Site-selective mapping of metastable states using electron-beam induced luminescence microscopy.
Metastable states created by electron or hole capture in crystal defects are widely used in dosimetry and photonic applications. Feldspar, the most abundant mineral in the Earth's crust (> 50%), generates metastable states with lifetimes of millions of years upon exposure to ionizing radiation. Although feldspar is widely used in dosimetry and geochronometry, the creation of metastable states and charge transfer across them is poorly understood. Understanding such phenomena requires next-generation methods based on high-resolution, site-selective probing of the metastable states. Recent studies using site-selective techniques such as photoluminescence (PL), and radioluminescence (RL) at 7 K have revealed that feldspar exhibits two near-infrared (NIR) emission bands peaking at 880 nm and 955 nm, which are believed to arise from the principal electron-trapping states. Here, we map for the first time the electron-trapping states in potassium-rich feldspar using spectrally-resolved cathodoluminescence microscopy at a spatial resolution of ~ 6 to 22 µm. Each pixel probed by a scanning electron microscope provides us a cathodoluminescence spectrum (SEM-CL) in the range 600-1000 nm, and elemental data from energy-dispersive x-ray (EDX) spectroscopy. We conclude that the two NIR emissions are spatially variable and, therefore, originate from different sites. This conclusion contradicts the existing model that the two emissions arise from two different excited states of a principal trap. Moreover, we are able to link the individual NIR emission peaks with the geochemical variations (K, Na and Fe concentration), and propose a model that explains the quenching of the NIR emission by Fe4+. Our study contributes to an improved understanding of charge storage in feldspathic minerals, with implications for developing sub-single grain (micrometer scale) measurement techniques in radiation dosimetry.


A numerical method for analysis of in vitro time-dependent inhibition data. Part 2. Application to experimental data.
Time-dependent inhibition (TDI) of cytochrome P450 enzymes is an important cause of drug-drug interactions. The standard approach to characterize the kinetics of TDI is to determine the rate of enzyme loss, kobs, at various inhibitor concentrations, [I], and replot the kobs versus [I] to obtain the key kinetic parameters, KI and kinact. In our companion manuscript (Part 1; Nagar et al., 2014) in this issue of Drug Metabolism and Disposition, we used simulated datasets to develop and test a new numerical method to analyze in vitro TDI data. Here, we have applied this numerical method to five TDI datasets. Experimental datasets include the inactivation of CYP2B6, CYP2C8, and CYP3A4. None of the datasets exhibited Michaelis-Menten-only kinetics, and the numerical method allowed use of more complex models to fit each dataset. Quasi-irreversible as well as partial inhibition kinetics were observed and parameterized. Three datasets required the use of a multiple-inhibitor binding model. The mechanistic and clinical implications provided by these analyses are discussed. Together with the results in Part 1, we have developed and applied a new numerical method for analysis of in vitro TDI data. This method appears to be generally applicable to model in vitro TDI data with atypical and complex kinetic schemes.


Fungal pathogenicity genes in the age of 'omics'.
The identification of the fungal genes essential for disease underpins the development of disease control strategies. Improved technologies for gene identification and functional analyses, as well as a plethora of sequenced fungal genomes, have led to the characterization of hundreds of genes, denoted as pathogenicity genes, which are required by fungi to cause disease. We describe recent technologies applied to characterize the fungal genes involved in disease and focus on some genes that are likely to attract continuing research activity.


Advances in immunotherapy of chronic myeloid leukemia CML.
Tyrosine kinase inhibitors induce sustained disease remissions in chronic myeloid leukemia by exploiting the addiction of this type of leukemia to the activity of the fusion oncogene BCR-ABL. However, these agents fail to eradicate CML stem cells which are ultimately responsible for disease relapses upon treatment discontinuation. Evidence that the immune system can effectively reject CML stem cells potentially leading to patient cure is provided by the experience with patients receiving allogeneic bone marrow transplantations. Compelling evidence indicates that more modern, antigen-specific immunotherapeutic approaches are also feasible and hold strong potential to be clinically effective. Amongst these, particularly promising is the use of autologous dendritic cells pulsed with antigens or direct application of in vitro transcribed RNA encoding for leukemia-associated antigens, since this approach allows to circumvent HLA-restriction of the leukemia-associated T cell epitopes that have been eventually identified. Combining these strategies with monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1, may help to obtain even stronger immune responses and better clinical results. This narrative review addresses this topic by focusing in particular on the cell-based immunotherapeutic strategies for CML and on the issue of the leukemia-associated antigens to be selected for targeting.


Platelet vesicular monoamine transporter 2 density in the disruptive behavior disorders.
In a former study, we reported decreased platelet vesicular monoamine transporter 2 (VMAT2) density (Bmax) in patients with ADHD. The current study aimed at measuring platelet VMAT2 in the disruptive behavior disorders (DBDs) to assess whether this finding is specific to ADHD or generalizable to the broader DBD concept. The study included 13 patients with DBDs aged 10-12 years and 16 healthy volunteers aged 8-17 years. All participants underwent a thorough clinical evaluation using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version for diagnosis, the Nisonger Child Behavior Rating Form, the Clinical Global Impressions Scale-Severity version, and the DSM-IV ADHD Scale (DAS). The study group's DAS scores did not differ from those of the control group. There was no significant difference between the patients with DBDs and the control group either in VMAT2 density (Bmax) or affinity (Kd) as measured by high-affinity [(3)H]TBZOH binding. We conclude that the formerly reported decreased platelet VMAT2 Bmax in patients with ADHD may be specific to ADHD and not present in DBDs. Larger-scale replication is needed.


Burden and characteristics of influenza A and B in Danish intensive care units during the 2009/10 and 2010/11 influenza seasons.
Influenza surveillance in Danish intensive care units (ICUs) was performed during the 2009/10 and 2010/11 influenza seasons to monitor the burden on ICUs. All 44 Danish ICUs reported aggregate data for incidence and point prevalence, and case-based demographical and clinical parameters. Additional data on microbiological testing, vaccination and death were obtained from national registers. Ninety-six patients with influenza A(H1N1)pdm09 were recorded in 2009/10; 106 with influenza A and 42 with influenza B in 2010/11. The mean age of influenza A patients was higher in 2010/11 than in 2009/10, 53 vs. 44 years (P = 0·004). No differences in other demographic and clinical parameters were detected between influenza A and B patients. In conclusion, the number of patients with severe influenza was higher in Denmark during the 2010/11 than the 2009/10 season with a shift towards older age groups in influenza A patients. Influenza B caused severe illness and needs consideration in clinical and public health policy.


Urethral Diverticulum in the Female. Etiologic Factors and Postoperative Results.
Among 32 female patients with urethral diverticulum, a high incidence of prior gonococcal infection suggests that periurethral infection with this organism may be a common etiologic factor. The voiding cystourethrogram appears to be the best technic for demonstrating the diverticulum and for differentiating it from other suburethral masses. In the cases not associated with urinary tract infections, local symptoms were uniformly relieved by successful surgical excision. In patients with infection, surgery accomplished clearing of chronic urinary tract infection in 47% and cure of local symptoms in 63%. Persistence of infection following operation calls for further investigation to search for other etiologic factors or the presence of a new or recurrent diverticulum.


Left ventricular diverticulum in two adult patients.
Left ventricular diverticulum is a rare congenital anomaly. In the adult population, the incidence was reported to be 0.26% in nonselected patients who underwent cardiac catheterization. Diverticula are usually localized near the apex and most often involve the inferior or anterior parietal walls of the left ventricle. In this report, two cases with congenital left ventricular diverticulum are presented, and the pathophysiologic, diagnostic, and therapeutic approaches of this cardiac malformation are discussed.


Unawareness of deficits in Huntington's disease.
People with Huntington's disease (HD) may show reduced awareness of physical and mental changes in themselves. This article reviews the evidence for loss of awareness (anosognosia) in an attempt to elucidate its characteristics and possible underlying mechanisms. It is shown that defective awareness occurs across domains. People with HD may under-report the presence or severity of involuntary movements, under-estimate cognitive impairment and deny behavioural change. Nevertheless, awareness is not all or none. Moreover, it may be affected differentially for different symptom domains and emerge at different stages of disease, raising the possibility of distinct contributory mechanisms. Findings of an inverse relationship between insight and severity of disease suggest that cognitive impairment, in particular executive dysfunction, may be an important contributory factor. Evidence has accrued to support this argument. However, cognitive impairment cannot fully account for patients' lack of awareness of involuntary movements. Findings that patients accurately report consequences but not the experience of involuntary movements, and better acknowledge their presence when watching videotapes of themselves suggests that physiological factors play an important role. The putative role of denial as a coping mechanism is discussed. Recognition by clinicians of deficient self-awareness is crucial because of its implications for diagnosis and optimal clinical management of HD.


Effects of magnesium supplementation on blood parameters of athletes at rest and after exercise.
The effects of magnesium supplementation on blood parameters were studied during a period of 4 wk in adult tae-kwon-do athletes at rest and exhaustion. Thirty healthy subjects of ages ranging in age from 18 to 22 yr were included in the study. The subjects were separated into three groups, as follows: Group 1 consisted of subjects who did not train receiving 10 mg/kg/d magnesium. Group 2 included subjects equally supplemented with magnesium and exercising 90-120 min/d for 5 d/wk. Group 3 were subject to the same exercise regime but did not receive magnesium supplements. The leukocyte count (WBC) was significantly higher in groups 1 and 2 than in the subjects who did not receive any supplements (p < 0.05). There were no significant differences in the WBC of the two groups under magnesium supplementation. The erythrocyte, hemoglobin, and trombocyte levels were significantly increased in all groups (p < 0.05), but the hematocrit levels did not show any differences between the groups although they were increased after supplementation and exercise. These results suggest that magnesium supplementation positively influences the performance of training athletes by increasing erythrocyte and hemoglobin levels.


