Clinical Interest of Serum Alpha-2 Macroglobulin, Apolipoprotein A1, and Haptoglobin in Patients with Non-Alcoholic Fatty Liver Disease, with and without Type 2 Diabetes, before or during COVID-19.
In patients with non-alcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM), alpha-2 macroglobulin (A2M), apolipoprotein A1 (ApoA1), and haptoglobin are associated with the risk of liver fibrosis, inflammation (NASH), and COVID-19. We assessed if these associations were worsened by T2DM after adjustment by age, sex, obesity, and COVID-19. Three datasets were used: the "Control Population", which enabled standardization of protein serum levels according to age and sex (N = 27,382); the "NAFLD-Biopsy" cohort for associations with liver features (N = 926); and the USA "NAFLD-Serum" cohort for protein kinetics before and during COVID-19 (N = 421,021). The impact of T2DM was assessed by comparing regression curves adjusted by age, sex, and obesity for the liver features in "NAFLD-Biopsy", and before and during COVID-19 pandemic peaks in "NAFLD-Serum". Patients with NAFLD without T2DM, compared with the values of controls, had increased A2M, decreased ApoA1, and increased haptoglobin serum levels. In patients with both NAFLD and T2DM, these significant mean differences were magnified, and even more during the COVID-19 pandemic in comparison with the year 2019 (all p < 0.001), with a maximum ApoA1 decrease of 0.21 g/L in women, and a maximum haptoglobin increase of 0.17 g/L in men. In conclusion, T2DM is associated with abnormal levels of A2M, ApoA1, and haptoglobin independently of NAFLD, age, sex, obesity, and COVID-19.


Effects of 5,7-dihydroxytriptamine (5,7-DHT) on circadian locomotor activity of the blow fly, Calliphora vicina.
The biogenic amine serotonin (5-HT) is a neuromodulator in both vertebrates and invertebrates. It has been shown that serotonin, apart from its distinct effects on behavior, also plays a morphoregulatory role during the ontogeny of the insect's nervous system. The role of serotonin in modulating circadian locomotor activity of the blow fly, Calliphora vicina was explored. Injection of a specific neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the hemolymph appeared to significantly reduced the level of locomotor activity and lengthened the period (tau) of circadian rhythmicity. After drug injection in constant darkness flies continued with their free-running rhythm of a locomotor activity, depending on the time of 5,7-DHT injection. This compound causes phase delay when administered in the early subjective day, and phase advance in the late subjective day. This effect is the opposite of the phase response curve obtained for 5-HT injections. This suggests that 5-HT might act as an entraining agent via the output pathway by feedback to clock neurons in the brain. Some of the injected insects regained their normal level of activity after a few days. These findings suggest a potential role for serotonin as modulator of circadian rhythms in insect including regulation of the level of locomotor activity.


Neuroanatomical localization of myelin basic protein in the late first and early second trimester human foetal spinal cord and brainstem.
The temporal and spatial expression of myelin basic protein in the first and second trimester human foetal spinal cord and brainstem from 9 to 20 gestational weeks was determined by immunocytochemistry in sections of cervical, thoracic and lumbosacral levels from 41 human foetal spinal cords and ten brainstems. Myelin basic protein-positive oligodendrocytes were observed peripheral to the ependyma at 9-10 gestational weeks. Oligodendrocytes expressing myelin basic protein were seen at 10-12 gestational weeks in the anterior and lateral funiculi. Myelin basic protein was detected later in the posterior funiculi than in the anterolateral white matter and most spinal cord tracts could not be identified by means of variation in myelin basic protein expression. Myelin basic protein was found in the midline of the brainstem at ten gestational weeks and spread laterally during the second trimester. We conclude that in the human foetal spinal cord, myelin basic protein is present by 10 gestational weeks in the anterolateral cervical spinal cord and midline of the brainstem. It is expressed in a rostral-to-caudal and anterolateral-to-posterior manner in most tracts of the spinal cord. However, an exception to these findings is that the fasciculus gracilis, upon developing into a defined region, had more myelin basic protein-positive cells at the lumbar level than in more rostral regions. Definition of the kinetics of myelin basic protein expression in the normal human foetal spinal cord provides a baseline for study of aberrant myelination and demyelination.


Language Disorder in Progressive Supranuclear Palsy and Corticobasal Syndrome: Neural Correlates and Detection by the MLSE Screening Tool.
Background: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) affect speech and language as well as motor functions. Clinical and neuropathological data indicate a close relationship between these two disorders and the non-fluent variant of primary progressive aphasia (nfvPPA). We use the recently developed Mini Linguistic State Examination tool (MLSE) to study speech and language disorders in patients with PSP, CBS, and nfvPPA, in combination with structural magnetic resonance imaging (MRI). Methods: Fifty-one patients (PSP N = 13, CBS N = 19, nfvPPA N = 19) and 30 age-matched controls completed the MLSE, the short form of the Boston Diagnostic Aphasia Examination (BDAE), and the Addenbrooke's Cognitive Examination III. Thirty-eight patients and all controls underwent structural MRI at 3 Tesla, with T1 and T2-weighted images processed by surface-based and subcortical segmentation within FreeSurfer 6.0.0 to extract cortical thickness and subcortical volumes. Morphometric differences were compared between groups and correlated with the severity of speech and language impairment. Results: CBS and PSP patients showed impaired MLSE performance, compared to controls, with a similar language profile to nfvPPA, albeit less severe. All patient groups showed reduced cortical thickness in bilateral frontal regions and striatal volume. PSP and nfvPPA patients also showed reduced superior temporal cortical thickness, with additional thalamic and amygdalo-hippocampal volume reductions in nfvPPA. Multivariate analysis of brain-wide cortical thickness and subcortical volumes with MLSE domain scores revealed associations between performance on multiple speech and language domains with atrophy of left-lateralised fronto-temporal cortex, amygdala, hippocampus, putamen, and caudate. Conclusions: The effect of PSP and CBS on speech and language overlaps with nfvPPA. These three disorders cause a common anatomical pattern of atrophy in the left frontotemporal language network and striatum. The MLSE is a short clinical screening tool that can identify the language disorder of PSP and CBS, facilitating clinical management and patient access to future clinical trials.


Evolution of oligomeric state through allosteric pathways that mimic ligand binding.
Evolution and design of protein complexes are almost always viewed through the lens of amino acid mutations at protein interfaces. We showed previously that residues not involved in the physical interaction between proteins make important contributions to oligomerization by acting indirectly or allosterically. In this work, we sought to investigate the mechanism by which allosteric mutations act, using the example of the PyrR family of pyrimidine operon attenuators. In this family, a perfectly sequence-conserved helix that forms a tetrameric interface is exposed as solvent-accessible surface in dimeric orthologs. This means that mutations must be acting from a distance to destabilize the interface. We identified 11 key mutations controlling oligomeric state, all distant from the interfaces and outside ligand-binding pockets. Finally, we show that the key mutations introduce conformational changes equivalent to the conformational shift between the free versus nucleotide-bound conformations of the proteins.


Gene expression profiles linked to the hormonal induction of male-effect pheromone synthesis in goats (Capra hircus).
The male effect is a well-known phenomenon in female sheep and goats whereby a pheromone-induced activation of reproductive function occurs. However, the molecule(s) involved in this phenomenon are unknown. We investigated gene expression profiles for the induction of male effect pheromone synthesis using a PCR-based cDNA subtraction strategy. We constructed two subtracted cDNA libraries using mRNA from the skin of the head or rump region of orchidectomized male goats with or without pheromone induction using testosterone or dihydrotestosterone (DHT). Both libraries were assumed to contain genes whose expression increases with pheromone induction. Clones (n = 480) from each library were sequenced and identified using BLAST to reveal 115 and 239 types of sequences in the libraries of the head and rump region, respectively. Among these, 12 genes were expressed in both libraries. We conducted real-time PCR to further analyze their expression using cDNA samples derived from pheromone-producing or nonproducing skin from the head of an ovariectomized female goat with or without DHT implantation, respectively. For nine genes, we observed significantly increased expression in samples following DHT implantation. Among these, stearoyl-CoA desaturase 1 (SCD1) and elongation of long chain fatty acids family member 5 (ELOVL5) genes showed more than 100-fold higher expression levels in pheromone-positive samples, suggesting that the products of these genes may be important in pheromone synthesis.


Def functions as a cell autonomous factor in organogenesis of digestive organs in zebrafish.
Digestive organs originate from the endoderm. Morphogenesis of the digestive system is precisely controlled by multiple factors that dictate the cell fate and behavior so that the specific digestive organs are timely formed in the right place and develop into right size and structure. We showed previously that digestive organ expansion factor (def) is a gene whose expression is enriched in the liver, pancreas and intestine. Loss-of-function of def in the def(hi429) mutant confers hypoplastic digestive organs partly due to alteration of expression of genes related to the p53 pathway. However, the molecular mechanism for the involvement of Def in the organogenesis of digestive organs is still largely unknown. For example, it is not known whether Def regulates specific pathways in a specific organ. To address this question, we generated four independent Tg(fabp10a:def) transgenic fish lines which over-expressed Def specifically in the liver. We characterized Tg-I, one of the transgenic lines, in detail with genetic, molecular and histological approaches. We found that Tg-I restored the liver but not exocrine pancreas and intestine development in the def(hi429) mutant. However, Tg-I adult fish in the wild type (WT) background exhibits reduced liver-to-body ratio and all four transgenic lines conferred abnormal intrahepatic structure. Microarray data analysis showed that certain specific functional pathways were affected in the liver of Tg-I. These results demonstrate that Def functions in a cell autonomous manner during early liver development and aberrant Def protein expression might lead to disruption of the structural integrity of a normal adult liver.


