Relaxin decreases the severity of established hepatic fibrosis in mice.
Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation and activation of the hepatic stellate cells. The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown. The aim of this study was to determine the effect of relaxin on an in vivo model after establishing hepatic fibrosis Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 μg/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride. Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases MMP13 and MMP3, decreased the expression of MMP2 and tissue inhibitor of metalloproteinase 2 (TIMP2) and increased the overall level of collagen-degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells. The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen-degrading activity, and impaired TGFβ signalling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.


Preferential activation of the epidermal growth factor receptor in human colon carcinoma liver metastases in nude mice.
Increased epidermal growth factor receptor (EGF-R) gene expression and functional protein levels correlate with the metastatic potential of human colon carcinoma (HCC) cells in nude mice. The purpose of this study was to determine whether the production of liver metastases by HCC cells depends on the EGF-R activation status and whether different organ microenvironments influence this activation. Using two independent monoclonal antibodies specific for the activated (i.e., tyrosine-phosphorylated) EGF-R, increased immunoreactivity was observed in HCC cells growing as metastatic lesions in the livers of athymic nude mice. Staining was observed throughout these lesions, both peripherally and centrally. In contrast, little or no immunoreactivity for activated EGF-R was observed in primary tumors growing orthotopically in the cecum or ectopically in the subcutis of nude mice. Immunohistochemistry for total EGF-R levels (irrelevant of activation status) demonstrated similar levels of immunoreactivity in HCC tumors growing in the cecum, subcutis, or liver of nude mice, indicating that total EGF-R levels are not altered after growth in these different microenvironments. Controls included immunohistochemistry for total and activated EGF-R levels in HCC cells growing in vitro under serum-free or EGF-stimulated conditions and A431-epidermoid carcinoma growing in nude mice. Western blot analyses confirmed the specificity of the antibodies for the activated EGF-R. These results suggest that the production of liver metastasis by HCC cells depends in part on the response of tumor cells to organ-derived growth factors and hence the activation of specific cell surface tyrosine kinase receptors.


Sensitive and fast identification of urinary human, synthetic and animal insulin by means of nano-UPLC coupled with high-resolution/high-accuracy mass spectrometry.
The double-chain polypeptide insulin and its synthetic (Insulin Glulisine, Insulin Aspart, Insulin Glargine, or Insulin Lispro) or animal analogues (porcine insulin or bovine insulin) are potential performance-enhancing agents in elite sports or potentially effective toxins in forensic science.The present study demonstrates an analytical method to purify the insulins simultaneously from urine specimens with an approach based on immunoaffinity isolation, using coated magnetic beads (anti-mouse) and a primary anti-insulin antibody (IgG, monoclonal). The extracts were purified sufficiently for separation by means of nano-flow liquid chromatography coupled with nano-scale high-resolution, high-accuracy ESI-MS/MS. Elucidation of collision-induced dissociations with product ion experiments using the fivefold protonated precursor ion of each target analyte enabled all synthetic and animal insulins to be differentiated from their human counterpart, which was particularly important for Lispro, possessing the same molecular mass as human insulin.The method was fully validated for specificity, limit of detection (LOD, 0.5 fmol/mL), precision (<20%), recovery (approximately 30%) and linearity (2-40 fmol/mL) for all target analytes.


Exploring the loss and disenfranchised grief of animal care workers.
This article explores the psychological distress of Animal Care Workers (ACWs), and the disenfranchisement of this distress through mixed methods study conducted as an online survey. In all, 139 participants responded about their experiences as an ACW, related psychological distress, and the systemic disenfranchisement of distress. Findings indicate that nearly half of ACWs experienced symptoms of depression in the previous month. Over 66% indicated it was difficult to cope. Limited support often resulted in a disenfranchized loss. Implications suggest ACW distress and disenfranchisement related to animals they serve is similar to that of individuals who lose animal companions.


Type-specific antigens of group A Neisseria meningitidis: lipopolysaccharide and heat-modifiable outer membrane proteins.
The solid-phase radioimmunoassay inhibition method was used to analyze the noncapsular surface antigens of group A Neisseria meningitidis for type specificity. By use of antisera prepared against group A strains, three serologically distinct lipopolysaccharide antigens and five outer membrane protein antigens were identified among group A strains from a variety of geographical origins. Two of the lipopolysaccharide antigens were unique to group A strains while the third was similar to those on strains of other meningococcal serogroups. Fractionation of outer membrane proteins in the presence of 2% sodium deoxycholate followed by quantitative inhibition of the typing reactions with the subfractions revealed that the protein responsible for type specificity was not the principal outer membrane protein, but, most likely, the 31,000-dalton, heat-modifiable outer membrane protein. Thus, although group A strains may share a common principal outer membrane protein, typing is feasible using other surface antigens. In a survey of 82 group A strains, 93% were typable with respect to outer membrane proteins.


Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.
Arsenic trioxide (ATO; As2O3) induces apoptotic cell death in various cancer cells including lung cancer via the induction of reactive oxygen species (ROS). However, little is known about the toxicological effects of ATO on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). ATO increased ROS levels including O2•- and GSH depleted cell numbers. NAC attenuated the growth inhibition, death and MMP (∆ψm) loss in ATO-treated HPF cells and also decreased the ROS levels in these cells. However, vitamin C enhanced the growth inhibition, death, MMP (∆ψm) loss and GSH depletion by ATO and even strongly increased mitochondrial O2•- levels in ATO-treated HPF cells. BSO showed a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. Moreover, superoxide dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO, which was not correlated with ROS and GSH level changes. In conclusion, ATO induced the growth inhibition and death of HPF cells, accompanied by increasing ROS levels and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and BSO enhanced the death.


Successional dynamics in the seasonally forced diamond food web.
Plankton seasonal succession is a classic example of nonequilibrium community dynamics. Despite the fact that it has been well studied empirically, it lacks a general quantitative theory. Here we investigate a food web model that includes a resource, two phytoplankton, and a shared grazer-the diamond food web-in a seasonal environment. The model produces a number of successional trajectories that have been widely discussed in the context of the verbal Plankton Ecology Group model of succession, such as a spring bloom of a good competitor followed by a grazer-induced clear-water phase, setting the stage for the late-season dominance of a grazer-resistant species. It also predicts a novel, counterintuitive trajectory where the grazer-resistant species has both early- and late-season blooms. The model often generates regular annual cycles but sometimes produces multiyear cycles or chaos, even with identical forcing each year. Parameterizing the model, we show how the successional trajectory depends on nutrient supply and the length of the growing season, two key parameters that vary among water bodies. This model extends nonequilibrium theory to food webs and is a first step toward a quantitative theory of plankton seasonal succession.


[Diagnosis and treatment of hepatocellular carcinoma].
Worldwide, hepatocellular carcinoma is one of the most common intra-abdominal malignancy. It occurs mostly in patients who are carriers of the hepatitis B or C virus and/or have liver cirrhosis. There is no screening-test for early recognition of the development of liver cancer and this delays often an accurate diagnosis and early treatment. Resection is the best form of treatment offering a chance of cure. In the last decades, considerable progress has been made in the field of liver diagnostic and operative techniques for liver resection. This has been followed by an increase in the resection rate of patients with malignant liver tumours and by a decrease in postoperative morbidity and mortality. Nowadays, after curative resection, 5-year survival rates up to 30% can be achieved. Promising results are also obtained by new adjuvant therapeutic modalities demonstrating improvement in survival. Therefore, in the field of malignant liver tumours there is no more space for therapeutic nihilismus.


Drug therapy of inflammatory bowel disease in fertile women.
Inflammatory bowel disease (IBD) is a disease that affects women of childbearing age. Active disease at conception increases the risk for adverse outcomes and thus postponement of pregnancy until the disease is in remission is the best advice that physicians can give their IBD patients. The majority of medications used to treat IBD are safe in pregnancy and breastfeeding; active, untreated, or undertreated disease is more deleterious than active therapy.


Evaluation of dynamic stereopsis in intermittent exotropia patients.
To delineate the characteristics of the dynamic stereopsis test and analyze related parameters in intermittent exotropia [X(T)] patients. Fifty-seven X(T) patients and 55 normal subjects were enrolled in this study. The normal and X(T) groups were used to test the reproducibility and reliability of the dynamic stereopsis test, and Bangerter filters with densities of 0.2 were then used to simulate suppression to test for traditional and dynamic stereopsis. In the X(T) group, the measurements included 1) dynamic stereopsis test comprising three parts: motion+disparity, motion only and disparity only; 2) ocular deviation angle; 3) Bagolini striated lens test; 4) disease course; and 5) Titmus stereopsis test. The test-retest reliability of the dynamic stereopsis method was 0.901 in the normal and X(T) groups, and none of the X(T) patients were able to pass the static and dynamic stereopsis tests after using the 0.2 Bangerter filter. The accuracy rate was greater than 80% in the normal group and 31.81%, 36.36%, and 45.45% for the motion+disparity, motion-only and disparity-only components of the traditional test for X(T) patients diagnosed with stereoblindness via traditional tests, respectively. Patients with a long disease course (>1y) had worse dynamic stereopsis than those with a short disease course (<1y; P<0.05, Chi-square test). The deviation angle was not correlated with the motion+disparity, disparity-only, or the motion-only test components (all P>0.05, Chi-square test). Dynamic stereopsis is preserved in certain X(T) patients diagnosed with stereoblindness via traditional tests. A long disease course was shown to be a negative factor for dynamic stereopsis in X(T) patients which might be associated with worse progression, and provide good references clinically.


