Inhibition of Sox2 Expression in the Adult Neural Stem Cell Niche In Vivo by Monocationic-based siRNA Delivery.
RNA interference (RNAi) is a major tool for basic and applied investigations. However, obtaining RNAi data that have physiological significance requires investigation of regulations and therapeutic strategies in appropriate in vivo settings. To examine in vivo gene regulation and protein function in the adult neural stem cell (NSC) niche, we optimized a new non-viral vector for delivery of siRNA into the subventricular zone (SVZ). This brain region contains the neural stem and progenitor cells populations that express the stem cell marker, SOX2. Temporally and spatially controlled Sox2 knockdown was achieved using the monocationic lipid vector, IC10. siRNA/IC10 complexes were stable over time and smaller (<40 nm) than jetSi complexes (≈400 nm). Immunocytochemistry showed that siRNA/IC10 complexes efficiently target both the progenitor and stem cell populations in the adult SVZ. Injection of the complexes into the lateral brain ventricle resulted in specific knockdown of Sox2 in the SVZ. Furthermore, IC10-mediated transient in vivo knockdown of Sox2-modulated expression of several genes implicated in NSC maintenance. Taken together, these data show that IC10 cationic lipid formulation can efficiently vectorize siRNA in a specific area of the adult mouse brain, achieving spatially and temporally defined loss of function.Molecular Therapy-Nucleic Acids (2013) 2, e89; doi:10.1038/mtna.2013.8; published online 23 April 2013.


Radiofrequency ablation for hepatocellular carcinoma abutting the diaphragm: the value of artificial ascites.
Ultrasound (US)-guided percutanoeus radiofrequency (RF) ablation is difficult to perform for treating a hepatic tumor abutting the diaphragm due to a poor sonic window and high risk of diaphragmatic thermal injury. RF ablation with assistance of the use of artificial ascites is a simple and safe technique for treating a hepatic dome tumor abutting the diaphragm. One can improve the sonic window and separate the RF ablation zone from the diaphragm by downward displacement of the liver with the use of a simple and inexpensive technique. Dextrose water solution is an ideal fluid due to its nonionic nature. Complications related to the use of artificial ascites including hemoperitoneum are rare. Peritoneal adhesion and tumor location in the bare area are the limitations for the application of this technique.


An approach to ablate and pace:AV junction ablation and pacemaker implantation performed concurrently from the same venous access site.
Atrioventricular junction (AVJ) ablation combined with permanent pacemaker implantation (the "ablate and pace" approach) remains an acceptable alternative treatment strategy for symptomatic, drug-refractory atrial fibrillation (AF) with rapid ventricular response. This case series describes the feasibility and safety of catheter ablation of the AVJ via a superior vena caval approach performed during concurrent dual-chamber pacemaker implantation. A total of 17 consecutive patients with symptomatic, drug-refractory, paroxysmal AF underwent combined AVJ ablation and dual-chamber pacemaker implantation procedure using a left axillary venous approach. Two separate introducer sheaths were placed into the axillary vein. The first sheath was used for implantation of the pacemaker ventricular lead, which was then connected to the pulse generator. Subsequently, a standard ablation catheter was introduced through the second axillary venous sheath and used for radiofrequency (RF) ablation of the AVJ. After successful ablation, the catheter was withdrawn and the pacemaker atrial lead was advanced through that same sheath and implanted in the right atrium. Catheter ablation of the AVJ was successfully achieved in all patients. The median number of RF applications required to achieve complete AV block was three (range 1-10). In one patient, AV conduction recovered within the first hour after completion of the procedure, and AVJ ablation was then performed using the conventional femoral venous approach. There were no procedural complications. Catheter ablation of the AVJ can be performed successfully and safely via a superior vena caval approach in patients undergoing concurrent dual-chamber pacemaker implantation.


Iron status and cellular immune competence.
There is increasing evidence that both iron overload and iron deficiency are associated with significant abnormalities of immune function. In diseases associated with iron overload there is increased susceptibility to both infection and neoplasia. The precise mechanisms are still being unravelled but iron overload has been shown to impair antigen-specific immune responses and to reduce the number of functional helper precursor cells. Similarly, iron in vitro in concentrations reported to be present in the serum of patients with iron overload impairs the generation of cytotoxic T-cells, enhances suppressor T-cell activity and reduces the proliferative capacity of helper T-cells. The predominant tumor seen in iron overload is primary hepatocellular carcinoma; however other aetiological factors appear to be involved in addition to iron overload, especially hepatic cirrhosis. Nevertheless, primary liver cancer occurs much more frequently in hemochromatosis than in other forms of cirrhosis. Iron deficiency is associated with an altered response to infection but the relationship is again a complex one. The cellular mechanisms involved have yet to be clearly defined, although impaired T and B cell function have been demonstrated.


System dynamics simulation of occupational health and safety management causal model based on NetLogo.
The occupational health and safety management factors of construction enterprises are critical influencing factors in their training management, and their causal principles are topics that warrant profound exploration. Drawing upon the conventional five factors, this study initially posited and authenticated a causal model among them, subsequently employing system dynamics on the NetLogo platform to dynamically simulate the model, and ultimately scrutinizing the interrelations and dynamic influence degree among the factors. The results show that the direct causes of management factors include human factors (weight coefficient of 0.583) and method factors (weight coefficient of 0.405), and environmental factors directly affect human factors (weight coefficient of 0.994), whereas material factors directly affect method factors (weight coefficient of 0.918). At the same time, it can be seen from the dynamic simulation results that the influence of human factors and method factors on management factors increases sharply in the nascent phase of the simulation cycle (the highest slope is .90), gradually decreases in the intermediary phase (the slope of the inflection point is .11), and is relatively stable in the final phase (the slope is less than 0.11). Three main conclusions have been drawn from this. Firstly, management factors are directly and positively affected by human factors and method factors respectively. Secondly, the interplay between diverse factors evinces a confluence of periodicity and exponential attributes. Thirdly, in each management cycle (set at 381 steps), the main focus is on controlling the causal factors in the early stages of management, with pivotal control points in steps 25 and 100, and the principal management factors comprising the management organization, operating procedures, and protective measures.


Efficacy of balloon dilation in the treatment of symptomatic Eustachian tube dysfunction: One year follow-up study.
Eustachian tube balloon dilation (ETBD) has been recently described as feasible treatment for patients with refractory Eustachian tube dysfunction (ETD). The aim of this study was to evaluate the efficacy of ETBD in the treatment of symptomatic Eustachian tube dysfunction (SETD) by subjective and objective analysis. Forty patients who underwent ETBD were included in the study. Subjects' inclusion criteria were as follows: symptoms of ETD (aural fullness predominantly, with or without otalgia, muffle hearing and tinnitus), normal tympanic membrane, type A or C tympanograms, and without a history of any middle ear diseases. Main outcomes including subjective improvement, otoscopy, pure-tone audiometry, impedance audiometry, R-value in tubomanometry (TMM) at three pressure measurements (30, 40, and 50 mbar), Eustachian Tube Score (ETS) and the ability to perform a Valsalva maneuver were assessed preoperatively, 1 week, 3 months and 12 months postoperatively. All cases were dilated successfully. A significant effect of treatment was documented when measuring subjective improvement, impedance audiometry, R-value in TMM, ETS and the ability to perform a Valsalva maneuver 1 week, 3 months and 12 month postoperatively. Subjective symptoms were not relieved only in one patient. The overall success rate for all patients was 98%. ETBD can provide both short- and long-term benefits to those who are diagnosed SETD and refractory to medical management. SETD might be an optimal indication for ETBD in the treatment of ETD.


Activation of normal and abnormal human factor IX with trypsin.
Human factor IX is activated to factor IXa beta when factor XIa cleaves two peptide bonds, Arg 145-Ala 146 and Arg 180-Val 181, to release an activation peptide. In factor IX Chapel Hill (IXCH), isolated from a hemophilia B patient with a mild bleeding disorder, the arginine 145 residue has been replaced with a histidine. Thus factor IXCH is activated by factor XIa by cleaving only at the Arg 180-Val 181 bond, leaving the activation peptide attached, and resulting in an activated species, factor IXa alpha CH, that, like normal factor IXa alpha, is only 20% as active as factor IXa beta. It is reported that both factor IX and factor IXCH could be activated by trypsin to forms of factor IXa beta and factor IXa beta CH that had clotting activities identical to factor XIa-activated factor IX. Amino-terminal amino acid sequence analysis showed that trypsin cleaved factor IX at the same bonds as did factor XIa; factor IXCH was cleaved at the Arg 180-Val 181 bond, as normal, and was cleaved near the histidine 145, at the Lys 142-Leu 143 bond, releasing a slightly larger activation peptide than from normal factor IXa beta. Metal ions had no effect on the rate of activation of factor IX by trypsin; however, metal ions had a profound effect on the rate at which further incubation with trypsin inactivated factor IXa. Calcium and manganese protected factor IXa from inactivation by trypsin more effectively than magnesium, which was more effective than no metal ion. It is concluded that trypsin can activate normal factor IX and factor IXCH to fully active IXa beta forms.


The troubles with peer review for allocating research funding: Funders need to experiment with versions of peer review and decision-making.
Peer review to allocate funding for researchers and projects has faced difficulties lately and come under criticism. Various alternatives and improvements are being tested to address these problems.


To evaluate whether there is a relationship between occlusion and body posture as delineated by a stabilometric platform: A systematic review.
To evaluate whether there is a relationship between occlusion and body posture evaluated using a stabilometric platform. Observational studies that analyzed the relationship between dental occlusion (changes in mandibular position and/or dental malocclusion) and body posture evaluated with a stabilometric platform in patients older than 13 years without orthodontic or orthopedic intervention and systemically healthy were considered eligible for inclusion. PubMed, EMBASE, Science Direct, LILACS, and Google Scholar databases were searched to obtain articles published from September 2019 up to March 2020. Twelve articles met the inclusion criteria, of which 66.7% showed a relationship between dental occlusion and body posture, and 33.3% found no relationship. The marked heterogeneity between studies did not allow data to be combined for meta-analyses. For the mandibular positions, the postural changes were mainly in the mediolateral direction, while in the malocclusions, they were in the anteroposterior direction.