Kidney stones during pregnancy: an investigation into stone composition.
Kidney stones can be a source of considerable morbidity for pregnant women. Although there is a body of literature confirming that different stone compositions predominate for different age and sex cohorts, there have been no similar reports characterizing the nature of stone disease during pregnancy. We performed a multi-institutional study to define the composition of renal calculi diagnosed during pregnancy. We retrospectively reviewed the records from two stone referral centers of all patients diagnosed with a de novo kidney stone during pregnancy who underwent a procedure for the purpose of stone removal from June 2001 through September 2007. A total of 27 patients were identified, with a mean age of 26.8 years (range, 21-34). Twenty patients (74%) had no history of prior stone formation. Seven patients (26%) had previously formed stones, although none of these patients had a known kidney stone at the time they became pregnant. Stones were removed in the first, second, third trimester and immediately post-partum in 4, 52, 22, and 22% respectively. Stone removal was performed without complication in all cases. Analysis found that in 74% of all cases (20 patients) stones were composed predominantly of calcium phosphate (hydroxyapatite). In 26% of cases, (7 patients) the stones were composed predominantly of calcium oxalate. Of the seven patients with prior stone history, three patients had previously formed calcium phosphate stones and four patients had previously formed calcium oxalate stones. Calcium oxalate calculi are the most common stone in non-pregnant women of a comparable age as our subjects. However, our present data suggest that stones detected during pregnancy are most commonly composed of calcium phosphate (hydroxyapatite). Indeed, it is the minority of stones that are composed of calcium oxalate. Although the reason for this unusual preponderance of calcium phosphate calculi is unclear, physiologic alterations that occur during pregnancy may be influential.


Prolonged complete remission in previously severe SLE.
Of 160 patients with systemic lupus erythematosus followed up in a long-term prospective study 4 with previously severe disease are in complete remission and have required no therapy for a median time of 75 months. The 4 females all presented with systemic features and a typical butterfly rash prompting early diagnosis and treatment. All patients have had complete remission of clinical and laboratory features of disease, without maintenance suppressive therapy.


DNA-based analysis of regurgitates: a noninvasive approach to examine the diet of invertebrate consumers.
DNA-based gut content analysis has become an important tool for unravelling feeding interactions in invertebrate communities under natural conditions. It usually implies killing of the consumer and extracting the DNA from its food, using either the whole animal or its dissected gut. This post-mortem approach, however, is not suitable for investigating the diet of rare or protected species and also prohibits tracking individual dietary preferences as each consumer can provide trophic information only once. Moreover, removing large numbers of consumers from a habitat for analysis might critically change population densities and affect species interactions. Here, we present DNA-based analysis of invertebrate regurgitates, a novel approach to overcome these limitations. Conducting feeding experiments where adult Poecilus cupreus (Coleoptera: Carabidae) were fed with larvae of Amphimallon solstitiale (Coleoptera: Scarabaeidae), we show that detection success in regurgitates compared to samples prepared from whole beetles was similar or significantly enhanced for small/medium and large prey DNA fragments, respectively. Prey DNA detection success remained high in regurgitates stored in ethanol for 21 months at room temperature prior to DNA extraction. We conclude that in those invertebrates where regurgitates can be obtained, examination of food DNA in regurgitates offers many advantages over conventional post-mortem gut content analysis.


On the origin of mesoscopic inhomogeneity of conducting polymers.
The mesoscopic inhomogeneity of conducting polymer films obtained by electropolymerization and spin-coating was studied using Kelvin probe force microscopy (KFM) and current-sensing atomic-force microscopy (CS-AFM). A well-pronounced correlation was established between the polymer morphology, on the one hand, and its local work function (which is related to the polymer oxidation degree) as well as polymer conductivity, on the other. The most conducting regions were associated with the tops of the polymer grains and showed Ohmic behavior. They were surrounded first by semiconducting and then by insulating polymer. The conductivity of the grain periphery could be lower by as much as 2 orders of magnitude. The grain cores also showed consistently higher values of the local work function as compared to the grain periphery. This fact suggested that the grain cores were more oxidized and/or more ordered as compared to the grain periphery, which is in good agreement with the local conductivity data. More uniform morphology corresponded to less variability in the other properties of the polymer. A model is proposed that relates the observed inhomogeneity to preferential deposition of polymer molecules with higher molecular weight at the early stages of the polymer phase formation. The polymer deposition in either electropolymerization or various solution-casting techniques involves the nucleation of a new phase from a solution containing polymer fractions of different molecular weights. The driving force of the nucleation process depends on the solubility of the polymer fractions, which decreases with an increase in the molecular weight. This gives rise to preferential deposition of more crystalline, higher molecular weight polymer at the early stages of the polymer deposition to form the cores of the polymer grains. The fractions with lower molecular weights are deposited later and form less ordered/less conducting grain periphery. On the basis of this model, we conclude that, to ensure the formation of materials with low inhomogeneity and high quality, one should use the starting polymer with as narrow molecular weight distribution as possible. Yet another possibility is to use solvents which would reduce the differences in the solubilities of polymer fractions with different molecular weight.


Radiographic evaluation of reactive osteitis in traumatic injury of sacroiliac joints.
After traumatic Sacroiliac (SI) joint injury, follow up radiographic imaging can demonstrate subchondral bone resorption resembling inflammatory sacroiliitis. No studies have described the incidence of marginal SI post-traumatic osteitis, the probable temporal relationship to the initial traumatic injury, or the possible effect of unilateral hardware fixation on the contralateral SI joint. A Level 1 trauma center imaging database was queried to identify patients with pelvic bony trauma between 2005 and 2017 with CT baseline preserved SI cortication and unilateral/bilateral traumatic SI diastasis. Serial radiographs were retrospectively evaluated by 2 musculoskeletal-trained radiologists at initial, 6 weeks, 3 months and 6 months following trauma, with documentation of diastasis, subchondral resorption, and operative fixation. 206 SI joints in 106 total patients met inclusion criteria. There was a statistically significant association between injury and presence of resorption at 6 weeks post-trauma for the right SI joint only. There was no other statistically significant relationship between injury and presence of resorption at any other post-trauma evaluation. There was no statistical relationship between resorption and surgical fixation. There was a statistically significant increased incidence of resorption in the post-traumatic population when compared to an atraumatic population undergoing CT pelvis study for non-SI related indications as well as compared to the incidence of inflammatory sacroiliitis in a general population. This study confirms an incidence of sub-acute subchondral bone resorption following traumatic joint injury above that expected for a general, non-traumatic population. Accurate interpretation of this traumatic finding minimizes inappropriate consultation and intervention for inflammatory sacroiliitis.


A study of video display terminal workers.
Workers who operate video display terminals (VDTs) are sometimes reported to experience high levels of physical and psychological distress. In an effort to investigate these reports, a study was conducted that compared the responses of 145 Directory Assistance operators who used VDTs to retrieve listings with 105 controls who referred to printed paper directories. The comparison was made on the basis of a single questionnaire that was administered to both groups. The questionnaire asked about the experience of 15 physical discomforts of the sort that are sometimes attributed to work with VDTs. There was only one statistically significant difference in the incidence of complaint: VDT operators were more likely to complain of neck discomfort. On the whole, VDT operators expressed greater satisfaction with their jobs than did operators who used paper records. VDTs may pose special problems, particularly if they are selected or installed without adequate regard for the physical limitations of workers who must use them. Several of these problems are discussed.


Late chronotypes are associated with neoadjuvant chemotherapy-induced nausea and vomiting in women with breast cancer.
Neoadjuvant chemotherapy, that is, the administration of chemotherapy before surgery, has been commonly used for locally advanced breast cancer to improve the surgical outcomes and increase the opportunity for breast-conserving therapy. Women with breast cancer often receive an anthracycline-based regimen as the neoadjuvant chemotherapy, which is associated with a high risk of emesis. Despite the development of novel antiemetics, chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as a major adverse effect, affecting the quality of life of the patients. However, the factors predicting CINV in women with breast cancer undergoing neoadjuvant chemotherapy remain unclear. In this single-institution, prospective, observational study conducted at an outpatient cancer centre in the Republic of Korea from November 2013 to March 2016, we analysed women with breast cancer who planned to be treated with neoadjuvant chemotherapy before surgery. Candidate factors associated with CINV were assessed before neoadjuvant chemotherapy using the Munich Chronotype Questionnaire, Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale. CINV was assessed after chemotherapy by using the Multinational Association of Supportive Care in Cancer Antiemesis Tool. Of a total of 143 participants, 7 patients were lost to follow-up and 2 patients were excluded due to changes in their treatment plan; thus, 134 patients were finally included in the analyses. Overall, 48.5% of the participants experienced CINV, with delayed CINV prevalence (42.5%) being more common than acute (39.6%). In the univariate analyses, overall CINV was significantly associated with late chronotypes (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.37-8.87; p = 0.009), a history of nausea/vomiting (OR, 2.19; 95% CI, 1.10-4.37; p = 0.026) and anxiety (OR, 2.25; 95% CI, 1.05-4.81; p = 0.036). In the multivariate analyses, late chronotypes (OR, 3.53; 95% CI, 1.27-9.79; p = 0.015) and a history of nausea/vomiting (OR, 2.83; 95% CI, 1.31-6.13; p = 0.008) remained significantly associated with CINV. In conclusion, in women with breast cancer undergoing neoadjuvant chemotherapy before surgery, late chronotypes were found to have an increased risk of CINV; these data suggest that clinicians need to assess and consider the chronotype in the management of CINV.


[Awareness of memory deficits in patients with dementias: a study with the Everyday Memory Checklist].
We examined the level of awareness of memory deficits in 63 patients with Alzheimer's disease (AD), 17 patients with dementia with Lewy bodies (DLB), 14 patients with vascular dementia (VaD), and 56 patients with amnestic mild cognitive impairment (MCI). The unawareness of memory impairment was evaluated with a standardized memory questionnaire system based on the Everyday Memory Checklist (EMC). The EMC scores for the patient's own rating, the caregivers' rating and the unawareness score, defined as the discrepancy between these (caregiver rating-patient rating), were analyzed. Although the EMC self-rating scores were comparable among the four groups, the EMC scores in caregivers were significantly higher in the AD group than in the DLB, VaD, and MCI groups. Therefore, the unawareness scores were significantly higher in the AD groups than in other groups. When an unawareness score of 9 or more was defined as significant, impaired awareness was found in 41 (65%) patients with AD, 1 (6%) patient with DLB, 5 (36%) patients with VaD, and in 19 (34%) patients with MCI. We found that impaired awareness was found in two-thirds of patients with mild AD and even in one-third of patients with MCI. However, other dementias, in particular DLB, had less severe and less frequent unawareness of memory deficits than AD, suggesting the difference in the pathophysiology between them.