Transactivation of the IGF-1R by aldosterone.
Activation of epithelial sodium channels (ENaC) by aldosterone, insulin, or insulin-like growth factor-1 (IGF-1) in renal epithelial cells (including the Xenopus laevis renal cell line A6) appears to share some common signaling elements subsequent to the initial insulin or IGF-1 receptor activation. Previously, the convergence point for insulin or IGF-1 and aldosterone signaling was assumed to be downstream of the receptor at the level of phosphatidylinositol 3-kinase (PI3-K); however, this study shows aldosterone directly transactivates the IGF-1 receptor (IGF-1R). In A6 cells, 10-min exposure to aldosterone increased the phosphorylation of the IGF-1 receptor, insulin receptor substrate-1 (IRS-1), and Akt (PKB). Furthermore, aldosterone activated PI3-K and phosphorylation of the most downstream element, Akt, was blocked by the specific PI3-K inhibitor LY-294002. Transactivation requires aldosterone binding to the mineralocorticoid/glucocorticoid receptor and does not require transcription.


Activation of antitumor agent gilvocarcins by visible light.
Gilvocarcins that are antitumor agents are activated by low doses of visible light to induce bacteriophage lambda in Escherichia coli. This result is dependent on interaction with DNA. Gilvocarcin M, an analog without antitumor activity, failed to induce the prophage after light exposure, thus demonstrating a correlation between photosensitizing and antitumor activities. These results raise several possibilities regarding the mode of action of gilvocarcins as antitumor agents in vivo, involving light or enzymatic activating systems, which could be exploited in human cancer therapy.


Cardiopulmonary effects of endothelin-1 in man.
Endothelin-1 levels are elevated in a number of conditions characterised by impaired cardiovascular performance and abnormal vasoconstriction such as congestive cardiac failure and primary and secondary pulmonary hypertension. The aim of the present study was to assess the effects of the vasoconstrictor peptide endothelin-1 on pulmonary and systemic haemodynamics and cardiovascular performance in normal man. Ten healthy male volunteers were studied on two occasions in a randomised, double-blind, placebo-controlled, cross-over study and received systemic infusions of either endothelin-1 (0.75, 1.5 and 3 pmol.kg-1.min-1 for 30 min each) or saline placebo. Systemic and pulmonary haemodynamic parameters were monitored non-invasively by pulsed-wave Doppler, as were parameters of left and right ventricular diastolic filling and inotropic state. Effects on renin-angiotensin and natriuretic peptide system activity were also measured. Endothelin-1 infusion produced dose-related falls in heart rate, stroke volume and cardiac output. Systemic vascular resistance (SVR) increased from 1156 +/- 57 to 1738 +/- 115 dyn.s.cm-5, and total pulmonary vascular resistance (TPR) increased from 142 +/- 12 to 329 +/- 22 dyn.s.cm-5. Endothelin-1 caused significant impairment of left and right ventricular diastolic filling, even at a low dose which had no pulmonary or systemic pressor effects. Electromechanical and Doppler acceleration indices of inotropic state were also significantly impaired. Activity of the renin-angiotensin system was suppressed by endothelin-1 whilst plasma levels of atrial natriuretic peptide (ANP) were unchanged. Thus, in addition to systemic and pulmonary pressor effects our results suggest that endothelin-1 impairs overall cardiovascular performance by causing diastolic dysfunction and acting as a negatively inotropic agent. These effects were associated with compensatory changes in the renin-angiotensin system.


Isolation and Reactivity of Trifluoromethyl Iodonium Salts.
The strategic incorporation of the trifluoromethyl (CF3) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF3 moiety onto an array of molecular architectures, and, in particular, CF3 λ(3)-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF3 iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF3 iodoniums is paramount for the development of new trifluoromethylative strategies involving λ(3)-iodanes. Here, we demonstrate that CF3 iodonium salts are readily prepared from common λ(3)-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF3 iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF3 iodonium intermediates in trifluoromethylative processes mediated by λ(3)-iodanes. The isolation of CF3 iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes.


Sensitivity to vasovagal maneuvers in normal children and adults.
In 15 male and 15 female healthy subjects who were 10 to 48 years of age, we studied alterations in heart rate and finger blood flow in response to the cold pressor test and four strong vasovagal maneuvers: diving response (apneic facial exposure to an ice water bag), Valsalva maneuver (forced expiration against a column of mercury to 40 to 50 mm Hg), unilateral carotid sinus massage, and oculocardiac reflex (inflation of a Honan balloon against one eye). Peripheral vasoconstriction as a consequence of the diving response paralleled the vasoconstriction from the cold pressor test, but it preceded the bradycardia that resulted from the diving response maneuver. In contrast, the rate of finger blood flow was high during the bradycardia that followed stage 4 of the Valsalva maneuver. Changes in heart rate correlated with age for the diving response, the Valsalva maneuver, and the oculocardiac reflex. Changes in heart rate and finger blood flow were not dependent on sex. The change in heart rate noted with the diving response was significantly correlated with that noted with the Valsalva maneuver and the oculocardiac reflex. Changes in finger blood flow did not correlate with changes in heart rate for any maneuver. This study provides a response profile of relative sensitivities to strong vasovagal maneuvers in normal children and adults.


Single-particle cryoEM analysis at near-atomic resolution from several thousand asymmetric subunits.
A single-particle cryoEM reconstruction of the large ribosomal subunit from Saccharomyces cerevisiae was obtained from a dataset of ∼75,000 particles. The gold-standard and frequency-limited approaches to single-particle refinement were each independently used to determine orientation parameters for the final reconstruction. Both approaches showed similar resolution curves and nominal resolution values for the 60S dataset, estimated at 2.9 Å. The amount of over-fitting present during frequency-limited refinement was quantitatively analyzed using the high-resolution phase-randomization test, and the results showed no apparent over-fitting. The number of asymmetric subunits required to reach specific resolutions was subsequently analyzed by refining subsets of the data in an ab initio manner. With our data collection and processing strategies, sub-nanometer resolution was obtained with ∼200 asymmetric subunits (or, equivalently for the ribosomal subunit, particles). Resolutions of 5.6 Å, 4.5 Å, and 3.8 Å were reached with ∼1000, ∼1600, and ∼5000 asymmetric subunits, respectively. At these resolutions, one would expect to detect alpha-helical pitch, separation of beta-strands, and separation of Cα atoms, respectively. Using this map, together with strategies for ab initio model building and model refinement, we built a region of the ribosomal protein eL6, which was missing in previous models of the yeast ribosome. The relevance for more routine high-resolution structure determination is discussed.


Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole.
Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been reported. We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.


Recursive cosmopolitization: Argentina and the global Human Rights Regime.
This paper illustrates how varieties of cosmopolitanism are shaped through a mutually constitutive set of cultural dispositions and institutional practices that emerge at the interstices of global human right norms and local legal practices. Converging pressures of 'cosmopolitan imperatives' and the multiplicity of particularized manifestations are co-evolving in the context of intercrossings during which distinctive cosmopolitanisms are established. This complex relationship of global normative expectations and their local appropriations is elucidated through the dynamic of recursive cosmopolitization. Suggesting that, local problems are resolved with recourse to global prescriptions while local solutions are inscribed in international institutions consolidating the global Human Rights Regime. The Argentinean case carries conceptual and empirical weight as it underscores the recursivity of cosmopolitization by calibrating the tensions of universalism and particularism at the intersection of global, national and regional scales. Argentina is a paradigmatic instantiation for how cosmopolitanism can emanate in the periphery as local problems are globalized. This, in turn, has resulted in the institutionalization of a global Human Rights Regime which exercises normative and political-legal pressures on how states legitimately deal with human rights abuses. It is this cosmopolitan balance, rather than presuppositions of universalistic exogenous pressures or particularistic national exceptions, which is shaping the cultural and political relevance of human rights norms.


Assessment of low-density lipoprotein oxidation, paraoxonase activity, and arterial distensibility in epileptic children who were treated with anti-epileptic drugs.
Studies show that anti-epileptic drugs increase oxidative stress. Thus, low-density lipoprotein oxidation increases and atherogenesis is induced. Paraoxonase-associated high-density lipoprotein protects low-density lipoprotein and high-density lipoprotein oxidation. The effects of anti-epileptic drugs on paraoxonase activity has not been investigated yet. The aim of this study is to investigate the effect of anti-epileptic drugs on paraoxonase activity, lipid profiles, folat, vitamin B12, homocysteine, thyroid hormones, apolipoprotein A-1, total anti-oxidant capacity, malondialdehyd, nitric oxide, and oxidised low-density lipoprotein. The association with carotid-femoral pulse wave velocity and current biochemical parameters had been searched for assessing the effects of anti-epileptic drugs on the vascular system. We recruited 59 epileptic patients treated with anti-epileptic drugs and 23 controls (group IV) at least 6 months ago. The epileptic group was divided into three groups by receiving anti-epileptic drugs as follows: group I: carbamazepine, group II: valproic acid, and group III: carbamazepine and valproic acid. Arterial distensibility was assessed with the Complior device. There was no difference between the current biochemical parameters in epileptic children. Serum-free T4 was decreased, when compared with group IV. Thyroid-stimulating hormone was increased in group II, compared with group IV. The carotid-femoral pulse wave velocity was increased in group III, compared with group IV. The carotid-femoral pulse wave velocity was correlated with thyroid-stimulating hormone and valproic acid levels. Anti-epileptic drugs may induce atherogenesis by affecting the thyroid hormones. According to the current data, the effects of thyroid hormones on vascular system may be independent of other biochemical markers. Epileptic patients using anti-epileptic drugs must be followed closely for arterial stiffness, and also for the development and progression of atherosclerosis.