Magnetic resonance imaging visualization of a vaginal septum.
Magnetic resonance imaging is considered the gold-standard imaging technique in cases of Müllerian and vaginal anomalies, however, vaginal delineation often proves difficult, owing to the fact that vaginal walls are normally collapsed and in close proximity. Instilling gel through the introitus allows for better depiction of the distal vagina.


Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics.
Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (p < 0.05, impact = 0.50), pyrimidine metabolism (p < 0.05, impact = 0.08), and β-alanine metabolism (p < 0.05, impact = 0.06). Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS.


Sustainability spillover effects and partnership between East Asia & Pacific versus North America: interactions of social, environment and economy.
The three sustainability pillars of social, environment and economy were initially introduced by the United Nations in 2002, addressing major global sustainability issues including economic problems, income inequality, environmental pollution and social shortcomings. Comparing East Asia & Pacific with North America, there is a growing concern over economic, political and even social competition as a result of recent development and industrialization that is taking place in Asian countries. This might lead to an unhealthy conflict that favors regional independency as opposed to the current globalization and trade facilitation trend. As a result, this study aims to assess the effects of development in three main pillars of sustainability (social, environment and economy) in the East Asia and Pacific on that of North America and vice versa. To estimate this interactive or spillover effects of sustainable development (or sustainability elasticities), our research employs Econometric methodologies including Simultaneous Equations System, Vector AutoRegressive (VAR) and Granger Causality approaches during 1971-2016. The results show that most of the sustainability elasticities are positive between and inside the two regions, supporting the synergetic character of the sustainability spillover effects and confirming constructive role of globalization and openness in the sustainability progress. Based on the results, this research suggests policy-makers to follow cooperative and flow-based governance rather than the placed-based or regional independent thinking that supports integrated sustainable development benefiting not only the two parties but also the overall global sustainability.


Masked face recognition with convolutional visual self-attention network.
With the global outbreak of COVID-19, wearing face masks has been actively introduced as an effective public measure to reduce the risk of virus infection. This measure leads to the failure of face recognition in many cases. Therefore, it is very necessary to improve the recognition performance of masked face recognition (MFR). Inspired by the successful application of self-attention in computer vision, we propose a Convolutional Visual Self-Attention Network (CVSAN), which uses self-attention to augment the convolution operator. Specifically, this is achieved by connecting a convolutional feature map, which enforces local features, to a self-attention feature map that is capable of modeling long-range dependencies. Since there is currently no publicly available large-scale masked face data, we generate a Masked VGGFace2 dataset based on the face detection algorithm to train the CVSAN model. Experiments show that the CVSAN algorithm significantly improves the performance of MFR compared to other algorithms.


Subcellular localization of intracellular protein tyrosine phosphatases in T cells.
A high protein tyrosine phosphatase (PTPase) activity is required to maintain circulating T lymphocytes in a resting phenotype, and to limit the initiation of T cell activation. We report that 15 of the currently known 24 intracellular PTPases are expressed in T cells, namely HePTP, TCPTP, SHP1, SHP2, PEP, PTP-PEST, PTP-MEG2, PTEN, PTPH1, PTP-MEG1, PTP36, PTP-BAS, LMPTP, PRL-1 and OV-1. Most were found in the cytosol and many were enriched at the plasma membrane. Only TCPTP and PTP-MEG2 had subcellular localizations that essentially excludes them from a direct role in early T cell antigen receptor signaling events. Overexpression of 6 of the PTPases reduced IL-2 gene activation, 3 of them thereby identified as novel candidates for negative regulators of TCR signaling. Our findings expand the repertoire of PTPases that should be considered for a regulatory role in T cell activation.


Normal vitreous promotes angiogenesi via the epidermal growth factor receptor.
Vitreous, a transparent tissue in our body, contains anti-angiogenesis factors. Our previous work reported that vitreous activates the signaling pathway of epidermal growth factor receptor (EGFR), which plays a critical role in angiogenesis. The aim of this study was to determine the role of EGFR in vitreous-induced angiogenesis-related cellular responses in vitro. Using a pharmacologic and molecular approach, we found that vitreous increased proliferation and migration via EGFR in human umbilical vein endothelial cells (HUVECs). Furthermore, we demonstrated that vitreous promoted tube formation via EGFR in HUVECs. Subsequently, depletion of EGFR using CRISPR/Cas9 and blockage with EGFR inhibitor AG1478 suppressed vitreous-induced Akt activation and cell proliferation, migration, and tube formation in HUVECs. The significance of the angiogenic effect derived from vitreous demonstrates the importance of vitreous in the ocular physiology and the pathobiology of angiogenesis-related ophthalmic diseases, such as proliferative diabetic retinopathy.


Comparison of mesenchymal stem cells obtained from different human tissues.
We studied mesenchymal stem cells from human bone marrow, adipose tissue, skin, placenta, and thymus. Morphological study and cytofluorometrical analysis by the main marker genes (CD10, CD13, CD31, CD44, CD90, CD105) were carried out. Mesemchymal stem cells of the studied tissues during isolation and culturing were morphologically similar and did not differ by the expression of the main marker genes.


Reciprocal associations between teacher-student relations and students' externalizing behavior in elementary education? A within-dyad analysis.
The goal of this study was to investigate the transactional link between the affective quality of teacher-student relations and students' externalizing behavior in upper elementary education. We studied teacher support and conflict separately and examined whether associations differed for boys and girls. Data were collected from 1452 Dutch fifth graders (Mage = 10.60 years) at three time points within one school year, including peer nominations of teacher-student relationships and external observations of teacher-student interactions. We used random-intercept cross-lagged panel models to examine the associations within the school year. Student behavior and teacher conflict and support were clearly interrelated within measurement moments. That is, within each time point, deviations from students' typical level of externalizing behavior were associated with deviations in teacher conflict and support in teacher-student relations. In contrast to earlier work, we found no transactional link between students' externalizing behavior and their relationships and interactions with their teacher over time, neither for teacher conflict nor for support. However, for boys, an association was found between externalizing behavior and later increased teacher conflict. We concluded that it remains important to invest in supportive teacher-student relations to prevent increasing conflict and that transactionality may occur within shorter time intervals.


On the enzymatic properties of Dnmt1: specificity, processivity, mechanism of linear diffusion and allosteric regulation of the enzyme.
In this short review the enzymatic properties of Dnmt1 are summarized. Studies on the specificity of Dnmt1 have shown that it has 30-40 fold preference for hemimethylated target sites. It methylates hemimethylated DNA in a processive reaction, moving on the DNA in a random walk. Binding of DNA to allosteric site(s) in the N-terminal part of the enzyme can lead to stimulation and inhibition of its catalytic activity depending on the nature of the substrate and effector.


In vivo mutant frequency rises among breast cancer patients after exposure to high doses of gamma-radiation.
Human in vivo mutant frequencies can be measured by cloning freshly isolated lymphocytes in selective media containing 6-thioguanine (TG). This method was applied to monitoring environmental mutagenesis, by studying lymphocytes separated from peripheral blood of 12 cancer patients undergoing radiotherapy. Before therapy, cancer patients had an average 8.6 X 10(-6) mutants/cell, compared to 2.4 X 10(-6) mutants/cell for heart patients and 1.1 X 10(-6) mutants/cell for healthy controls. After exposure of cancer patients to 50 Gy of gamma-radiation delivered to the treated area, or an estimated 4 Gy received by each lymphocyte, patients averaged 36.8 X 10(-6) mutants/viable cell.


Estimation of Antibody-Verified Eplet Mismatch Load, 2-Field HLA Resolution vs Imputation in a Large Cohort of European Donors.
The assessment of class II eplet mismatch load is useful to determine the risk of chronic rejection in solid organ transplantation. However, high-resolution (2-field) HLA typing is mandatory to accurately define eplet mismatches. The imputation of the most frequent allele has been used in retrospective studies. Here, we sought to investigate the concordant of antibody-verified (AbV) eplet load in different class II alelles between real 2-field HLA typing and HLA imputed by most frequent allele in a large White cohort. The allelic frequency of the different HLA class II loci was calculated using a database of high-resolution typing of 23,628 voluntary Spanish bone marrow donors obtained from the Spanish Registry of Bone Marrow Donors, managed by the Josep Carreras Foundation. The AbV eplet count in the different class II alleles was performed using the HLA-Matchmaker v3.1 algorithm. The probability of imputing the correct allele compared to the most frequent for DRB1 and DQB1 loci was 69.3% and 53.0%, respectively. However, studying the less frequent alleles, the same AbV eplet load was observed in 82.22% and 76.15%, respectively. Our data show that despite the potential error in the imputation of class II HLA typing, the number of AbV eplets is not significantly over- or underestimated in our population. Until high-resolution typing is widely established for solid organ transplantation, retrospective studies of AbV eplet mismatch load with imputed high-resolution types provide an acceptable outcome in White people.