High WFDC3 gene expression is associated with poor prognosis and reduced immune cells infiltration in pancreatic adenocarcinoma: A study using the TCGA database and bioinformatics analysis.
Whey-acidic-protein (WAP) four-disulfide core domain protein 3 (WFDC3) is one of the WAP family proteins. This protein family is associated with the development of solid tumors and affects the tumor immunological microenvironment. However, the prognostic value of WFDC3 in pancreatic adenocarcinoma (PAAD) and its effect on the tumor immune microenvironment is yet to be clarified. The Cancer Genome Atlas database and Genotype-Tissue Expression database were used to analyze the differential expression of WFDC3 between the tumor and adjacent tissues. The clinical significance of WFDC3 was analyzed in The Cancer Genome Atlas and International Cancer Genome Consortium database using WFDC3 transcripts and clinical information. In order to elucidate the underlying mechanisms, gene set enrichment analysis was conducted to determine potential activated pathways. Immune score evaluation and publicly available pharmacogenomics database [the Genomics of Drug Sensitivity in Cancer] were utilized to quantify immune cell infiltration and the effect on chemotherapeutic drug sensitivity. WFDC3 levels were higher in PAAD tissues than in normal pancreatic tissues. High levels of WFDC3 expression progressively increased as PAAD tumor stages progressed. Patients with elevated WFDC3 expression showed a poor prognosis. The gene set enrichment analysis analysis revealed that glutamate, arginine, and proline, and histidine metabolism levels were elevated in patients with a high WFDC3 expression phenotype. B, CD4+ T, and CD8+ T cell infiltration was diminished in PAAD tissues with elevated WFDC3 expression. According to pharmacogenomics, PAAD tissues with high WFDC3 expression are susceptible to gemcitabine. WFDC3 is highly expressed in PAAD, and patients with a high level of WFDC3 expression have a shorter overall survival time, indicating a poorer prognosis. High expression of WFDC3 may lead to the development of PAAD by affecting the amino acid metabolism and the tumor immunological microenvironment. WFDC3 may serve as a potential diagnostic and prognostic biomarker for PAAD patients.


[Features of rat behavior associated with alternative choice in Y-maze and their interpretation in terms of complex probability amplitudes].
The two-way alternative avoidance of a weak electric shock by male Wistar rats in Y-maze was studied. The following behavioral characteristics of a rat were determined in each test series: total time of an arm choice (going away into one of two safe maze arms), number and sequence of alternate turnings to the outlets in the process of choice, time of immobility in the Y-maze center, and "freezing" reaction. Rat behavior of choice of safe arms in Y-maze be interpreted on the basis of the rules of summation of complex probability amplitudes, which characterize a predictive estimation of achievement by a rat of its relative safety. With the need to avoid an electric shock, rat's estimations of suitabilities of two different avoidance ways can interfere. This makes it difficult for an animal to take a choice decision (if both pathways are equally acceptable for a rat). After entering a safe arm, sometimes a rat can leave it for another arm, such passages occur quasiperiodically.


A Self-Supervised Deep Learning Approach for Blind Denoising and Waveform Coherence Enhancement in Distributed Acoustic Sensing Data.
Fiber-optic distributed acoustic sensing (DAS) is an emerging technology for vibration measurements with numerous applications in seismic signal analysis, including microseismicity detection, ambient noise tomography, earthquake source characterization, and active source seismology. Using laser-pulse techniques, DAS turns (commercial) fiber-optic cables into seismic arrays with a spatial sampling density of the order of meters and a time sampling rate up to one thousand Hertz. The versatility of DAS enables dense instrumentation of traditionally inaccessible domains, such as urban, glaciated, and submarine environments. This in turn opens up novel applications such as traffic density monitoring and maritime vessel tracking. However, these new environments also introduce new challenges in handling various types of recorded noise, impeding the application of traditional data analysis workflows. In order to tackle the challenges posed by noise, new denoising techniques need to be explored that are tailored to DAS. In this work, we propose a Deep Learning approach that leverages the spatial density of DAS measurements to remove spatially incoherent noise with unknown characteristics. This approach is entirely self-supervised, so no noise-free ground truth is required, and it makes no assumptions regarding the noise characteristics other than that it is spatio-temporally incoherent. We apply our approach to both synthetic and real-world DAS data to demonstrate its excellent performance, even when the signals of interest are well below the noise level. Our proposed methods can be readily incorporated into conventional data processing workflows to facilitate subsequent seismological analyses.


Landau-de Gennes theory of surface-enhanced ordering in smectic films.
A Landau theory for surface-enhanced ordering in smectic-A free-standing films is described, based on a generalization of de Gennes' model for a "presmectic" fluid confined between two walls. According to the theory, smectic ordering in free-standing films heated above the bulk smectic melting temperature is due to an intrinsic surface contribution rather than an external field. The theory yields a persistent finite-size effect, in that the film melting temperatures do not tend to the bulk transition temperature in the limit of infinite film thickness. It also predicts that a continuous transition from (N+1)- to N-layer films is impossible without an external field. The theory closely fits existing experimental data on layer-thinning transitions in compounds which exhibit a bulk smectic-A to nematic phase transition. Possible origins of the intrinsic surface contribution are discussed.


High molecular weight DNA extraction strategies for long-read sequencing of complex metagenomes.
By offering extremely long contiguous characterization of individual DNA molecules, rapidly emerging long-read sequencing strategies offer comprehensive insights into the organization of genetic information in genomes and metagenomes. However, successful long-read sequencing experiments demand high concentrations of highly purified DNA of high molecular weight (HMW), which limits the utility of established DNA extraction kits designed for short-read sequencing. The challenges associated with input DNA quality intensify further when working with complex environmental samples of low microbial biomass, which requires new protocols that are tailored to study metagenomes with long-read sequencing. Here, we use human tongue scrapings to benchmark six HMW DNA extraction strategies that are based on commercially available kits, phenol-chloroform (PC) extraction and agarose encasement followed by agarase digestion. A typical end goal of HMW DNA extractions is to obtain the longest possible reads during sequencing, which is often achieved by PC extractions, as demonstrated in sequencing of cultured cells. Yet our analyses that consider overall read-size distribution, assembly performance and the number of circularized elements found in sequencing results suggest that column-based kits with enzyme supplementation, rather than PC methods, may be more appropriate for long-read sequencing of metagenomes.


Chronic heart failure: contemporary diagnosis and management.
Chronic heart failure (CHF) remains the only cardiovascular disease with an increasing hospitalization burden and an ongoing drain on health care expenditures. The prevalence of CHF increases with advancing life span, with diastolic heart failure predominating in the elderly population. Primary prevention of coronary artery disease and risk factor management via aggressive blood pressure control are central in preventing new occurrences of left ventricular dysfunction. Optimal therapy for CHF involves identification and correction of potentially reversible precipitants, target-dose titration of medical therapy, and management of hospitalizations for decompensation. The etiological phenotype, absolute decrease in left ventricular ejection fraction and a widening of QRS duration on electrocardiography, is commonly used to identify patients at increased risk of progression of heart failure and sudden death who may benefit from prophylactic implantable cardioverter-defibrillator placement with or without cardiac resynchronization therapy. Patients who transition to advanced stages of disease despite optimal traditional medical and device therapy may be candidates for hemodynamically directed approaches such as a left ventricular assist device; in selected cases, listing for cardiac transplant may be warranted.


Cardiovascular consequences of obstructive sleep apnea in different study models and novel perspectives.
Obstructive sleep apnea (OSA) is heterogeneous in terms of contributing pathophysiological mechanisms, clinical presentation, and consequences. Different study models from animal models of intermittent hypoxia over case-control, cohort, and population-based observational studies to uncontrolled interventional and randomized controlled interventional trials have contributed to the knowledge base. Controversial findings on underlying mechanisms and consequences of untreated OSA have challenged the field and resulted in uncertainty in treatment recommendations. The heterogeneity of OSA in pathogenesis and clinical outcomes and strengths and limitations of different study models and designs used for studying OSA pathophysiology and cardiovascular consequences are discussed on the background of controversial findings on cardiovascular outcomes in OSA. In addition, recent findings from randomized controlled continuous positive airway pressure therapy withdrawal trials, an efficient and controlled study model, are highlighted. Novel designs for clinical trials on long-term outcomes in the highly prevalent patient group with OSA addressing the heterogeneity in underlying mechanisms, different phenotypes in terms of cardiovascular risk, and new treatment concepts are needed to improve clinical practice standards.


Slowing down lipolysis significantly enhances the oral absorption of intact solid lipid nanoparticles.
Only a limited amount of orally administered lipid nanoparticles are absorbed as intact particles due to lipolysis by lipases in the gastrointestinal tract. It is hypothesized that by counteracting lipolysis, more particles will survive gastrointestinal digestion and be absorbed as intact particles. In this study, incorporation of a lipase inhibitor orlistat (OLST), as well as polyethylene glycol (PEG) coating, is employed to slow down the lipolysis using solid lipid nanoparticles (SLNs) as model particles. To explore the in vivo behaviors of the particles, near-infrared fluorescent probes with absolute aggregation-caused quenching (ACQ) properties are used to label and track the unmodified, PEG-coated and OLST-loaded SLNs. The in vitro lipolysis study indicates very fast first-order degradation of unmodified SLNs and significantly decreased degradation of OLST-SLNs. Live imaging reveals the same trend of slowed-down lipolysis in vivo which correlates well with the in vitro lipolysis. The scanning of ex vivo gastrointestinal segments confirms the considerably prolonged residence time of OLST-SLNs, mirroring the significantly decreased lipolysis rate. The observation of fluorescence in the blood, though very weak, and in the liver speaks of the oral absorption of intact SLNs. The substantially higher hepatic levels of OLST-SLNs than unmodified SLNs should be attributed to the significantly enhanced survival rate because both particles exhibit similar cellular recognition as well as similar physicochemical properties except for the survival rate. Similarly, slowing down lipolysis also contributes to the significantly enhanced cumulative lymphatic transport of OLST-SLNs (7.56% vs. 1.27% for the unmodified SLNs). The PEG coating slows down the lipolysis rate as well but not to the degree as done by OLST. As a result, the gastrointestinal residence time of PEG-SLNs has been moderately prolonged and the hepatic levels moderately increased. The weakened cellular recognition of PEG-SLNs implies that the enhanced oral absorption is solely ascribed to the slowed-down lipolysis and enhanced mucus penetration. In conclusion, the oral absorption of intact SLNs can be significantly enhanced by slowing down lipolysis, especially by OLST, showing potential as carriers for the oral delivery of labile biomacromolecules.