Medical options for treating perianal Crohn's disease.
Perianal Crohn's disease can cause significant morbidity for patients affected by the disease. However, diagnostic modalities and treatment options have progressed changing the goals of treatment from fistula "improvement" to complete cessation of drainage. Fistula closure and fibrosis of the fistula track is achieved in some patients. Furthermore, treatment has become a combined effort between medical physicians and surgeons. Simple disease can be treated with medical therapy alone consisting of antibiotics and immunomodulators. Infliximab should be added to refractory simple disease or simple disease with the presence of inflammation. If complex fistula disease is evident a surgical evaluation should also be done to determine if intervention is indicated. Complex disease should be treated with antibiotics, immunomodulators and biologic therapy from the onset. This review will summarise current data regarding medical options for treatment of fistulising Crohn's disease.


A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B.
The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. Fifty-nine patients who had Niemann-Pick disease type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.


Multi-state Markov models in cancer screening evaluation: a brief review and case study.
This work presents a brief overview of Markov models in cancer screening evaluation and focuses on two specific models. A three-state model was first proposed to estimate jointly the sensitivity of the screening procedure and the average duration in the preclinical phase, i.e. the period when the cancer is asymptomatic but detectable by screening. A five-state model, incorporating lymph node involvement as a prognostic factor, was later proposed combined with a survival analysis to predict the mortality reduction associated with screening. The strengths and limitations of these two models are illustrated using data from French breast cancer service screening programmes. The three-state model is a useful frame but parameter estimates should be interpreted with caution. They are highly correlated and depend heavily on the parametric assumptions of the model. Our results pointed out a serious limitation to the five-state model, due to implicit assumptions which are not always verified. Although it may still be useful, there is a need for more flexible models. Over-diagnosis is an important issue for both models and induces bias in parameter estimates. It can be addressed by adding a non-progressive state, but this may provide an uncertain estimation of over-diagnosis. When the primary goal is to avoid bias, rather than to estimate over-diagnosis, it may be more appropriate to correct for over-diagnosis assuming different levels in a sensitivity analysis. This would be particularly relevant in a perspective of mortality reduction estimation.


A Lower Leg Physical Activity Intervention for Individuals With Chronic Venous Leg Ulcers: Randomized Controlled Trial.
Individuals with venous leg ulcers (VLUs) suffer disproportionately with multiple chronic conditions, are often physically deconditioned, and demonstrate high levels of physical inactivity. The primary objective of this randomized controlled trial was to establish the feasibility of a mobile health (mHealth) physical activity exercise app for individuals with VLUs to improve lower leg function. In a 6-week study, adults with VLUs were recruited from 2 wound centers in South Carolina, United States, and enrolled if they were aged 18 years or older with impaired functional mobility and an ankle-brachial index between 0.8 and 1.3. Participants were randomized 1:1 to receive evidence-based, phased, nonexertive physical conditioning activities for lower leg function (FOOTFIT) or FOOTFIT+ with an added patient-provider communication feature. The mHealth Conditioning Activities for Lower Leg Function app also provided automated educational and motivational messages and user reports. Foot movement on the VLU-affected leg was tracked by a Bluetooth-enabled triaxial accelerometer. The study was guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to assess the feasibility of reach, adherence, acceptability, implementation, and maintenance. A total of 24 patients were recruited, enrolled, and randomized in the study. Most patients reported difficulty following the protocol for exercising and using the accelerometer and mobile phone and did not use the provider contact feature. However, all patients were adherent to the 6-week exercise program more than 85% of the time for duration, whereas 33% (8/24) of patients adhered more than 85% for the frequency of performing the exercises. Across the three exercise levels, adherence did not differ between the two groups. Confidence limits around the difference in proportions ranged from -0.4 to 0.7. Providers in FOOTFIT+ were inconsistent in checking participant progress reports because of lack of time from competing work commitments. The technology became outdated quickly, making maintenance problematic. Participants said they would continue to exercise their foot and legs and liked being able to follow along with the demonstrations of each level of exercise provided through the app. The findings of this study suggest that despite initial interest in using the app, several components of the program as originally designed had limited acceptability and feasibility. Future refinements should include the use of more modern technology including smaller wearable accelerometers, mobile phones or tablets with larger screens, an app designed with larger graphics, automated reporting for providers, and more engaging user features. ClinicalTrials.gov NTC02632695; https://clinicaltrials.gov/ct2/show/NCT02632695.


Exploring Perceived Interactions Between Consequences of Traumatic Brain Injury.
To explore the perceived interactions between consequences of traumatic brain injury (TBI). Fifteen clinicians experienced in working with patients with TBI. Participating clinicians completed an online questionnaire in which they estimated the degree to which consequences of TBI (taken from the Brief ICF Core Set for Traumatic Brain Injury) causally relate to each other. Based on these perceived interactions, a visual network was constructed and centrality measures for this network were computed. The resulting network demonstrates various strong perceived causal relations between the consequences of TBI. Impairments in consciousness were perceived to most strongly cause other TBI consequences in the network. Difficulties with acquiring, keeping, and terminating a job were perceived to be most strongly caused by other TBI consequences. Difficulties in partaking in complex interpersonal interactions were also perceived to play a central role in the network. In the perception of clinicians, consequences of TBI interact with each other and are thus not solely a direct result of the injury. While more research is needed to map the interactions between consequences of TBI, our results could have important implications for the way we understand and treat the problems patients are faced with after TBI.


Diterpene Lipo-Alkaloids with Selective Activities on Cardiac K+ Channels.
Aconitum diterpene alkaloids are known for their remarkable toxicity, which is due to their effect on ion channels. Activation of voltage-gated Na+ channels is the major cause of their cardiotoxicity, however, influence on K+ channels may also play a role in the overall effect.Here we report the synthesis of a series of lipo-alkaloids, including four new compounds, based on the 14-benzoylaconine structure, which is the core of a vast number of diterpene alkaloids naturally occurring in Aconitum species. The activities of these compounds were measured in vitro on K+ ion channels using the whole-cell patch-clamp technique. Structure-activity analysis was carried out based on the data of 51 compounds (32 genuine diterpene alkaloids, 5 fatty acids, and 14 lipo-alkaloids). Depending on their substitution, these compounds exert different activities on GIRK (G protein-coupled inwardly-rectifying potassium channel) and hERG (human ether-à-go-go-related gene) channels. Fatty acids and diterpene alkaloids show lower activity on the GIRK channel than lipo-alkaloids. Lipo-alkaloids also have less pronounced hERG inhibitory activity compared to the cardiotoxic aconitine. Considering the GIRK/hERG selectivity as an indicator of perspective therapeutic applicability, lipo-alkaloids are significantly more selective than the genuine diterpene alkaloids. 14-Benzoyl-8-O-eicosa-8Z,11Z,14Z-trienoate and 14-benzoyl-8-O-eicosa-11Z,14Z,17Z-trienoate are strong and selective inhibitors of GIRK channels, thus, they are promising subjects for further studies to develop diterpene alkaloid-based antiarrhythmic pharmacons.


An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers.
The presence of BRCA1 protein was determined immunohistochemically in normal and benign breast biopsies, non-familial breast carcinomas and breast carcinomas from one or more individuals from 8 BRCA1 families. Strikingly, little staining was detected in breast carcinomas from BRCA1 families, regardless of the position or type of mutation, whereas strong immunostaining was observed in 28/28 of non-malignant breast biopsies. Furthermore, BRCA1 staining was reduced in non-familial breast carcinomas, since loss of nuclear BRCA1 staining was evident in 19% of non-familial breast carcinomas whilst a similar proportion (20%) showed absence of either cytoplasmic or nuclear BRCA1 staining. Statistical analysis indicates that breast cancer is characterised by a reduction in levels of nuclear BRCA1 in familial (p < 0.001) and non-familial breast cancer (p = 0.001). In non-familial breast cancer absence of nuclear BRCA1, but not cytoplasmic BRCA1, is more common in high grade breast carcinomas (p = 0.03) and in patients with evidence of lymph node involvement (p = 0.05). Correlation between the absence of BRCA1 protein with high grade is consistent with previous findings of a correlation between mutations in the BRCA1 gene and high grade. Our findings provide new evidence in support of BRCA1 as a tumour suppressor protein in non-familial breast cancer.


Changes in serum tumor markers in type 2 diabetes mellitus with microalbuminuria.
The objective of this study was to investigate changes in serum tumor markers in type 2 diabetes mellitus (T2DM) with microalbuminuria and analyze the relationship between tumor markers and microalbuminuria. A total of 956 T2DM patients aged 40-70 years hospitalized in the Department of Endocrinology, Xinhua Hospital, China, affiliated with Shanghai Jiaotong University School of Medicine, were enrolled from January 2018 to December 2020. The sample comprised 313 T2DM patients with microalbuminuria and 643 T2DM patients with normal urinary microalbumin levels. After assessing the changes in serum tumor markers in T2DM with microalbuminuria, we analyzed the risk of microalbuminuria by the serum tumor marker category using multiple logistic regression analysis. Serum CEA, CA199, CA125, CA153, CA211, SCC, CA242, and CA50 levels were significantly higher in T2DM patients with microalbuminuria than in those without microalbuminuria, while serum AFP levels were lower in the microalbuminuria group (P < 0.05). Following adjustment of confounders, serum CEA, CA211, and SCC were independently associated with microalbuminuria in T2DM. An ROC curve was used to estimate the cutoff point of tumor markers for microalbuminuria. Taking the values under the cutoff points as a reference, values for CEA, CA211, and SCC above the cutoff points indicated a significantly high risk of microalbuminuria. The OR of increased CEA for microalbuminuria was 2.006 (95%CI 1.456-2.765), the OR of increased CA211 for microalbuminuria was 1.505 (95%CI 1.092-2.074), and the OR of increased SCC for microalbuminuria was 1.958 (95%CI 1.407-2.724). Several serum tumor markers were related to microalbuminuria in T2DM. Serum tumor markers such as CEA, SCC, and CA211 may indicate early diabetic nephropathy, particularly when elevated in combination.