Inhibition of stress and spontaneous respiration: Efficacy and safety of monitored anesthesia care by target-controlled infusion remifentanil in combination with dexmedetomidine in fibreoptic bronchoscopy for patients with severe tracheal stenosis.
This study aimed to determine the effective concentration of target-controlled infusion (TCI) of remifentanil used to inhibit stress during the treatment of severe tracheal stenosis with fibreoptic bronchoscopy and to evaluate the monitored anesthesia care (MAC) by remifentanil. 60 patients with severe tracheal stenosis who underwent fibreoptic bronchoscopy was performed. Dexmedetomidine was initially administered at a bolus dose (0.8 mcg/kg), followed by a 0.5 mcg/(kg⋅h) continuous infusion. Remifentanil was administered by TCI. The effective concentration (EC) of remifentanil was titrated by the improved sequential method, and 30 patients were included. The EC95 of remifentanil was set as the plasma target concentration to evaluate the safety of the MAC, and another 30 patients were included. The half effective effect-chamber concentration of remifentanil (EC50) was 2.243 ng/ml, and the EC95 was 2.710 ng/ml. Among the 30 patients who received an EC95 of remifentanil as the target concentration, one patient was remedied by injecting propofol, the score of Ramsay sedation was three. The incidence of subclinical hypoxemia (SPO2 of 90-95%) was 30%, the incidence of moderate hypoxemia (SPO2 of 75-89%, ≤60 s) was 20 and 86.7% of patients with oxygen saturation was less than 95% returned to normal by awakening. The satisfaction score of the operator was nine, the satisfaction score of the anesthesiologist was eight, the satisfaction score of the patients was 10, the rate of patient willingness to re-accept the procedure was 93.3% and the circulation was stable during the operation. MAC using TCI of remifentanil with continuous pumping dexmedetomidine can effectively inhibit the stress response to fibreoptic bronchoscopy in patients with severe tracheal stenosis while maintaining spontaneous breathing. Under the anesthesia management of an experienced anesthesiologist, it provides a reference to tracheoscopic anesthesia of autonomous breathing. [http://www.chictr.org.cn/], identifier [ChiCTR 2100043380].


A facile and environmentally friendly NaCl nonaqueous ionic liquid route to prepare crystalline β-CaSiO3 nanowires.
We described an environmentally friendly and facile NaCl nonaqueous ionic liquid route for the first time to synthesize β-CaSiO3 nanowires. β-CaSiO3 nanowires were prepared by annealing precursor calcium silicate hydrate (CSH) nanostructures in NaCl nonaqueous ionic liquid, in which the precursor CSH nanostructures were first prepared by a facile one-step, solid state reaction, ground with both NaCl and surfactant nonyl phenyl ether (9) (NP-9), and heated at 850 °C for 2 h. β-CaSiO3 nanowires were characterized by XRD, TEM and HRTEM. The comparative experiments have been conducted systemically to investigate the growth mechanism of β-CaSiO3 nanowires, and the roles of salt NaCl nonaqueous ionic liquid and NP-9 on the formation of β-CaSiO3 nanowires. The results demonstrated that both salt NaCl nonaqueous ionic liquid and surfactant NP-9 played key roles on the formation of β-CaSiO3 nanowires. A rational growth mechanism of β-CaSiO3 nanowires has been proposed on the basis of experimental results.


CRISPR/Cas-mediated plant genome editing: outstanding challenges a decade after implementation.
The discovery of the CRISPR/Cas genome-editing system has revolutionized our understanding of the plant genome. CRISPR/Cas has been used for over a decade to modify plant genomes for the study of specific genes and biosynthetic pathways as well as to speed up breeding in many plant species, including both model and non-model crops. Although the CRISPR/Cas system is very efficient for genome editing, many bottlenecks and challenges slow down further improvement and applications. In this review we discuss the challenges that can occur during tissue culture, transformation, regeneration, and mutant detection. We also review the opportunities provided by new CRISPR platforms and specific applications related to gene regulation, abiotic and biotic stress response improvement, and de novo domestication of plants.


Item response analysis of the Geriatric Anxiety Inventory among the elderly in China: dimensionality and differential item functioning test.
Anxiety symptoms are pervasive among elderly populations around the world. The Geriatric Anxiety Inventory (the GAI) has been developed and widely used in screening those suffering from severe symptoms. Although debates about its dimensionality have been mostly resolved by Molde et al. (2019) with bifactor modeling, evidence regarding its measurement invariance across sex and somatic diseases is still missing. This study attempted to provide complemental evidence to the dimensionality debates of the GAI with Mokken scale analysis and to examine its measurement invariance across sex and somatic diseases by conducting differential item functioning (DIF) analysis among a sample of older Chinese adults. The data was from responses of a large representative sample (N = 1314) in the Chinese National Survey Data Archive, focusing on the mental health of elderly adults. The results of Mokken scale analysis confirmed the unidimensionality of the GAI, and DIF analysis indicated measurement invariance of this inventory across individuals with different sex and somatic diseases, with just a few items exhibiting item bias but all of them negligible. All these findings supported the use of this inventory among Chinese elders to screen anxiety symptoms and to make comparisons across sex and somatic diseases.


Structural insight into unique cardiac myosin-binding protein-C motif: a partially folded domain.
The structural role of the unique myosin-binding motif (m-domain) of cardiac myosin-binding protein-C remains unclear. Functionally, the m-domain is thought to directly interact with myosin, whereas phosphorylation of the m-domain has been shown to modulate interactions between myosin and actin. Here we utilized NMR to analyze the structure and dynamics of the m-domain in solution. Our studies reveal that the m-domain is composed of two subdomains, a largely disordered N-terminal portion containing three known phosphorylation sites and a more ordered and folded C-terminal portion. Chemical shift analyses, d(NN)(i, i + 1) NOEs, and (15)N{(1)H} heteronuclear NOE values show that the C-terminal subdomain (residues 315-351) is structured with three well defined helices spanning residues 317-322, 327-335, and 341-348. The tertiary structure was calculated with CS-Rosetta using complete (13)C(α), (13)C(β), (13)C', (15)N, (1)H(α), and (1)H(N) chemical shifts. An ensemble of 20 acceptable structures was selected to represent the C-terminal subdomain that exhibits a novel three-helix bundle fold. The solvent-exposed face of the third helix was found to contain the basic actin-binding motif LK(R/K)XK. In contrast, (15)N{(1)H} heteronuclear NOE values for the N-terminal subdomain are consistent with a more conformationally flexible region. Secondary structure propensity scores indicate two transient helices spanning residues 265-268 and 293-295. The presence of both transient helices is supported by weak sequential d(NN)(i, i + 1) NOEs. Thus, the m-domain consists of an N-terminal subdomain that is flexible and largely disordered and a C-terminal subdomain having a three-helix bundle fold, potentially providing an actin-binding platform.


Three-dimensional in vivo magnetic resonance microscopy of beech (Fagus sylvatica L.) wood.
Spatial structure and water distribution in branch tissues after mechanical injury were investigated in vivo by three-dimensional (3D) magnetic resonance (MR) microscopy. On a beech tree (Fagus sylvatica L.), transplanted in a portable pot, a branch was topped and then MR imaged. High-resolution 3D MR images revealed structures which could not be identified by conventional MR images or by light microscopy. MR measurements confirmed our assumption that moisture content is decreasing towards the wounded part of the branch. This indicates that quick moisture loss from mechanically wounded tissues represents the initial passive response of compromised tissue.


Risk of idiopathic nephrotic syndrome among children with asthma: a nationwide, population-based cohort study.
Although clinical and immunological studies have shown a possible link between allergy and idiopathic nephrotic syndrome (INS), the nature of the relationship remains unclear. Asthma is the most common chronic allergic airway inflammation. However, no study has used a longitudinal design with a population cohort to investigate INS in children with asthma. Using nationwide claims data from 2000 through 2007, we randomly selected 251,698 asthma cases and 1,006,791 frequency-matched controls. Incidence rates of INS and hazard ratios (HRs) were calculated. The INS incidence was 3.36-fold greater in the asthma cohort than in the nonasthma control (9.26 vs. 2.76 per 100,000 person-years; 95% confidence interval (CI): 2.65-4.26). The HR for INS increased for those with more asthma-related medical visits per year, from 1.49 (95% CI: 1.06-2.11) for <3 visits to 15.7 (95% CI: 11.5-21.5) for ≥6 visits (trend test, P < 0.0001). The HR for INS slightly decreased during the follow-up period, from 3.41 (95% CI: 2.66-4.38) for ≤5.5 y to 2.90 (95% CI: 1.33-6.30) for >5.5 y. We conclude that children with asthma had an increased incidence rate of INS, and increased incidence rate correlated with asthma-related medical visits.


Characterization of sterilized CP titanium implant surfaces.
Surface analysis techniques and in vitro biologic assays were used to characterize sterilized commercially pure titanium surfaces. Significant surface alterations were observed following sterilization treatments. These alterations led to decreased fibroblast cell attachment and altered cellular spreading phenomena compared to nonsterilized control surfaces.


Imagining our moral values in the present and future.
Imaginary worlds allow us to safely develop, crystallize, and criticize our moral values - at times even serving as catalysts for change in the real world. Fans of imaginary worlds sometimes form groups to advocate for social change in the real world, and it is part of Leftist ideology to imagine radically different, possible futures aligned around shared moral values.


Development of urban runoff model FFC-QUAL for first-flush water-quality analysis in urban drainage basins.
An urban runoff model that is able to compute the runoff, the pollutant loadings, and the concentrations of water-quality constituents in urban drainages during the first flush was developed. This model, which is referred to as FFC-QUAL, was modified from the existing ILLUDAS model and added for use during the water-quality analysis process for dry and rainy periods. For the dry period, the specifications of the coefficients for the discharge and water quality were used. During rainfall, we used the Clark and time-area methods for the runoff analyses of pervious and impervious areas to consider the effects of the subbasin shape; moreover, four pollutant accumulation methods and the washoff equation for computing the water quality each time were used. According to the verification results, FFC-QUAL provides generally similar output as the measured data for the peak flow, total runoff volume, total loadings, peak concentration, and time of peak concentration for three rainfall events in the Gunja subbasin. In comparison with the ILLUDAS, SWMM, and MOUSE models, there is little difference between these models and the model developed in this study. The proposed model should be useful in urban watersheds because of its simplicity and its capacity to model common pollutants (e.g., biological oxygen demand, chemical oxygen demand, Escherichia coli, suspended solids, and total nitrogen and phosphorous) in runoff. The proposed model can also be used in design studies to determine how changes in infrastructure will affect the runoff and pollution loads.