Brazilian recommendations on the safety and effectiveness of the yellow fever vaccination in patients with chronic immune-mediated inflammatory diseases.
In Brazil, we are facing an alarming epidemic scenario of Yellow fever (YF), which is reaching the most populous areas of the country in unvaccinated people. Vaccination is the only effective tool to prevent YF. In special situations, such as patients with chronic immune-mediated inflammatory diseases (CIMID), undergoing immunosuppressive therapy, as a higher risk of severe adverse events may occur, assessment of the risk-benefit ratio of the yellow fever vaccine (YFV) should be performed on an individual level. Faced with the scarcity of specific orientation on YFV for this special group of patients, the Brazilian Rheumatology Society (BRS) endorsed a project aiming the development of individualized YFV recommendations for patients with CIMID, guided by questions addressed by both medical professionals and patients, followed an internationally validated methodology (GIN-McMaster Guideline Development). Firstly, a systematic review was carried out and an expert panel formed to take part of the decision process, comprising BRS clinical practitioners, as well as individuals from the Brazilian Dermatology Society (BDS), Brazilian Inflammatory Bowel Diseases Study Group (GEDIIB), and specialists on infectious diseases and vaccination (from Tropical Medicine, Infectious Diseases and Immunizations National Societies); in addition, two representatives of patient groups were included as members of the panel. When the quality of the evidence was low or there was a lack of evidence to determine the recommendations, the decisions were based on the expert opinion panel and a Delphi approach was performed. A recommendation was accepted upon achieving ≥80% agreement among the panel, including the patient representatives. As a result, eight recommendations were developed regarding the safety of YFV in patients with CIMID, considering the immunosuppression degree conferred by the treatment used. It was not possible to establish recommendations on the effectiveness of YFV in these patients as there is no consistent evidence to support these recommendations. This paper approaches a real need, assessed by clinicians and patient care groups, to address specific questions on the management of YFV in patients with CIMID living or traveling to YF endemic areas, involving specialists from many areas together with patients, and might have global applicability, contributing to and supporting vaccination practices. We recommended a shared decision-making approach on taking or not the YFV.


Histochemistry as an irreplaceable approach for investigating functional cytology and histology.
In agreement with the evolution of histochemistry over the last fifty years and thanks to the impressive advancements in microscopy sciences, the application of cytochemical techniques to light and electron microscopy is more and more addressed to elucidate the functional characteristics of cells and tissue under different physiological, pathological or experimental conditions. Simultaneously, the mere description of composition and morphological features has become increasingly sporadic in the histochemical literature. Since basic research on cell functional organization is essential for understanding the mechanisms responsible for major biological processes such as differentiation or growth control in normal and tumor tissues, histochemical Journals will continue to play a pivotal role in the field of cell and tissue biology in all its structural and functional aspects.


Score-Based Data Generation for EEG Spatial Covariance Matrices: Towards Boosting BCI Performance.
The efficacy of Electroencephalogram (EEG) classifiers can be augmented by increasing the quantity of available data. In the case of geometric deep learning classifiers, the input consists of spatial covariance matrices derived from EEGs. In order to synthesize these spatial covariance matrices and facilitate future improvements of geometric deep learning classifiers, we propose a generative modeling technique based on state-of-the-art score-based models. The quality of generated samples is evaluated through visual and quantitative assessments using a left/right-hand-movement motor imagery dataset. The exceptional pixel-level resolution of these generative samples highlights the formidable capacity of score-based generative modeling. Additionally, the center (Fréchet mean) of the generated samples aligns with neurophysiological evidence that event-related desynchronization and synchronization occur on electrodes C3 and C4 within the Mu and Beta frequency bands during motor imagery processing. The quantitative evaluation revealed that 84.3% of the generated samples could be accurately predicted by a pre-trained classifier and an improvement of up to 8.7% in the average accuracy over ten runs for a specific test subject in a holdout experiment.


Timing of renal replacement therapy in critically ill patients with acute kidney injury.
Timing of renal replacement therapy in critically ill patients with acute kidney injury is highly subjective, and may influence outcome. We discuss renal and nonrenal criteria for timing considering the recent literature. Two randomized and four nonrandomized controlled trials investigated the effects of timing on patient outcome. All but one randomized controlled trial indicated better outcome with early renal replacement therapy but had poor methodological quality. The heterogeneity of timing definition, study population and mode of therapy, however, hampered comparison among studies. In the absence of large randomized controlled trials we can make no firm recommendations for timing of renal replacement therapy in acute kidney injury. Since rapid recovery of renal function is unlikely when other organ failure persists and the consequences of acute kidney injury may be more severe in critically ill patients, we suggest other organ failure is also considered. Patients with acute kidney injury, persisting shock and poorly recovering functions of other organs may benefit from early therapy. For future studies, we recommend describing renal replacement therapy timing according to the 'RIFLE' classification, as modified by the Acute Kidney Injury Network, and quantifying the severity of other organ failure. Biomarkers may refine acute kidney injury and timing definitions in the future.


Structures of Pathogenic Fungal FKBP12s Reveal Possible Self-Catalysis Function.
Invasive fungal infections remain difficult to treat and require novel targeting strategies. The 12-kDa FK506-binding protein (FKBP12) is a ubiquitously expressed peptidyl-prolyl isomerase with considerable homology between fungal pathogens and is thus a prime candidate for future targeting efforts to generate a panfungal strategy. Despite decades of research on FKBPs, their substrates and mechanisms of action remain unclear. Here we describe structural, biochemical, and in vivo analyses of FKBP12s from the pathogenic fungi Candida albicans, Candida glabrata, and Aspergillus fumigatus Strikingly, multiple apo A. fumigatus and C. albicans FKBP12 crystal structures revealed a symmetric, intermolecular interaction involving the deep insertion of an active-site loop proline into the active-site pocket of an adjacent subunit. Such interactions have not been observed in previous FKBP structures. This finding indicates the possibility that this is a self-substrate interaction unique to the A. fumigatus and C. albicans fungal proteins that contain this central proline. Structures obtained with the proline in the cis and trans states provide more data in support of self-catalysis. Moreover, cysteine cross-linking experiments captured the interacting dimer, supporting the idea that it forms in solution. Finally, genetic studies exploring the impact of mutations altering the central proline and an adjacent residue provide evidence that any dimeric state formed in vivo, where FKBP12 concentrations are low, is transient. Taken together, these findings suggest a unique mechanism of self-substrate regulation by fungal FKBP12s, lending further novel understanding of this protein for future drug-targeting efforts. FKBP12 is a cis-trans peptidyl-prolyl isomerase that plays key roles in cellular protein homeostasis. FKBP12s also bind the immunosuppressive drug FK506 to inhibit the phosphatase calcineurin (CaN). CaN is required for virulence of A. fumigatus, C. albicans, C. glabrata, and other deadly fungal pathogens, marking FKBP12 and CaN as potential broad-spectrum drug targets. Here we describe structures of fungal FKBP12s. Multiple apo A. fumigatus and C. albicans FKBP12 structures reveal the insertion of a proline, conspicuously conserved in these proteins, into the active sites of adjacent molecules. This suggests that these proteins might serve as their own substrates. Cysteine disulfide trapping experiments provide support for this self-interaction and hence possible intermolecular catalysis by these enzymes.


Participation and detection rates by age and sex for colonoscopy versus fecal immunochemical testing in colorectal cancer screening.
To compare two strategies for colorectal cancer screening: one-time colonoscopy versus fecal immunochemical testing (FIT) (and colonoscopy for positive) every 2 years, in order to determine which strategy provides the highest participation and detection rates in groups of sex and age. This analysis was performed with data from the first screening round within the COLONPREV study, a population-based, multicenter, nationwide trial carried out in Spain. Several logistic regression models were applied to identify the influence of the screening test on participation rates and detection of proximal and distal neoplasms, as well to identify the influence of age and sex: women aged 50-59 years, women aged 60-69 years, men aged 50-59 years, and men aged 60-69 years. Participation was higher in women than in men, especially among women aged 50-59 years (25.91 % for colonoscopy and 35.81 % for FIT). Crossover from colonoscopy to FIT was higher among women than men, especially among those aged 60-69 years (30.37 %). In general, detection of any neoplasm and advanced adenoma was higher with colonoscopy than with FIT, but no significant differences were found between the two strategies for colorectal cancer detection. Detection of advanced adenoma in both arms was lower in women [specifically in women aged 50-59 years (OR 0.31; 95 % CI 0.25-0.38) than in men aged 60-69 years]. Women aged 50-59 years in the colonoscopy arm had a higher probability of detection of advanced adenoma (OR 4.49; 95 % CI 3.18-6.35), as well as of detection of neoplasms in proximal and distal locations (proximal OR 19.34; 95 % CI 12.07-31.00; distal OR 11.04; 95 % CI 8.13-15.01) than women of the same age in the FIT arm. These differences were also observed in the remaining groups but to a lesser extent. Women were more likely to participate in a FIT-based strategy, especially those aged 50-59 years. The likelihood of detection of any neoplasm was higher in the colonoscopy arm for all the population groups studied, especially in women aged 50-59 years. Distinct population groups should be informed of the benefits of each screening strategy so that they may take informed decisions.