[Risk predictive models of healthcare-seeking delay among imported malaria patients in Jiangsu Province based on the machine learning].
To create risk predictive models of healthcare-seeking delay among imported malaria patients in Jiangsu Province based on machine learning algorithms, so as to provide insights into early identification of imported malaria cases in Jiangsu Province. Case investigation, first symptoms and time of initial diagnosis of imported malaria patients in Jiangsu Province in 2019 were captured from Infectious Disease Report Information Management System and Parasitic Disease Prevention and Control Information Management System of Chinese Center for Disease Control and Prevention. The risk predictive models of healthcare-seeking delay among imported malaria patients were created with the back propagation (BP) neural network model, logistic regression model, random forest model and Bayesian model using thirteen factors as independent variables, including occupation, species of malaria parasite, main clinical manifestations, presence of complications, severity of disease, age, duration of residing abroad, frequency of malaria parasite infections abroad, incubation period, level of institution at initial diagnosis, country of origin, number of individuals travelling with patients and way to go abroad, and time of healthcare-seeking delay as a dependent variable. Logistic regression model was visualized using a nomogram, and the nomogram was evaluated using calibration curves. In addition, the efficiency of the four models for prediction of risk of healthcare-seeking delay among imported malaria patients was evaluated using the area under curve (AUC) of receiver operating characteristic curve (ROC). The importance of each characteristic was quantified and attributed by using SHAP to examine the positive and negative effects of the value of each characteristic on the predictive efficiency. A total of 244 imported malaria patients were enrolled, including 100 cases (40.98%) with the duration from onset of first symptoms to time of initial diagnosis that exceeded 24 hours. Logistic regression analysis identified a history of malaria parasite infection [odds ratio (OR) = 3.075, 95% confidential interval (CI): (1.597, 5.923)], long incubation period [OR = 1.010, 95% CI: (1.001, 1.018)] and seeking healthcare in provincial or municipal medical facilities [OR = 12.550, 95% CI: (1.158, 135.963)] as risk factors for delay in seeking healthcare among imported malaria cases. BP neural network modeling showed that duration of residing abroad, incubation period and age posed great impacts on delay in healthcare-seek among imported malaria patients. Random forest modeling showed that the top five factors with the greatest impact on healthcare-seeking delay included main clinical manifestations, the way to go abroad, incubation period, duration of residing abroad and age among imported malaria patients, and Bayesian modeling revealed that the top five factors affecting healthcare-seeking delay among imported malaria patients included level of institutions at initial diagnosis, age, country of origin, history of malaria parasite infection and individuals travelling with imported malaria patients. ROC curve analysis showed higher overall performance of the BP neural network model and the logistic regression model for prediction of the risk of healthcare-seeking delay among imported malaria patients (Z = 2.700 to 4.641, all P values < 0.01), with no statistically significant difference in the AUC among four models (Z = 1.209, P > 0.05). The sensitivity (71.00%) and Youden index (43.92%) of the logistic regression model was higher than those of the BP neural network (63.00% and 36.61%, respectively), and the specificity of the BP neural network model (73.61%) was higher than that of the logistic regression model (72.92%). Imported malaria cases with long duration of residing abroad, a history of malaria parasite infection, long incubation period, advanced age and seeking healthcare in provincial or municipal medical institutions have a high likelihood of delay in healthcare-seeking in Jiangsu Province. The models created based on the logistic regression and BP neural network show a high efficiency for prediction of the risk of healthcare-seeking among imported malaria patients in Jiangsu Province, which may provide insights into health management of imported malaria patients.


Specific storage of glycoconjugates with terminal α-galactosyl moieties in the exocrine pancreas of Fabry disease patients with blood group B.
Blood group B glycosphingolipids (B-GSLs) are substrates of the lysosomal alpha-galactosidase A (AGAL). Similar to its major substrate-globotriaosylceramide (Gb3Cer)-B-GSLs are not degraded and accumulate in the cells of patients affected by an inherited defect of AGAL activity (Fabry disease-FD).The pancreas is a secretory organ known to have high biosynthesis of blood group GSLs. Herein, we provide a comprehensive overview of the biochemical and structural abnormalities in pancreatic tissue from two male FD patients with blood group B. In both patients, we found major accumulation of a variety of complex B-GSLs carrying predominantly hexa- and hepta-saccharide structures. The subcellular pathology was dominated by deposits containing B-glycoconjugates and autofluorescent ceroid. The contribution of Gb3Cer to the storage was minor. This abnormal storage pattern was specific for the pancreatic acinar epithelial cells. Other pancreatic cell types including those of islets of Langerhans were affected much less or not at all.Altogether, we provide evidence for a key role of B-antigens in the biochemical and morphological pathology of the exocrine pancreas in FD patients with blood group B. We believe that our findings will trigger further studies aimed at assessing the potential pancreatic dysfunction in this disease.


The ketogenic diet--update on recent clinical trials.
The ketogenic diet (KD) has been used in the treatment of epilepsy for almost 100 years. Several cohort studies have emphasized its possible benefit, although use became less at the introduction of anticonvulsant medication. However, the KD has regained recognition over the past 15 years. Resources remain scarce and its availability for children may be limited. One argument has been the lack of evidence from suitably designed trials. Systematic reviews and meta-analyses have revealed that studies are limited to class 3 and 4 data. A recently published randomized controlled trial has shown that the benefit of the KD is equivalent to any of the new anticonvulsant medications, emphasizing the need for more resources to ensure greater diet availability.


The influence of M. P. Bryden's work on lateralization of motor skill: Is the preferred hand selected for and better at tasks requiring a high degree of skill?
One question of interest to Dr M. P. Bryden was how skilled motor behaviour, task complexity, and the degree of handedness are linked. His research suggested that there would be dissociation between hand preference and performance for skilled versus unskilled actions. The thought was that "simple" or unskilled tasks such reaching or grasping could be performed equally well by either hand, and thus either could be selected. Skilled tasks such as fine manipulation would be performed best by the preferred hand and thus it would be selected more frequently. Over the past two decades, researchers have attempted to determine whether such a definition of skilled action best encapsulates the specialization of the preferred hand. The current paper will review M. P. Bryden's research on skilled motor behaviour, as well as more recent work, and explore the question of whether the preferred hand is actually superior and preferred for actions requiring manipulation.


Immunization of arctic foxes (Alopex lagopus) with oral rabies vaccine.
Arctic foxes (Alopex lagopus) were successfully immunized against rabies using an orally-administered, liquid SAD-BHK21 live virus vaccine in a sausage bait. Immunization was determined by serologic response and by resistance to challenge with an arctic rabies virus strain. Virus was not shed in saliva following oral vaccination, indicating that arctic foxes would not infect other foxes after ingesting this vaccine. High antibody levels were present in all experimental foxes 2 wk following initial vaccination. A booster vaccination at 56 wk induced a significant serologic response within 1 wk, suggesting an anamnestic response but titers began to decline within 8 wk in most foxes. Foxes were observed for 16 mo following the challenge and exhibited no symptoms of rabies. The SAD-BHK21 rabies vaccine in a sausage bait system has a strong potential for vaccinating wild populations of arctic fox.


Cytokines and autoimmune beta cell destruction in NOD mouse fetal pancreas isografts in cyclophosphamide-induced diabetes.
The role of cytokines in a model of cyclophosphamide (CP)-accelerated beta cell destruction in fetal pancreas isografts transplanted into NOD mice was studied. One group of prediabetic NOD mice was injected with CP at a dose of 300 mg/kg i.p. and 7 days later isografts of organ cultured fetal pancreas (FP) were transplanted under the kidney capsule of these and untreated control mice. The mice were killed at several time points post-transplantation and the histological appearance of the host pancreas used to evaluate the disease progress in the grafts since previous studies had shown good correlation between isograft and native pancreas pathology. Intragraft cytokine gene expression was monitored by reverse-transcriptase polymerase chain reaction (RT-PCR) at the same time points and the expression levels between the experimental groups compared to normal kidney tissue. In comparison to isografts from non-CP injected mice, isografts from CP-treated mice showed increased expression of IFN-gamma, TNF-alpha, TNF-beta, IL-5, and eotaxin but no increase in IL-10 expression. The enhanced transcription of these cytokines correlated with massive infiltration of immune cells and ongoing beta cell destruction in the host pancreas of the CP-treated recipients.


Early understanding of the representational function of pictures.
An important function of pictures is the communication of information--a function that has been ignored in research on the development of pictorial perception and comprehension. When are young children first capable of using pictures as a source of information to guide their behavior? The six studies reported here reveal a dramatic developmental change between 24 and 30 months of age in the use of pictorial information about the location of a hidden object. When presented with a picture that showed the location of a hidden toy, 30-month-olds readily retrieved the toy, but 24-month-olds did not. The extremely poor performance of the 24-month-olds was replicated and shown to persist in spite of various modifications made in the task in an effort to improve performance. We conclude that our 24-month-old subjects did not interpret the pictures as representations of current reality. We propose that very young children's early pictorial experience may predispose them to be overly conservative in interpreting the relation between pictures and their referents.


Identifying key multi-modal predictors of incipient dementia in Parkinson's disease: a machine learning analysis and Tree SHAP interpretation.
Persons with Parkinson's disease (PD) differentially progress to cognitive impairment and dementia. With a 3-year longitudinal sample of initially non-demented PD patients measured on multiple dementia risk factors, we demonstrate that machine learning classifier algorithms can be combined with explainable artificial intelligence methods to identify and interpret leading predictors that discriminate those who later converted to dementia from those who did not. Participants were 48 well-characterized PD patients (Mbaseline age = 71.6; SD = 4.8; 44% female). We tested 38 multi-modal predictors from 10 domains (e.g., motor, cognitive) in a computationally competitive context to identify those that best discriminated two unobserved baseline groups, PD No Dementia (PDND), and PD Incipient Dementia (PDID). We used Random Forest (RF) classifier models for the discrimination goal and Tree SHapley Additive exPlanation (Tree SHAP) values for deep interpretation. An excellent RF model discriminated baseline PDID from PDND (AUC = 0.84; normalized Matthews Correlation Coefficient = 0.76). Tree SHAP showed that ten leading predictors of PDID accounted for 62.5% of the model, as well as their relative importance, direction, and magnitude (risk threshold). These predictors represented the motor (e.g., poorer gait), cognitive (e.g., slower Trail A), molecular (up-regulated metabolite panel), demographic (age), imaging (ventricular volume), and lifestyle (activities of daily living) domains. Our data-driven protocol integrated RF classifier models and Tree SHAP applications to selectively identify and interpret early dementia risk factors in a well-characterized sample of initially non-demented persons with PD. Results indicate that leading dementia predictors derive from multiple complementary risk domains.


DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production.
C-type lectin receptors (CLRs) expressed on APCs play a pivotal role in the immune system as pattern-recognition and antigen-uptake receptors. In addition, they may signal directly, leading to cytokine production and immune modulation. To this end, some CLRs, like dectin-1 and dendritic cell immunoreceptor (DCIR), contain intracellular ITIMs or ITAMs. In this study, we explored expression and function of the ITIM-containing CLR DCIR on professional APCs. DCIR is expressed on immature and mature monocyte-derived DCs (moDC) but also on monocytes, macrophages, B cells, and freshly isolated myeloid and plasmacytoid DCs. We show that endogenous DCIR is internalized efficiently into human moDC after triggering with DCIR-specific mAb. DCIR internalization is clathrin-dependent and leads to its localization in the endo-/lysosomal compartment, including lysosome-associated membrane protein-1+ lysosomes. DCIR triggering affected neither TLR4- nor TLR8-mediated CD80 and CD86 up-regulation. Interestingly, it did inhibit TLR8-mediated IL-12 and TNF-alpha production significantly, and TLR2-, TLR3-, or TLR4-induced cytokine production was not affected. Collectively, the data presented characterize DCIR as an APC receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. These data provide further support to the concept of CLR/TLR cross-talk in modulating immune responses.


A Different Perspective for Management of Diabetes Mellitus: Controlling Viral Liver Diseases.
Knowing how to prevent and treat diabetes mellitus (DM) earlier is essential to improving outcomes. Through participating in synthesis and catabolism of glycogen, the liver helps to regulate glucose homeostasis. Viral related liver diseases are associated with glycometabolism disorders, which means effective management of viral liver diseases may be a therapeutic strategy for DM. The present article reviews the correlation between DM and liver diseases to give an update of the management of DM rooted by viral liver diseases.


Perceived time: its relationship with locus of control, filled versus unfilled time intervals, and perceiver's sex.
The present study examined the role of locus of control and the perceiver 's sex in the estimation of filled and unfilled time intervals. One hundred male and 100 female undergraduates, ranging in age between 16 and 21 years, were administered Collins' I-E Scale followed by a time-estimation task. The latter involved judging 10 time intervals which were either "filled" with a tapping sound presented by the E, or were "unfilled." Results indicate that (a) high internals, compared to low internals, were less likely to overestimate filled intervals, but were more likely to overestimate unfilled intervals, possibly because high internals are more time-conscious; (b) the extent of absolute error in estimation is jointly affected by internality, filled/unfilled intervals, and the perceiver 's sex, but the last-mentioned variable had the most prominent independent effect. In general, males made less error in time estimation than females. It is suggested that the observed sex differences in the present study was probably due to socially learned differences in time consciousness.


Effect of Plasma Protein Binding on the Pharmacokinetics of Erdafitinib: Results of an Integrated Cross-Study Analysis.
Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (fu ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (fu , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) fu was 0.510% (39.4%) for healthy participants and 0.316% (64.0%) for patients, with a 2.1-fold higher AGP and 10% lower albumin. Linear binding of erdafitinib to AGP and albumin was observed, with >1000-fold higher binding constant for AGP than albumin (17.6 vs 0.017 µM-1 ). The fu decreased with increasing AGP in a nonlinear relationship. Despite its abundance in plasma relative to AGP, albumin contributed to <4% of the overall binding of erdafitinib (1.8% in patients; 4.0% in healthy participants). The AGP-binding constant was 68.0% lower in predose (spiked) versus postdose (ex vivo) samples. Total oral clearance was generally proportional to the fu and higher in healthy participants than in patients, consistent with the differences in AGP. Correcting for fu accounted for the majority of the relationship between oral clearance and fu as expected with a low extraction ratio drug. Characterizing free erdafitinib concentrations is critical to accounting for differences in fu and to further investigating its clinical relevance.


Piezosurgery: basics and possibilities.
Useful in a variety of oral surgery procedures, piezosurgery has therapeutic features that include a micrometric cut (precise and secure action to limit tissue damage, especially to osteocytes), a selective cut (affecting mineralized tissues, but not surrounding soft tissues), and a clear surgical site (the result of the cavitation effect created by an irrigation/cooling solution and oscillating tip). Because the instrument's tip vibrates at different ultrasonic frequencies, since hard and soft tissues are cut at different frequencies, a "selective cut" enables the clinician to cut hard tissues while sparing fine anatomical structures (e.g., schneiderian membrane, nerve tissue). An oscillating tip drives the cooling-irrigation fluid, making it possible to obtain effective cooling as well as higher visibility (via cavitation effect) compared to conventional surgical instruments (rotating burs and oscillating saws), even in deep spaces. As a result, implantology surgical techniques such as bone harvesting (chips and blocks), crestal bone splitting, and sinus floor elevation can be performed with greater ease and safety.


Depressive Symptoms as a Predictor of Memory Complaints in the PRISM Sample.
The current study investigated baseline and longitudinal relationships between memory complaints, depressive symptoms, and cognition in older adults. Using the sample from the Personal Reminder Information and Social Management trial, we generated path models predicting self-rated memory complaints measured by the Memory Functioning Questionnaire (MFQ). Our baseline models showed that more depressive symptoms were associated with reporting more frequent forgetting incidents and a greater decline in memory function. The baseline models also revealed that higher scores in a latent cognitive function were associated with reporting a greater decline in memory functioning and a greater use of mnemonics. However, cognitive predictors did not mediate the baseline associations between the MFQ measures and depressive symptoms. Further, these predictors were not able to directly predict the 12-month MFQ measures over and above the baseline effects. Including personality traits (neuroticism and conscientiousness) did not significantly affect the models. Our results suggest that memory complaints about frequency of forgetting can be the most reliable indicator of depression risk among the four factors in the MFQ. We discuss theoretical implications for longitudinal relationships between memory complaints, depressive symptoms, and cognitive function in older adults.


Cytotoxic T-cell clone against rectal carcinoma induced by stimulation of a patient's peripheral blood mononuclear cells with autologous cultured tumor cells.
In an effort to establish cytolytic T lymphocytes (CTLs) against colorectal carcinoma (CRC) by stimulating patients' lymphocytes with autologous tumor cells, we used peripheral blood mononuclear cells (PBMC) from a patient with minimal residual rectal carcinoma following removal of the primary lesion and involved regional lymph nodes as a source to generate CTLs in culture. A CTL line and clone were established from the patient's PBMC following stimulation of PBMC with autologous, cultured tumor cells and interleukin-2. The CTL line and the clone consisted predominantly of CD4+ lymphocytes. The CTL clone expressed two T-cell receptor variable alpha chains (V alpha11 and V alpha22) and one beta chain (Vbeta14). The cytokine secretion pattern of the CTL line was of the Th1-type. Both the CTL line and the clone lysed the autologous rectal carcinoma cells, but not the allogeneic, partially human lymphocyte antigen (HLA)-matched or nonmatched CRC cells, autologous Epstein-Barr virus-transformed B cells, K562 (natural killer target) cells or Daudi (lymphokine-activated killer target) cells. Lysis of autologous tumor cells most likely was HLA class I-restricted. Our unique success in generating CTLs against this tumor type may rest in the inclusion of a patient with minimal residual, rather than advanced, disease.


Health Meanings among Foreign Domestic Workers in Singapore: A Culture-Centered Approach.
Economic migration is integral to processes of globalization, with large numbers of the global poor moving across borders in search of employment in the face of structural adjustment programs and large-scale displacement of the poor from traditional forms of livelihood. One such group are foreign domestic workers (FDWs). In this culture-centered study, we listen to the voices of FDWs in Singapore to understand the key meanings of health held by this group of migrant workers as they negotiate living and working in Singapore. Through the representation of FDW voices at sites where they have previously been excluded, we hope to co-create participatory spaces in national discourse so that policies and interventions can be developed to address the health needs of FDWs. The results represented in this essay are part of a larger project engaging the CCA to foster communicative platforms for structural transformation.


Comparative in vitro antimicrobial efficacy of commercial ear cleaners.
The aim of this study was to compare the antimicrobial efficacy of ear cleaners against Staphylococcus intermedius, Pseudomonas aeruginosa and Malassezia pachydermatis. Single isolates of each organism were incubated in duplicate at 38 degrees C for 30 min with each ear cleaner diluted 1/2 to 1/256 in phosphate-buffered saline. Positive and negative controls were included. Aliquots were then incubated for 16-18 h on sheep blood agar (bacteria) or for 3 days on Sabouraud's dextrose agar (Malassezia) at 38 degrees C. The lowest dilutions exhibiting 100% antimicrobial efficacy for S. intermedius were: Cleanaural Dog 1/32; Sancerum 1/16; Otoclean 1/4; EpiOtic 1/2; MalAcetic 1/2; and Triz Plus 1/2. The results for P. aeruginosa were Sancerum and Triz Plus 1/16; Cleanaural Dog and EpiOtic 1/8; Otoclean 1/4; and MalAcetic 1/2. Results for M. pachydermatis were: Cleanaural Dog 1/32; Sancerum, Otoclean, EpiOtic and Triz Plus 1/8; and MalAcetic 1/4. Cleanaural Cat, MalAcetic HC and Triz EDTA did not display any antimicrobial activity at any dilution. Antimicrobial activity appeared to be associated with the presence of isopropyl alcohol, parachlorometaxylenol and a low pH. The results of this study may help clinicians make evidence-based decisions when selecting ear cleaners for use in individual cases.


A virtual screening approach to finding novel and potent antagonists at the melanin-concentrating hormone 1 receptor.
Melanin-concentrating hormone (MCH) has been known to be an appetite-stimulating peptide for a number of years. However, it is only recently that MCH has been discovered to be the natural ligand for a previously "orphan" G-protein-coupled receptor, now designated MCH-1R. This receptor has been shown to mediate the effects of MCH on appetite and body weight, and consequently, drug discovery programs have begun to exploit this information in the search for MCH-1R antagonists for the treatment of obesity. In this paper, we report the rapid discovery of multiple, structurally distinct series of MCH-1R antagonists using a variety of virtual screening techniques. The most potent of these compounds (12) demonstrated an IC(50) value of 55 nM in the primary screen and exhibited antagonist properties in a functional cellular assay measuring Ca(2+) release. More potent compounds were identified by follow-up searches around the initial hit. A proposed binding mode for compound 12 in a homology model of the MCH-1R is also presented.


