classified into 5 categories based on the reported minimal important difference (MID) for the instrument. Change in the CCS grade correlated moderately with the MID-based change in the 15D (r = 0.33, 95% confidence interval 0.27-0.39). Correlations between these instruments were similar in different age groups, between sexes and treatment modalities. Of the individual 15D dimensions, changes in breathing (r = 0.40) and vitality (r = 0.30) had the strongest correlations with CCS change. The symptom-based evaluation of the change in the CCS grade may not catch the full benefit or harm of the treatment and vice versa, a generic instrument, such as 15D, likely does not fully capture change in disease-specific symptoms. Thus, generic and disease-specific instruments are complementary and should be used in conjunction.


Spatiotemporal characteristics of organic contaminant concentrations and ecological risk assessment in the Songhua River, China.
To control source pollution and improve water quality, an understanding of the spatiotemporal characteristics of organic contaminant concentrations in affected receiving waters is necessary. The Songhua River in northeast China is the country's third-largest domestic river and loadings of organic contaminants along an industrialized section have made it the focal point of a national pollution reduction plan. In addition to water quality issues, management of the Songhua River basin must also address local economic development, aquatic ecosystem sustainability and political relationships with Russia. In three periods spanning 2006 to 2010, eight polycyclic aromatic hydrocarbons (PAHs) and eight phenols were measured in surface waters at ten monitoring sites along the river. A generalized linear model (GLM) was used to characterize water quality at different sites and time periods. Chemical concentrations of the organic compounds showed significant sinusoidal seasonal patterns and the concentrations declined significantly from 2006 to 2010, possibly due to management practices designed to control water pollution. A critical body residue analysis showed that water concentrations measured during the winter of 2007 across all monitoring sites, but especially at S1-Shaokou and S2-Songhuajiangcun, presented a high risk for fish species. The spatiotemporal characteristics of water quality and estimated ecological risks shown here add to the body of knowledge to develop policies on industrial output and pollution management strategies for the Songhua River basin.


Lack of correlation between nutritional status and seroprotection against influenza in a long term care facility.
We conducted a prospective study in a long-term care facility. Virologic diagnosis was assessed using viral isolation, polymerase chain reaction and serology for all patients with a flu-like syndrome. Albumin, vitamins and trace elements were also measured. The risk of influenza increased 6.5-fold in patients with an antibody titer of 40 during the influenza outbreak (P=0.04). Micronutrients and vitamins deficiencies were important. Patients with antibody titer >1:40 could still be infected by the virus without correlation with the nutritional status. Humoral protection with a titer >1:40 might not be protective in the elderly. Nutritional deficiencies were too prevalent to detect any effect on the results.


Incidence, risk factors and outcomes of Escherichia coli bloodstream infections in a large Canadian region.
Although Escherichia coli is the most common cause of bloodstream infection, its epidemiology has not been well defined in non-selected populations. We sought to describe the incidence of risk factors for, and outcomes associated with, E. coli bacteraemia. Population-based surveillance for E. coli bacteraemia was conducted in the Calgary Health Region (population 1.2 million) during the period 2000-2006. In total, 2368 episodes of E. coli bacteraemia were identified for an overall annual population incidence of 30.3/100 000; 15% were nosocomial, 32% were healthcare-associated community-onset and 53% were community-acquired bacteraemias. The very young and the elderly were at highest risk for E. coli bacteraemia. Sixty per cent of the episodes occurred in females (relative risk 1.5; 95% CI 1.4-1.6). Dialysis, solid organ transplantation and neoplastic disease were the most important risk factors for acquiring E. coli bacteraemia. Rates of resistance to ampicillin, trimethoprim-sulphamethoxazole, gentamicin, ciprofloxacin, cefazolin and ceftriaxone increased significantly during the period 2000-2006. The case-fatality rate was 11% and the annual population mortality rate was 2.9/100 000. Increasing age, ciprofloxacin resistance, non-urinary focus and a number of comorbid illnesses were independently associated with an increased risk of death, and community acquisition and urinary focus were associated with a lower risk of death. This study documents the major burden of illness associated with E. coli bacteraemia and identifies groups at increased risk for acquiring and dying from these infections. The emergence of ciprofloxacin resistance and its adverse effect on patient outcome is a major concern.