Nectin: an adhesion molecule involved in formation of synapses.
The nectin-afadin system is a novel cell-cell adhesion system that organizes adherens junctions cooperatively with the cadherin-catenin system in epithelial cells. Nectin is an immunoglobulin-like adhesion molecule, and afadin is an actin filament-binding protein that connects nectin to the actin cytoskeleton. Nectin has four isoforms (-1, -2, -3, and -4). Each nectin forms a homo-cis-dimer followed by formation of a homo-trans-dimer, but nectin-3 furthermore forms a hetero-trans-dimer with nectin-1 or -2, and the formation of each hetero-trans-dimer is stronger than that of each homo-trans-dimer. We show here that at the synapses between the mossy fiber terminals and dendrites of pyramidal cells in the CA3 area of adult mouse hippocampus, the nectin-afadin system colocalizes with the cadherin-catenin system, and nectin-1 and -3 asymmetrically localize at the pre- and postsynaptic sides of puncta adherentia junctions, respectively. During development, nectin-1 and -3 asymmetrically localize not only at puncta adherentia junctions but also at synaptic junctions. Inhibition of the nectin-based adhesion by an inhibitor of nectin-1 in cultured rat hippocampal neurons results in a decrease in synapse size and a concomitant increase in synapse number. These results indicate an important role of the nectin-afadin system in the formation of synapses.


TFIIH moonlighting at telomeres.
Although telomeres are essential for chromosome stability, they represent fragile structures in our genome. Telomere shortening occurs during aging in cells lacking telomerase due to the end replication problem. In addition, recent work uncovered that the bulk of telomeric DNA poses severe hurdles for the semiconservative DNA replication machinery, requiring the assistance of an increasing number of specialized factors that prevent accidental telomere loss or damage events. In this issue of Genes & Development, Yang and colleagues (pp. 956-969) discover that TFIIH, a basic component of the PolII transcription initiation and nucleotide excision repair machinery, facilitates telomere replication. TFIIH is recruited to telomeres by the shelterin component TRF1, taking on at telomeres a moonlighting function.


Unraveling the complex interplay between genes, environment, and climate in ALS.
Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration. While the risk exerted by many environmental factors may appear small, their effect could be magnified by the presence of a genetic predisposition. We postulate that gene-environment interactions account for at least a portion of the unknown etiology in ALS. Climate underlies multiple environmental factors, some of which have been implied in ALS etiology, and the impact of global temperature increase on the gene-environment interactions should be carefully monitored. We describe the main concepts underlying such interactions. Although a lack of large cohorts with detailed genetic and environmental information hampers the search for gene-environment interactions, newer algorithms and machine learning approaches offer an opportunity to break this stalemate. Understanding how genetic and environmental factors interact to cause ALS may ultimately pave the way towards precision medicine becoming an integral part of ALS care.


Teacher-student training and triplet loss to reduce the effect of drastic face occlusion: Application to emotion recognition, gender identification and age estimation.
We study a series of recognition tasks in two realistic scenarios requiring the analysis of faces under strong occlusion. On the one hand, we aim to recognize facial expressions of people wearing virtual reality headsets. On the other hand, we aim to estimate the age and identify the gender of people wearing surgical masks. For all these tasks, the common ground is that half of the face is occluded. In this challenging setting, we show that convolutional neural networks trained on fully visible faces exhibit very low performance levels. While fine-tuning the deep learning models on occluded faces is extremely useful, we show that additional performance gains can be obtained by distilling knowledge from models trained on fully visible faces. To this end, we study two knowledge distillation methods, one based on teacher-student training and one based on triplet loss. Our main contribution consists in a novel approach for knowledge distillation based on triplet loss, which generalizes across models and tasks. Furthermore, we consider combining distilled models learned through conventional teacher-student training or through our novel teacher-student training based on triplet loss. We provide empirical evidence showing that, in most cases, both individual and combined knowledge distillation methods bring statistically significant performance improvements. We conduct experiments with three different neural models (VGG-f, VGG-face and ResNet-50) on various tasks (facial expression recognition, gender recognition, age estimation), showing consistent improvements regardless of the model or task.


Inhibition of the mitogen activated protein kinase ERK1/2 amplifies ochratoxin A toxicity in the proximal tubule of the kidney.
Ochratoxin A (OTA) is a mycotoxin showing nephrotoxic properties. OTA activates the mitogen activated protein kinases ERK, JNK and p38 in renal epithelial cells. In brief, activation of ERK supports mitosis, growth and differentiation, whereas JNK and p38 are considered to induce the opposite effects. The balance of the mentioned key protein kinases decides the further fate of the cell. In renal disease, the proximal tubule of the nephron often is affected first.Thus, we investigated the effect of OTA incubation (24 or 48 hours) on proximal tubular OK cells (oppossum) and/or NRK-52E cells (rat) in presence of an inhibitor of ERK1/2 activation (U0126). U0126 (25 µM) completely abolished ERK1/2 activation induced by OTA. Parameters indicating necrosis, apoptosis, epithelial tightness, fibrosis, dedifferentiation and inflammation were determined. In presence of U0126, OTA led to a decrease of cell number as compared to OTA alone. U0126 in presence of OTA increased LDH release as compared to OTA alone. OTA alone did not change epithelial integrity, whereas OTA in presence of U0126 reduced epithelial tightness. 100 nM OTA alone did not increase apoptosis, while addition of U0126 to OTA induced apoptotis. U0126 stimulated the basolateral deposition of collagen induced by OTA. Furthermore, as investigated by RT-PCR, the effect of OTA on markers of inflammation (NF-κB) and dedifferentiation (α-smooth muscle actin) was also more pronounced when ERK1/2 was inhibited. ERK1/2 inhibition enhanced the effects of OTA. Thus, activation of ERK1/2 after OTA is a protective mechanism. We conclude that ERK1/2 not only acts anti-apoptotic but also is beneficial on cell viability, epithelial tightness, interstitial fibrosis, inflammation and trans-differentiation. We further conclude that ERK1/2 is a key protection factor in the proximal tubule. However, long term OTA exposition could lead to clonal selection of kidney cells overexpressing ERK1/2. As strong expression of ERK1/2 is found in various tumours not only of the kidney, we hypothesize that the mentioned clonal selection could be a mechanism inducing the cancerogenic action discussed for OTA.


[Use of long term administration of ATP in repeated heart injury with isoprenaline and its effect on the reparative process in the myocardium].
ATP failed to influence the rate of myocardial healing having been administered to rats 1 hour after Isoprenaline. Further long-term administering of ATP diminished the intensity of repeated myocardial lesion due to catecholamine. However, myocardial fibrosis was not sure to be influenced.


Impact of CPOE on doctor-nurse cooperation for the medication ordering and administration process.
The objective of this study was to analyze the impact of medication ordering and administration functions of CPOE on doctor-nurse communications and cooperation. We performed an extensive analysis of the work situations in several departments of three different hospitals. One of the hospitals is still using paper-based orders, the second one is currently implementing a patient care information system (PCIS), but the analysis was carried out with paper-based orders. The third hospital has a PCIS installed with available medication ordering functions. We used standard methods from cognitive psychology to analyze physicians, and nurses' activity, communications and cooperation. This approach was combined with a usability analysis of both work systems, paper and computer-based. The paper-based situation is characterized by a synchronous cooperation with a distributed decision-making where physicians and nurses rely mostly on verbal communications to coordinate their actions; paper order sheets are weakly structured and poorly support the documentation task. In the computer situation, physicians and nurses work in an asynchronous mode, and leave to the system the coordination of their actions. Orders are exhaustively documented but some data may be misinterpreted. Some of these problems are due to usability flaws of the Human Computer Interface. We conclude with recommendations for usability improvement of CPOE systems, combined with recommendations for the organization of doctor-nurse communication when implementing such systems.


[Pseudo-tumor form of neuro-Behçet disease: case study and literature review].
Mass lesions of the brain are not always a tumor. We report the case of a patient followed for Behcet syndrome presenting with expansive intracranial process revealed by right hemiparesis associated with signs of intracranial hypertension. Brain magnetic resonance imaging (MRI) showed a lesion suggesting glial tumor. Clinical and radiological assessments as well as laboratory tests helped to establish the diagnosis of pseudo-tumor form of neuro-Behçet disease. This study report is followed by a clinical analysis based on the available literature on this disorder.


The affinity of low-density lipoproteins and of very-low-density lipoprotein remnants for the low-density lipoprotein receptor in homozygous familial defective apolipoprotein B-100.
We have identified two familial defective apo B-100 (FDB) homozygotes by DNA sequencing and have measured affinity of low-density lipoproteins (LDL) and very-low-density lipoprotein (VLDL) remnants for the LDL receptor in vitro. The patients were a 66-year-old man with coronary heart disease (plasma cholesterol level, 9.5 mmol/l before treatment) and his 69-year-old sister, without signs of cardiovascular disease (plasma cholesterol, 12.0 mmol/l before treatment). In both patients, treatment with statins caused a marked fall in plasma cholesterol level. Binding affinity of LDL from the two patients was 10%-20% of normal at 4 degrees C and 37 degrees C. Binding affinity of VLDL remnants was normal. We conclude that (1) residual affinity of LDL in homozygous FDB is high enough to permit significant catabolism via the LDL-receptor pathway, and (2) normal affinity of VLDL remnants permits normal hepatic clearance of precursors of LDL and increased clearance of LDL precursors when receptor activity is stimulated by statins. Residual affinity of LDL and normal affinity of remnants could explain why expression of the FDB mutation is generally milder than that of LDL receptor mutations causing familial hypercholesterolaemia.


Course of induced infection by Eimeria krijgsmannni in immunocompetent and immunodeficient mice.
Recently, we have demonstrated the utility of Eimeria krijgsmanni as a novel mouse eimerian parasite for elucidating the biological diversity. The parasite showed notable infectivity to mice with various levels of immune status and susceptibility to antimicrobial agents including coccidiostat. However, the detailed lifecycle of E. krijgsmanni had not yet been determined and this information was lacking in discussion of previous findings. In the present study, we clarified the morphological characteristics of E. krijgsmanni and its lifecycle in normal mice, and examined the effects in immunodeficient mice and lifecycle stage for challenge infections after the primary inoculation. In immunocompetent mice, the lifecycle consisted of four asexual stages and the sexual sages followed by formation of oocysts during the prepatent periods. Interestingly, the second-generation meronts were detected in all observation periods after the disappearance of the other stages. For the challenge infection of immunodeficient mice, all developmental stages except for the second generation meronts were temporarily vanished. This finding suggests a "rest" or marked delay in development and a "restart" of the promotion toward the next generations. The second generation meronts may play an important role in the lifecycle of E. krijgsmanni.