SBRT Treatment of Multiple Recurrent Auricular Squamous Cell Carcinomas Following Surgical and Conventional Radiation Treatment Failure.
The treatment of recurrent skin cancers of the head and neck following curative doses of radiotherapy and/or surgery is usually palliative radiation therapy (RT) but with mediocre control rates leading to symptomatic local recurrences. We present a 93-year-old male treated with 50 Gy in five fractions for a subauricular cutaneous squamous cell carcinoma who initially underwent partial auriculectomy and accelerated concomitant boost radiotherapy (60 Gy in 21 fractions over 23 days), and then two additional surgeries ending with completion auriculectomy. Re-irradiation with SBRT was well tolerated despite prior high-dose therapy.


Antibody preparation, gene expression and subcellular localization of L-idonate dehydrogenase in grape berry.
L-Idonate dehydrogenase (L-IdnDH) is the only known enzyme of the tartaric acid (TA) biosynthetic pathway in grape berries. Previous studies on this enzyme only focused on the transcriptional expression of this gene. Here, the antibody against L-IdnDH was prepared by cloning the full-length cDNAs of VvIdnDH from grape berries, highly expressing fusion protein in Escherichia coli cells, and then immunizing rabbits. Expression of VvIdnDH at the transcriptional and translational levels in grape berries increased within 3 weeks after full bloom and then decreased, similarly to the trend for TA contents. Almost no VvIdnDH transcript was detected in the mature berries, but VvIdnDH protein was detectable. In the 21-d berries, this enzyme was largely located in the cytoplasm and a few in the cell wall, secondary cell wall, and chloroplast, whereas in the 60 berries, it was distributed mainly in the vacuole and cytoplasm.


Real-Time Detection of Traces of Benzaldehyde in Benzyl Alcohol as a Solvent by a Flexible Lanthanide Microporous Metal-Organic Framework.
Luminescent 3D lanthanide metal-organic framework (Ln-MOF) {[Tb2 (TATAB)2 ]⋅4 H2 O⋅6 DMF}n (1) was synthesized under solvothermal conditions by using flexible ligand 4,4',4''-s-triazine-1,3,5-triyltri-p-aminobenzoate (TATAB). A phase transition was observed between low temperature and room temperature. The luminescence of 1 could be enhanced by formaldehyde and quenched efficiently by trace amounts of benzaldehyde in solvents such as benzyl alcohol (0.01-2.0 vol %) and ethanol (0.01-2.5 vol %). This is the first use of a Ln-MOF as chemical sensor for both formaldehyde and benzaldehyde. The high sensitivity and selectivity of the luminescence response of 1 to benzaldehyde allows it to be used as an excellent sensor for identifying benzaldehyde and provides a simple and convenient method for detecting traces of benzaldehyde in benzyl alcohol based injections. This work establishes a new strategy for detection of benzaldehyde in benzyl alcohol by luminescent MOFs.


Anticholinergic Burden and Functional Status in Older People with Cognitive Impairment: Results from the Regal Project.
The use of drugs with intrinsic anticholinergic properties is widespread among old age persons. A growing body of evidences suggest that a high anticholinergic burden is associated with physical and cognitive impairment. However, the association between anticholinergic drug use and functional status is still poorly investigated, particularly among subjects with initial cognitive impairment. Cross-sectional study examining the association between drug-related anticholinergic burden and functional status in cognitively healthy (CH) (n=691), mild cognitive impairment (MCI) (n=541) or mild Alzheimer's diseases (AD) (n=1127) subjects. Data were gathered from the ReGAl project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large longitudinal Italian multicentric clinical-based study, promoted by the Italian Society of Gerontology and Geriatrics (SIGG). 2359 outpatients, older than 65 years, admitted to memory clinics. The total sample size, estimated according to a global effect size of 25% with type I error of 0.05 and a power of 95% is 2010 subjects. Functional status was evaluated by the Katz Index of Independence in Activities of Daily Living (ADL) and the Lawton-Brody Instrumental Activities of Daily Living (IADL) scales. The drug-related anticholinergic burden was estimated by the Anticholinergic Risk Scale (ARS). The 15.9 % (n=375) of total population used at least one drug with anticholinergic properties. Such a drug use was associated with partially dependence in ADL (OR:1.42, CI95%: 1.10-1.83; p=0.006), independently of gender, number of drugs, comorbidity index, presence of clinically relevant neuropsychiatric symptoms and adjusted MMSE. Anticholinergic drug use was associated with un-ability at each IADL task only in male MCI subjects, with significant impairment in shopping (p=0.011), and drug management (p=0.05). The use of medications with anticholinergic properties is common among older persons cognitively health as well as with cognitive impairment. Our results suggest that the use of anticholinergic drugs is associated with functional impairment, especially in old age subjects with initial cognitive impairment. Minimizing anticholinergic burden should result in maintaining daily functioning, especially in a vulnerable population, such as MCI and mild AD.


Differential regulation of two myo-inositol transporter genes of Saccharomyces cerevisiae.
We previously isolated two distinct Saccharomyces cerevisiae myo-inositol transporter genes, ITR1 and ITR2 (Nikawa et al., 1991). Here, we studied the regulation of their expression by measuring steady-state mRNA levels and beta-galactosidase activities of lacZ fusion genes under different conditions. The results show that the expression of the two ITR genes is differently regulated: ITR1 was repressed by inositol and choline whereas ITR2 was constitutive. Deletion analysis of the ITR1 upstream region and comparison with the upstream regions of other genes involved in phospholipid synthesis indicate that the octamer sequence 5'-TTCACATG-3' is important for the expression and inositol/choline regulation of the ITR1 gene.


Adrenocortical neoplasms: role of prognostic markers MIB-1, P53, and RB.
Differentiation between benign and malignant adrenocortical neoplasms is made using a combination of clinical and pathologic parameters. Despite these parameters, it is still difficult to predict the biologic potential of some tumors. Forty adrenocortical lesions, including 10 hyperplasias, 10 adenomas, 12 carcinomas and eight metastatic/recurrent adrenocortical carcinomas were studied for the expression of MiB-1, p53, and the retinoblastoma gene product (RB) utilizing immunohistochemical techniques. The mean tumor proliferating fraction (TPF), expressed as the number of MiB-1-positive nuclei per 1,000 tumor cells, was 14.9 in adenomas, 31.5 in hyperplasias, 208.1 in carcinomas and 166.1 in recurrent or metastatic disease. None of the 20 benign lesions had a TPF of > 80, and only one of the 20 malignancies had a TPF of < 80. Nine of the 20 carcinomas were positive for p53. None of the benign lesions were p53 positive. Thirty-nine cases, including benign and malignant ones, were RB positive, and one was uninterpretable. We conclude that prognostic markers can be of great assistance in recognizing adrenocortical carcinomas. High TPF (> 80), as measured by staining with MiB-1, and positive p53 strongly correlate with malignant behavior and therefore may be useful in distinguishing benign from malignant adrenal lesions. Staining for RB does not appear to be a helpful technique.


Supplementation of glycerol or fructose via drinking water to grazing lambs on tissue glycogen level and lipogenesis.
Lambs ( = 18; 40.1 ± 7.4 kg BW) were used to assess supplementation of glycerol or fructose via drinking water on growth, tissue glycogen levels, postmortem glycolysis, and lipogenesis. Lambs were blocked by BW and allocated to alfalfa paddocks (2 lambs/paddock and 3 paddocks/treatment). Each paddock within a block was assigned randomly to drinking water treatments for 30 d: 1) control (CON), 2) 120 g fructose/L of drinking water (FRU), or 3) 120 g glycerol/L of drinking water (GLY). Lambs grazed alfalfa with free access to water treatments for 28 d and then were fasted in indoor pens for a final 2 d with access to only water treatments. Data were analyzed using the MIXED procedure of SAS with water treatment and time (when appropriate) in the model. During the 28-d grazing period, ADG was greater ( < 0.05) for GLY than for CON or FRU. During the 2-d fasting period, BW shrink was lower ( < 0.05) for GLY compared with CON or FRU. Hot carcass weight was greater ( < 0.05) for GLY than for FRU. The interaction for glycogen content × postmortem time was significant ( = 0.003) in LM and semitendinosus (ST) muscles. Glycogen content in the LM was greater ( < 0.05) for GLY at 2 and 3 h and for FRU at 1 h postmortem compared with CON. Glycogen content in ST did not differ between treatments ( > 0.05). Liver glycogen content was over 14-fold greater ( < 0.05) for GLY compared with FRU or CON. Liver free glucose was greater ( < 0.05) for GLY than for CON, whereas liver lipid content was higher ( < 0.05) for CON than for GLY. Supplementation with GLY increased ( < 0.05) odd-chain fatty acids in LM, subcutaneous fat (SQ), and the liver. Stearic acid (C18:0) concentrations were reduced in LM ( = 0.064) and subcutaneous adipose tissue (SQ; = 0.018), whereas oleic acid (C18:1 -9) concentration tended to be increased ( = 0.066) in SQ with FRU and GLY. Linolenic acid (C18:3 -3) was reduced ( = 0.031) and all long-chain -3 fatty acid (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) concentrations were increased ( < 0.05) with FRU and GLY compared with CON. Glycerol supplementation upregulated ( < 0.05) stearoyl-CoA desaturate () and fatty acid synthase () mRNA by over 40-fold in the SQ and 5-fold in the liver. Glycerol supplementation also upregulated ( < 0.05) glucose transporters and glycogen branching enzyme in the liver. Overall, glycerol supplementation improved growth, reduced BW shrink during fasting, increased glycogen content in muscle and the liver, and stimulated de novo lipogenesis.