User-friendly restorative approach combining shaping indices and PTFE-based stamp techniques: a feasibility example performed by an undergraduate dental student in a dentition damaged by caries and tooth wear.
The rehabilitation of patients with wear on multiple teeth, in which a recovery of the occlusal/incisal vertical dimension is required to acquire satisfactory levels of functionality and esthetics, is often a difficult procedure even for experienced dental practitioners. Based on wax-ups simulating an ideal structural/functional reconstruction of the teeth, the use of shaping indices is a reliable way to plan predictable patient-oriented results when using resin-based composites. The proposal to combine shaping indices with PTFE-based stamp techniques also helps clinicians to easily achieve satisfactory modeling results giving them the unique opportunity to eliminate the presence of composite over-contours before polymerization. By using PTFE-based stamps the requirement to use conventional, strictly transparent indices becomes superfluous. In a clinical case with multiple caries lesions and tooth wear, the advantage of several simple operative measures including PTFE-based stamp procedures are presented as a feasibility example of this noninvasive or minimally invasive restorative approach performed by an undergraduate dental student.


Primary and secondary leiomyosarcoma of the oral and perioral region--clinicopathological and immunohistochemical analysis of a rare entity with a review of the literature.
Leiomyosarcoma (LMS) rarely occurs in the head and neck region. These tumors present with a wide range of clinical features, so the diagnosis is predicated on conventional microscopic findings coupled with immunohistochemical analysis. Clinical and histologic data of 7 patients with LMS of the head and neck were recorded retrospectively. In addition to routine immunohistochemistry, staining for cell cycle regulator proteins p16 and p21 was performed. Five LMSs (4 intraoral, 1 dermal cheek) occurred primarily in the oral and perioral region. Two LMSs (parietal and sinonasal) were diagnosed as metastases originating from the uterus and pelvis. Treatment of the primary LMSs consisted of radical tumor resection with clear margins. Distant metastases from LMSs were irradiated or excised as palliative treatment. Three of 5 patients (60%) with primarily excised LMS developed recurrence after an average of 7 months, with lung metastases occurring after 17 months. In 1 patient, cervical lymph node metastases were detected after 10 months. Of all patients, 5 died after an average survival period of 2.4 years. The mean survival period of the 5 patients with primary LMS of the head and neck was 3.3 years. All tumors were positive for vimentin and α-smooth muscle actin, with 57% of tumors showing positive nuclear expression of p16 and 71% of p21. Lack of p16 nuclear expression was associated with a shorter mean survival time (1.3 vs 4.3 yr for p16 positivity). Lung and cervical lymph node metastases often occur in LMS of the head and neck. Presurgical staging, including gynecologic examination, whole-body computed tomography, and sometimes positron-emission or computed tomography, to rule out LMS metastasis is mandatory. Surgical resection of the tumor should be given top priority. Lack of p16 reactivity may have a prognostic value for LMS because it was related to a trend toward poorer survival.


Influence of microstructure on the transitions between mesoscopic thin-film morphologies in ballistic-diffusive models.
We study the influence of the symmetries of competing microstructures on the emergence of different mesoscopic morphologies in the growth by vapor deposition of thin solid films. We show the results of numerical simulations in (1+1) - and (2+1) -dimensional systems including different microstructures, as well as thermally activated surface diffusion in combination with a ballistic algorithm to model the deposition process. We focus on the characterization of the transitional structures that appear in the empirical structure zone model (SZM) through the evaluation of the mean packing density and the mean coordination number. We show that the maximum coordination number of the underlying microstructure classifies the statistics of the transitional morphologies at the border between zone I in the SZM, characterized by the formation of fractal-like patterns, and zone II, where pronounced faceting develops. We analyze the appearance of lattice frustration and texture competition effects in complex microstructures having mutually exclusive symmetries.


Death with functioning graft--a preventable cause of graft loss.
Patient death continues to be a leading cause of renal transplant failure. This mortality of transplant patients is mainly due to cardiovascular disease (CVD). Identification of predictions of early CVD may provide targets for intervention.