Dose-effect relationship for X-ray-induced reciprocal translocations in mouse spermatogonia following pretreatment with 3-aminobenzamide.
The influence of 3-aminobenzamide (3-AB) pretreatment on the dose-response relationship for radiation-induced reciprocal translocations in mouse spermatogonial stem cells was studied. The results show that at doses of 3-10 Gy of X-rays the frequencies of translocations were higher in 3-AB-pretreated animals as compared to animals that received X-rays only. The 3-AB pretreatment was not effective at dose levels of 1 and 2 Gy. The shape of the dose-effect curve was similar to that obtained without 3-AB pretreatment, i.e., a humped curve, but the initial slope was clearly steeper and the position of the peak was shifted from 7 to 9 Gy. The effects observed can be explained by a 3-AB-mediated sensitization of normally radioresistant stem cells that are at the stage of stimulation to enter the mitotic cycle, thus increasing the population of radiosensitive spermatogonial stem cells.


A comparative study of prostacyclin infusion given before and during cardiopulmonary bypass to assess the first pass effect of the circuit on platelet number and function.
Platelet damage during cardiopulmonary bypass (CPB), although proportional to the duration of bypass, may result in significant dysfunction after the initial contact with an extracorporeal circuit, the so-called 'first pass' phenomenon. The platelet sparing effect of prostacyclin (PGI2) infusion was studied in a double-blind randomized trial on male patients undergoing coronary artery bypass grafts to assess the effect of the 'first pass' through the CPB circuit. Prostacyclin infusion was begun before the onset of CPB or during CPB in two groups which were compared to a placebo control group. A standardized anaesthetic, surgical and perfusion technique were used. Preoperatively and during surgery at pre-set intervals, whole blood platelet aggregation was studied using ADP and collagen agonists. Platelet numbers and function measured by ADP aggregation were conserved in the two PGI2 groups. There was no significant difference between the treated groups. We conclude, therefore, that the initial contact of platelets with the CPB circuit, in the absence of PGI2 did not irreversibly affect platelet function. In addition, the hypotensive action of PGI2 was easier to control once on bypass. It may therefore be preferable to delay PGI2 infusion until CPB has been established.


Nanobody-Based Assays for the Detection of Environmental and Agricultural Contaminants.
Compared with traditional polyclonal and monoclonal antibodies, nanobodies derived from camelid heavy-chain antibodies have several advantages including small size, unique structure and binding geometry, high stability, and robust expression yields in numerous systems. Nanobody-based assays can also exhibit superior performance for immunodetection. Here, we describe protocols for three nanobody-based immunoassays for the detection of small chemical contaminants in environmental or agricultural samples: enzyme-linked immunosorbent assay (ELISA), fluorescence enzyme immunoassay (FEIA), and bioluminescent enzyme immunoassay (BLEIA). These methods are based on hapten-specific nanobodies, nanobody-alkaline phosphatase fusion proteins, and nanobody-nanoluciferase fusion proteins, respectively.


Prolactin monitoring in the acute psychiatry setting.
Hyperprolactinaemia is a common side effect associated with psychotropic medication. Limited guidance on its monitoring and management results in inconsistency in practice due to individual clinical variability. A retrospective service evaluation study was conducted on all patients admitted to an acute psychiatric assessment unit in South Wales, United Kingdom, over one calendar year (n=524), to assess the prevalence and possible causes of hyperprolactinaemia, correlation with symptomatology and monitoring and management by clinicians. The prevalence of hyperprolactinaemia in this population (n=67, 13%) was higher than in the general population. The most common association was medication (n=39, 58%), particularly Risperidone (n=19). Illicit substance use (n=10, 15%), and physical conditions (n=12, 18%) may also have contributed. However, only 44 (66%) received follow-up for their hyperprolactinaemia. There was a statistically significant difference in the sample means of those that did receive follow-up and those who did not, suggesting a degree of bias in patients selected to receive follow-up. These findings suggest that hyperprolactinaemia is relatively common in patients with mental illness, and that comprehensive guidelines need to be established for the monitoring and management thereof.


Multiple enteroliths in a chronically obstructed duodenal loop after Roux-en-Y biliary diversion.
A case of chronic mechanical obstruction of the duodenal loop due to stricturing of the enteroenterostomy after diversion following a Polya gastrectomy for bile reflux gastritis is reported. The dilated loop contained several hundred enteroliths. The clinical and chemical evidence strongly supports the view that the enteroliths were formed in the intestinal loop. This complication of Roux-en-Y reconstruction has not previously been recognized.


The Vascular System: Anatomical, Physiological, Pathological, and Aging Considerations.
The vascular system is one of the earliest recognized anatomical systems. It is composed of 3 parts; arterial, capillary, and venous, each with their own unique anatomy and physiology. Blood flow through this system is compromised in aging, atherosclerosis and peripheral vascular disease, and the practicing anesthesiologist must understand both the physiology and pathophysiology of the vascular tree.


Lessons from the field: An evidence-informed resiliency model for child abuse organizations.
Child abuse organizations are keenly aware of the impact helping abused and neglected children has on the people who do that work. In their efforts to address this issue, they look to their colleagues for recommendations on what works. Of particular value is testimony from those who have used evidence-informed programs to mitigate the impact on staff, so services to children do not suffer. The Resiliency Project provided that evidence-informed program, one that was developed for and by the child abuse field in 2009. With funding from the Office for Victims of Crime, The University of Texas at Austin team of researchers, educators and practitioners developed the Organizational Resiliency Model (ORM) specifically for the child abuse field. The model draws from research on strengths individuals who are resilient have, and offers strategies for organizations to use to build resiliency in their staff. The ORM was piloted with 24 leaders from the field, including children's advocacy centers (CACs); court-appointed special advocate (CASA) programs; and government-based child welfare agencies. This article reviews the research basis for the ORM and new research supporting the model, and offers lessons learned through structured interviews with 10 child abuse leaders who piloted the ORM and continue to use it ten years later. Using the ORM, based on evidence available at the time, supported by new research and attested to by child abuse leaders who have sustained the model in their organizations, can promote a healthy and resilient workforce.


Effects of medium-pressure UV lamps radiation on water quality in a chlorinated indoor swimming pool.
The aim of our study was to determine the impact of medium-pressure UV lamps radiation on water quality in a chlorinated indoor swimming pool. An indoor swimming pool was equipped with two medium-pressure UV lamps. We collected eight samples of water daily over a four-weeks period and measured total and free chlorine, pH, water temperature, bacteriological parameters, total organic carbon and trihalomethanes. During the first week, which served as control, medium-pressure UV lamps were turned off. During the next three weeks, medium-pressure UV lamps were kept on 24 h per day. The third week, we reduced the level of the injected chlorine into water, and the last week we also reduced the water renewal volume by 27%. Our results showed that bacteriological parameters remained within allowable french limits. When medium-pressure UV lamps were kept on, total, free and active chlorine levels were significantly increased (P<0.001), whereas combined chlorine level were significantly decreased (P<0.001 and P<0.05, respectively). The levels of chloroform and bromodichloromethane were significantly increased when medium-pressure UV lamps were kept on (P<0.001), whereas chlorodibromomethane and bromoform levels significantly decreased (P<0.05 and P<0.001, respectively). The additional formation of chloroform and bromodichloromethane may be explained by the increase in active chlorine and by radicalizing mechanisms initiated by UV radiation.


Effects of copper and cadmium on ion transport and gill metal binding in the Amazonian teleost tambaqui (Colossoma macropomum) in extremely soft water.
Metal toxicity in fish is expected to be most severe in soft waters because of the low availability of cations (particularly Ca(2+)) to out-compete the metal forms for binding sites on the gills. Natural waters in the Amazon basin are typically soft due to regional geochemistry, but few studies have focused on metal toxicity in fish native to the basin. We assessed the ionoregulatory effects of waterborne copper (Cu) and cadmium (Cd) on tambaqui (Colossoma macropomum) in extremely soft water (10 micromoll(-1) Ca(2+)). Tambaqui had a very high tolerance to Cu (50-400 microgl(-1)), as indicated by a complete lack of inhibition of Na(+) uptake and an ability to gradually recover over 6h from elevated diffusive Na(+) losses caused by Cu. The insensitivity of active Na(+) influx to Cu further supports the notion that Amazonian fish may have a unique Na(+) transport system. Addition of 5-10 mgCl(-1) of dissolved organic matter (DOM) did not prevent initial (0-3h) negative Na(+) balance in tambaqui exposed to Cu. Exposure to 40 mgCl(-1) DOM prevented Na(+) losses in tambaqui even at 400 microgl(-1) Cu, probably because most Cu was complexed to DOM. Tambaqui exposed to waterborne Cd (10-80 microgl(-1)) experienced an average of 42% inhibition in whole body Ca(2+) uptake relative to controls within 3h of exposure to the metal. Inhibition of Ca(2+) uptake increased over time and, at 24h, Ca(2+) uptake was suppressed by 51% and 91% in fish exposed to 10 and 80 microgl(-1) Cd, respectively. Previous acclimation of fish to either elevated [Ca(2+)] or elevated [DOM] proved to be very effective in protecting against acute short-term metal accumulation at the gills of tambaqui in soft water (in the absence of the protective agent during metal exposure), suggesting a conditioning effect on gill metal binding physiology.