Influence of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) on appetite and thrombosis.
Preclinical pharmacological characterization of a novel inhibitor (UM8190) of prolylcarboxypeptidase (PRCP) was investigated. We synthesized and evaluated a library of proline-based analogs as prospective recombinant PRCP (rPRCP) inhibitors and inhibitors of PRCP-dependent prekallikrein (PK) activation on human pulmonary artery endothelial cells (HPAEC). Among the newly synthesized compounds, UM8190 was further characterized in vivo using methods that encompassed a mouse carotid artery thrombosis model and animal model of food consumption. (S)-N-dodecyl-1-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide [Compound 3 (UM8190)] was selected for further evaluation from the initial assessment of its PRCP inhibitory action (K(i)= 43 μM) coupled with its ability to block PRCP-dependent PK activation on HPAEC (K(i)= 34 μM). UM8190 demonstrated excellent selectivity against a panel of carboxypeptidases and serine proteases and blocked bradykinin (BK) generation and BK-induced permeability by 100%, suggesting that it may be useful in preventing the local production of large amounts of BK. Furthermore, UM8190 showed an anorexigenic effect when systemically administered to fasted mice, reducing food intake in a dose- and time-dependent manner. In a mouse carotid artery thrombosis model, it also demonstrated an antithrombotic effect. UM8190 is a selective PRCP inhibitor and it may represent a new anorexigenic, and antithrombotic drug, that works by inhibiting PRCP-mediated mechanisms.


Magnetic resonance imaging of overall and regional body fat, estrogen metabolism, and ovulation of athletes compared to controls.
The association of menstrual dysfunction of athletes with changes in body composition has been controversial, because most estimations of body fatness have been indirect. Using magnetic resonance imaging, we quantified the sc and internal fat over a specific volume from the fifth thoracic vertebra to femoral fat in the upper thigh and at 4 other anatomical landmarks of 17 athletes (13 oarswomen and 4 runners) compared to that in 11 nonathletic controls. The magnetic resonance imaging data were also analyzed for the athletes and controls in relation to ovulatory status, which was determined by assay of urinary pregnanediol glucuronide, and in relation to the extent of 2-hydroxylation of estradiol to a nonpotent metabolite, 2-hydroxyestrone, which was evaluated by radiometric analysis. We found that 1) the relative and absolute body fat values of the athletes were significantly less (P < 0.05) than those of the controls overall and at each of the six regional sites, although the body weights of the rowers were significantly heavier than those of the controls, and the runners did not differ from the controls; 2) the ratio of sc fat to internal fat was 80%:20% among both athletes and controls, even though the athletes had significantly less fat; 3) the extent of estradiol 2-hydroxylation was significantly (P = 0.005) inversely related to total fat as a percentage of the total volume and to sc fat as a percentage of the total volume (P = 0.004) overall and at each of the regional fat depots; 4) athletes with menstrual disorders had significantly decreased sc and internal fat overall and at all regional sites compared to controls; and 5) a subgroup of ovulatory rowers had an apparent increase or lack of decrease in internal fat at the level of vertebrae lumbar 4, sacral 1, and sacral 4, compared to controls, whereas their sc fat was decreased at these sites compared to that in controls. Changes in regional fat deposits of both sc and internal fat may be involved in the menstrual dysfunction of the athletes in addition to their decreased overall fatness. The body weight and body mass index of well trained athletes can be a misleading index of body composition.


New bifurcations in the simplest passive walking model.
This paper uncovers several new stable periodic gaits in the simplest passive walking bipedal model proposed in the literature. It is demonstrated that the model has period-3 to period-7 gaits beside the period-1 gaits found by Garcia et al. By simulations, this paper shows that each of these new gaits leads to chaos via period-doubling bifurcation and loses its stability by cyclic-fold bifurcation. This interesting phenomenon suggests a series of new bifurcation scenarios that have not been observed before. To confirm the new gaits and their bifurcations, this paper presents computer assisted proofs on the existence and stability of each periodic gait and its period-doubling gaits with the interval Newton method. To verify that the routes indeed lead to chaos, computer-assisted proofs are also given by means of topological horseshoes theory.


Redox reaction between amino-(3,4-dihydroxyphenyl)methyl phosphonic acid and dopaquinone is responsible for the apparent inhibitory effect on tyrosinase.
Amino-(3,4-dihydroxyphenyl)methyl phosphonic acid, the phosphonic analog of 3,4-dihydroxyphenylglycine, had been previously reported as a potent inhibitor of tyrosinase. The mechanism of the apparent enzyme inhibition by this compound has now been established. Amino-(3,4-dihydroxyphenyl)methyl phosphonic acid turned out to be a substrate and was oxidized to o-quinone, which evolved to a final product identified as 3,4-dihydroxybenzaldehyde, the same as for 3,4-dihydroxyphenylglycine. Monohydroxylated compounds (amino-(3-hydroxyphenyl)methyl phosphonic acid and amino-(4-hydroxyphenyl)methyl phosphonic acid) were not oxidized, neither was 4-hydroxy-l-phenylglycine. However, the relatively high Km for amino-(3,4-dihydroxyphenyl)methyl phosphonic acid (0.52 mm) indicated that competitive inhibition could not entirely explain the previously reported strong inhibitory effect (Ki = 50 and 97 micro m for tyrosine and 3-(3,4-dihydroxyphenyl)alanine (Dopa) as substrates, respectively). Neither was the enzyme covalently inactivated to a significant degree. Spectroscopic and electrochemical analysis of the oxidation of a mixture of Dopa and the inhibitor demonstrated that the phosphonic compound reduced dopaquinone back to Dopa, thus diminishing and delaying the formation of dopachrome. This produces an apparent strong inhibitory effect when the reaction is monitored spectrophotometrically at 475 nm. In this peculiar case Dopa acts as a redox shuttle mediating the oxidation of the shorter phosphonic homolog. Decomposition of the phosphonic o-quinone to 3,4-dihydroxybenzaldehyde drives the reaction against the slightly unfavorable difference in redox potentials.


Thirty years of evolution of oral health behaviours and dental caries in urban and rural areas in Poland.
34 years ago, children living in rural areas had almost 2 more teeth affected by decay than those living in cities. Environmental differences are being reduced along with Poland's civilization development. The aim of the study is to assess the extent to which the differences in the intensity of caries and oral health behaviours between the urban rural environment have been reduced have been reduced in the past 3 decades. The data from 9 national surveys of 14,338 children aged 12 years and 5,425 adults aged 35-44 who lived in the city and in the countryside were analysed. Mean number of decayed (D), missing (M) and filled (F) teeth (DMFT) was determined during the examination, as well as oral health behaviours. During the past 3 decades, in the statistical 12-year-old Polish child, tooth decay has been reduced from 7.3 to 3.6 teeth, and the environmental difference between the town and village children is now almost 5 times smaller. A similar trend is observed in children's dental behaviours. Improving the oral health status and levelling of the environmental differences in the population aged 35-44 is much slower than in children. In the last three decades, the level of tooth decay has been reduced by half, but it is still 3 times higher than in other European countries. Environmental differences have been reduced particularly in children. Both the oral health status and urban/rural environment differences in the intensity of tooth decay may be regarded as one of the many measures of Poland's social and civilization development. However, the analysed process is not monotonic; instead, it has some turning points.


A role for the cell-wall protein silacidin in cell size of the diatom Thalassiosira pseudonana.
Diatoms contribute 20% of global primary production and form the basis of many marine food webs. Although their species diversity correlates with broad diversity in cell size, there is also an intraspecific cell-size plasticity owing to sexual reproduction and varying environmental conditions. However, despite the ecological significance of the diatom cell size for food-web structure and global biogeochemical cycles, our knowledge about genes underpinning the size of diatom cells remains elusive. Here, a combination of reverse genetics, experimental evolution and comparative RNA-sequencing analyses enabled us to identify a previously unknown genetic control of cell size in the diatom Thalassiosira pseudonana. In particular, the targeted deregulation of the expression of the cell-wall protein silacidin caused a significant increase in valve diameter. Remarkably, the natural downregulation of the silacidin gene transcript due to experimental evolution under low temperature also correlated with cell-size increase. Our data give first evidence for a genetically controlled regulation of cell size in T. pseudonana and possibly other centric diatoms as they also encode the silacidin gene in their genomes.


ASSA: Fast identification of statistically significant interactions between long RNAs.
The discovery of thousands of long noncoding RNAs (lncRNAs) in mammals raises a question about their functionality. It has been shown that some of them are involved in post-transcriptional regulation of other RNAs and form inter-molecular duplexes with their targets. Sequence alignment tools have been used for transcriptome-wide prediction of RNA-RNA interactions. However, such approaches have poor prediction accuracy since they ignore RNA's secondary structure. Application of the thermodynamics-based algorithms to long transcripts is not computationally feasible on a large scale. Here, we describe a new computational pipeline ASSA that combines sequence alignment and thermodynamics-based tools for efficient prediction of RNA-RNA interactions between long transcripts. To measure the hybridization strength, the sum energy of all the putative duplexes is computed. The main novelty implemented in ASSA is the ability to quickly estimate the statistical significance of the observed interaction energies. Most of the functional hybridizations between long RNAs were classified as statistically significant. ASSA outperformed 11 other tools in terms of the Area Under the Curve on two out of four test sets. Additionally, our results emphasized a unique property of the [Formula: see text] repeats with respect to the RNA-RNA interactions in the human transcriptome. ASSA is available at https://sourceforge.net/projects/assa/.


Spontaneous buckling of compressible droplet chains in free standing smectic-C films.
Isotropic spheres or droplets dispersed in a smectic freely suspended film can self-organize in chains that interact with the c-director field of the embedding smectic material. Spontaneous buckling of such chains has been reported when the chains grow under geometrical restrictions, by incorporation of additional droplets. We refine the original model for incompressible chains by taking into account a finite energy associated with the variation of the intrachain droplet-droplet-distance. In addition to the wavelength selection described already by the inelastic chain model, the refined model yields a critical threshold for spontaneous buckling, in agreement with experimental observations.


Thin-layer chromatography of hydroxamic acids.
The separation of very short-chain from long-chain fatty acyl hydroxamates by thin-layer chromatography is described. The detection limit was 2 micrograms.