Free flap monitoring: a review of current practice.
Individual techniques for the postoperative monitoring of free flaps vary considerably. In order to establish the currently preferred protocols, a survey was conducted among micro-surgeons in North America using a mailed questionnaire. Data were received from 95 centers for the monitoring of 2,825 free flaps performed during 1994. Results indicate that rates for flap salvage and overall success with free tissue transfer are closely related to surgical experience (number of cases performed per month). Ninety percent of microsurgeons routinely use monitoring devices, with external and laser doppler having achieved greatest popularity. An account is given of the preferred postoperative regimens for flap surveillance, and the overall results are discussed.


Reaction pathways of 2-iodoacetic acid on Cu(100): coverage-dependent competition between C-I bond scission and COOH deprotonation and identification of surface intermediates.
The chemistry of 2-iodoacetic acid on Cu(100) has been studied by a combination of reflection-absorption infrared spectroscopy (RAIRS), X-ray photoelectron spectroscopy (XPS), temperature-programmed reaction/desorption (TPR/D), and theoretical calculations based on density functional theory for the optimized intermediate structures. In the thermal decomposition of ICH(2)COOH on Cu(100) with a coverage less than a half monolayer, three surface intermediates, CH(2)COO, CH(3)COO, and CCOH, are generated and characterized spectroscopically. Based on their different thermal stabilities, the reaction pathways of ICH(2)COOH on Cu(100) at temperatures higher than 230 K are established to be ICH(2)COOH --> CH(2)COO + H + I, CH(2)COO + H --> CH(3)COO, and CH(3)COO --> CCOH. Theoretical calculations suggest that the surface CH(2)COO has the skeletal plane, with delocalized pi electrons, approximately parallel to the surface. The calculated Mulliken charges agree with the detected binding energies for the two carbon atoms in CH(2)COO on Cu(100). The CCOH derived from CH(3)COO decomposition has a CC stretching frequency at 2025 cm(-1), reflecting its triple-bond character which is consistent with the calculated CCOH structure on Cu(100). Theoretically, CCOH at the bridge and hollow sites has a similar stability and is adsorbed with the molecular axis approximately perpendicular to the surface. The TPR/D study has shown the evolution of the products of H(2), CH(4), H(2)O, CO, CO(2), CH(2)CO, and CH(3)COOH from CH(3)COO decomposition between 500 and 600 K and the formation of H(2) and CO from CCOH between 600 and 700 K. However, at a coverage near one monolayer, the major species formed at 230 and 320 K are proposed to be ICH(2)COO and CH(3)COO. CH(3)COO becomes the only species present on the surface at 400 K. That is, there are two reaction pathways of ICH(2)COOH --> ICH(2)COO + H and ICH(2)COO + H --> CH(3)COO + I (possibly via CH(2)COO), which are different from those observed at lower coverages. Because the C-I bond dissociation of iodoethane on copper single crystal surfaces occurs at approximately 120 K and that the deprotonation of CH(3)COOH on Cu(100) occurs at approximately 220 K, the preferential COOH dehydrogenation of monolayer ICH(2)COOH is an interesting result, possibly due to electronic and/or steric effects.


The Snail-killing Flies (Diptera: Sciomyzidae) of West Africa.
A review of the West African "snail-killing flies" or "marsh flies" (Sciomyzidae) shows that the fauna is not as dominated by the generally aquatic, predaceous genus Sepedon as was previously considered. Twenty species in seven genera, including three new species, Colobaea occidentalis, Pteromicra zariae and Sepedonella castanea are recorded. The Holarctic-Oriental genera Colobaea and Pteromicra are documented from Africa south of the Sahara for the first time. Biogeographical analyses based on the discovery of "Palaearctic" genera of Diptera south of the Sahara, faunal connections, and dispersal routes are presented. A key for identification and illustrations of diagnostic characters for some species are included.