The temporal dynamics of Large-Scale brain network changes in disorders of consciousness: A Microstate-Based study.
The resting-state brain is composed of several discrete networks, which remain stable for 10-100 ms. These functional microstates are considered the building blocks of spontaneous consciousness. Electroencephalography (EEG) microstate analysis may provide insight into the altered brain dynamics underlying consciousness recovery in patients with disorders of consciousness (DOC). We aimed to analyze microstates in the resting-state EEG source space in patients with DOC, the relationship between state-specific features and consciousness levels, and the corresponding patterns of microstates and functional networks. We obtained resting-state EEG data from 84 patients with DOC (27 in a minimally conscious state [MCS] and 57 in a vegetative state [VS] or with unresponsive wakefulness syndrome). We conducted a microstate analysis of the resting-state (EEG) source space and developed a state-transition analysis protocol for patients with DOC. We identified seven microstates with distinct spatial distributions of cortical activation. Multivariate pattern analyses revealed that different functional connectivity patterns were associated with source-level microstates. There were significant differences in the microstate properties, including spatial activation patterns, temporal dynamics, state shifts, and connectivity construction, between the MCS and VS groups. Our findings suggest that consciousness depends on complex dynamics within the brain and may originate from the anterior cortex.


Visible-Light-Accelerated Pd-Catalyzed Cascade Addition/Cyclization of Arylboronic Acids to γ- and β-Ketodinitriles for the Construction of 3-Cyanopyridines and 3-Cyanopyrrole Analogues.
The one-pot synthetic strategies for 2,4,6-triarylnicotinonitriles and 2,5-diaryl-1H-pyrrole-3-carbonitriles have been accomplished via a Pd-catalyzed coupling of arylboronic acid with 2-(3-oxo-1,3-diarylpropyl)malononitrile and 2-(2-oxo-2-arylethyl)malononitrile, respectively, under mild reaction conditions, followed by intramolecular cyclization of an intermediate formed after the regeneration of the catalyst under acidic reaction conditions. The cascade reactions proceed in 1,2-dichloroethane solvent under visible-light irradiation, and the active catalyst is generated in situ in the presence of catalytic amounts of Pd(OAc)2 and 2,2'-bipyridine. The active Pd catalyst undergoes photoexcitation by the virtue of metal-to-ligand charge transfer (MLCT), and subsequent redox trans-metalation occurs with arylboronic acid, thus obviating the necessity of any exogenous photosensitizer. The targeted products, composed of a new C-C, a C-N, a C═N, and two new C═C bonds, were isolated in good yields.


Novel crAssphage marker genes ascertain sewage pollution in a recreational lake receiving urban stormwater runoff.
Considerable efforts have been made in recent years in developing novel marker genes for fecal pollution tracking in environmental waters. CrAssphage are recently discovered DNA bacteriophage that are highly abundant in human feces and untreated sewage. In this study, we evaluated the host-sensitivity and -specificity of the newly designed crAssphage qPCR assays (Stachler et al., 2017) CPQ_056 and CPQ_064 (i.e., marker genes) in fecal samples collected from various human and several animal host groups in Australia. We also investigated the utility of these marker genes to detect sewage pollution in an urban recreational lake (i.e., Lake Parramatta) in Sydney, NSW. The mean concentrations of CPQ_056 and CPQ_064 marker genes in untreated sewage were 9.43 ± 0.14 log10 GC/L and 8.91 ± 0.17 log10 GC/L, respectively, 2 to 3 orders of magnitude higher than other sewage-associated viruses used in microbial source tracking studies. Among 177 animal fecal samples tested from 11 species, the host-specificity values for CPQ_056 and CPQ_064 marker genes were 0.95 and 0.93, respectively. Limited cross-reactivity was observed with cat fecal and cattle wastewater samples. Abundance of crAssphage markers were monitored in an urban lake that receives stormwater runoff. The concentrations of both markers were higher (CPQ_056 ranging from 3.40 to 6.04 log10 GC/L and CPQ_064 ranging from 2.90 to 5.47 log10 GC/L) in 20 of 20 (for CPQ_056) and 18 of 20 (for CPQ_064) samples collected after storm events with gauged sewer overflows compared to dry weather event (10 of 10 samples were qPCR negative for the CPQ_056 and 8 of 10 were negative for the CPQ_064 marker genes) suggesting sewage pollution was transported by urban stormwater runoff to Lake Parramatta. The results of the study may provide context for management of sewage pollution from gauged overflow points of the sewerage system in the catchment.


Nitrogenous compounds reversibly inhibit the adenosine 3',5'-monophosphate response to thyrotropin: this effect is dissociated from altered guanine 3',5'-monophosphate levels.
Nitrogenous compounds were studied for their effect on cGMP levels in the thyroid. Several agents, including sodium nitrite and hydroxylamine, could generate a rise of over 100-fold in cGMP. At a concentration of 20 mM, HN2OH and NaNO2 significantly reduced cAMP levels previously generated by 0.5 mU/ml TSH. If the slices were rinsed and placed in new buffer without the latter nitrogenous compound, the cAMP response to TSH was restored even though intracellular cGMP levels remained elevated. Thus, the counterregulatory effect of these agents on cAMP levels is not correlated with the presence of high levels of cGMP per se. Both the rise in cGMP and the fall in cAMP could still be detected when Ca++ was deleted from the incubation medium, in contrast to other reported stimuli that elevate cGMP levels in the thyroid.


Artificial neural networks enable genome-scale simulations of intracellular signaling.
Mammalian cells adapt their functional state in response to external signals in form of ligands that bind receptors on the cell-surface. Mechanistically, this involves signal-processing through a complex network of molecular interactions that govern transcription factor activity patterns. Computer simulations of the information flow through this network could help predict cellular responses in health and disease. Here we develop a recurrent neural network framework constrained by prior knowledge of the signaling network with ligand-concentrations as input and transcription factor-activity as output. Applied to synthetic data, it predicts unseen test-data (Pearson correlation r = 0.98) and the effects of gene knockouts (r = 0.8). We stimulate macrophages with 59 different ligands, with and without the addition of lipopolysaccharide, and collect transcriptomics data. The framework predicts this data under cross-validation (r = 0.8) and knockout simulations suggest a role for RIPK1 in modulating the lipopolysaccharide response. This work demonstrates the feasibility of genome-scale simulations of intracellular signaling.


Does intraprostatic vasopressin prevent the transurethral resection syndrome?
To determine whether intraprostatic vasopressin (IPVP) prevents the transurethral resection (TUR) syndrome during prostatectomy. The study comprised 36 consecutive patients (mean age 68 years) with prostates clinically assessed as >/= 20 g who underwent standard transurethral prostatectomy (TURP). Ten units of vasopressin in 0.5 mL were diluted with 9.5 mL isotonic saline and injected into the prostate transrectally before TURP. Blood samples were taken before and immediately after TURP to measure serum sodium concentration and free haemoglobin levels. The TURP irrigant used was cooled, boiled water maintained at 70-80 cmH2O pressure during resection. Twenty patients had alcohol added to the irrigant and their breath alcohol assessed at 10-min intervals during TURP. All patients had their pulse rate, blood pressure and sensorium monitored continuously. Extreme care was taken to avoid and/or identify capsular damage during resection. The mean weight of tissue resected was 36 g and the mean resection time 24 min. There was no significant change in clinical variables during TURP. In 19 patients the breath alcohol changes were insignificant. Changes in free haemoglobin were not significant, but the levels decreased after TURP in four patients, caused by the dilution consequent on the infusion of 800-1000 mL isotonic saline during surgery. Serum sodium concentrations showed only insignificant decreases, except in one patient whose breath alcohol suggested the absorption of 500 mL of irrigant. This patient's serum sodium concentration decreased by 9 mmol/L; 1 L of 5% dextrose was infused during the procedure and capsular damage was recognized early during TURP. Insignificant volumes of irrigant entered the circulation of the patients during TURP with water irrigation and IPVP. The greatest risk factor for fluid entry during TURP is capsular damage. IPVP decreases bleeding and therefore improves visibility, so allowing the early identification of capsular damage. IPVP seems therefore to be of help during TURP by decreasing bleeding and allowing insignificant volumes of irrigant to enter the vasoconstricted vessels; it appears to prevent the TUR syndrome.


Asymptomatic infection of mouse hepatitis virus in the rat. Brief report.
After intranasal inoculation of suckling rats mouse hepatitis virus multiplied mostly in the nasal epithelium; though there were no symptoms, antibodies were produced. Antibodies were also demonstrated in adult rats. These findings suggest that the rat may be a natural host for the virus.


An investigator-sponsored pragmatic randomized controlled trial of AntiCoagulation vs AcetylSalicylic Acid after Transcatheter Aortic Valve Implantation: Rationale and design of ACASA-TAVI.
The optimal antithrombotic therapy after transcatheter aortic valve implantation (TAVI) is unknown. Bioprosthetic valve dysfunction (BVD) is associated with adverse outcomes and may be prevented by anticoagulation therapy. A dedicated randomized trial comparing monotherapy NOAC to single antiplatelet therapy has not been performed previously. We hypothesize that therapy with any anti-factor Xa NOAC will reduce BVD compared to antiplatelet therapy, without compromising safety. ACASA-TAVI is a multicenter, prospective, randomized, open-label, blinded endpoint, all-comers trial comparing a monotherapy anti-factor Xa NOAC strategy (intervention arm) with a single antiplatelet therapy strategy (control arm) after successful TAVI. Three-hundred and sixty patients without indication for oral anticoagulation will be randomized in a 1:1 ratio to either apixaban 5 mg twice per day, edoxaban 60 mg daily, or rivaroxaban 20 mg daily for 12 months followed by acetylsalicylic acid 75 mg daily indefinitely, or to acetylsalicylic acid 75 mg daily indefinitely. The 2 co-primary outcomes are (1) incidence of Hypo-Attenuated Leaflet Thickening (HALT) on 4-dimensional cardiac CT at 12 months, and (2) a Safety Composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction and stroke), and death from any cause, at 12 months. The first 100 patients had a mean age of 74 ± 3.6 years, 33% were female, the average body-mass index was 27.9 ± 4.4 kg/m2, and 15% were smokers. A balloon-expanded valve was used in 82% and a self-expandable valve in 18%. The trial is planned, initiated, funded, and conducted without industry involvement. ClinicalTrials.gov Identifier NCT05035277.