Ezrin and radixin both regulate the apical membrane localization of ABCC2 (MRP2) in human intestinal epithelial Caco-2 cells.
Multidrug resistance-associated protein ABCC2 (MRP2) is widely expressed in mammalian tissues including intestine, liver and kidney, and it has been shown to be located exclusively on the apical membrane of polarized cells. Recently, several reports suggest that apical membrane localization of ABCC2 (Mrp2) was regulated by radixin in rodent liver. To investigate the mechanism underlying this apical membrane targeting of MRP2 in human intestine, we chose Caco-2 cells as a model to examine the unique roles of ezrin and radixin. Following immunostaining, radixin and ezrin were found to be concentrated at the apical membrane of Caco-2 cells. Using the RNAi method, radixin and ezrin stable knockdown Caco-2 cells were constructed. A cell surface biotinylation experiment with radixin or ezrin stable knockdown Caco-2 cells showed that radixin or ezrin deficiency caused the loss of ABCC2 (MRP2) from the cell surface. An immunoprecipitation assay showed that radixin and ezrin were associated with ABCC2 (MRP2). These findings indicate that both ezrin and radixin are independently required for the apical membrane localization of ABCC2 (MRP2) in Caco-2 cells. Radixin and ezrin play similar roles in the apical membrane localization of ABCC2 (MRP2) and their expression level and subcellular distribution are important factors in the regulation of ABCC2 (MRP2) at the post-transcriptional level.


The Role of Transversus Abdominis Plane Blocks in Enhanced Recovery After Surgery Pathways for Open and Laparoscopic Colorectal Surgery.
The concepts of Enhanced Recovery After Surgery (ERAS®) have steadily increased in usage, with benefits in patient outcomes and hospital length of stay. One important component of successful implementation of ERAS protocol is optimized pain control, via the multimodal approach, which includes neuraxial or regional anesthesia techniques and reduction of opioid use as the primary analgesic. Transversus abdominis plane (TAP) block is one such regional anesthesia technique, and it has been widely studied in abdominal surgery. We performed an extensive literature search in MEDLINE and PubMed. We review the benefits of TAP blocks for colorectal surgery, both laparoscopic and open. We organize the data by surgery type, by method of TAP block performance, and by a comparison of TAP block to alternative analgesic techniques or to placebo. We examine different endpoints, such as postoperative pain, analgesic use, return of bowel function, and length of stay. The majority of studies examined TAP blocks in the context of laparoscopic colorectal surgery, with many, but not all, demonstrating significantly less use of postoperative opioids in comparison to placebo, wound infiltration, and standard postoperative patient-controlled analgesia with intravenous opioid administration. There is evidence that use of liposomal bupivacaine may be more effective than conventional long-acting local anesthetics. Noninferiority of TAP infusions has been demonstrated, compared with continuous thoracic epidural infusions. TAP blocks are easily performed, cost-effective, and an opioid-sparing adjunct for laparoscopic colorectal surgery, with minimal procedure-related morbidity. The evidence is in concordance with several of the goals of ERAS pathways.


The infant brain in the social world: Moving toward interactive social neuroscience with functional near-infrared spectroscopy.
Typically developing infants rapidly acquire a sophisticated array of social skills within the first year of life. These social skills are largely learned within the context of day-to-day interactions with caregivers. While social neuroscience has made great gains in our knowledge of the underlying neural circuitry of social cognition and behavior, much of this work has focused on experiments that sacrifice ecological validity for experimental control. Functional near-infrared spectroscopy (fNIRS) is a promising methodology for measuring brain activity in the context of naturalistic social interactions. Here, we review what we have learned from fNIRS studies that have used traditional experimental stimuli to study social development during infancy. We then discuss recent infant fNIRS studies that have utilized more naturalistic social stimuli, followed by a discussion of applications of this methodology to the study of atypical social development, with a focus on infants at risk for autism spectrum disorder. We end with recommendations for applying fNIRS to studies of typically developing and at-risk infants in naturalistic social situations.


Lactate provocation of panic attacks. I. Clinical and behavioral findings.
To assess the pharmacologic and phenomenologic comparability of lactate-induced and naturally occurring panic attacks, patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks were infused with 0.5M racemic sodium lactate before and after successful drug treatment. Lactate-induced and naturally occurring panic attacks were symptomatically similar. Following treatment, the patients' response to lactate did not differ from that of normal controls, whereas the pretreatment panic rate was much higher. These data suggest that lactate acts, by as yet unidentified mechanisms, to trigger the same panic attacks as occur spontaneously in vulnerable persons.


Key Ring Fixator: A Novel External Fixation Technique for Avian Long Bone Stabilization.
A 12-year-old blue-fronted Amazon parrot (Amazona aestiva) of unknown sex (case 1) and a 14-year-old female hybrid Catalina macaw (Ara ararauna × Ara macao) (case 2) were evaluated and treated for an open tarsometatarsal fracture and a tibiotarsal fracture, respectively. In case 1, 1 month of external coaptation resulted in a delayed union, significant osteolysis, and presumptive osteomyelitis, which led to the decision to treat with a key ring fixator. In case 2, a key ring fixator was chosen for fracture repair because of presumed resistance to destruction by the bird. In both cases, fractures were stabilized with makeshift circular external fixators composed of key rings, K-wires, orthopedic wire, and acrylic resin. After key ring fixator removal, radiographs confirmed complete bone healing. Both patients had acceptable function of the affected limbs 5 years (case 1) and 2 years (case 2) after their procedures. The key ring fixator described in this report is a viable option for fracture repair in pelvic limbs of moderately sized birds (300-1500 g).


Prognostic value of thyrotrophin binding inhibiting immunoglobulins (TBII) in longterm antithyroid treatment, 131I therapy given in combination with carbimazole and in euthyroid ophthalmopathy.
Thyrotrophin binding inhibiting immunoglobulins (TBII) were measured in 27 patients with Graves' disease during and after longterm antithyroid treatment. The median observation period after treatment was 24 months. During the first 6 months of treatment the TBII index increased significantly in both the relapse and the remission group, but during the rest of the treatment and the observation no further change was observed. Patients with a TBII index below 0.35 at drug withdrawal (n = 8) all relapsed and patients with values above 1.00 (n = 5) all stayed in remission. There was a significant correlation between the TBII index at drug withdrawal and the time elapsed before a relapse. Graves' disease was treated with 131I in combination with carbimazole in 22 patients. The TBII index of these patients decreased after 131I and increased towards normal values during longterm observation of median 33 months. Of 4 patients with euthyroid ophthalmopathy one was TBII positive. This patient became overt hyperthyroid after an observation period of two years of prednisone treatment. It is concluded, that the TBII index is of some prognostic value after longterm antithyroid treatment, but is of no clinical importance following 131I treatment.


Celiac Disease and the Susceptibility of COVID-19 and the Risk of Severe COVID-19: A Mendelian Randomization Study.
Previous observational studies have found that the susceptibility of coronavirus disease 2019 (COVID-19) and the risk of severe COVID-19 are not increased in patients with celiac disease (CeD). However, the findings of observational studies are prone to bias due to reverse causation and confounding factors, especially in the case of a newly emerged disease. In this study, we aimed to further clarify the underlying relationship by both observational and Mendelian randomization (MR) analysis. This observational study was conducted in the UK Biobank cohort. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of COVID-19 susceptibility and severe COVID-19. To understand the causality between CeD and COVID-19 susceptibility and severe COVID-19, we performed a 2-sample MR analysis. Our observational study showed that patients with CeD had a lower susceptibility of COVID-19 (odds ratio [OR] = 0.699, P = 0.006) while CeD was not significantly associated with severe COVID-19 (P > 0.05). The findings from our MR study further demonstrated that both the susceptibility to COVID-19 (OR = 0.963, P = 0.006) and severe COVID-19 (OR = 0.919, P = 0.049) were lower in patients with CeD, although the former seemed to be specific to the UK Biobank cohort. Our results suggested that it may be unnecessary to take extra COVID-19 precaution in patients with CeD.


Antibody-incompatible kidney transplantation in 2015 and beyond.
Rejection caused by donor-specific antibodies (principally ABO and HLA antibodies) has become one of the major barriers to successful long-term transplantation. This review focuses on clinical outcomes in antibody-incompatible transplantation, the current state of the science underpinning clinical observations, and how these may be translated into further novel therapies. The clinical outcomes for allografts facing donor-specific antibodies are at present determined largely by the use of agents developed in the 20th century for the treatment of T-lymphocyte-mediated cellular rejection, such as interleukin-2 agents and anti-thymocyte globulin. These treatments are partially effective, because acute antibody-mediated rejection is mediated to a considerable extent by T lymphocytes. However these treatments are essentially ineffective in chronic antibody-mediated rejection. Future therapies for the prevention and treatment of antibody-mediated rejection are likely to fall into the categories of those that reduce antibody production, extracorporeal antibody removal and disruption of the effector arms of antibody-mediated tissue damage.


Amphipathic dendritic poly-peptides carrier to deliver antisense oligonucleotides against multi-drug resistant bacteria in vitro and in vivo.
Outbreaks of infection due to multidrug-resistant (MDR) bacteria, especially Gram-negative bacteria, have become a global health issue in both hospitals and communities. Antisense oligonucleotides (ASOs) based therapeutics hold a great promise for treating infections caused by MDR bacteria. However, ASOs therapeutics are strangled because of its low cell penetration efficiency caused by the high molecular weight and hydrophilicity. Here, we designed a series of dendritic poly-peptides (DPP1 to DPP12) to encapsulate ASOs to form DSPE-mPEG2000 decorated ASOs/DPP nanoparticles (DP-AD1 to DP-AD12) and observed that amphipathic DP-AD2, 3, 7 or 8 with a positive charge ≥ 8 showed great efficiency to deliver ASOs into bacteria, but only the two histidine residues contained DP-AD7 and DP-AD8 significantly inhibited the bacterial growth and the targeted gene expression of tested bacteria in vitro. DP-AD7anti-acpP remarkably increased the survival rate of septic mice infected by ESBLs-E. coli, exhibiting strong antibacterial effects in vivo. For the first time, we designed DPP as a potent carrier to deliver ASOs for combating MDR bacteria and demonstrated the essential features, namely, amphipathicity, 8-10 positive charges, and 2 histidine residues, that are required for efficient DPP based delivery, and provide a novel approach for the development and research of the antisense antibacterial strategy.