Internalization and dissemination of human norovirus and animal caliciviruses in hydroponically grown romaine lettuce.
Fresh produce is a major vehicle for the transmission of human norovirus (NoV) because it is easily contaminated during both pre- and postharvest stages. However, the ecology of human NoV in fresh produce is poorly understood. In this study, we determined whether human NoV and its surrogates can be internalized via roots and disseminated to edible portions of the plant. The roots of romaine lettuce growing in hydroponic feed water were inoculated with 1 × 10(6) RNA copies/ml of a human NoV genogroup II genotype 4 (GII.4) strain or 1 × 10(6) to 2 × 10(6) PFU/ml of animal caliciviruses (Tulane virus [TV] and murine norovirus [MNV-1]), and plants were allowed to grow for 2 weeks. Leaves, shoots, and roots were homogenized, and viral titers and/or RNA copies were determined by plaque assay and/or real-time reverse transcription (RT)-PCR. For human NoV, high levels of viral-genome RNA (10(5) to 10(6) RNA copies/g) were detected in leaves, shoots, and roots at day 1 postinoculation and remained stable over the 14-day study period. For MNV-1 and TV, relatively low levels of infectious virus particles (10(1) to 10(3) PFU/g) were detected in leaves and shoots at days 1 and 2 postinoculation, but virus reached a peak titer (10(5) to 10(6) PFU/g) at day 3 or 7 postinoculation. In addition, human NoV had a rate of internalization comparable with that of TV as determined by real-time RT-PCR, whereas TV was more efficiently internalized than MNV-1 as determined by plaque assay. Taken together, these results demonstrated that human NoV and animal caliciviruses became internalized via roots and efficiently disseminated to the shoots and leaves of the lettuce.


Prediction of Response to Systemic Corticosteroids in Active UC by Microbial Composition-A Prospective Multicenter Study.
Corticosteroids are used for induction of remission in patients with moderately to severely active ulcerative colitis. However, up to one-third of patients fail to this therapy. We investigated if fecal microbial composition or its metabolic capacity are associated with response to systemic corticosteroids. In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥4) receiving systemic corticosteroids were eligible. Data were assessed and fecal samples collected before and after 4 weeks of treatment. Patients were divided into responders (decrease of Lichtiger Score ≥50%) and nonresponders. The fecal microbiome was assessed by the 16S rRNA gene marker and analyzed with QIIME 2. Microbial metabolic pathways were predicted using parsimonious flux balance analysis. Among 93 included patients, 69 (74%) patients responded to corticosteroids after 4 weeks. At baseline, responders could not be distinguished from nonresponders by microbial diversity and composition, except for a subgroup of biologic-naïve patients. Within 4 weeks of treatment, responders experienced changes in beta diversity with enrichment of ascribed beneficial taxa, including Blautia, Anaerostipes, and Bifidobacterium, as well as an increase in predicted butyrate synthesis. Nonresponders had only minor longitudinal taxonomic changes with a significant increase of Streptococcus salivarius and a microbial composition shifting away from responders. Baseline microbial diversity and composition seem to be of limited use to predict response to systemic corticosteroids in active ulcerative colitis. Response is longitudinally associated with restoration of microbial composition and its metabolic capacity.


Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest.
PC-SPES is an eight-herb mixture that was shown to have activity against prostate cancer. Recently, we isolated a major component (6% of the total ethanolic extract) known as baicalin from PC-SPES by high performance liquid chromatography (HPLC). Baicalin was evaluated for its ability to inhibit clonal growth, and to induce cell cycle arrest of various cancer types (PC-3, DU145, LNCaP prostate cancer cell lines, MCF-7 breast cancer cell line, HL-60 myeloblastic leukemia cell line, and NB4 promyelocytic leukemia cell line). The ability of baicalin to induce apoptosis of cancer cells was examined by both staining with Annexin V and detection of cleavage of Poly (ADP-ribose) polymerase (PARP)(3). Western blot analysis examined the effect of baicalin on levels of p21(waf1) and p27(kip1) in those cells. Futhermore, induction of differentiation in HL-60 cells was measured by expression of CD11b. Baicalin inhibited the clonal proliferation of LNCaP and PC3 prostate cancer cell lines, and the HL-60 and NB4 myeloblastic/promyelocytic leukemia cell lines with a 50% inhibition (ED(50)) that ranged between 6.4 x 10(-6) to 12 x 10(-6) mol/L. Cell cycle analysis showed that baicalin (2 x 10(-5) mol/L, 4 days) caused a G(0)/G(1) and G(2)/M accumulation of LNCaP and HL-60 cells, respectively. Concomitantly, differentiation and apoptosis were induced in HL-60 cells, as measured by expression of CD11b antigen, staining with annexin V, and detection of cleavage of PARP. Moreover, baicalin enhanced the expression of the cyclin-dependent kinase inhibitor, p27(kip1) in LNCaP and HL-60 cells. Baicalin inhibited the proliferation of cancer cells via apoptosis and cell cycle arrest, in which p27(kip1) may play a role. Baicalin may be a novel, adjunctive therapy for selected malignancies including prostate cancer.


Error analysis of a natural breathing calibration method for respiratory inductive plethysmography.
Respiratory volumes are measured non-invasively by recording rib cage and abdominal motions using respiratory inductive plethysmography (RIP). Qualitative diagnostic calibration (QDC) of RIP is based on the natural variability in the relative rib-cage-to-abdomen contribution during tidal breathing. ODC does not require subject cooperation but it has previously been shown that accuracy may deteriorate when breathing pattern changes. The aim of this study was to investigate the causes and situations where QDC accuracy deteriorates. The QDC method was compared to PRA (calibration during voluntarily preferential rib cage or abdomen breathing) in ten adults. A reference RIP calibration was obtained from all validation data (REF). The PRA method had better accuracy than the ODC method (p<0.01). The volumetric error ranged between 10% and 136% with QDC and between 5% and 33% with PRA. The PRA calibration factors were within 6% of those from REF, while the QDC rib-cage factor was underestimated by 15% and the abdominal factor was overestimated by 38%. Small natural variability in the relative rib-cage-to-abdomen contribution was related to poor accuracy. Each compartment's variability depended on its magnitude, which is a violation of the QDC assumptions.


Geographic differences in the epidemiological features of HCV infection in Korea.
The prevalence of hepatitis C virus (HCV) infection in Korea exhibits significant geographic variation, with it being higher in Busan and Jeonam than in other areas. The reason for this intranational geographic difference was investigated in this study by conducting a comparative analysis of the risk factors related to HCV infection among three geographic areas: the capital (Seoul), Busan, and the province of Jeolla. In total, 990 patients with chronic HCV infection were prospectively enrolled at 5 university hospitals located in Seoul (n=374), Busan (n=264), and Jeolla (n=352). A standardized questionnaire survey on the risk factors for HCV infection was administered to these three groups of patients, and a comparative analysis of the findings was performed. The analysis revealed significant regional differences in exposure to the risk factors of HCV infection. By comparison with patients in Seoul as a control group in the multivariate analysis, patients in Busan had significantly more experience of invasive medical procedures, acupuncture, cosmetic procedures, and multiple sex partners. In contrast, patients in Jeolla were significantly older, and they had a higher prevalence of hepatocellular carcinoma, a lower prevalence of multiple sex partners, and had experienced fewer invasive procedures. There was a significant geographic difference in the exposure to potential risk factors of HCV infection between patients from the three studied regions. This may explain the regional variation of the prevalence of HCV infection in Korea, and should be taken into account when planning strategies for the prevention and management of HCV infection.


Analysis of insulin signalling by RNAi-based gene silencing.
Using siRNA-mediated gene silencing in cultured adipocytes, we have dissected the insulin-signalling pathway leading to translocation of GLUT4 glucose transporters to the plasma membrane. RNAi (RNA interference)-based depletion of components in the putative TC10 pathway (CAP, CrkII and c-Cbl plus Cbl-b) or the phospholipase Cgamma pathway failed to diminish insulin signalling to GLUT4. Within the phosphoinositide 3-kinase pathway, loss of the 5'-phosphatidylinositol 3,4,5-trisphosphate phosphatase SHIP2 was also without effect, whereas depletion of the 3'-phosphatase PTEN significantly enhanced insulin action. Downstream of phosphatidylinositol 3,4,5-trisphosphate and PDK1, silencing the genes encoding the protein kinases Akt1/PKBalpha, or CISK(SGK3) or protein kinases Clambda/zeta had little or no effect, but loss of Akt2/PKBbeta significantly attenuated GLUT4 regulation by insulin. These results show that Akt2/PKBbeta is the key downstream intermediate within the phosphoinositide 3-kinase pathway linked to insulin action on GLUT4 in cultured adipocytes, whereas PTEN is a potent negative regulator of this pathway.