Group 4 dimethylsilylenebisamido complexes bearing the 6-[2-(diethylboryl)phenyl]pyrid-2-yl motif: synthesis and use in tandem ring-opening metathesis/vinyl-insertion copolymerization of cyclic olefins with ethylene.
Two novel Zr(IV)- and Hf(IV)-based bisamido complexes bearing the 6-[2-(diethylboryl)phenyl]pyrid-2-yl motif, that is, [ZrCl(2){Me(2)Si(DbppN)(2)}(thf)] (9) and [HfCl(2){Me(2)Si(DbppN)(2)}(thf)(2)] (10) (DbppN=6-[2-(diethylboryl)phenyl]pyridine-2-amido) have been prepared. Their reactivities have been compared with that of a model precatalyst that does not bear the aminoborane motif. Upon activation with methylalumoxane, precatalysts 9 and 10 are active in the homopolymerization of ethylene (E) yielding high-density polyethylene (HDPE). In the copolymerization of E with cyclopentene (CPE), for example by the action of 9, the presence of CPE resulted in a dramatic increase in the polymerization activity of E, while CPE incorporation remained close to or at zero. In the vinyl-insertion copolymerization of norborn-2-ene (NBE) with E by the action of 9, statistical cyclic olefin copolymers of these two monomers were obtained. At higher NBE concentrations, however, 9 gave rise to reversible ring-opening metathesis (ROMP)/vinyl-insertion polymerization (VIP) of NBE with E, resulting in the formation of multi-block copolymers of the general formula poly(NBE)(ROMP)-co-poly(NBE)(VIP)-co-poly(E). This particular feature of precatalyst 9, that is, the ability to induce a reversible α-H elimination/α-H addition reaction, is attributed to the unique role of the 6-[2-(diethylboryl)phenyl]pyrid-2-yl ligand. Accordingly, a model precatalyst lacking this ligand does not have the ability to induce α-H elimination/α-H addition reactions. The different (11)B NMR shifts of various diethylborylphenylpyrid-2-ylamines and -amides permit a ranking of the strengths of the B-N bonds in these compounds. This strength of the B-N bond is correlated with the propensity of 9/MAO to produce poly(NBE)(ROMP)-co-poly(NBE)(VIP)-co-poly(E) at different temperatures.


Regulation and order of involvement of molybdoproteins during synthesis of molybdoenzymes in Clostridium pasteurianum.
The accumulation of 99Mo (from 99MoO4(2-) into molybdenum-containing species in Clostridium pasteurianum was investigated to identify the molybdoprotein(s) involved in Mo metabolism. Mo accumulation by clostridial cells during the derepression of the nitrogenase system increased substantially beginning 1.5 h before nitrogenase activity was detected. The increase in Mo accumulation by the cells is a result of the incorporation of Mo into a high-molecular-weight molybdenum species (suspected membrane fragments), a low-molecular-weight molybdenum species, a Mo binding-storage protein, a 30-kilodalton molybdoprotein, and formate dehydrogenase. Mo incorporation into the MoFe protein was detected 1 h after the onset of metal uptake. Kinetics of Mo accumulation into the molybdoproteins during the derepression of nitrogenase suggests that Mo incorporation or uptake or both occur in the following sequence: (i) membranes and MoO4(2-), (ii) a low-molecular-weight molybdenum species, (iii) Mo binding-storage protein and a 30-kilodalton molybdoprotein, (iv) formate dehydrogenase, and (v) the MoFe protein. The intracellular level of all molybdenum components except the MoFe protein appears to be influenced by the availability of Mo. Clostridial cells grown in the presence of a limiting amount of Mo became Mo deficient as a result of growth and a MoO4(2-) supplement added to such cells rapidly accumulated within the cells to levels five times that found in steady-state nitrogen-fixing cells. The Mo accumulated by the Mo-deficient cells was rapidly incorporated into preformed demolybdoproteins in the absence of de novo protein synthesis. The increase in Mo accumulation by Mo-deficient cells was a result of an increase in all molybdoproteins except the MoFe protein.


[The health problems of computer operators].
The data presented demonstrate that quality of PCs and protective filters is sometimes inadequate. Electric puncture examination was conducted to assess functional state of PC operators before and after the work and of other specialists working in the same conditions without exposure to radiation. Finding is that share of individuals with functional vascular disorders of breast and brain increases annually with constant work at PC.


Relationship between hexokinase and cytokinin in the regulation of leaf senescence and seed germination.
Arabidopsis hexokinase (AtHXK1), an enzyme that catalyses hexose phosphorylation, accelerates leaf senescence, whereas the plant hormone cytokinin inhibits senescence. Previous work in our laboratory has shown that isopentenyl transferase (IPT), a key gene in the biosynthesis of cytokinin, expressed under promoters of the senescence-associated genes SAG12 or SAG13 (P(SAG12)::IPT and P(SAG13)::IPT, respectively), inhibits leaf senescence in tomato plants. To study the relationship between hexokinase and cytokinin in the regulation of leaf senescence, we created and analysed double-transgenic tomato plants expressing both AtHXK1 and either P(SAG12)::IPT or P(SAG13)::IPT. We found that expression of IPT in the double-transgenic plants could not prevent the accelerated senescence induced by over-expression of AtHXK1. Since cytokinin inhibits senescence via an apoplastic invertase that produces extracellular hexoses, whereas AtHXK1 is an intracellular mitochondria-associated hexokinase, our results suggest that intracellular sugar sensing via AtHXK1 is dominant over extracellular sugar sensing with regard to leaf senescence. Interestingly, the heterologous SAG12 and SAG13 promoters are also expressed in germinating tomato seed, around the radicle penetration zone, suggesting that seed germination involves a senescence process that is probably necessary for radicle emergence. Indeed, seed expressing P(SAG12)::IPT and P(SAG13)::IPT exhibited delayed radicle emergence, possibly due to delayed endosperm senescence.


[Chromosome aberrations in the cells of monkeys that have undergone acute irradiation with the use of chemical protection].
The rate and type of chromosomal aberrations in the bone marrow cells and circulating lymphocytes of the gamma-irradiated monkeys prophylactically treated with cystamine and mexamine 5-10 minutes before the irradiation was studied. The number of chromosomal aberrations 9-10 years after the gamma-irradiation (600-650 r) of the protected monkeys was similar to that in the animals irradiated without protection. Symmetrical chromosomal changes were most freuqent in all the monkeys long after the irradition, including the animals treated with radioprotectors.


Dietary metabolites derived from gut microbiota: critical modulators of epigenetic changes in mammals.
The mammalian gastrointestinal tract harbors trillions of commensal microorganisms, collectively known as the microbiota. The microbiota is a critical source of environmental stimuli and, thus, has a tremendous impact on the health of the host. The microbes within the microbiota regulate homeostasis within the gut, and any alteration in their composition can lead to disorders that include inflammatory bowel disease, allergy, autoimmune disease, diabetes, mental disorders, and cancer. Hence, restoration of the gut flora following changes or imbalance is imperative for the host. The low-molecular-weight compounds and nutrients such as short-chain fatty acids, polyamines, polyphenols, and vitamins produced by microbial metabolism of nondigestible food components in the gut actively participate in various epigenomic mechanisms that reprogram the genome by altering the transcriptional machinery of a cell in response to environmental stimuli. These epigenetic modifications are caused by a set of highly dynamic enzymes, notably histone acetylases, deacetylases, DNA methylases, and demethylases, that are influenced by microbial metabolites and other environmental cues. Recent studies have shown that host expression of histone acetylases and histone deacetylases is important for regulating communication between the intestinal microbiota and the host cells. Histone acetylases and deacetylases influence the molecular expression of genes that affect not only physiological functions but also behavioral shifts that occur via neuroepigenetic modifications of genes. The underlying molecular mechanisms, however, have yet to be fully elucidated and thus provide a new area of research. The present review provides insights into the current understanding of the microbiota and its association with mammalian epigenomics as well as the interaction of pathogens and probiotics with host epigenetic machinery.


The prevalence of isolated calf deep vein thrombosis in patients with pulmonary embolism.
Due to discordant results, the risk of isolated calf deep vein thrombosis (DVT) -associated pulmonary embolism (PE) is not well established. This study aimed to detect the prevalence of isolated calf DVT in patients with PE, discussing the importance of isolated calf DVT. We retrospectively reviewed all the inpatients that were both diagnosed PE and DVT between November 2002 and February 2010 in our hospital, analyzed the prevalence of isolated calf DVT and the relevance details. Among all the 63 patients who were diagnosed both PE and DVT, isolated calf DVT was detected in 23 limbs in 16 patients (16/63=25.4%). Soleal vein was the most frequently involved, with 14 limbs. Ten of the patients had low risk PE, 3 had submassive PE and 3 had massive PE. In the 6 patient who had submassive and massive PE, 4 had bilateral leg calf DVT and all 6 were multiple calf vein involvement. Our results reflected the prevalence of PE at presentation, which was high and included severe cases. Though, as reported, PE during surveillance was the most precisely way to reflect PE in isolated calf DVT, but such a risk of PE at presentation should not just be ignored and its importance still needs to be discussed. Well-designed and adequately powered studies are needed to give strong evidence to recognize the real risk of isolated calf DVT, either at presentation or at surveillance, to distinguish the one with high risk and determine appropriate way to treat it.


Human biases limit cumulative innovation.
Is technological advancement constrained by biases in human cognition? People in all societies build on discoveries inherited from previous generations, leading to cumulative innovation. However, biases in human learning and memory may influence the process of knowledge transmission, potentially limiting this process. Here, we show that cumulative innovation in a continuous optimization problem is systematically constrained by human biases. In a large (n = 1250) behavioural study using a transmission chain design, participants searched for virtual technologies in one of four environments after inheriting a solution from previous generations. Participants converged on worse solutions in environments misaligned with their biases. These results substantiate a mathematical model of cumulative innovation in Bayesian agents, highlighting formal relationships between cultural evolution and distributed stochastic optimization. Our findings provide experimental evidence that human biases can limit the advancement of knowledge in a controlled laboratory setting, reinforcing concerns about bias in creative, scientific and educational contexts.