The impact of coronavirus disease 2019 pandemic on bronchiolitis (lower respiratory tract infection) due to respiratory syncytial virus: A systematic review and meta-analysis.
The coronavirus disease 2019 (COVID-19) pandemic has changed the epidemiology of respiratory syncytial virus (RSV) infection which accounts for most bronchiolitis and viral pneumonias in infants. This systematic review and meta-analysis aimed to quantitatively assess the effect of the COVID-19 pandemic on RSV-associated bronchiolitis among hospitalized infants. The study protocol was registered in the PROSPERO database (CRD42022314000) and was designed based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines updated in May 2020. The meta-analysis component was modified appropriately to synthesize the pooled proportion of infants having RSV-associated bronchiolitis before the COVID-19 pandemic in 2019 and during the pandemic with 95% confidence interval (CI). We identified and screened 189 articles and systematically reviewed 50 full texts. Eight qualified studies from Europe and China, including 109,186 symptomatic cases of bronchiolitis before the pandemic in 2019 and 61,982 cases in 2020-2021 were pooled by random-effects meta-analysis. The quantitative analysis included laboratory-confirmed RSV infection in 7691 infants with bronchiolitis reported before the pandemic in 2019. Meanwhile, during the pandemic, 4964 bronchiolitis cases were associated with RSV infection. The pooled proportion of RSV-associated bronchiolitis cases before the pandemic in 2019 was 16.74% (95% CI 11.73, 22.43%, 95% prediction interval 0.032, 34.16). The pooled proportion of confirmed RSV cases during the pandemic in 2020/2021 was 19.20% (95% CI 12.01, 27.59%, 95% prediction interval 0.046, 42.35). There was an increase in RSV activity after the relaxation of stringent public health measures during the COVID-19 pandemic.


Serum chromogranin A for the diagnosis of gastroenteropancreatic neuroendocrine neoplasms and its association with tumour expression.
The aim of the present study was to assess the clinical value of serum chromogranin A (CgA) levels in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and to compare them with tumour expression of CgA. A total of 109 consecutive patients with confirmed GEP-NENs were enrolled in this prospective study between December 2012 and August 2016, including 73 patients with primary or recurrent GEP-NENs and 36 patients with GEP-NENs that were treated following surgery. Furthermore, 30 patients with benign gastrointestinal diseases and 30 healthy volunteers served as control groups. Serum CgA levels were measured by ELISA, using different reference values, in order to evaluate its diagnostic efficacy. Serum neuron-specific enolase was also measured to evaluate its diagnostic efficacy and analyse its association with serum CgA levels. The levels of CgA, synaptophysin and neural cell adhesion molecule 1 in the tumour tissue were assessed by immunohistochemical assays. The results indicated that serum CgA levels were significantly higher in patients with GEP-NENs compared with the control groups (P<0.05). No association was observed between serum CgA levels and tumour grade (G1, G2 and G3), but serum CgA levels differed significantly between patients with GEP-NENs of different origins (P<0.05). A serum CgA cut-off value of 85.3 ng/ml was associated with high sensitivity (64.4%) and specificity (92.7%). Different reference values were recommended for NENs of different origins, with serum CgA cut-off values of 96.72, 51.13 and 86.19 ng/ml for the stomach, intestines and pancreas, respectively. The serum CgA levels were consistent with the CgA expression in the tumour. In conclusion, serum CgA may serve as a circulating pathological biomarker for the diagnosis of GEP-NENs. The use of different reference values for different tumour origins may improve the diagnostic efficacy of CgA for GEP-NENs. A cut-off value of 85.3 ng/ml is recommended in the Chinese population.


Resonant fermi gases with a large effective range.
We calculate the equation of state of a Fermi gas with resonant interactions when the effective range is appreciable. Using an effective field theory for a large scattering length and large effective range, we show how calculations in this regime become tractable. Our results are model independent, and as an application, we study the neutron matter equation of state at low densities of astrophysical interest 0.002 fm(-3) < rho < 0.02 fm(-3), for which the interparticle separation is comparable to the effective range. We compare our simple results with those of conventional many-body calculations.


How "mixed" is mixed language phonology? An acoustic analysis of the Michif vowel system.
Michif, a severely endangered language still spoken today by an estimated 100-200 Métis people in Western Canada, is generally classified as a mixed language, meaning it cannot be traced back to a single language family [Bakker (1997). A Language of Our Own (Oxford University Press, Oxford); Thomason (2001). Language Contact: An Introduction (Edinburgh University Press and Georgetown University Press, Edinburgh and Washington, DC); Meakins (2013). Contact Languages: A Comprehensive Guide (Mouton De Gruyter, Berlin), pp. 159-228.]. It has been claimed to maintain the phonological grammar of both of its source languages, French and Plains Cree [Rhodes (1977). Actes du Huitieme congrès des Algonqunistes (Carleton University, Ottawa), pp. 6-25; Bakker (1997). A Language of Our Own (Oxford University Press, Oxford); Bakker and Papen (1997). Contact Languages: A Wider Perspective (John Benjamins, Amsterdam), pp. 295-363]. The goal of this paper is twofold: to offer an instrumental analysis of Michif vowels and to investigate this claim of a stratified grammar, based on this careful phonetic analysis. Using source language as a variable in the analysis, the authors argue the Michif vowel system does not appear to rely on historical information, and that historically similar French and Cree vowels pattern together within the Michif system with regards to formant frequencies and duration. The authors show that there are nine Michif oral vowels in this system, which has merged phonetically similar French- and Cree-source vowels.