Security use of the chiral photonic film made of helical liquid crystal structures.
The color change of photonic crystals (PCs) has been widely studied due to their beauty and anti-counterfeiting applications. Herein, we demonstrated security codes based on chiral PCs that cannot be easily mimicked and are quite different from the conventional technology used currently. The chiral PCs can be made by self-assembly and the structural colors change based on the polarization of the light in the transmission mode. These color changes are easily detected in real-time and are useful in the fabrication of anti-counterfeiting patterns that show beautiful and diverse color changes with rotating polarizers. We believe this can provide a new platform in various security and color-based applications.


Antiphytopathogenic activity of Psoralea glandulosa (Fabaceae) against Botrytis cinerea and Phytophthora cinnamomi.
The resinous exudate, three meroterpenes, namely bakuchiol (1), 3-hydroxybakuchiol (2), 12-hydroxyisobakuchiol (3), and one furanocoumarin, psoralen (4), were isolated from the leaves of culen (Psoralea glandulosa). In addition to these, two semi-synthetic derivatives, bakuchiol acetate (5) and bakuchiol methyl eter (6), were obtained from 1, and were subsequently evaluated in vitro for the inhibitory effect of resin and compounds on the mycelial growth of Botrytis cinerea Pers.: Fr. and Phytophthora cinnamomi Rands. The resinous exudate inhibited the mycelial growth of both the pathogens, while bakuchiol (1) exhibited an inhibitory effect on the mycelial growth of B. cinerea up to 94% at a concentration of 150 mg/L and psoralen (4) reduced the mycelial growth of P. cinnamomi up to 80% at a concentration of 150 mg/L. These compounds have the ability of blocking the development of mycelial growth and may be used as a potential biopesticide in the agricultural sector once the in vivo test results have been validated.


[Color coded Doppler ultrasound in diagnosis of gastroesophageal reflux].
We report the possibility to detect small gastro-oesophageal refluxes by means of colour coded Doppler(CD)ultrasonography. The choice of an adequate pulse repetition frequency, which coded velocities up to 30 cm/s into colour without aliasing phenomenon, is an important premise for a colour coded proof of reflux. The sensitivity has been increased from 87% to 94% in sonographically detection of reflux, if the results are compared with the pH metry, measured about 24 hours. It is shown by comparison of the three methods (B-mode-, CD-ultrasonography and 24 hours pH-monitoring), that there are in each case equal false negative and false positive results. So the over all agreement was just 83% of all three methods. In our opinion it should be performed an additional ultrasonography in completion to the customary pH metry, which can detect even short term and pH neutral refluxes. If it is used supplementary, the colour coded Doppler ultrasonography improves the diagnostic sensitivity especially in trifle refluxes.


Systematic Assessment of Well-Being in Mice for Procedures Using General Anesthesia.
In keeping with the 3R Principle (Replacement, Reduction, Refinement) developed by Russel and Burch, scientific research should use alternatives to animal experimentation whenever possible. When there is no alternative to animal experimentation, the total number of laboratory animals used should be the minimum needed to obtain valuable data. Moreover, appropriate refinement measures should be applied to minimize pain, suffering, and distress accompanying the experimental procedure. The categories used to classify the degree of pain, suffering, and distress are non-recovery, mild, moderate, or severe (EU Directive 2010/63). To determine which categories apply in individual cases, it is crucial to use scientifically sound tools. The well-being-assessment protocol presented here is designed for procedures during which general anesthesia is used. The protocol focuses on home cage activity, the Mouse Grimace Scale, and luxury behaviors such as burrowing and nest building behavior as indicators of well-being. It also uses the free exploratory paradigm for trait anxiety-related behavior. Fecal corticosterone metabolites as indicators of acute stress are measured over the 24-h post-anesthetic period. The protocol provides scientifically solid information on the well-being of mice following general anesthesia. Due to its simplicity, the protocol can easily be adapted and integrated in a planned study. Although it does not provide a scale to classify distress in categories according to the EU Directive 2010/63, it can help researchers estimate the degree of severity of a procedure using scientifically sound data. It provides a way to improve the assessment of well-being in a scientific, animal-centered manner.


Accuracy and clinical utility of a point-of-care HbA1c testing device.
Point-of-care testing (POCT) is widely used to measure blood glucose levels in people with diabetes, although its use in measuring glycated hemoglobin (HbA1c) levels is less common, perhaps due to perceived performance issues and access to the technology. Forty blood samples were analyzed in duplicate using Bayer's A1CNow + ® Multi-Test A1C system (A1CNow + ) with 3 different reagent lots; HbA1c levels of the samples spanned the clinically relevant range of 4% to 10%. Corresponding samples were sent to a National Glycohemoglobin Standardization Program (NGSP) secondary reference laboratory (University of Missouri Secondary Reference Laboratory #9), which analyzed the samples with a Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 (Tosoh G8; Tosoh Bioscience, Inc). Glycated hemoglobin levels measured with the A1CNow + aligned with measurements obtained using the laboratory method, with correlation coefficients of 0.985, 0.987, and 0.989 for the 3 lots, respectively. The 95% CIs for the differences between the A1CNow + levels and the mean HbA1c levels were within -0.55% to +0.50% for the 3 reagent lots, which is well within the currently acceptable limits of ±0.75% HbA1c required by the NGSP. Results were further analyzed per the new tighter NGSP performance criteria effective September 1, 2012, requiring that 37 of 40 results be within ±7% (relative bias) of the NGSP reference laboratory measures. All 3 lots met the tighter NGSP criteria. The A1CNow + provides accuracy and precision when performing POCT of HbA1c as an aid in diabetes management. Ongoing improvements in this and other HbA1c POCT devices may lead to a greater global acceptance of the role of POCT of HbA1c in diabetes management.


A long non-coding RNA promotes full activation of adult gene expression in the chicken α-globin domain.
Long non-coding RNAs (lncRNAs) were recently shown to regulate chromatin remodelling activities. Their function in regulating gene expression switching during specific developmental stages is poorly understood. Here we describe a nuclear, non-coding transcript responsive for the stage-specific activation of the chicken adult α(D) globin gene. This non-coding transcript, named α-globin transcript long non-coding RNA (lncRNA-αGT) is transcriptionally upregulated in late stages of chicken development, when active chromatin marks the adult α(D) gene promoter. Accordingly, the lncRNA-αGT promoter drives erythroid-specific transcription. Furthermore, loss of function experiments showed that lncRNA-αGT is required for full activation of the α(D) adult gene and maintenance of transcriptionally active chromatin. These findings uncovered lncRNA-αGT as an important part of the switching from embryonic to adult α-globin gene expression, and suggest a function of lncRNA-αGT in contributing to the maintenance of adult α-globin gene expression by promoting an active chromatin structure.


Community Use of Antibiotics in Turkey: The Role of Knowledge, Beliefs, Attitudes, and Health Anxiety.
Turkey has been among the leading countries in antibiotic consumption. As a result of the 4-year National Action Plan for Rational Drug Use, antibiotic prescriptions had declined from 34.9% in 2011 to 24.6% in 2018. However, self-medication with antibiotics without prescription is common, which is not reflected in official statistics. The present study aims at investigating antibiotic use in the community and the factors related to it. A web-based survey was conducted among 945 Turkish-speaking respondents (61.3% female). The questionnaire included questions about antibiotic use for different illnesses, ways to obtain and handle leftover antibiotics, knowledge, beliefs of the antibiotic effectiveness, attitudes, health anxiety, and background factors. According to the results, 34.2% of the sample had self-medicated themselves with antibiotics without a valid prescription. The most common way to self-medicate was to use leftover antibiotics. While 80.4% knew that antibiotics are used to treat bacterial infections, 51.4% thought that antibiotics are effective for viral diseases. The most important predictor of antibiotic use frequency was the belief in their efficiency for various illnesses and symptoms, followed by negative attitudes to antibiotics, health anxiety, knowledge level, positive attitudes, and health status. The results underline the importance of targeting misbeliefs about antibiotics in future campaigns.


Community Business in Scotland: An Alternative Vision of 'Enterprise Culture', 1979-97.
The force and coherency with which Margaret Thatcher and her inner circle outlined their vision for 'enterprise culture', like so many aspects of Thatcherism, have masked the complexity of its origins and the histories of alternative responses. This article provides a history of an alternative vision for enterprise culture by examining the community business movement in Scotland, the largest experiment of its kind in the UK in the 1980s and a forerunner of social enterprise. Working across Scotland, but with a hub of activity in the Strathclyde region, practitioners worked with local people to find ways to develop their neighbourhood economy while improving their environment, creating jobs, and developing services needed in their area. This article outlines the origins of the movement, the shared values of its founding members, and how their training in community development informed the community business model. It analyses how practitioners put their ideas into practice and the reasons behind the fragmentation of the movement in the 1990s. It argues that although at face value the concept of community business may appear to chime with the dominant political rhetoric of Thatcher's 'enterprise culture', the history of the movement provides a signpost to an alternative, if unrealised, vision for Scotland's recovery from social and economic depression. Where previous historical research has focused on the political consequences of Thatcher's policies in Scotland, this research connects this discussion to the transformation of Scotland's civic society in the wake of deindustrialization.