Cav 2.3 (R-type) calcium channels are critical for mediating anticonvulsive and neuroprotective properties of lamotrigine in vivo.
Lamotrigine (LTG) is a popular modern antiepileptic drug (AED); however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav 2.3 (R-type) calcium currents, which contribute to kainic-acid (KA)-induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to two other AEDs in Cav 2.3-deficient mice and controls on KA-induced seizures. Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg (and 30 mg/kg) KA. One hour before KA injection, mice were pretreated with 30 mg/kg LTG, 50 mg/kg topiramate (TPM), or 30 mg/kg lacosamide (LSM). Ablation of Cav 2.3 reduced total seizure scores by 28.6% (p = 0.0012), and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p = 0.02). In Cav 2.3-deficient mice, LTG pretreatment increased seizure activity by 22.1% (p = 0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p = 0.02). All three AEDs reduced seizure activity in control mice; however, only the non-calcium channel modulating AED, LSM, had an anticonvulsive effect in Cav 2.3-deficient mice. Furthermore, LTG altered electrocorticographic parameters differently in the two genotypes: decreasing relative power of ictal spikes in control mice but increasing relative power of high frequency fast ripple discharges during seizures in Cav 2.3-deficient mice. These findings provided the first in vivo evidence for an essential role for Cav 2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav 2.3-deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA1. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation observed in clinical practice.


The effect of probiotics on Helicobacter pylori eradication.
Conflicting results have been reported on the effect of a variety of probiotic strains on Helicobacter pylori (HP) eradication. In this study, we evaluated the outcome of a probiotic strain composed of bacillus subtilis and Streptococcus faecium on HP eradication. We recruited 352 HP infected patients who were randomized into a triple-plus-probiotics group or a triple-only group; the participants received 1 week of PPI-based triple therapy with or without probiotics supplements. For the triple-plus-probiotics group, probiotics was continued for 8 weeks. All patients in the two groups were evaluated for 4 weeks after completion of therapy. Using the intention to treat analysis, evaluation of the triple-plus-probiotics group showed a higher eradication rate than the triple-only group (83.5% vs. 73.3%, p=0.027). Diarrhea and overall side effects were more common in the triple-only group (p<0.05). Supplementation with probiotic strains, composed of Bacillus subtilis and Streptococcus faecium, were shown to improve drug compliance, reduce side effects and enhance the intention-to-treat eradication rate of HP.


What's in a name? A naming convention for geomorphic river types using the River Styles Framework.
Meaningful iteration between place-based knowledge of rivers and generalised, theoretically-framed understandings is a significant challenge in river science and management. How can we communicate knowledge of the inherent complexity of river systems in light of managerial quests for simple, easy-to-apply frameworks that can be used by a wide range of practitioners, such that we can meaningfully transfer experiences in river science and management from one situation to another? Identification, definition, classification and naming are vital parts of this process. In a sense, a name is like a 'brand', for which a consistency of product is expected. The River Styles Framework is a flexible, open-ended approach to river science and management. The Framework applies a set of hierarchical principles to differentiate reaches, interpret their process-based behaviour and examine interactions between patterns of reaches at the catchment scale. Here we outline an evolution and tightening of the Framework to better communicate how to identify and name types of river at the reach scale. Like the River Styles Framework itself, the naming convention applies hierarchical procedures, starting at the valley setting scale, and incorporating analyses of river planform, channel and floodplain landforms (geomorphic units) and bed material texture. Using a series of examples from around the world, we show how this naming convention can be applied to name river reaches and can be adapted to particular purposes in a consistent, readily communicable manner. We outline various challenges that are faced in managing the use of such a naming convention.


The helminth community of the sand smelt (Atherina boyeri Risso, 1810) from Lake Iznik, Turkey.
Metazoan parasites of the sand smelt Atherina boyeri Risso, 1810 in Lake Iznik were studied. A total of 271 specimens of A. boyeri, 208 female and 63 male, mean ( ± SD) total length 8.4 ± 2.2 cm (range 3.1-12.2 cm) and mean total weight 4.7 ± 3.5 g (range 0.1-11.7 g) were examined between June 2008 and May 2009 at monthly intervals. In 33 fish no parasites were found. In the other fish, four parasite species were recorded: Diplostomum sp. (prevalence 39.13%, mean intensity 3.50 ± 3.03); Tylodelphys clavata (prevalence 74.16%, mean intensity 10.41 ± 14.89); Bothriocephalus cf. acheilognathi (prevalence 40.59%, mean intensity 31.83 ± 57.74); and Eustrongylides excisus (prevalence 6.64%, mean intensity 1.16 ± 0.39). The mean abundance of Diplostomum sp., T. clavata and E. excisus was higher during the winter and early spring months. In contrast, the mean abundance of B. cf. acheilognathi was higher in the summer and autumn months. This distribution of the parasites was related to a change in the environment of A. boyeri from the pelagic zone to deeper water at the end of autumn and a change in food supply.


Estrogen oversees the maintenance of the female genetic program in terminally differentiated gonochorists.
The sexual plasticity of the gonads is not retained after the completion of sex differentiation in vertebrates, except in some hermaphroditic species. Here, we report that the depletion of estradiol-17β (E2) by aromatase inhibitors (AI) for up to six months resulted in a functional female-to-male sex reversal in sexually-mature adults of two gonochoristic fish species, Nile tilapia and medaka. The sex-reversed fish showed a typical male pattern of E2 and androgen levels, secondary sexual characteristics, and male-like sex behavior, producing fertile sperm. Conversely, co-treatment of E2 inhibited AI-induced sex reversal. In situ hybridization of medaka gonads during AI-induced sex reversal indicated that cysts on the dorsal side of the adult ovaries are the origin of germ cells and Sertoli cells in the newly formed testicular tissue. Gonochoristic fish maintain their sexual plasticity until adulthood and E2 plays a critical role in maintaining the female phenotype.


[Echography in focal non-steatosis of the liver; diagnostic problems].
After a brief review of different patterns of steatosis of the liver three patients with focal non-steatosis are presented in whom the sonographic aspects were confused with neoplastic liver processes. CT established the diagnosis of focal non-steatosis in all three patients and liver biopsy in one. If in a steatotic liver one or more focal relatively echo-poor lesions are detected on ultrasonography, CT and (or) biopsy should be considered for definitive diagnosis.


Dynamics and structure of colloidal aggregates under microchannel flow.
The kinetics of colloidal gels under narrow confinement are of widespread practical relevance, with applications ranging from flow in biological systems to 3D printing. Although the properties of such gels under uniform shear have received considerable attention, the effects of strongly nonuniform shear are far less understood. Motivated by the possibilities offered by recent advances in nano- and microfluidics, we explore the generic phase behavior and dynamics of attractive colloids subject to microchannel flow, using mesoscale particle-based hydrodynamic simulations. Whereas moderate shear strengths result in shear-assisted crystallization, high shear strengths overwhelm the attractions and lead to melting of the clusters. Within the transition region between these two regimes, we discover remarkable dynamics of the colloidal aggregates. Shear-induced surface melting of the aggregates, in conjunction with the Plateau-Rayleigh instability and size-dependent cluster velocities, leads to a cyclic process in which elongated threads of colloidal aggregates break up and reform, resulting in large crystallites. These insights offer new possibilities for the control of colloidal dynamics and aggregation under confinement.


Characterization of the novel factor paa involved in the early steps of the adhesion mechanism of attaching and effacing Escherichia coli.
Nonenterotoxigenic porcine Escherichia coli strains belonging to the serogroup O45 have been associated with postweaning diarrhea in swine and adhere to intestinal epithelial cells in a characteristic attaching and effacing (A/E) pattern. O45 porcine enteropathogenic E. coli (PEPEC) strain 86-1390 induces typical A/E lesions in a pig ileal explant model. Using TnphoA transposon insertion mutagenesis on strain 86-1390, we found a mutant that did not induce A/E lesions. The insertion was identified in a gene designated paa (porcine A/E-associated gene). Sequence analysis of paa revealed an open reading frame of 753 bp encoding a 27.6-kDa protein which displayed 100, 51.8, and 49% homology with Paa of enterohemorrhagic E. coli O157:H7 strains (EDL933 and Sakai), PEB3 of Campylobacter jejuni, and AcfC of Vibrio cholerae, respectively. Chromosomal localization studies indicated that the region containing paa was inserted between the yciD and yciE genes at about 28.3 min of the E. coli K-12 chromosome. The presence of paa and eae sequences in the porcine O45 strains is highly correlated with the A/E phenotype. However, the observation that three eae-positive but paa-negative PEPEC O45 strains were A/E negative provides further evidence for the importance of the paa gene in the A/E activity of O45 strains. As well, the complementation of the paa mutant restored the A/E activity of the 86-1390 strain, showing the involvement of Paa in PEPEC pathogenicity. These observations suggest that Paa contributes to the early stages of A/E E. coli virulence.


[The so-called metastasizing thyroid adenoma from the orthopaedic viewpoint (author's transl)].
The so-called metastasizing thyroid adenomas, which are now know as follicular thyroid carcinomas, present diagnostic problems again and again on account of their high degree of differentiation, since the primary tumour is often recognized as malignoma only after metastases have put in their appearance in other parts of the body. In this article, the authors report on a case of a follicular thyroid carcinoma which became manifest via a tumour of the size of an infant's head at the right upper part of the ilium.


Crystal Structure of l-2,4-Diketo-3-deoxyrhamnonate Hydrolase Involved in the Nonphosphorylated l-Rhamnose Pathway from Bacteria.
2,4-Diketo-3-deoxy-l-rhamnonate (L-DKDR) hydrolase (LRA6) catalyzes the hydrolysis reaction of L-DKDR to pyruvate and l-lactate in the nonphosphorylated l-rhamnose pathway from bacteria and belongs to the fumarylacetoacetate hydrolase (FAH) superfamily. Most of the members of the FAH superfamily are involved in the microbial degradation of aromatic substances and share low sequence similarities with LRA6, by which the underlying catalytic mechanism remains unknown at the atomic level. We herein elucidated for the first time the crystal structures of LRA6 from Sphingomonas sp. without a ligand and in complex with pyruvate, in which a magnesium ion was coordinated with three acidic residues in the catalytic center. Structural, biochemical, and phylogenetic analyses suggested that LRA6 is a close but distinct subfamily of the fumarylpyruvate hydrolase (FPH) subfamily, and amino acid residues at equivalent position to 84 in LRA6 are related to different substrate specificities between them (Leu84 and Arg86 in LRA6 and FPH, respectively). Structural transition induced upon the binding of pyruvate was observed within a lid-like region, by which a glutamate-histidine dyad that is critical for catalysis was arranged sufficiently close to the ligand. Among several hydroxylpyruvates (2,4-diketo-5-hydroxycarboxylates), L-DKDR with a C6 methyl group was the best substrate for LRA6, conforming to the physiological role. Significant activity was also detected in acylpyruvate including acetylpyruvate. The structural analysis presented herein provides a more detailed understanding of the molecular evolution and physiological role of the FAH superfamily enzymes (e.g., the FAH like-enzyme involved in the mammalian l-fucose pathway).