High Performance Liquid Chromatography-mass Spectrometry Analysis of High Antioxidant Australian Fruits with Antiproliferative Activity Against Cancer Cells.
High antioxidant capacities have been linked to the treatment and prevention of several cancers. Recent reports have identified several native Australian fruits with high antioxidant capacities. Despite this, several of these species are yet to be tested for anticancer activity. Solvent extracts prepared from high antioxidant native Australian fruits were analyzed for antioxidant capacity by the di (phenyl)-(2,4,6-trinitrophenyl) iminoazanium free radical scavenging assay. Antiproliferative activities against CaCo2 and HeLa cancer cells were determined by a multicellular tumor spheroid-based cell proliferation assay. Toxicity was determined by Artemia franciscana bioassay. Methanolic extracts of all plant species displayed high antioxidant contents (equivalent to approximately 7-16 mg of vitamin C per gram of fruit extracted). Most aqueous extracts also contained relatively high antioxidant capacities. In contrast, the ethyl acetate, chloroform, and hexane extracts of most species (except lemon aspen and bush tomato) had lower antioxidant contents (below 1.5 mg of vitamin C equivalents per gram of plant material extracted). The antioxidant contents correlated with the ability of the extracts to inhibit proliferation of CaCo2 and HeLa cancer cell lines. The high antioxidant methanolic extracts of all species were potent inhibitors of cell proliferation. The methanolic lemon aspen extract was particularly effective, with IC50 values of 480 and 769 μg/mL against HeLa and CaCo2 cells, respectively. In contrast, the lower antioxidant ethyl acetate and hexane extracts (except the lemon aspen ethyl acetate extract) generally did not inhibit cancer cell proliferation or inhibited to only a minor degree. Indeed, most of the ethyl acetate and hexane extracts induced potent cell proliferation. The native tamarind ethyl acetate extract displayed low-moderate toxicity in the A. franciscana bioassay (LC50 values below 1000 μg/mL). All other extracts were nontoxic. A total of 145 unique mass signals were detected in the lemon aspen methanolic and aqueous extracts by nonbiased high-performance liquid chromatography-mass spectrometry analysis. Of these, 20 compounds were identified as being of particular interest due to their reported antioxidant and/or anticancer activities. The lack of toxicity and antiproliferative activity of the high antioxidant plant extracts against HeLa and CaCo2 cancer cell lines indicates their potential in the treatment and prevention of some cancers. Australian fruit extracts with high antioxidant contents were potent inhibitors of CaCo2 and HeLa carcinoma cell proliferationMethanolic lemon aspen extract was particularly potent, with IC50 values of 480 μg/mL (HeLa) and 769 μg/mL (CaCo2)High-performance liquid chromatography-mass spectrometry-quadrupole time-of-flight analysis highlighted and putatively identified 20 compounds in the antiproliferative lemon aspen extractsIn contrast, lower antioxidant content extracts stimulated carcinoma cell proliferationAll extracts with antiproliferative activity were nontoxic in the Artemia nauplii assay. Abbreviations used: DPPH: di (phenyl)- (2,4,6-trinitrophenyl) iminoazanium, HPLC: High-performance liquid chromatography, IC50: The concentration required to inhibit by 50%, LC50: The concentration required to achieve 50% mortality, MS: Mass spectrometry.