Fungal natural alkaloid schizocommunin activates the aryl hydrocarbon receptor pathway.
Fungi, including mushrooms and mycelia, are a rich source for natural products with medicinal properties. In some cases, they can lead to opportunistic infections in humans and other mammals. In 1994, the first case of bronchopulmonary mycosis caused by the Schizophyllum commune fungus was described. Culture of the isolated specimen led to the extraction of an alkaloid compound, schizocommunin, which was more recently synthesised for biological characterization. Herein we describe schizocommunin and one of its analogues as cytotoxic against human hepatoma cells at low micromolar concentrations. Schizocommunin is shown to be a potent activator of the aryl hydrocarbon receptor (AhR) gene battery, more specifically increasing expression of the CYP1A1, CYP1B1 and UGT1A genes in human liver and lung cells. A luciferase reporter assay further confirms induction of transcription by these compounds at the xenobiotic response element. This study improves our understanding of the interaction between this fungal metabolite and xenobiotic detoxifying mechanisms in the body, and points to schizocommunin as a putative mediator of the allergic response and a useful molecule for the study of the AhR pathway.


Multifunctional Porous and Magnetic Silicone with High Elasticity, Durability, and Oil-Water Separation Properties.
Frequent oil spills and industrial emissions of organic solvents cause serious environmental problems. Therefore, finding a high-performance absorbent material is necessary but also challenging. Here we present a very simple method to fabricate a magnetic porous silicone that exhibits excellent absorbency, fast magnetic responsiveness, high elasticity, stretchability, and high chemical stability. The porous silicone instantly adsorbs any oil floating on water in a complex environment under magnetic field driving, without human operation, and can also separate the oil/water mixture automatically and quickly at high efficiency using an external pump. The oil absorption capacity and mechanical properties, such as compressibility and stretchability, were robust even under corrosive conditions or UV exposure. The robust, reusable magnetic porous silicone is a promising candidate for the large-scale industrial separation of organic solvents/water mixtures in harsh conditions.


[Antifungal activity of the novel adduct, GX-95, of silver with nanometer-scale particles to peptidic hydrolysates from collagen].
Silver has long been known to have an antimicrobial activity against bacteria and other microorganisms, and has been used as eating utensils, as dental fillings and so on. We developed a novel adduct, GX-95, of silver with nanometer-scale particles to peptidic hydrolysates from collagen. Antifungal activity of the adduct against pathogenic yeasts and filamentous fungi was examined in terms of minimal inhibitory concentrations (MICs). GX-95 was found to possess strong and broad antifungal activities against all fungi examined in the following MICs: 0.25 to 0.31 microg/ml for Candida albicans including resistant strains to fluconazole, itraconazole and flucytosine, 0.05 to 0.2 microg/ml for Cryptococcus neoformans strains, 0.025 to 0.4 microg/ml for Aspergillus fumigatus strains, 0.4 microg/ml for Trichophyton rubrum, and 0.05 microg/ml for Cladophialophora carrionii.


Partial purification of fatty-acid binding protein by ammonium sulphate fractionation.
By fractionation of rat liver cytosol with 70% saturation ammonium sulphate, a soluble fraction showing high affinity for oleic acid was obtained. The binding of oleic acid to this fraction was inhibited by flavaspidic acid. The molecular weight of the main protein present in this fraction was 12 000 as determined by SDS-poly-acrylamide-gel electrophoresis. This soluble fraction stimulated the transfer of oleic acid from microsomes to phosphatidylcholine liposomes as demonstrated by a transfer assay in vitro. The behaviour of this fraction is similar to that described for fatty-acid binding protein.


Neuroendocrine tumours of rare location.
Neuroendocrine tumours (NETs) arising from dispersed endocrine system may originate from almost every location, although they are most commonly found in the gastrointestinal tract and respiratory system. NETs are considered as particularly rare if they constitute less than 1% of all neuroendocrine tumours. The aim of the paper is to present ten rare NETs from the database of the Endocrinology Department of the Jagiellonian University, Medical College: 4 NETs of the ampulla of Vater, 2 of the gallbladder, and 1 of the ovary, sphenoid sinus, Meckel's diverticulum, and epiglottis. The clinical presentation of such tumours and their management are discussed.


Chemical warfare in Colombia, evidentiary ecologies and senti-actuando practices of justice.
Between 1994 and 2015, militarized aerial fumigation was a central component of US-Colombia antidrug policy. Crop duster planes sprayed a concentrated formula of Monsanto's herbicide, glyphosate, over illicit crops, and also forests, soils, pastures, livestock, watersheds, subsistence food and human bodies. Given that a national peace agreement was signed in 2016 between FARC-EP guerrillas and the state to end Colombia's over five decades of war, certain government officials are quick to proclaim aerial fumigation of glyphosate an issue of the past. Rural communities, however, file quejas (complaints or grievances) seeking compensation from the state for the ongoing effects of the destruction of their licit agro-forestry. At the interfaces of feminist science and technology studies and anthropology, this article examines how evidentiary claims are mobilized when war deeply politicizes and moralizes technoscientific knowledge production. By ethnographically tracking the grievances filed by small farmers, I reveal the extent to which evidence circulating in zones of war - tree seedlings, subsistence crops, GPS coordinates and bureaucratic documents - retains (or not) the imprints of violence and toxicity. Given the systematic rejection of compensation claims, farmers engage in everyday material practices that attempt to transform chemically degraded ecologies. These everyday actualizations of justice exist both alongside and outside contestation over the geopolitically backed violence of state law. Rather than simply contrasting everyday acts of justice with denunciatory claims made against the state, farmers' reparative practices produce an evidentiary ecology that holds the state accountable while also ' senti-actuando' (feel-acting) alternative forms of justice.


Tyrannosaur paleobiology: new research on ancient exemplar organisms.
Tyrannosaurs, the group of dinosaurian carnivores that includes Tyrannosaurus rex and its closest relatives, are icons of prehistory. They are also the most intensively studied extinct dinosaurs, and thanks to large sample sizes and an influx of new discoveries, have become ancient exemplar organisms used to study many themes in vertebrate paleontology. A phylogeny that includes recently described species shows that tyrannosaurs originated by the Middle Jurassic but remained mostly small and ecologically marginal until the latest Cretaceous. Anatomical, biomechanical, and histological studies of T. rex and other derived tyrannosaurs show that large tyrannosaurs could not run rapidly, were capable of crushing bite forces, had accelerated growth rates and keen senses, and underwent pronounced changes during ontogeny. The biology and evolutionary history of tyrannosaurs provide a foundation for comparison with other dinosaurs and living organisms.


γ-Aminobutyric acid transporter 2 mediates the hepatic uptake of guanidinoacetate, the creatine biosynthetic precursor, in rats.
Guanidinoacetic acid (GAA) is the biosynthetic precursor of creatine which is involved in storage and transmission of phosphate-bound energy. Hepatocytes readily convert GAA to creatine, raising the possibility that the active uptake of GAA by hepatocytes is a regulatory factor. The purpose of this study is to investigate and identify the transporter responsible for GAA uptake by hepatocytes. The characteristics of [(14)C]GAA uptake by hepatocytes were elucidated using the in vivo liver uptake method, freshly isolated rat hepatocytes, an expression system of Xenopus laevis oocytes, gene knockdown, and an immunohistochemical technique. In vivo injection of [(14)C]GAA into the rat femoral vein and portal vein results in the rapid uptake of [(14)C]GAA by the liver. The uptake was markedly inhibited by γ-aminobutyric acid (GABA) and nipecotinic acid, an inhibitor of GABA transporters (GATs). The characteristics of Na(+)- and Cl(-)-dependent [(14)C]GAA uptake by freshly isolated rat hepatocytes were consistent with those of GAT2. The Km value of the GAA uptake (134 µM) was close to that of GAT2-mediated GAA transport (78.9 µM). GABA caused a marked inhibition with an IC(50) value of 8.81 µM. The [(14)C]GAA uptake exhibited a significant reduction corresponding to the reduction in GAT2 protein expression. GAT2 was localized on the sinusoidal membrane of the hepatocytes predominantly in the periportal region. This distribution pattern was consistent with that of the creatine biosynthetic enzyme, S-adenosylmethionine:guanidinoacetate N-methyltransferase. GAT2 makes a major contribution to the sinusoidal GAA uptake by periportal hepatocytes, thus regulating creatine biosynthesis in the liver.


Comprehensive Dual- and Triple-Feature Intersectional Single-Vector Delivery of Diverse Functional Payloads to Cells of Behaving Mammals.
The resolution and dimensionality with which biologists can characterize cell types have expanded dramatically in recent years, and intersectional consideration of such features (e.g., multiple gene expression and anatomical parameters) is increasingly understood to be essential. At the same time, genetically targeted technology for writing in and reading out activity patterns for cells in living organisms has enabled causal investigation in physiology and behavior; however, cell-type-specific delivery of these tools (including microbial opsins for optogenetics and genetically encoded Ca2+ indicators) has thus far fallen short of versatile targeting to cells jointly defined by many individually selected features. Here, we develop a comprehensive intersectional targeting toolbox including 39 novel vectors for joint-feature-targeted delivery of 13 molecular payloads (including opsins, indicators, and fluorophores), systematic approaches for development and optimization of new intersectional tools, hardware for in vivo monitoring of expression dynamics, and the first versatile single-virus tools (Triplesect) that enable targeting of triply defined cell types.