Constitutional de novo and postzygotic mutations in isolated cases of cerebral cavernous malformations.
Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can be found in sporadic or autosomal dominantly inherited forms and manifest with headaches, seizures, and hemorrhagic stroke. The precise proportion of de novo mutations in the CCM1,CCM2, and CCM3 genes remains unknown. We here present a series of six trios with de novo mutations that have been analyzed by amplicon deep sequencing to differentiate between constitutional and postzygotic mutations. In one case, allelic ratios clearly indicated mosaicism for a CCM3 splice site mutation found in blood and buccal mucosa of a 2-year-old boy with multiple CCMs. The remaining five de novo mutations proved to be constitutional. In addition to three CCM3, two CCM1, and one CCM2 de novo point mutations, a deletion of the entire CCM3 gene was identified in an index case that most likely originated from an early postzygotic event. These are the first high-level mosaic mutations reported in blood samples of isolated CCM cases. Our data demonstrate that de novo mutations in CCM1-3 might be more frequent than previously thought. Furthermore, amplicon deep sequencing is useful to discriminate between patients with constitutional and postzygotic mutations, and thereby improves genetic counseling.


Polyamines and hair: a couple in search of perfection.
Polyamines (spermidine, putrescine and spermine) are multifunctional cationic amines that are indispensable for cellular proliferation; of key significance in the growth of rapidly regenerating tissues and tumors. Given that the hair follicle (HF) is one of the most highly proliferative organs in mammalian biology, it is not surprising that polyamines are crucial to HF growth. Indeed, growing (anagen) HFs show the highest activity of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis, while inhibition of ODC, using eflornithine, results in a decreased rate of excessive facial hair growth in vivo and inhibits human scalp hair growth in organ culture. In sheep, manipulation of dietary intake of polyamines also results in altered wool growth. Polyamine-containing nutraceuticals have therefore been proposed as promoters of human hair growth. Recent progress in polyamine research, coupled with renewed interest in the role of polyamines in skin biology, encourages one to revisit their potential roles in HF biology and highlights the need for a systematic evaluation of their mechanisms of action and clinical applications in the treatment of hair disorders. The present viewpoint essay outlines the key frontiers in polyamine-related hair research and defines the major open questions. Moreover, it argues that a renaissance in polyamine research in hair biology, well beyond the inhibition of ODC activity in hirsutism therapy, is important for the development of novel therapeutic strategies for the manipulation of human hair growth. Such targets could include the manipulation of polyamine biosynthesis and the topical administration of selected polyamines, such as spermidine.


Efficacy of open dialogue about complementary and alternative medicine compared with standard care in improving quality of life in patients undergoing conventional oncology treatment (CAMONCO 2): protocol for a randomised controlled trial.
Complementary and alternative medicine (CAM) has been shown to reduce symptoms and adverse effects and improve quality of life of patients undergoing conventional oncology treatment, but CAM might also cause symptoms and adverse effects such as headache and fatigue. Thus, patients need guidance towards safe and healthy use of CAM. According to published results, open dialogue about CAM (OD-CAM) between health professionals and patients as an integral part of anticancer treatment may improve patients' quality of life and well-being. Since the literature on the issue is sparse, the aim of this study is to assess the efficacy of OD-CAM integrated early in conventional oncology treatment versus standard care (SC) in patients undergoing standard anticancer treatment. The study is a randomised controlled trial, being conducted at an oncology outpatient clinic in Denmark. 207 patients undergoing curative or palliative oncology treatment for breast, gynaecological, prostate, pulmonary, colorectal, anal or pancreatic cancer will be randomly assigned to SC with or without OD-CAM. A nurse specialist will facilitate the OD-CAM in one or two sessions. The primary endpoint is patient reported quality of life in relation to psychological well-being 8 weeks after enrollment. Secondary endpoints are patient reported level of depression and anxiety, top concerns, and decision regret 8, 12 and 24 weeks after enrolment, and overall survival. According to the Committee on Health Research Ethics for Southern Denmark, ethics approval of this study is not required (S-20202000-5, 20/1019). The Region of Southern Denmark (Journal no. 20/11100) approved the storing and handling of data. Participants' informed consent will be obtained before inclusion and randomisation. The results of the study, whether positive, negative or inconclusive, will be disseminated through open-access, peer-reviewed publications, stake-holder-reporting and presentations at relevant conferences. NCT04299451.


Sex differences in kidney gene expression during the life cycle of F344 rats.
The kidney functions in key physiological processes to filter blood and regulate blood pressure via key molecular transporters and ion channels. Sex-specific differences have been observed in renal disease incidence and progression, as well as acute kidney injury in response to certain drugs. Although advances have been made in characterizing the molecular components involved in various kidney functions, the molecular mechanisms responsible for sex differences are not well understood. We hypothesized that the basal expression levels of genes involved in various kidney functions throughout the life cycle will influence sex-specific susceptibilities to adverse renal events. Whole genome microarray gene expression analysis was performed on kidney samples collected from untreated male and female Fischer 344 (F344) rats at eight age groups between 2 and 104 weeks of age. A combined filtering approach using statistical (ANOVA or pairwise t test, FDR 0.05) and fold-change criteria (>1.5 relative fold change) was used to identify 7,447 unique differentially expressed genes (DEGs). Principal component analysis (PCA) of the 7,447 DEGs revealed sex-related differences in mRNA expression at early (2 weeks), middle (8, 15, and 21 weeks), and late (104 weeks) ages in the rat life cycle. Functional analysis (Ingenuity Pathway Analysis) of these sex-different genes indicated over-representation of specific pathways and networks including renal tubule injury, drug metabolism, and immune cell and inflammatory responses. The mRNAs that code for the qualified urinary protein kidney biomarkers KIM-1, Clu, Tff3, and Lcn2 were also observed to show sex differences. These data represent one of the most comprehensive in-life time course studies to be published, assessing sex differences in global gene expression in the F344 rat kidney. PCA and Venn analyses reveal specific periods of sexually dimorphic gene expression which are associated with functional categories (xenobiotic metabolism and immune cell and inflammatory responses) of key relevance to acute kidney injury and chronic kidney disease, which may underlie sex-specific susceptibility. Analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.


[Uncalibrated Positioning Method for Puncture Robots Based on Optical Navigation].
Robotic puncture system has been widely used in modern minimally invasive surgery, which usually uses hand-eye calibration to calculate the spatial relationship between the robot and the optical tracking system. However, the hand-eye calibration process is time-consuming and sensitive to environmental changes, which makes it difficult to guarantee the puncture accuracy of the robot. This study proposes an uncalibrated positioning method for puncture robot based on optical navigation. The method divides the target path positioning into two stages, angle positioning and position positioning, and designs angle image features and position image features respectively. The corresponding image Jacobian matrix is constructed based on the image features and updated by online estimation with a cubature Kalman filter to drive the robot to perform target path localization. The target path positioning results show that the method is more accurate than the traditional hand-eye calibration method and saves significant preoperative preparation time by eliminating the need for calibration.


Diverse phenotype of hypokalaemic periodic paralysis within a family.
Hypokalaemic periodic paralysis typically presents with intermittent mild-to-moderate weakness lasting hours to days. We report a case with an uncommon phenotype of late-onset myopathy without episodic paralytic attacks. Initial work-up including muscle biopsy was inconclusive. A subsequent review of the right deltoid biopsy, long exercise testing and repeated family history was helpful, followed by appropriate genetic testing. We identified a heterozygous pathogenic mutation in calcium ion channel (CACNA1S:c.1583G>A p.Arg528His) causing hypokalaemic periodic paralysis. Myopathy can present without episodic paralysis and the frequency of paralytic episodes does not correlate well with the development and progression of a fixed myopathy. Our report also highlights the intrafamilial phenotypic variation of hypokalaemic periodic paralysis secondary to a CACNA1S gene mutation.


Validity of the Stanford-Binet Intelligence Scale-IV: its use in young adults with mental retardation.
The validity of the Stanford Binet-IV (SB-IV) was assessed. This test and the WAIS-R and WRAT-R were administered to 42 adults previously classified with mild to moderate mental retardation. Validity coefficients between scores on the SB-IV and the other two measures were significant. The mean IQ on the SB-IV (mean Test Composite = 43.26) was significantly lower than that on the Wechsler Adult Intelligence Scale-Revised--WAIS-R (mean Full-Scale IQ = 57.91). With regard to the internal validity of the SB-IV, the intersubtest relationships of each of the four Area scores correlated significantly with the Test Composite (range = .66 to .91). Verbal Reasoning earned the highest correlation (.91). Results support the SB-IV's concurrent, criterion-related, and internal validity for use with young adults who have mental retardation.