Short-term and long-term memory deficits in handedness learning in mice with absent corpus callosum and reduced hippocampal commissure.
The corpus callosum (CC) and hippocampal commissure (HC) are major interhemispheric connections whose role in brain function and behaviors is fascinating and contentious. Paw preference of laboratory mice is a genetically regulated, adaptive behavior, continuously shaped by training and learning. We studied variation with training in paw-preference in mice of the 9XCA/WahBid ('9XCA') recombinant inbred strain, selected for complete absence of the CC and severely reduced HC. We measured sequences of paw choices in 9XCA mice in two training sessions in unbiased test chambers, separated by one-week. We compared them with sequences of paw choices in model non-learner mice that have random unbiased paw choices and with those of C57BL/6JBid ('C57BL/6J') mice that have normal interhemispheric connections and learn a paw preference. Positive autocorrelation between successive paw choices during each session and change in paw-preference bias between sessions indicate that 9XCA mice have weak, but not null, learning skills. We tested the effect of the forebrain commissural defect on paw-preference learning with the independent BTBR T+ tf/J ('BTBR') mouse strain that has a genetically identical, non-complementing commissural trait. BTBR has weak short-term and long-term memory skills, identical to 9XCA. The results provide strong evidence that CC and HC contribute in memory function and formation of paw-preference biases.


Phylogenomics and historical biogeography of the cleptoparasitic bee genus Nomada (Hymenoptera: Apidae) using ultraconserved elements.
The genus Nomada Scopoli (Hymenoptera: Apidae) is the largest genus of brood parasitic bees with nearly 800 species found across the globe and in nearly all biogeographic realms except Antarctica. There is no previous molecular phylogeny focused on Nomada despite their high species abundance nor is there an existing comprehensive biogeography for the genus. Using ultraconserved element (UCE) phylogenomic data, we constructed the first molecular phylogeny for the genus Nomada and tested the monophyly of 16 morphologically established species groups. We also estimated divergence dates using fossil calibration points and inferred the geographic origin of this genus. Our phylogeny recovered 14 of the 16 previously established species groups as monophyletic. The superba and ruficornis groups, however, were recovered as non-monophyletic and need to be re-evaluated using morphology. Divergence dating and historic biogeographic analyses performed on the phylogenetic reconstruction indicates that Nomada most likely originated in the Holarctic ∼ 65 Mya. Geodispersal into the southern hemisphere occurred three times: once during the Eocene into the Afrotropics, once during the Oligocene into the Neotropics, and once during the Miocene into Australasia. Geodispersal across the Holarctic was most frequent and occurred repeatedly throughout the Cenozoic era, using the De Geer, Thulean, and the Bering Land Bridges. This is the first instance of a bee using both the Thulean and De Geer land bridges and has implications of how early bee species dispersed throughout the Palearctic in the late Cretaceous and early Paleogene.


Acute myocardial infarction and transient elevated anticardiolipin antibody in a young adult with possible familial hypercholesterolemia: a case report : Anticardiolipin antibody and myocardial infarction.
Familial hypercholesterolemia (FH) can lead to premature coronary heart disease. Anticardiolipin antibody may be a contributor for thrombosis. Here, we report an adult with possible FH suffered from premature myocardial infarction that may be triggered by transient increased anticardiolipin antibody. A 29-year-old male had presented with a history of 2-h chest pain and numbness of left upper arm before 5 days. The electrocardiogram (ECG) had demonstrated inferior wall myocardial infarction (MI). Five days later he was admitted to our hospital and diagnosed as acute MI and possible FH (premature coronary heart disease, low density lipoprotein cholesterol of 5.90 mmol/L) with increased anticardiolipin antibody (up to 120 RU/ml). Other auto-antibodies including β2-glicoprotein antibodies IgM, IgA, IgG, lupus anticoagulant (LA), antinuclear antibodies, anti-myocardial antibody were normal. Coronary artery angiography (CAG) showed right coronary artery was total occlusion from the middle segment. Then he underwent percutaneous coronary intervention with a stent. Four days later, he was discharged with complete recovery. CAG showed intra-stent restenosis and anticardiolipin antibody level was normal and the patient had no any symptoms at 6-month follow-up. Transient elevated anticardiolipin antibody may be a trigger or biomarker of cardiac thrombotic events in younger atherosclerotic patients.