Predicting categories of drugs used by suspected drug-impaired drivers using the Drug Evaluation and Classification Program tests.
Objective: The purpose of this study was to statistically determine which combination(s) of drug-related signs and symptoms from the Drug Evaluation and Classification (DEC) protocol best predict the drug category used by the suspected drug-impaired driver. Methods: Data from 1,512 completed DEC evaluations of suspected impaired drivers subsequently found to have ingested central nervous system (CNS) depressants, CNS stimulants, narcotic analgesics, and cannabis were analyzed using a multinomial logistic regression procedure. A set of evaluations completed on drug-free subjects was also included. The relative importance of clinical, behavioral, and observational measures in predicting drug categories responsible for impairment was also examined. Results: Thirteen drug-related indicators were found to significantly contribute to the prediction of drug category, including being under the care of a doctor or dentist, condition of the eyes, condition of the eyelids, mean pulse rate, assessment of horizontal gaze nystagmus (HGN), convergence, performance on the One Leg Stand (OLS) Test, eyelid tremors, pupil size in darkness, reaction to light, presence of visible injection sites, systolic blood pressure, and muscle tone. Indicators related to the appearance and physiological response of the eye contributed the most to the prediction of drug category, followed closely by clinical indicators and performance on the psychophysical tests. Conclusions: The findings from this study suggest that drug recognition experts (DREs) should be careful to review a set of key signs and symptoms when determining the category of drug used by suspected drug-impaired drivers. Drug use indicators related to the appearance and physiological response of the eye were found to contribute the most to the prediction of the drug category responsible for the impairment. These results could help form the basis of a core set of indicators that DREs could initially consult to form their opinion of drug influence. This in turn may enhance the validity, effectiveness, and efficiency of drug detection and identification by DREs and lead to a more effective and efficient DEC program, improved enforcement of drug-impaired driving, and greater acceptance of the DEC program by the courts.


Environmental Attitudes in 28 European Countries Derived From Atheoretically Compiled Opinions and Self-Reports of Behavior.
People differ in their personal commitment to fighting climate change and protecting the environment. The question is, can we validly measure people's commitment by what they say and what they claim they do in opinion polls? In our research, we demonstrate that opinions and reports of past behavior can be aggregated into comparable depictions of people's personal commitment to fighting climate change and protecting the environment (i.e., their environmental attitudes). In contrast to the commonly used operational scaling approaches, we ground our measure of people's environmental attitudes in a mathematically formalized psychological theory of the response process-the Campbell paradigm. This theory of the response process has already been extensively validated, and its relevance for manifest behavior has repeatedly been shown as well. In our secondary analysis of Eurobarometer data (N = 27,998) from 28 European countries, we apply the Campbell paradigm to a set of indicators that was not originally collected to be aggregated into a single scale. With our research, we propose a distinct way to measure behavior-relevant environmental attitudes that can be used even with a set of indicators that was originally atheoretically compiled. Overall, our study suggests that the Campbell paradigm provides a sound psychological measurement theory that can be applied to cross-cultural comparisons in the environmental protection domain.


The pst operon of Bacillus subtilis has a phosphate-regulated promoter and is involved in phosphate transport but not in regulation of the pho regulon.
Genes from Bacillus subtilis predicted to encode a phosphate-specific transport (Pst) system were shown by mutation to affect high-affinity Pi uptake but not arsenate resistance or phosphate (Pho) regulation. The transcription start of the promoter upstream of the pstS gene was defined by primer extension. The promoter contains structural features analogous to the Escherichia coli pst promoter but not sequence similarity. Expression from this promoter was induced >5,000-fold upon phosphate starvation and regulated by the PhoP-PhoR two-component regulatory system. These data indicate that the pst operon is involved in phosphate transport and is a member of the Pho regulon but is not involved in Pi regulation.


SARFIMA model prediction for infectious diseases: application to hemorrhagic fever with renal syndrome and comparing with SARIMA.
The early warning model of infectious diseases plays a key role in prevention and control. This study aims to using seasonal autoregressive fractionally integrated moving average (SARFIMA) model to predict the incidence of hemorrhagic fever with renal syndrome (HFRS) and comparing with seasonal autoregressive integrated moving average (SARIMA) model to evaluate its prediction effect. Data on notified HFRS cases in Weifang city, Shandong Province were collected from the official website and Shandong Center for Disease Control and Prevention between January 1, 2005 and December 31, 2018. The SARFIMA model considering both the short memory and long memory was performed to fit and predict the HFRS series. Besides, we compared accuracy of fit and prediction between SARFIMA and SARIMA which was used widely in infectious diseases. Model assessments indicated that the SARFIMA model has better goodness of fit (SARFIMA (1, 0.11, 2)(1, 0, 1)12: Akaike information criterion (AIC):-631.31; SARIMA (1, 0, 2)(1, 1, 1)12: AIC: - 227.32) and better predictive ability than the SARIMA model (SARFIMA: root mean square error (RMSE):0.058; SARIMA: RMSE: 0.090). The SARFIMA model produces superior forecast performance than the SARIMA model for HFRS. Hence, the SARFIMA model may help to improve the forecast of monthly HFRS incidence based on a long-range dataset.


First Report in China of Soft Rot of Ginger Caused by Pythium aphanidermatum.
Ginger (Zingiber officinale Roscoe) is an important commercial crop planted on more than 13,000 ha annually in Anqiu city, Shandong Province, China. From 2010 to 2011, the incidence of Pythium soft rot disease on cv. Laiwu Big Ginger reached 40 to 75% in Anqiu and yield losses of up to 60% were observed. The disease symptoms included brown spots on ginger rhizomes followed by soft rot, stems and leaves above ground becoming withered and yellow, and water soaking on the collar region. The soft rot did not produce offensive odors, which is different from bacterial rots (2). Forty symptomatic rhizomes were sampled from eight farms. Martin's method (1) was used to isolate the pathogen. Ten pieces from each rhizome were washed with sterile distilled water for 30 s and plated on Martin's selective medium at 26°C in a chamber without light. Colonies grew with cottony aerial mycelium. Main hyphae were 5.7 to 9.6 μm wide. Globose sporangia consisting of terminal complexes of swollen hyphal branches were 11.4 to 18.3 μm wide. The average diameter of zoospores was 9.2 μm. The oogonia were globose and smooth, with a diameter of 21 to 33 μm. The sequences of the rRNA gene internal transcribed spacer (ITS) regions 1 and 2 and the 5.8S gene of five isolates were amplified using primers ITS1 and ITS4 (4), and the nucleotide sequence was the same as isolate No. 2, which was deposited in GenBank (Accession No. KC594034). A BLAST search showed 99% identity with Pythium aphanidermatum strain 11-R-8 (Accession No. JQ898455.1). Pathogenicity tests of five isolates were carried out in a greenhouse. Sixty plants (cv. Laiwu Big Ginger) were grown for 30 days in plastic pots (diameter 20 cm) in sandy soil (pH 5.48) and inoculated. Ten plants were used as untreated controls. Five isolates were grown on Martin's liquid medium for 72 h and the spores were harvested in sterile distilled water. Aqueous spore suspensions of the five isolates were adjusted with deionized water to 1 × 108 CFU/ml and injected with a syringe into the soil around the rhizome of the plants. Plants were then placed in the greenhouse at 24 to 26°C and assessed for rhizome rot on the 14th day after inoculation. The inoculated isolates were recovered from the diseased rhizomes, confirming their pathogenicity. To our knowledge, this is the first report of ginger Pythium soft rot caused by P. aphanidermatum in China. Ginger Pythium soft rot caused by P. myriotylum is reported in Taiwan (3). References: (1) F. N. Martin. Page 39 in: The Genus Pythium. American Phytopathological Society, St. Paul, MN, 1992. (2) E. E. Trujillo. Diseases of Ginger (Zingiber officinale) in Hawaii, Circular 62, Hawaii Agricultural Experiment Station, University of Hawaii, December 1964. (3) P. H. Wang. Lett. Appl. Microbiol. 36:116, 2003. (4) T. J. White. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990.


Is blood pressure reduction a valid surrogate endpoint for stroke prevention? An analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the Biomarker-Surrogacy (BioSurrogate) Evaluation Schema (BSES).
Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit. We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3). In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure. In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.


The association of multiple chronic conditions and healthcare expenditures among adults with epilepsy in the United States.
Epilepsy is a frequent neurologic condition with important financial strains on the US healthcare system. The co-occurrence of multiple chronic conditions (MCC) may have additional financial repercussions on this patient population. We aimed to assess the association of coexisting chronic conditions on healthcare expenditures among adult patients with epilepsy. We identified a total of 1,942,413 adults (≥18 years) with epilepsy using the clinical classification code 83 from the MEPS-HC (Medical Expenditure Panel Survey Household Component) database between 2003 and 2014. Chronic conditions were selected using the clinical classification system (ccs), and categorized into 0, 1, or 2 chronic conditions in addition to epilepsy. We computed unadjusted healthcare expenditures per year and per individual (total direct healthcare expenditure, inpatient expenditure, outpatient expenditure, prescription medication expenditure, emergency room visit expenditure, home healthcare expenditure and other) by number of chronic conditions. We applied a two-part model with probit (probability of zero vs non-zero cost) and generalized linear model (GLM) gamma family and log link (for cost greater than zero) to examine the independent association between chronic conditions, and annual expenditures per individual, generating incremental costs with 0 chronic condition as reference. Over half of the patients with epilepsy had at least two chronic conditions (CC). Yearly, for each patient with one and two chronic conditions, unadjusted total healthcare expenditures were two times ($10,202; 95 %CI $6,551-13,853) to nearly three times ($21,277; 95 %CI $12,971-25,583) higher than those with no chronic conditions ($6,177; 95 %CI $4,895-7,459), respectively. In general healthcare expenditures increased with the number of chronic conditions for pre-specified cost categories. The incremental (adjusted) total healthcare expenditure increased with the number of chronic conditions (1CC vs 0 CC: $3,238; 95 %CI $524-5,851 p-value = 0.015 and ≥2 CC vs 0 CC: $8,145; 95 %CI $5,935-10,895 p-value < 0.001). In general, for all cost categories, incremental healthcare expenditures increased with the number of chronic conditions with the largest increment noted between those with 2 CC and those with 0 CC for inpatient ($2,025: 95 %CI $867-3,1830), outpatient ($2,141; 95 %CI $1,321-2,962), and medication ($1,852; 95 %CI $1,393-2,310). Chronic conditions are frequent among adult patients with epilepsy and are associated with a dose-response increase in healthcare expenditure, a difference driven by inpatient, outpatient, and medication prescription expenditures. Greater coordination of epilepsy care accounting for the presence of multiple chronic conditions may help lower the cost of epilepsy.