Laparoscopic transcystic duct balloon dilatation of the sphincter of Oddi.
Balloon dilatation of the sphincter of Oddi has been performed via a laparoscopic transcystic duct technique. Small common duct stones and stone debris have been successfully lavaged into the duodenum in 17 of 20 cases (85%) by this method. Postoperative hyperamylasemia was noted in four patients. Mild clinical pancreatitis was observed in three patients (15%). Further evaluation of this technique as an adjunct to laparoscopic common bile duct stone extraction is warranted.


Temporal changes in disaccharide composition of dermatan sulfate in the skin after epicutaneous application of hapten.
Glycosaminoglycans change their amount, structure and distribution with age, differentiation and pathologic conditions. In order to investigate temporal changes in dermatan sulfate in the skin during inflammation and subsequent healing, 2,4-dinitrofluorobenzene (DNFB) was applied once to the dorsal skin of female BALB/cA mice, and the disaccharide composition of dermatan sulfate was examined. Application of DNFB induced a transient increase in the thickness of the dermis, which reached a maximum on day 15 and decreased to the control level on day 35. The total amount of unsaturated disaccharides from dermatan sulfate per cm2 in the DNFB-treated skin showed a temporal pattern similar to that of the thickness of the dermis. Mol% of 4,5-unsaturated 2-sulfo-hexuronic acid-4-sulfated N-acetylgalactosamine (deltaDi-diSB), the second most abundant unsaturated disaccharide from dermatan sulfate, decreased rapidly on day 3 in the DNFB-treated skin, remained less than the control on days 7 and 15, and returned to the control level on day 35. These results suggest that a single application of DNFB induces temporal changes not only in the amount but also in the structure of dermatan sulfate.


Sinus Node Dysfunction After Extracardiac Conduit and Lateral Tunnel Fontan Operation: The Importance of the Type of Prior Superior Cavopulmonary Anastomosis.
This review summarizes the influence of the type of prior superior cavopulmonary anastomosis in the studies that report a difference in the occurrence of sinus node dysfunction among extracardiac conduit Fontan and lateral tunnel Fontan operations along with clinical implications.


Dermatomyositis.
Dermatomyositis and polymyositis are diseases which must be carefully defined in each patient. Criteria such as those suggested by Bohan and Peter will help define the disease and exclude other possible causes of myositis. Immunological factors are probably involved in the pathogenesis of the disease, although varied types of injury may manifest in clinically similar disease. Dermatomyositis, not polymyositis, is related to internal malignancy in adults; however, an extensive malignancy evaluation is not indicated. Therapy with corticosteroids will improve the quality of life, will prevent contractures and calcinosis and may improve the chance of survival. In cases where steroids are ineffective, immunosuppressives may be helpful.


Targeted Delivery Methods for Anticancer Drugs.
Several drug-delivery systems have been reported on and often successfully applied in cancer therapy. Cell-targeted delivery can reduce the overall toxicity of cytotoxic drugs and increase their effectiveness and selectivity. Besides traditional liposomal and micellar formulations, various nanocarrier systems have recently become the focus of developmental interest. This review discusses the preparation and targeting techniques as well as the properties of several liposome-, micelle-, solid-lipid nanoparticle-, dendrimer-, gold-, and magnetic-nanoparticle-based delivery systems. Approaches for targeted drug delivery and systems for drug release under a range of stimuli are also discussed.


Understanding the excitation wavelength dependent spectral shift and large exciton binding energy of tungsten disulfide quantum dots and its interaction with single-walled carbon nanotubes.
Herein, we investigate the origin of excitation wavelength dependent spectral features and high fluorescence quantum yield in fluorescent 2D tungsten disulfide (WS2) quantum dots (QDs) of average size 2.4 nm. The as-prepared WS2 QDs possess high optical bandgap and reasonably high fluorescence quantum yield ~15.4% in the green region without any functionalization. The broad photoluminescence (PL) spectrum consists of multiple peaks owing to emissions from excitonic transitions and surface defect-related transitions. The excitation wavelength-dependent spectral redshift and narrowing of line shape in the PL peak are analyzed carefully, and it is attributed to the selective excitation/recombination of carriers from different energy levels. The temperature-dependent PL analysis yields an exciton binding energy of ~301 meV in the QDs. Furthermore, we study the interaction between fluorescent WS2 QDs and single-walled carbon nanotubes (SWCNTs) and explore the mechanism of systematic quenching of PL of QDs by SWCNTs. The nature of the Stern-Volmer plot is found to be linear, and the time-resolved fluorescence measurements reveal that the quenching follows primarily the static behavior. Our study further reveals that defect sites in SWCNTs primarily act as the binding sites for WS2 QDs and form non-fluorescent complexes for effective quenching of the PL. The strong interaction between the WS2 QDs and the SWCNTs is evidenced from the spectral shift in the X-ray photoelectron spectroscopy and Raman peaks. Our study reveals the origin of excitation wavelength dependent PL emission from WS2 QDs and the nature of the interaction between WS2 QDs and SWCNTs, which are important for their applications in biomedical imaging and sensing, such as surface-enhanced Raman scattering, etc.


Sex, size, competition and escape-strategies of reproduction and dispersal in Lasallia pustulata (Umbilicariaceae, Ascomycetes).
The lichen Lasallia pustulata has a mixed strategy of asexual and sexual reproduction. Close-dispersed, asexual, symbiotic isidia are produced early, when the thalli are small. The asexual propagules are subsequently supplemented by far-dispersed, sexually generated ascospores when the thalli grow larger. This observation is consistent with evolutionary stable strategy (ESS) models of dispersal allocations in heterocarpic plants accordin to which the production of far-dispersed propagules should increase as clutch size and sibcompetition in the local habitat increases. The observation is also consistent with the "tangled bank" or "elbow room" hypothesis for the maintenance of sexuality, according to which sex, by generating genetic variation, represents an escape from competition in biologically saturated environments. Thus the advantage of sex is density dependent. L. pustulata grows in densely packed populations where intraspecific competition results in self-thining and the development of distinct sizehierarchies.


A conserved trans-regulatory landscape for scute expression on the notum of cyclorraphous Diptera.
Bristles on the notum of many cyclorraphous flies are arranged into species-specific stereotyped patterns. The positions of bristles correlate with differences in the spatial expression of the scute (sc) gene in those species examined so far. However, a major upstream activator of scute, Pannier (Pnr), is expressed in a conserved domain over the entire medial notum. Here we examine the expression patterns in Calliphora vicina of stripe (sr), u-shaped (ush), caupolican (caup) and wingless (wg), genes known to modify the activity of Pnr or to act downstream of Pnr in Drosophila. We find that, with minor differences, their expression patterns are conserved. This suggests that the function of a trans-regulatory network of genes is relatively unchanged in derived Diptera and that many differences are likely to be due to changes in cis-regulatory sequences of scute.


The human Y chromosome: an evolutionary marker comes of age.
Until recently, the Y chromosome seemed to fulfil the role of juvenile delinquent among human chromosomes--rich in junk, poor in useful attributes, reluctant to socialize with its neighbours and with an inescapable tendency to degenerate. The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution. Y-chromosome research is growing up.


Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.
Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.


Automating radiologist workflow, part 2: hands-free navigation.
Although digital imaging and information technologies provide the mechanism to dramatically enhance radiologist workflow, this theoretical workflow improvement is not always realized in everyday practice. A high degree of interradiologist workflow variability currently exists because of differences in technology, radiologist education and training, and computer proclivity. Much of the time and effort spent by radiologists during image review, interpretation, and reporting is spent performing manual steps that could potentially be automated. One solution to address existing workflow deficiencies would be the creation of automated workflow templates, which could be context and user specific and created in accordance with data-driven "best practice" guidelines. The creation of these automated workflow templates would have the potential of minimizing workflow variability, improving radiologists' productivity, and improving diagnostic accuracy. By automating workflow, radiologists could in effect allocate 100% of their attention to imaging data sets, thereby creating a mechanism for "hands-free" navigation.


Development of a medical record audit for continuing medical education.
A self-instructional audit package for the identification and management of hypertensive patients was developed. The materials were field tested in the clinics of seven institutions to assess their clarity and collect data to illustrate the usefulness of an audit as an educational tool.


p53 expression in concurrent chemoradiotherapy with docetaxel for head and neck squamous cell carcinoma.
The current study aimed to evaluate the significance of an immunohistochemical assessment of tumor suppressor p53 as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) patients treated with docetaxel and radiotherapy. The expression of tumor suppressor p53 and its phosphorylated form at the Ser392 residue was retrospectively evaluated by immunohistochemistry in 51 Stage T1-3N0-2M0 (except T1N0 glottis) HNSCC patients who were treated with 10mg/m(2)/week docetaxel four to six times and received concurrent chemoradiotherapy. Kaplan-Meier univariate analysis revealed that no difference in rates for overall and disease-free survival (DFS) between patients with p53-positive and -negative tumors (p=0.786 and p=0.924, respectively). The prognostic significance of phosphorylated p53 at the Ser392 residue was neither observed. An immunohistochemical assessment of the expression of p53 and its phosphorylated form might not be of clinical use in defining subgroups of patients with poor prognosis.


A diploid-triploid human mosaic with cytogenetic evidence of double fertilization.
The karyotype 46,XX/69,XXY was found in a 13-year-old mentally subnormal patient with club feet, strabismus, eunuchoid habitus, small penis, midscrotal urethrovaginal opening, small descended left testis, and small undescended right testis; no ovarian tissue could be found at laparotomy. Triploid:diploid cell ratios were 60:40 and 4:96 in skin fibroblasts and curculating lymphocytes, respectively. In the triploid line, two of the no. 13 chromosomes had unusually large satellites and one of the no. 22 chromosomes had a brightly fluorescent zone on its short arms. The patient's father was heterozygous for both these autosomal markers; the mother carried neither marker. This, together with the single Y, indicated that the extra haploid set was derived from the father. Of several possible mechanisms, we favor the suggestion that double fertilization occurred; one sperm nucleus immediately fused with the egg nucleus producing the diploid line; the second sperm nucleus was incorporated later into one of the two cells resulting from the first division of the zygote, producing the triploid line.