Dendritic Architecture of Principal Basolateral Amygdala Neurons Changes Congruently with Endocrine Response to Stress.
Animals cope with changing environments through changes in behavior. Such plasticity is, however, marked by substantial inter-individual variability. Neuroendocrine reactivity to challenging environments can be an important predictor of resilience. Both basolateral amygdala (BLA) neurons and adrenal glucocorticoid signaling are integral parts of the stress neuroendocrine response. In this report, we test if individual variation in hormonal response to stress is associated with individual variation in the dendritic complexity of BLA neurons. We report a positive correlation between inter-individual variability in glucocorticoid response and neuronal plasticity in the BLA subsequent to a stressor. This suggests that stressful experiences in the past act as significant sculptors of BLA neuronal plasticity and congruent neuroendocrine response.


Association study of wheat grain protein composition reveals that gliadin and glutenin composition are trans-regulated by different chromosome regions.
Wheat grain storage protein (GSP) content and composition are the main determinants of the end-use value of bread wheat (Triticum aestivum L.) grain. The accumulation of glutenins and gliadins, the two main classes of GSP in wheat, is believed to be mainly controlled at the transcriptional level through a network of transcription factors. This regulation network could lead to stable cross-environment allometric scaling relationships between the quantity of GSP classes/subunits and the total quantity of nitrogen per grain. This work conducted a genetic mapping study of GSP content and composition and allometric scaling parameters of grain N allocation using a bread wheat worldwide core collection grown in three environments. The core collection was genotyped with 873 markers for genome-wide association and 167 single nucleotide polymorphism markers in 51 candidate genes for candidate association. The candidate genes included 35 transcription factors (TFs) expressed in grain. This work identified 74 loci associated with 38 variables, of which 19 were candidate genes or were tightly linked with candidate genes. Besides structural GSP genes, several loci putatively trans-regulating GSP accumulation were identified. Seven candidate TFs, including four wheat orthologues of barley TFs that control hordein gene expression, were associated or in strong linkage disequilibrium with markers associated with the composition or quantity of glutenin or gliadin, or allometric grain N allocation parameters, confirming the importance of the transcriptional control of GSP accumulation. Genome-wide association results suggest that the genes regulating glutenin and gliadin compositions are mostly distinct from each other and operate differently.


Call of the wild: creating a formal wilderness medicine elective for Canadian pre-clerkship medical students.
Wilderness medicine education is interesting to medical students, yet not widely implemented in Canadian medical curricula. We describe a curriculum for a pre-clerkship wilderness medicine elective at a Canadian medical school. Our study reports increased student awareness of career opportunities in wilderness medicine after elective completion, and interest in hands-on learning for wilderness medicine topics. Medical schools may benefit from incorporating feedback from our elective towards a successful wilderness medicine curriculum in their own programs.


An explicit algorithm for fully flexible unit cell simulation with recursive thermostat chains.
Through the combination of the recursive multiple thermostat (RMT) Nose-Poincare and Parrinello-Rahman methods, the recursive multiple thermostat chained fully flexible unit cell (RMT-NsigmaT) molecular dynamics method is proposed for isothermal-isobaric simulation. The RMT method is known to have the advantage of achieving the ergodicity that is required for canonical sampling of the harmonic oscillator. Thus, an explicit time integration algorithm is developed for RMT-NsigmaT. We examine the ergodicity for various parameters of RMT-NsigmaT using bulk and thin film structures with different numbers of copper atoms and thicknesses in various environments. Through the numerical simulations, we conclude that the RMT-NsigmaT method is advantageous in the cases of lower temperatures.


Evaluation of WO2013125543, WO2013146963 and EP2634185: the first Tyk2 inhibitors from Takeda and Sareum.
Three patent applications, from two different companies, claim structurally novel Tyk2 inhibitors and their uses for the treatment of autoimmune diseases. In EP-2634185 Sareum claims 5-anilino-2-(2-halophenyl)-oxazole-4-carboxamide derivatives which are shown to be nanomolar potency Tyk2 inhibitors with 10 - 100-fold selectivity over JAK1, JAK2 and JAK3. Takeda's WO-2013125543 and WO-2013146963 claim two distinct structural classes of Tyk2 inhibitors. The first application claims inhibitors based on an unusual 1,5-dihydro-4H-pyrazolo[4,3-c]pyridine-4-one scaffold and the second claims 1-(2-arylaminopyrimidin-4-yl)-pyrrolidin-2-one derivatives. One example of the latter was shown to be orally active in an IL-23-induced inflammation model.