[Effect of ethanol on isometric tone of aorta from guinea pig].
Using aortic strips isolated from guinea pig, effects of ethanol on vascular smooth muscle tone were studied. Low concentrations (5, 50, 100 mM) of ethanol potentiated norepinephrine and serotonin-induced contractions, but not KCl-induced one. Ethanol (100 mM) potentiated calcium-induced contraction in the presence of norepinephrine, but not that in the presence of KCl. Ethanol (100 mM) showed no effects on norepinephrine-induced contraction in the calcium-free medium. Ethanol (100 mM) augmented 45Ca uptake stimulated with norepinephrine, but not that with KCl. Ethanol at the higher concentration of 600 mM by itself induced contraction, which was inhibited by trifluoperazine or in the calcium-free medium, but not by phentolamine, diphenhydramine, methysergide, indomethacin or nifedipine. Ethanol (600 mM) directly increased 45Ca uptake, which was not affected by nifedipine. These findings indicate that the low concentrations of ethanol potentiate receptor-mediated vascular smooth muscle contraction and the higher concentration of ethanol directly contracts it via facilitation of transmembranous calcium influx.


The importance of immunocytochemistry in the detection of high-grade cervical lesions.
Despite the implementation of various screening programs in many countries, cervical cancer continues to be a major health problem. Cervical cytology is the most used screening method, but human papillomavirus (HPV) genotyping, alone or in combination with cytology, has gained ground during the last years. Still, one of the major limitations of HPV-genotyping is the low specificity of HPV as a screening method in young women that are HPV-positive, but with no potential for future disease. Obviously, there is a need for a better screening algorithm. The ideal screening test for cervical high-grade lesions should detect the effect of high-risk (HR)-HPV infection after cell transformation, but not before, and should accurately identify the cases that are more likely to experience disease progression to neoplasia. Solid data regarding the benefit of immunocytochemistry in the evaluation of the patients with modified cervical cytology have been published recently. The use of the dual staining with p16INK4a and Ki-67 could increase specificity of the method for the detection of atypical cells and may perform better in predicting the risk of high-grade dysplasia in the near future.


Optimal profit of the parasitation by Aphelinus mali in an IPM complementary strategy for the control of Eriosoma lanigerum.
During summer the parasitoid Aphelinus mali may certainly reduce the infestation of woolly apple aphid (Eriosoma lanigerum), but studies on the single interaction rarely indicate sufficient biological control in the period May-June. In this period chemical control by spirotetramat or pirimicarb remains indispensable in order to anticipate on dense migration waves and subsequent colonization of extension shoots by E. lanigerum. The limited parasitation by A. mali around flowering is linked with a delayed emergence from diapause and with a slower reproduction rate than its host. In 2010 and 2011 the first adult flights monitored on yellow sticky traps corresponded perfectly with the currently used prediction models for A. mali. Further accurate monitoring all along the season enabled also to determine a well defined endo-parasitic phase of A. mali occurring after the small peak observed around flowering. During this endo-parasitic phase A. mali larvae reside inside their mummified host. Compounds with higher acute toxicity on A. mali adults, like chloronicotinyl insecticides (CNI's), are preferably positioned here. Selectivity in the time can then be claimed. Respecting this principle, the further parasitation potential of A. mali in summer is not hampered. Preservation of the first peak of flights of A. mali in the pre-flowering period is essential for an exponential flight increase. This is essential for the parasitation of E. lanigerum in summer, which constitutes a valuable complement in the integrated control strategy.


Engineered PRINT(®) nanoparticles for controlled delivery of antigens and immunostimulants.
Particle replication in non-wetting templates (PRINT) is a novel nanoparticle platform that provides compositional flexibility with the ability to specify size and shape in formulating vaccines. The PRINT platform also offers manufacturing and cost advantages over traditional particle technologies. Across multiple antigen and adjuvant formulations, robust antibody and cellular responses have been achieved using PRINT particles in mouse models. Preclinical studies applying PRINT technology in the disease areas of influenza, malaria, and pneumonia are described in this commentary. The proof of principle studies pave the way toward significant cost-effective solutions to global vaccine supply needs.


Direct Alkylation of Amines with Alcohols Catalyzed by Base.
A base-catalyzed/promoted transition-metal-free direct alkylation of amines with alcohols has been developed, giving the desired amines in generally high yields from either aromatic or aliphatic alcohols. On the basis of the (1)H NMR and in situ IR (React-IR) monitoring experiments, isotope-labeling experiments, as well as control experiments, a novel "hemiaminal" model is proposed to understand the mechanism, which explains the formation of the "extra" aldehyde in the reaction.


Evaluation of synergism by a novel three-dimensional model for the combined action of cisplatin and etoposide on the growth of a human small-cell lung-cancer cell line, SBC-3.
Although the combination of cisplatin and etoposide has been used as standard therapy for small-cell lung cancer, it is difficult to demonstrate combination effects between cisplatin and etoposide in vitro. We therefore adopted a 3-dimensional (3-D) model to analyze the combination effects of anticancer drugs, and compared the results of analysis by the new 3-D model with those obtained from traditional 2-D models for the cisplatin-etoposide combination. In this study, using a human small-cell lung-cancer cell line (SBC-3), 3-D model analysis clearly identified a relationship depending on the concentrations of both drugs, and demonstrated that peak synergy occurred at the higher concentrations of cisplatin and etoposide. Antagonistic interactions were noted with a nadir at low concentrations of etoposide and cisplatin. In contrast, 2-D models such as combination index and isobologam analysis fail to characterize the complex interactions between cisplatin and etoposide, since their joint effects are concentration-dependent. Combination index (CI) plots show that synergy is evident only for molar ratios of cisplatin: etoposide of 2:1 to 1:5. On isobologram analysis, synergy could be detected when great inhibitory effects on cell growth were present (high endpoint), but not with small inhibitory effects (lower endpoints). Thus, either synergy or antagonism may occur, but depend on the selection of variables, such as the molar ratios or the endpoints chosen for the experiments. This could explain the inconsistency in the in vitro combination effects reported to date. The 3-D model, which compensates for the above deficiencies of 2-D models, can facilitate rigorous analysis of drug interactions over the entire clinical dose range, using microcomputers and sophisticated graphics programs. This direct and pragmatic method offers investigators a practical new tool with which to analyze drug combinations for cancer chemotherapy.


Complications in the transition from fetal to neonatal life.
The transition from fetus to neonate is a time of significant physiologic adaptation. In addition to the normal physiologic tasks of transition, some neonates must also cope with underlying congenital abnormalities, birth injury, or disease. Careful assessment and astute nursing care are needed during the period of transition to ensure that the neonate who is experiencing problems with transition is recognized and appropriate interventions are initiated. This article examines the physiology of transition and discusses factors placing the neonate at risk of illness. A plan of care for neonates experiencing symptoms of underlying disease during transition is presented.


Detection of SARS-CoV-2 Virus on Stainless-Steel Surfaces: AOAC Performance Tested MethodSM 022102.
The SureFast® SARS-CoV-2 PLUS Test is a reverse transcription qPCR (RT-qPCR) assay for the direct, qualitative detection of novel coronavirus (SARS-CoV-2) RNA from stainless-steel environmental sample swabs. To validate the SureFast SARS-CoV-2 PLUS Kit as part of the AOAC Research Institute's Emergency Response Validation Performance Tested Method(s)SM program. The SureFast SARS-CoV-2 PLUS Kit was evaluated for specificity using in silico analysis of 15 764 SARS-CoV-2 sequences and 65 exclusivity organisms (both near neighbors and background organisms) using the ThermoBLAST program. The candidate method was evaluated in an unpaired study design for one environmental surface (stainless steel) and compared to the US Centers for Disease Control and Prevention 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel, Instructions for Use (Revision 4, Effective 6/12/2020). Results of the in silico analysis demonstrated 99.99% selectivity of the method in being able to detect target sequences of the known CoV-2 genomes and discriminate them from near neighbors. In the matrix study, the candidate method demonstrated statistically significant better recovery of the target analyte than the PCR detection reference method. The SureFast SARS-CoV-2 PLUS Kit is a rapid and accurate method that can be utilized by food producers to detect the causative agent of COVID-19 on stainless-steel contact surfaces. SureFast SARS-CoV-2 PLUS test method is highly specific for primer/probe binding to the E target genome region for the SARS-CoV-2 virus, 99.99% binding specificity using in silico analysis.


Case reports on acute toluene poisoning during parquet flooring.
We report two cases of acute toluene poisoning occurring during parquet flooring. Inhalation is the major route of absorption in the workplace, owing to the high volatility of the compound. Such patients should be monitored closely for respiratory distress, central nervous system (CNS) depression and cardiac arrhythmias. Both our patients manifested signs of CNS depression and one had bronchospasm aborted by salbutamol Industries using toluene must ensure that precautions like adequate ventilation are taken to protect their workers.


Ghost cell odontogenic carcinoma: A case report.
Ghost cell odontogenic carcinoma (GCOC) is a rare malignant neoplasm characterized by the presence of ghostcells. It is considered to originate from either a calcifying odontogenic cyst (COC) or a dentinogenic ghost cell tumor(DGCT). Its clinical and radiographic characteristics are non-specific, including slow growth, locally aggressivebehavior, and eventual metastasis. This case report describes a 43-year-old Thai man with plain radiographs and cone-beam computed tomographic images revealing a unilocular radiolucency with non-corticated borders surrounding an impacted left canine associated with radiopaque foci around the cusp tip. Based on the microscopic findings, the lesion was diagnosed as GCOC. Partial maxillectomy of the right maxilla was performed, and radiotherapy was administered. An obturator was made to support masticatory functions Three years later, the lesion showed complete boneremodeling and no signs of recurrence, and long-term follow-up was done regularly.


Examining parents' ratings of middle-school students' academic self-regulation using principal axis factoring analysis.
This study examined the reliability and validity of a parent rating scale, the Self-Regulation Strategy Inventory: Parent Rating Scale (SRSI-PRS), using a sample of 451 parents of sixth- and seventh-grade middle-school students. Principal axis factoring (PAF) analysis revealed a 3-factor structure for the 23-item SRSI-PRS: (a) Managing Behavior and Learning (α = .92), (b) Maladaptive Regulatory Behaviors (α = .76), and (c) Managing Environment (α = .84). The majority of the observed relations between these 3 subscales, and the SRSI-SR, student motivation beliefs, and student mathematics grades were statistically significant and in the small to medium range. After controlling for various student variables and motivation indices of parental involvement, 2 SRSI-PRS factors (Managing Behavior and Learning, Maladaptive Regulatory Behaviors) reliably predicted students' achievement in their mathematics course. This study provides initial support for the validity and reliability of the SRSI-PRS and underscores the advantages of obtaining parental ratings of students' SRL behaviors.