Serum-myocardium gradients of non-esterified fatty acids in dog, rat and man.
In the three species under investigation (dog, rat and man) a gradient from serum to heart tissue for total non-esterified fatty acids was assessed. The ratios serum/left ventricular tissue in dogs, serum/right auricular appendage in dogs, serum/whole heart tissue in rats and serum/right auricular appendage in man were found to be 6.4, 2.5, 5.6 and 2.8, respectively. The highest gradient was found for oleic acid, whereas no significant gradient for arachidonic acid could be detected. In the dog the arterio:local venous differences of non-esterified fatty acids across the left ventricular tissue correlated better with the serum/tissue ratio of non-esterified fatty acids than with the arterial non-esterified fatty acid level. Since the correlation coefficient (0.74) was still far from excellent, more factors than the non-esterified fatty acid serum/tissue gradient are likely to be involved in determining the extent to which non-esterified fatty acids are extracted by myocardial tissue.


Are ants sensitive to the geometry of tunnel bifurcation?
The ability to orient and navigate in space is essential for all animals whose home range is organized around a central point. Because of their small home range compared to vertebrates, central place foraging insects such as ants have for a long time provided a choice model for the study of orientation mechanisms. In many ant species, the movement of individuals on their colony home range is achieved essentially collectively, on the chemical trails laid down by their nest mates. In the initial stage of food recruitment, these trails can cross each other and thus form a network of interconnected paths in which ants have to orient. Previous simulation studies have shown that ants can find the shortest path between their nest and a food source in such a network only if there is a bias in the branch they choose when they reach an asymmetrical bifurcation. In this paper, we studied the choice of ants when facing either a symmetrical or an asymmetrical bifurcation between two tunnels. Ants were tested either on their way to a food source or when coming back to their nest, and either in the presence or in the absence of a chemical trail. Overall, our results show that the choice of an ant at a tunnel bifurcation depends more on the presence/absence of a trail pheromone than on the geometry of the bifurcation itself.


In vivo attachment site to attachment site length and strain of the ACL and its bundles during the full gait cycle measured by MRI and high-speed biplanar radiography.
The purpose of this study was to measure in vivo attachment site to attachment site lengths and strains of the anterior cruciate ligament (ACL) and its bundles throughout a full cycle of treadmill gait. To obtain these measurements, models of the femur, tibia, and associated ACL attachment sites were created from magnetic resonance (MR) images in 10 healthy subjects. ACL attachment sites were subdivided into anteromedial (AM) and posterolateral (PL) bundles. High-speed biplanar radiographs were obtained as subjects ambulated at 1 m/s. The bone models were registered to the radiographs, thereby reproducing the in vivo positions of the bones and ACL attachment sites throughout gait. The lengths of the ACL and both bundles were estimated as straight line distances between attachment sites for each knee position. Increased attachment to attachment ACL length and strain were observed during midstance (length = 28.5 ± 2.6 mm, strain = 5 ± 4%, mean ± standard deviation), and heel strike (length = 30.5 ± 3.0 mm, strain = 12 ± 5%) when the knee was positioned at low flexion angles. Significant inverse correlations were observed between mean attachment to attachment ACL lengths and flexion (rho = -0.87, p < 0.001), as well as both bundle lengths and flexion (rho = -0.86, p < 0.001 and rho = -0.82, p < 0.001, respectively). AM and PL bundle attachment to attachment lengths were highly correlated throughout treadmill gait (rho = 0.90, p < 0.001). These data can provide valuable information to inform design criteria for ACL grafts used in reconstructive surgery, and may be useful in the design of rehabilitation and injury prevention protocols.


Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials.
Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP-1 receptor agonists and DPP-4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient-years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP-1 receptor agonists and DPP-4 inhibitors. Neither data on individual CVOTs of GLP-1 receptor agonists nor their meta-analysis [rate ratio: 1.05 (0.78-1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP-4 inhibitors displayed a non-significant trend towards an increased risk of acute pancreatitis, which was significant in the meta-analysis [1.75 (1.14-2.70); P = 0.01]. Neither GLP-1 receptor agonists nor DPP-4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo-controlled, prospective cardiovascular outcomes studies with GLP-1 receptor agonists and DPP-4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.


Detection of toxigenic Clostridioides [Clostridium] difficile: Usefulness of two commercially available enzyme immunoassays and a PCR assay on stool samples and stool isolates.
The best laboratory diagnostic approach to detect Clostridioides [Clostridium] difficile infection (CDI) is a subject of ongoing debate. With the aim of evaluating four laboratory diagnostic methods, 250 unformed stools from patients with suspected CDI submitted to nine medical center laboratories from November 2010 to December 2011, were studied using: (1) an immunochromatographic rapid assay test that combines the qualitative determination of glutamate dehydrogenase (GDH) plus toxins A and B (QAB), the CDIFF QUIK CHEK COMPLETE assay; (2) an enzyme immunoassay for qualitative determination of toxins A and B, the RIDASCREEN™ C. difficile Toxin A/B assay (RAB); (3) a PCR for the toxin B gene assay (PCR); and (4) the toxigenic culture (TC). C. difficile isolates from direct toxin negative stools by QAB, RAB and PCR were evaluated for toxigenicity by the same direct tests, in order to assess the contribution of the TC (QAB-TC, RAB-TC, PCR-TC). A combination of the cell culture cytotoxicity neutralization assay (CCCNA) in stools, and the same assay on isolates from direct negative samples (CCCNA-TC) was considered the reference method (CCCNA/CCCNA-TC). Of the 250 stools tested, 107 (42.8%) were positive by CCCNA/CCCNA-TC. The GDH and PCR/PCR-TC assays were the most sensitive, 91.59% and 87.62%, respectively. The QAB, RAB, QAB/QAB-TC and RAB/RAB-TC had the highest specificities, ca. 95%. A negative GDH result would rule out CDI, however, its low positive likelihood ratio (PLR) of 3.97 indicates that a positive result should always be complemented with the detection of toxins. If the RAB, QAB, and PCR assays do not detect toxins from direct feces, the toxigenic culture should be performed. In view of our results, the most accurate and reliable methods to be applied in a clinical microbiology laboratory were the QAB/QAB-TC, and RAB/RAB-TC, with PLRs >10 and negative likelihood ratios <0.30.


Crystal structure of GSK3β in complex with the flavonoid, morin.
GSK3β is a key kinase that plays a role in cellular signaling pathways. In Alzheimer's disease (AD), GSK3β has been implicated in hyperphosphorylation of tau proteins in the neuron, which is a hallmark of AD. Morin, a flavonoid that is abundant in nature, was found as an inhibitor of GSK3β that can reduce tau pathology in vivo and in vitro. In this study, we determined the crystal structure of GSK3β in complex with morin. The structure revealed that morin inhibits GSK3β by binding to the ATP binding pocket. Our findings augment the potential of morin as a functional food to help prevent AD, as well as to provide structural information to develop new therapeutics based on the morin skeleton.


Seasonal and diurnal leaf movements of Rhododendron maximum L. in contrasting irradiance environments.
Leaf orientation (azimuth and angle) and leaf curling were measured seasonally and diurnally on Rhododendron maximum L. under an evergreen and a deciduous canopy. The microclimatic conditions under the evergreen canopy (mixed pine and hemlock) were characterized by lower irradiance but similar temperature, and vapor pressure deficit (vpd) to that under the deciduous canopy (mixed oak and maple). Under both canopies irradiance was more intense during winter months.On a seasonal basis leaf angle was closer to horizontal under the evergreen canopy but there was no difference between leaf curling in the two sites. Stomatal conductance was higher under the deciduous canopy but stomata were closed in the winter (following canopy abscission) under the evergreen and deciduous canopies even during warm winter days. Leaf water potentials were lower in the winter and Rhododendron maximum had higher leaf water potentials under the evergreen canopy.Significant association between mean leaf angle and curling index were found above a mean leaf angle of 70°. Leaf curling was highly associated with leaf temperature where 0° C was a critical value stimulating leaf curling. Leaf angle was linearly related to leaf temperatures above 0° C although this relationship was different under the two canopy types as a result of differing irradiance or differing water potential.


Oral food challenge to wheat: a near-fatal anaphylaxis and review of 93 food challenges in children.
Wheat allergy is among the most common food allergy in children, but few publications are available assessing the risk of anaphylaxis due to wheat. In this study, we report the case of near-fatal anaphylaxis to wheat in a patient undergoing an oral food challenge (OFC) after the ingestion of a low dose (256 mg) of wheat. Moreover, for the first time, we analyzed the risk of anaphylaxis during an OFC to wheat in 93 children, compared to other more commonly challenged foods such as milk, egg, peanuts, and soy in more than 1000 patients. This study, which includes a large number of OFCs to wheat, shows that wheat is an independent risk factor that is associated with anaphylaxis requiring epinephrine administration (Odds Ratio [OR] = 2.4) and anaphylaxis requiring epinephrine administration to low dose antigen (OR = 8.02). Other risk factors for anaphylaxis, anaphylaxis requiring epinephrine administration, and anaphylaxis to low dose antigen was a history of a prior reaction not involving only the skin (OR = 1.8, 1.9 and 1.8 respectively). None of the clinical variables available prior to performing the OFC could predict which children among those undergoing OFCs to wheat would develop anaphylaxis or anaphylaxis for low dose antigen. This study shows that wheat is an independent risk factor that is associated with anaphylaxis requiring epinephrine administration and anaphylaxis requiring epinephrine administration to low dose antigen.