Environmental constraints influencing survival of an African parasite in a north temperate habitat: effects of temperature on egg development.
Factors affecting survival of parasites introduced to new geographical regions include changes in environmental temperature. Protopolystoma xenopodis is a monogenean introduced with the amphibian Xenopus laevis from South Africa to Wales (probably in the 1960s) where low water temperatures impose major constraints on life-cycle processes. Effects were quantified by maintenance of eggs from infections in Wales under controlled conditions at 10, 12, 15, 18, 20 and 25°C. The threshold for egg viability/ development was 15°C. Mean times to hatching were 22 days at 25°C, 32 days at 20°C, extending to 66 days at 15°C. Field temperature records provided calibration of transmission schedules. Although egg production continues year-round, all eggs produced during >8 months/ year die without hatching. Output contributing significantly to transmission is restricted to 10 weeks (May-mid-July). Host infection, beginning after a time lag of 8 weeks for egg development, is also restricted to 10 weeks (July-September). Habitat temperatures (mean 15·5°C in summer 2008) allow only a narrow margin for life-cycle progress: even small temperature increases, predicted with 'global warming', enhance infection. This system provides empirical data on the metrics of transmission permitting long-term persistence of isolated parasite populations in limiting environments.


Supplemental parenteral nutrition in critically ill patients: a study protocol for a phase II randomised controlled trial.
Nutrition is one of the fundamentals of care provided to critically ill adults. The volume of enteral nutrition received, however, is often much less than prescribed due to multiple functional and process issues. To deliver the prescribed volume and correct the energy deficit associated with enteral nutrition alone, parenteral nutrition can be used in combination (termed "supplemental parenteral nutrition"), but benefits of this method have not been firmly established. A multi-centre, randomised, clinical trial is currently underway to determine if prescribed energy requirements can be provided to critically ill patients by using a supplemental parenteral nutrition strategy in the critically ill. This prospective, multi-centre, randomised, stratified, parallel-group, controlled, phase II trial aims to determine whether a supplemental parenteral nutrition strategy will reliably and safely increase energy intake when compared to usual care. The study will be conducted for 100 critically ill adults with at least one organ system failure and evidence of insufficient enteral intake from six intensive care units in Australia and New Zealand. Enrolled patients will be allocated to either a supplemental parenteral nutrition strategy for 7 days post randomisation or to usual care with enteral nutrition. The primary outcome will be the average energy amount delivered from nutrition therapy over the first 7 days of the study period. Secondary outcomes include protein delivery for 7 days post randomisation; total energy and protein delivery, antibiotic use and organ failure rates (up to 28 days); duration of ventilation, length of intensive care unit and hospital stay. At both intensive care unit and hospital discharge strength and health-related quality of life assessments will be undertaken. Study participants will be followed up for health-related quality of life, resource utilisation and survival at 90 and 180 days post randomisation (unless death occurs first). This trial aims to determine if provision of a supplemental parenteral nutrition strategy to critically ill adults will increase energy intake compared to usual care in Australia and New Zealand. Trial outcomes will guide development of a subsequent larger randomised controlled trial. NCT01847534 (First registered 5 February 2013, last updated 14 October 2015).


Tailoring a coherent control solution landscape by linear transforms of spectral phase basis.
Finding an optimal phase pattern in a multidimensional solution landscape becomes easier and faster if local optima are suppressed and contour lines are tailored towards closed convex patterns. Using wideband second harmonic generation as a coherent control test case, we show that a linear combination of spectral phase basis functions can result in such improvements and also in separable phase terms, each of which can be found independently. The improved shapes are attributed to a suppressed nonlinear shear, changing the relative orientation of contour lines. The first order approximation of the process shows a simple relation between input and output phase profiles, useful for pulse shaping at ultraviolet wavelengths.


Biogas from waste materials as transportation fuel-benefits from an environmental point of view.
In this paper various biogas systems based on waste materials have been analysed from an environmental point of view. The analyses are based on Swedish conditions using a systems analysis approach from an energy and life cycle perspective. The biogas produced is used as a transportation fuel replacing petrol in light-duty vehicles. The overall aims are to quantify the potential environmental effects when current waste handling and transportation fuel systems are replaced. A general conclusion is that the indirect environmental benefits (e.g. reduced emissions of ammonia and methane, and nitrogen leaching) from altered handling of organic waste materials and land-use may often significantly exceed the direct environmental benefits achieved when biogas replaces petrol (e.g. reduced emissions of carbon dioxide and air pollutants). Such indirect benefits are seldom considered when biogas is evaluated from an environmental point of view. However, the environmental impact from different biogas systems can vary significantly due to factors such as the waste materials utilised, different reference systems being replaced, and local conditions.


Quantitation of immunoglobulin-bearing lymphocytes and the lymphocyte response to PHA in experimental pyelonephritis.
In these experiments the effect of experimental pyelonephritis on the distri-ution of B lymphocytes in the peripheral blood and lymphoid sites in the rat has been determined and the functional capacity of T cells during the course of infection has been investigated. The studies have shown that renal infection affects the distribution of lymphocytes and has a marked effect on the functional capacity of splenic T lymphocytes early in infection. Most of the lymphocytes forming the round cell infiltrate in the kidney have been identified as thymus-derived lymphocytes on their surface labelling characteristics. Evidence is presented to demonstrate the inability of T lymphocytes to function normally in the environment of the kdiney. It is suggested that ablation of cell-mediated immunity may be a factor contributing to the persistence of renal infection.


Modification of the rapid fermentation test for Neisseria gonorrhoeae.
A modification of the rapid sugar fermentation procedure has been developed because of difficulties encountered in reproducing the reported results. Changes in the method have made the test more sensitive and reproducible.


Impaired expression of noncollagenous bone matrix protein mRNAs during fracture healing in ascorbic acid-deficient rats.
In scorbutic patients, fractures are slow to heal because of impaired collagen synthesis. To investigate the influence of impaired collagen synthesis on the differentiation and proliferation of osteogenic and chondrogenic cells, we examined the expression of genes encoding bone matrix proteins, including osteonectin (ON), osteopontin (OPN), osteocalcin (OC), and matrix Gla protein (MGP), as differentiation markers for osteogenic and chondrogenic cells during fracture healing in Osteogenic Disorder Shionogi (ODS) rats, which have a hereditary defect in the ability to synthesize ascorbic acid (Asc). In ODS rats without Asc supplementation, intramembranous ossification was completely inhibited. Although a few fibroblast-like cells expressing ON mRNA were observed, no OPN mRNA-expressing cells were detected. During endochondral ossification, a small amount of metachromatic staining cartilage appeared at the fracture site, but there was no provisional calcification zone in the cartilage. Chondrocytes expressed ON and MGP mRNAs, but not OPN mRNA. When Asc was given to these rats, callus formation was soon detected around the fracture site, while OPN mRNA was expressed by differentiated osteoblasts and hypertrophic chondrocytes. Our data indicate that impaired collagen synthesis due to Asc deficiency inhibited the increase of ON and MGP mRNA-expressing cells as well as the appearance of OPN mRNA-expressing cells. Since OPN is considered to play an important role in normal and pathological mineralization, lack of OPN mRNA expression accompanying impaired collagen synthesis may have a role in defective mineralization and delayed fracture healing in scurvy.


Regulation of metformin response by breast cancer associated gene 2.
Adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, has emerged as a promising molecular target in the prevention of breast cancer. Clinical trials using the United States Food and Drug Administration (FDA)-approved, AMPK-activating, antidiabetic drug metformin are promising in this regard, but the question of why metformin is protective for some women but not others still remains. Breast cancer associated gene 2 (BCA2/Rabring7/RNF115), a novel Really Interesting New Gene (RING) finger ubiquitin E3 ligase, is overexpressed in >50% of breast tumors. Herein, we report that BCA2 is an endogenous inhibitor of AMPK activation in breast cancer cells and that BCA2 inhibition increases the efficacy of metformin. BCA2 overexpression inhibited both basal and inducible Thr172 phosphorylation/activation of AMPKα1, while BCA2-specific small interfering RNA (siRNA) enhanced phosphorylated AMPKα1 (pAMPKα1). The AMPK-suppressive function of BCA2 requires its E3 ligase-specific RING domain, suggesting that BCA2 targets some protein controlling (de)phosphorylation of AMPKα1 for degradation. Activation of AMPK by metformin triggered a growth inhibitory signal but also increased BCA2 protein levels, which correlated with AKT activation and could be curbed by an AMPK inhibitor, suggesting a potential feedback mechanism from pAMPKα1 to pAkt to BCA2. Finally, BCA2 siRNA, or inhibition of its upstream stabilizing kinase AKT, increased the growth inhibitory effect of metformin in multiple breast cancer cell lines, supporting the conclusion that BCA2 weakens metformin's efficacy. Our data suggest that metformin in combination with a BCA2 inhibitor may be a more effective breast cancer treatment strategy than metformin alone.


Associations among health behaviors, body mass index, hypertension, and diabetes mellitus: A path analysis.
Hypertension (HTN) and type 2 diabetes are common diseases; however, the effects of health behavior and body mass index (BMI) on their incidence and relationship are unclear. The purpose of this study was to investigate the associations among health behaviors, BMI, HTN, and type 2 diabetes.This study was a secondary data analysis using Korean Longitudinal Study of Aging data between 2010 and 2014 (third and fifth). The sample consisted of 3481 people aged 45 years or older. Path analysis was conducted using the generalized structural equation modeling of STATA 13.1 that enabled analyzing the types of binary variables and logit links.There were 129 underweight, 1714 normal, and 1638 overweight and obese individuals. In underweight and normal groups who had regular meals (B = 0.670, P < .001), BMI was higher. However, for those who were older (B = -0.041, P < .001) and female (B = -0.229, P = .021), BMI was lower. The incidence of HTN increased with age (B = 0.038, P = .001). In addition, the incidence of type 2 diabetes increased with age (B = 0.051, P = .005) and smoking (B = 1.539, P = .001). However, the incidence of type 2 diabetes was lower (B = -1.077, P = .036) for those who had regular meals. In the normal and overweight groups, BMI decreased with age (B = -0.033, P < .001). The incidence of HTN increased with age (B = 0.042, P < .001) and BMI (B = 0.145, P < .001). Moreover, the incidence of type 2 diabetes increased with age (B = 0.046, P < .001), smoking (B = 0.682, P = .020), and higher BMI (B = 0.151, P = .001).In the underweight and normal group, health behaviors were related to BMI. In the normal and overweight group, health behaviors were not related to BMI, but high BMI was related to the incidence of HTN and type 2 diabetes. Smoking has a direct effect on the incidence of type 2 diabetes. Thus, the importance of maintaining an ideal BMI and smoking cessation are highlighted.