Electric-field driven director oscillations in a nematic liquid crystal: a NMR investigation.
We have investigated the oscillatory behavior of the nematic director for 4-pentyl-4'-cyanobiphenyl (5CB) when it is subjected to a static magnetic field and a sinusoidal electric field. In these experiments the two fields were inclined at about 50 degrees and the frequency of the electric field was varied from several hertz to approximately 1000 Hz. The director orientation was measured using time-resolved deuterium NMR spectroscopy since this has the advantage of being able to determine the state of director alignment in the sample. In fact, for all of the frequencies studied the director is found to remain uniformly aligned. Since the diamagnetic and dielectric anisotropies are both positive the director oscillates in the plane formed by the two fields. These oscillations were observed to continue for many cycles, indicating that the coherence in the director orientation was not lost during this motion. The maximum and minimum angles made by the director with the magnetic field were determined, as a function of frequency, from the NMR spectrum averaged over many thousand cycles of the oscillations. At low frequencies (several hertz) these limiting angles are essentially independent of frequency but as the frequency increases the two angles approach each other and become equal at high frequencies, typically 1000 Hz. Our results are well explained by a hydrodynamic theory in which the sinusoidal time dependence of the electric field is included in the torque-balance equation. This analysis also shows that, for a range of frequencies between the high and low limits, these NMR experiments can give dynamic as well as static information concerning the nematic phase.


Simple scheme for identification of common species of enterobacteriaceae.
We propose a simple scheme for the identification of enterobacteriaceae species which routinely necessitates numerous biochemical tests and prolonged time span. In the scheme, family enterobacteriaceae is initially divided into four major groups depending on two important biochemical reactions viz. Lactose fermentation (L) and Methyl red test (MR). Each of the four groups, Group I (L + MR+), Group II (L + MR-), Group III (L- MR-), Group IV (L- MR+) can further be differentiated by using few tests. Eleven genera and 23 species can be identified by this scheme using limited biochemical tests. As many as 990 strains of enterobacteriaceae were subjected to standard biochemical tests and proposed simple scheme for identification. The discrepancy was observed only with 8 atypical strains of E. coli.


Using Enhanced Green Fluorescence Protein-expressing Escherichia Coli to Assess Mouse Peritoneal Macrophage Phagocytosis.
This manuscript describes a simple and reproducible method to perform a phagocytosis assay. The first part of this method involves building a pET-SUMO-EGFP vector (SUMO = small ubiquitin-like modifier) and expressing enhanced green fluorescence protein (EGFP) in Escherichia coli (BL21DE). EGFP-expressing E. coli is coincubated with macrophages for 1 h at 37 °C; the negative control group is incubated on ice for the same amount of time. Then, the macrophages are ready for assessment. The advantages of this technique include its simple and straightforward steps, and phagocytosis can be measured by both flow cytometer and fluorescence microscope. The EGFP-expressing E. coli are stable and display a strong fluorescence signal even after the macrophages are fixed with paraformaldehyde. This method is not only suitable for the assessment of macrophage cell lines or primary macrophages in vitro but also suitable for the evaluation of granulocyte and monocyte phagocytosis in peripheral blood mononuclear cells. The results show that the phagocytic capability of peritoneal macrophages from young (eight-week-old) mice is higher than that of macrophages from aged (16-month-old) mice. In summary, this method measures macrophage phagocytosis and is suitable for studying the innate immune system function.


The JAK-STAT pathway promotes persistent viral infection by activating apoptosis in insect vectors.
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved signaling pathway that can regulate various biological processes. However, the role of JAK-STAT pathway in the persistent viral infection in insect vectors has rarely been investigated. Here, using a system that comprised two different plant viruses, Rice stripe virus (RSV) and Rice black-streaked dwarf virus (RBSDV), as well as their insect vector small brown planthopper, we elucidated the regulatory mechanism of JAK-STAT pathway in persistent viral infection. Both RSV and RBSDV infection activated the JAK-STAT pathway and promoted the accumulation of suppressor of cytokine signaling 5 (SOCS5), an E3 ubiquitin ligase regulated by the transcription factor STAT5B. Interestingly, the virus-induced SOCS5 directly interacted with the anti-apoptotic B-cell lymphoma-2 (BCL2) to accelerate the BCL2 degradation through the 26S proteasome pathway. As a result, the activation of apoptosis facilitated persistent viral infection in their vector. Furthermore, STAT5B activation promoted virus amplification, whereas STAT5B suppression inhibited apoptosis and reduced virus accumulation. In summary, our results reveal that virus-induced JAK-STAT pathway regulates apoptosis to promote viral infection, and uncover a new regulatory mechanism of the JAK-STAT pathway in the persistent plant virus transmission by arthropod vectors.


Tremorgenic mycotoxins from Aspergillus caespitosus.
Two tremorgenic mycotoxins were isolated from Aspergillus caespitosus, and identified as verruculogen and fumitremorgin B. They were produced at the rate of 172 and 325 mg per kg, respectively, on autoclaved cracked field corn.


Safety assessment of drug metabolites: Characterization of chemically stable metabolites.
Drug molecules are typically subjected to a variety of biotransformation reactions, and the metabolites formed through these reactions must be considered when conducting safety testing programs for new chemical entities. Metabolites that are chemically stable sometimes have pharmacological activity profiles similar to those of the parent compound but rarely have potent activity against off-target receptors that is unique relative to the parent profile. This fact argues for the thorough testing of drug metabolites for their pharmacological activity. It also argues for a significantly lower need for the thorough characterization and quantitation of stable metabolites not thought to substantially contribute to the pharmacodynamic effect. Given the tremendous resource requirements involved in the thorough characterization of drug metabolites, a more flexible, tiered approach to stable metabolite characterization would seem to provide the best utilization of resources while still allowing a complete evaluation of the toxicological profile of a new drug.


3-D Neural denoising for low-dose Coronary CT Angiography (CCTA).
CCTA has become an important tool for coronary arteries assessment in low and medium risk patients. However, it exposes the patient to significant radiation doses, resulting from high image quality requirements and acquisitions at multiple cardiac phases. For widespread use of CCTA for coronary assessment, significant reduction of radiation exposure with minimal image quality loss is still needed. A neural denoising scheme, relying on a fully convolutional neural network (FCNN) architecture, is developed and applied to noisy CCTA. In contrast to previously published methods, the proposed FCNN is trained directly on 3-D CT data patches (blocks), implementing 3-D convolutions. Considering that anatomy is inherently tridimensional, the proposed 3-D approach may better capture and enforce inter-slice continuity of tiny structures. While training is performed on individual blocks, whole input scans can be fed and denoised in one piece, thus leveraging the fully convolutional architecture to maximize processing speed. The proposed method is compared to state-of-the-art denoising algorithms on a dataset of 45 CCTA scans. Low-dose scans are simulated by synthetic Poisson noise applied to the sinogram corresponding to a 90% reduction in radiation dose. The average feature similarity score (0.864) and the peak signal-to-noise ratio (41.47) obtained for the proposed algorithm outperformed the compared methods while requiring significantly shorter processing time. A set of 2-D FCNNs, structurally similar to the proposed 3-D network, are also implemented to demonstrate contribution of the additional dimension to the improved denoising. For further validation of the method coronary reconstruction using the Intellispace cardiac tool (Philips, Holland) is performed both on a real noisy CCTA scan and on the denoised scan using the proposed method. It is shown that the cardiac tool succeeds in reconstructing more coronaries using the scan denoised by the proposed method. The obtained results suggest the proposed method provides an efficient and powerful approach to low-dose CCTA denoising.


Immune and inflammatory mechanisms of abdominal aortic aneurysm.
Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. Immune-mediated infiltration and a destruction of the aortic wall during AAA development plays significant role in the pathogenesis of this disease. While various immune cells had been found in AAA, the mechanisms of their activation and function are still far from being understood. A better understanding of mechanisms regulating the development of aberrant immune cell activation in AAA is essential for the development of novel preventive and therapeutic approaches. In this review we summarize current knowledge about the role of immune cells in AAA and discuss how pathogenic immune cell activation is regulated in this disease.


[Thoracic diseases with predominant abdominal symptomatology].
Common and uncommon diseases whose symptom picture includes signs that may lead to an incorrect diagnosis are examined. Questions of this kind are obviously important in both medicine and emergency surgery, since incorrect diagnosis may involve either delay in the commencement of suitable treatment or the taking of what may even be dangerous therapeutic measures. Instances of heart and lung disease frequetly marked by abdominal symptomatologies are presented: bronchopulmonitis of various aetiologies, myocardial infarct, rhythm disturbances. In addition to the more atypical signs, such as epigastric pain in infarct and right hypochondriac pain in right basal bronchopulmonitis, manifestations such as vomiting, diarrhoea, diffuse abdominal pains and intestinal occlusion must be borne in mnd in establishing the correct diagnosis.


[Crystal morphology of cholesterol monohydrate in cholesterol gallstones and gallbladder bile].
To understand the pathogenesis of cholesterol gallstones from a crystallographic point of view, we investigated gallstones and precipitates in gallbladder bile by the optical method used in crystallography. First, ground thin sections of cholesterol gallstones in 28 cases were examined by a polarizing microscope. The crystalline fragments which were peeled off from gallstones by sonication were also examined in the same manner. Secondly, the cholesterol monohydrate crystals in gallbladder bile were examined by a polarizing and phase contrast microscope. The bile samples were obtained from 15 patients with cholesterol gallstones by the needle puncture of gallbladder during surgery. The results of observation were as follows. 1) The cholesterol gallstones were composed of many small plated cholesterol monohydrate crystals aggregated radially. 2) Each small plated crystal was grown by the lateral growth mechanism in bile. Spiral growth patterns were often observed on the (001) faces. 3) The cholesterol gallstones were formed by two successive mechanisms: The aggregation of cholesterol monohydrate crystals and the lateral growth of each single crystal.