[A method for performing stimulation electromyography of the masticatory muscles in man].
A principal block scheme of an apparatus complex is suggested and a method for examination of masticatory muscle function is described. The method is based on electrostimulation of masticatory nerve followed by registration and analysis of the masticatory muscle action evoked potentials. The block scheme of the apparatus complex includes a universal electrostimulator ESU-2. Examinations of 30 healthy volunteers and 30 patients with unilateral fractures of the mandible helped define the major parameters of stimulation electromyography. The patients were treated by splints applied on the teeth with fixation on both jaws. By day 28 of the investigation the M-response amplitude dropped more than twofold and its length by 1.5 times as against the mean parameters in health.


Disease Suppressive Soils: New Insights from the Soil Microbiome.
Soils suppressive to soilborne pathogens have been identified worldwide for almost 60 years and attributed mainly to suppressive or antagonistic microorganisms. Rather than identifying, testing and applying potential biocontrol agents in an inundative fashion, research into suppressive soils has attempted to understand how indigenous microbiomes can reduce disease, even in the presence of the pathogen, susceptible host, and favorable environment. Recent advances in next-generation sequencing of microbiomes have provided new tools to reexamine and further characterize the nature of these soils. Two general types of suppression have been described: specific and general suppression, and theories have been developed around these two models. In this review, we will present three examples of currently-studied model systems with features representative of specific and general suppressiveness: suppression to take-all (Gaeumannomyces graminis var. tritici), Rhizoctonia bare patch of wheat (Rhizoctonia solani AG-8), and Streptomyces. To compare and contrast the two models of general versus specific suppression, we propose a number of hypotheses about the nature and ecology of microbial populations and communities of suppressive soils. We outline the potential and limitations of new molecular techniques that can provide novel ways of testing these hypotheses. Finally, we consider how this greater understanding of the phytobiome can facilitate sustainable disease management in agriculture by harnessing the potential of indigenous soil microbes.


Intracranial perianeurysmal cysts: case series and review of the literature.
Intracranial perianeurysmal cysts are a rare finding associated with cerebral aneurysms. Patients may present with symptoms secondary to mass effect from perianeurysmal cysts requiring drainage. These lesions can masquerade as neoplasms if dedicated vascular imaging is not performed, leading to misdiagnosis. A retrospective search of our database was done for intracranial aneurysms that have been treated between 1998 and 2020. A literature search was then performed on PubMed and Google Scholar with the search terms 'aneurysm', 'intracranial/intracerebral', 'cyst', and 'perianeurysmal cyst'. Patient demographics, aneurysms and cysts characteristics were then summarized as a table and in the discussion. Three cases where intracranial aneurysm had associated perianeurysmal cysts were found in our database. Combined with the available literature a total of 19 cases of perianeurysmal cysts have thus far been reported since this entity was first described in 2002. A significant number of perianeurysmal cysts (5/19) required intervention. In 5/19 cases the patient presented with a perianeurysmal cyst without a history of subarachnoid hemorrhage. Of the 10 cases where aneurysm follow-up was reported there were 5 cases where there was aneurysm recurrence necessitating re-treatment. Significant variability exists in the patient demographics, aneurysm and cyst characteristics of perianeurysmal cysts. This suggests that there is no single unified etiology and pathogenesis. These lesions are a rare finding and at present do not appear to carry diagnostic or prognostic significance. Management of perianeurysmal cysts is case-dependent and intervention should be considered when treating the related aneurysm, especially in patients with secondary symptoms.


The effects of diphenyleneiodonium on mitochondrial reactions. Relation of binding of diphenylene[125I]iodonium to mitochondria to the extent of inhibition of oxygen uptake.
1. Several ring-substituted derivatives of diphenyleneiodonium catalyse the exchange of Cl- and OH- ions across the inner membrane of rat liver mitochondria. They also inhibit state 3 and state 3u oxidations of glutamate plus malate in the presence of Cl- more than in its absence. Most have activities similar to diphenyleneiodonium, although 2,4-dichlorodiphenyleneiodonium is up to 50 times more active. 2. Diphenyleneiodonium inhibits soluble rat liver NADH dehydrogenase and NADH oxidation by rat liver sub-mitochondrial particles directly; 2,4-dichlorodiphenyleneiodonium is only about twice as inhibitory. 3. Liver mitochondria contain two classes of binding sites for diphenylene[125I]iodonium, namely high-affinity sites with an affinity constant of 3 X 10(5) M-1 (1--2 nmol/mg of protein), and low-affinity sites with an affinity constant of 1.3 X 10(3) M-1 (80 nmol/mg of protein). Both sites occur in hepatocytes with a relative enrichment of the low-affinity site. Nadh dehydrogenase preparations only apparently contain high-affinity binding sites. Only low-affinity sites occur in erythrocytes. 4. 2,4-Dichlorodiphenyleneiodonium competes with diphenylene[125I]iodonium for both low- and high-affinity sites, whereas tri-n-propyltin only competes for the low-affinity sites. 5. The high-affinity sites are apparently associated with NADH dehydrogenase and the low-affinity sites probably represent electrostatic binding of diphenylene[125I]iodonium to phospholipids. The high-affinity site does not appear to be associated with a rate-limiting stage of NADH oxidation.


Activation of proteinase-activated receptor-2 in mesothelial cells induces pleural inflammation.
Pleural inflammation underlies many pleural diseases, but its pathogenesis remains unclear. Proteinase-activated receptor-2 (PAR(2)) is a novel seven-transmembrane receptor with immunoregulatory roles. We hypothesized that PAR(2) is present on mesothelial cells and can induce pleural inflammation. PAR(2) was detected by immunohistochemistry in all (19 parietal and 11 visceral) human pleural biopsies examined. In cultured murine mesothelial cells, a specific PAR(2)-activating peptide (SLIGRL-NH(2)) at 10, 100, and 1,000 muM stimulated a 3-, 42-, and 1,330-fold increase of macrophage inflammatory protein (MIP)-2 release relative to medium control, respectively (P < 0.05 all) and a 2-, 32-, and 75-fold rise over the control peptide (LSIGRL-NH(2), P < 0.05 all). A similar pattern was seen for TNF-alpha release. Known physiological activators of PAR(2), tryptase, trypsin, and coagulation factor Xa, also stimulated dose-dependent MIP-2 release from mesothelial cells in vitro. Dexamethasone inhibited the PAR(2)-mediated MIP-2 release in a dose-dependent manner. In vivo, pleural fluid MIP-2 levels in C57BL/6 mice injected intrapleurally with SLIGRL-NH(2) (10 mg/kg) were significantly higher than in mice injected with LSIGRL-NH(2) or PBS (2,710 +/- 165 vs. 880 +/- 357 vs. 88 +/- 46 pg/ml, respectively; P < 0.001). Pleural fluid neutrophil counts were higher in SLIGRL-NH(2) group than in the LSIGRL-NH(2) and PBS groups (by 40- and 26-fold, respectively; P < 0.05). This study establishes that activation of mesothelial cell PAR(2) potently induces the release of inflammatory cytokines in vitro and neutrophil recruitment into the pleural cavity in vivo.


Soil pH is equally important as salinity in shaping bacterial communities in saline soils under halophytic vegetation.
While saline soils account for 6.5% of the total land area globally, it comprises about 70% of the area in northwestern China. Microbiota in these saline soils are particularly important because they are critical to maintaining ecosystem services. However, little is known about the microbial diversity and community composition in saline soils. To investigate the distribution patterns and edaphic determinants of bacterial communities in saline soils, we collected soil samples across the hypersaline Ebinur Lake shoreline in northwestern China and assessed soil bacterial communities using bar-coded pyrosequencing. Bacterial communities were diverse, and the dominant phyla (>5% of all sequences) across all soil samples were Gammaproteobacteria, Actinobacteria, Firmicutes, Alphaproteobacteria, Bacteroidetes and Betaproteobacteria. These dominant phyla made a significant (P < 0.05) contribution to community structure variations between soils. Halomonas, Smithella, Pseudomonas and Comamonas were the indicator taxa across the salinity gradient. Bacterial community composition showed significant (P < 0.05) correlations with salt content and soil pH. Indeed, bacterial phylotype richness and phylogenetic diversity were also higher in soils with middle-level salt rates, and were significantly (P < 0.05) correlated with salt content and soil pH. Overall, our results show that both salinity and pH are the determinants of bacterial communities in saline soils in northwest China.


[Effect of ultraviolet irradiation on properties and physicochemical properties of lactate dehydrogenase].
Catalytic and some physicochemical properties of lactate dehydrogenase have been studied as affected by UV-irradiation. The degree of lactate dehydrogenase inactivation has been determined both at UV-irradiation of a free enzyme and of the enzyme in complex with NADH. It is shown that at pH 7.4 NADH makes a photosensitizing effect on the enzyme. Based on the analysis of changes in the absorption spectrum and molecular weight of lactate dehydrogenase caused by UV-irradiation it is supposed that this irradiation induces the process of unrolling-rolling up of the protein globule.