Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice.
Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.


Epigenetic regulation of Atoh1 guides hair cell development in the mammalian cochlea.
In the developing cochlea, sensory hair cell differentiation depends on the regulated expression of the bHLH transcription factor Atoh1. In mammals, if hair cells die they do not regenerate, leading to permanent deafness. By contrast, in non-mammalian vertebrates robust regeneration occurs through upregulation of Atoh1 in the surviving supporting cells that surround hair cells, leading to functional recovery. Investigation of crucial transcriptional events in the developing organ of Corti, including those involving Atoh1, has been hampered by limited accessibility to purified populations of the small number of cells present in the inner ear. We used µChIP and qPCR assays of FACS-purified cells to track changes in the epigenetic status of the Atoh1 locus during sensory epithelia development in the mouse. Dynamic changes in the histone modifications H3K4me3/H3K27me3, H3K9ac and H3K9me3 reveal a progression from poised, to active, to repressive marks, correlating with the onset of Atoh1 expression and its subsequent silencing during the perinatal (P1 to P6) period. Inhibition of acetylation blocked the increase in Atoh1 mRNA in nascent hair cells, as well as ongoing hair cell differentiation during embryonic organ of Corti development ex vivo. These results reveal an epigenetic mechanism of Atoh1 regulation underlying hair cell differentiation and subsequent maturation. Interestingly, the H3K4me3/H3K27me3 bivalent chromatin structure observed in progenitors persists at the Atoh1 locus in perinatal supporting cells, suggesting an explanation for the latent capacity of these cells to transdifferentiate into hair cells, and highlighting their potential as therapeutic targets in hair cell regeneration.


Role of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in re-recurrent cervical cancer.
Cervical cancer patients with histologically documented re-recurrence after curative salvage therapy or unexplained tumor marker elevation (negative computed tomography and/or magnetic resonance imaging [CT-MRI]) proven to be a re-recurrence when a further attempt for cure (or control of cancer) appeared feasible were enrolled. Lesion status was determined from pathology or clinical follow-up for at least 12 months. Management decisions were recorded with CT-MRI alone and incorporating [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), respectively. The benefits calculated were based on clinical impact because of the FDG-PET findings. Cox proportional hazards model was used to select independent prognostic covariates. Of the 26 patients who were eligible for analysis, 12 (46.2%) patients had positive impacts due to PET. Squamous cell carcinoma (SCC, P = 0.029), re-recurrence at distant metastasis only (P = 0.012), and level of SCC antigen < or = 4 ng/mL (P = 0.005) were significantly associated with better survival. A scoring system using these covariates defined three distinct prognostic groups (P = 0.0001). Patients with score 0 had a 36-month cumulative survival rate of 80%. Using this prognostic scoring system, FDG-PET may facilitate selecting appropriate management for the individual patient with re-recurrent cervical cancer.


Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin.
Contact hypersensitivity (CHS) is a T cell response to hapten skin challenge of sensitized individuals proposed to be mediated by hapten-primed CD8 cytolytic T cells. Effector CD8 T cell recruitment into hapten challenge sites to elicit CHS requires prior CXCL1- and CXCL2-mediated neutrophil infiltration into the site. We investigated whether neutrophil activities directing hapten-primed CD8 T cell skin infiltration in response to 2,4-dinitro-1-fluorobenzene (DNFB) required Fas ligand (FasL) and perforin expression. Although DNFB sensitization of gld/perforin-/- mice induced hapten-specific CD8 T cells producing IFN-γ and IL-17, these T cells did not infiltrate the DNFB challenge site to elicit CHS but did infiltrate the challenge site and elicit CHS when transferred to hapten-challenged naive wild-type recipients. Hapten-primed wild-type CD8 T cells, however, did not elicit CHS when transferred to naive gld/perforin-/- recipients. Wild-type bone marrow neutrophils expressed FasL and perforin, and when transferred to sensitized gld/perforin-/- mice, they restored hapten-primed CD8 T cell infiltration into the challenge site and CHS. The FasL/perforin-mediated activity of wild-type neutrophils induced the expression of T cell chemoattractants, CCL1, CCL2, and CCL5, within the hapten-challenged skin. These results indicate FasL/perforin-independent functions of hapten-primed CD8 T cells in CHS and identify new functions for neutrophils in regulating effector CD8 T cell recruitment and immune responses in the skin.


Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes.
Apolipoprotein E (apoE) has anti-atherosclerotic properties, being involved in the transport and clearance of cholesterol-rich lipoproteins as well as in cholesterol efflux from cells. We hypothesized that glucocorticoids may exert anti-inflammatory properties by increasing the level of macrophage-derived apoE. Our data showed that glucocorticoids increased apoE expression in macrophages in vitro as well as in vivo. Dexamethasone increased ~6 fold apoE mRNA levels in cultured peritoneal macrophages and RAW 264.7 cells. Administered to C57BL/6J mice, dexamethasone induced a two-fold increase in apoE expression in peritoneal macrophages. By contrast, glucocorticoids did not influence apoE expression in hepatocytes, in vitro and in vivo. Moreover, dexamethasone enhanced apoE promoter transcriptional activity in RAW 264.7 macrophages, but not in HepG2 cells, as tested by transient transfections. Analysis of apoE proximal promoter deletion mutants, complemented by protein-DNA interaction assays demonstrated the functionality of a putative glucocorticoid receptors (GR) binding site predicted by in silico analysis in the -111/-104 region of the human apoE promoter. In hepatocytes, GR can bind to their specific site within apoE promoter but are not able to modulate the gene expression. The modulatory blockade in hepatocytes is a consequence of partial involvement of transcription factors and other signaling molecules activated through MEK1/2 and PLA2/PLC pathways. In conclusion, our study indicates that glucocorticoids (1) differentially target apoE gene expression; (2) induce a significant increase in apoE level specifically in macrophages. The local increase of apoE gene expression in macrophages at the level of the atheromatous plaque may have therapeutic implications in atherosclerosis.


Osteomyelitis in hospitalized children with chickenpox: imaging findings in four cases.
The most common complications of chickenpox are skin and soft-tissue infections. Pneumonia and CNS involvement occur less often, and skeletal complications are considered rare. The purpose of this study was to evaluate the imaging findings of osteomyelitis in children after chickenpox. We retrospectively reviewed the records of children admitted to our institution because of chickenpox and analyzed the imaging findings in those who had skeletal involvement. Ninety-seven patients were admitted between January 1991 and January 1993 because of chickenpox or a complication thereof. Four previously healthy patients, three boys and one girl, between 1 and 6 years old had osteomyelitis. Staphylococcus aureus was isolated from bone in one patient, and group A beta-hemolytic streptococcus was isolated from blood cultures in another. No organism was grown in the other two; necrotic bone was recovered from one lesion and the other healed with periosteal formation of new bone typical of osteomyelitis. All patients were treated with IV antibiotics, and their recoveries were uncomplicated. Conventional radiographs showed loss of fat planes in three patients and destruction of bone in two. Bone scintigraphy showed increased uptake of radionuclide in early and late phases in three patients. Uptake in one case was extensive, with a central area of relatively little uptake corresponding to a subperiosteal fluid collection. CT in two and MR imaging in one showed subperiosteal fluid collections surrounding the involved bones in association with bone and marrow changes. Osteomyelitis was the fourth most common complication of chickenpox in our series. The appearances on conventional radiographs and scintigrams are indistinguishable from those of typical bacterial osteomyelitis. However, CT and MR imaging showed subperiosteal fluid collections in three of four patients, an appearance only occasionally seen with typical osteomyelitis.


Archaea Dominate the Ammonia-Oxidizing Community in Deep-Sea Sediments of the Eastern Indian Ocean-from the Equator to the Bay of Bengal.
Ammonia-oxidizing Archaea (AOA) and ammonia-oxidizing Bacteria (AOB) oxidize ammonia to nitrite, and therefore play essential roles in nitrification and global nitrogen cycling. To better understand the population structure and the distribution of AOA and AOB in the deep Eastern Indian Ocean (EIO), nine surface sediment samples (>3,300 m depth) were collected during the inter-monsoon Spring 2013. One sediment sample from the South China Sea (SCS; 2,510 m) was also included for comparison. The community composition, species richness, and diversity were characterized by clone libraries (total 1,238 clones), and higher diversity of archaeal amoA genes than bacterial amoA genes was observed in all analyzed samples. Real time qPCR analysis also demonstrated higher abundances (gene copy numbers) of archaeal amoA genes than bacterial amoA genes, and the ratios of AOA/AOB ranged from 1.42 to 8.49 among sites. In addition, unique and distinct clades were found in both reconstructed AOA and AOB phylogeny, suggesting the presence of niche-specific ammonia-oxidizing microorganisms in the EIO. The distribution pattern of both archaeal and bacterial amoA genes revealed by NMDS (non-metric multidimensional scaling) showed a distinct geographic separation of the sample from the SCS and most of the samples from the EIO following nitrogen gradients. Higher abundance and diversity of archaeal amoA genes indicated that AOA may play a more important role than AOB in the deep Indian Ocean. Environmental parameters shaping the distribution pattern of AOA were different from that of AOB, indicating distinct metabolic characteristics and/or adaptation mechanisms between AOA and AOB in the EIO, especially in deep-sea environments.


Who uses height-adjustable desks? - Sociodemographic, health-related, and psycho-social variables of regular users.
Sit-to-stand height-adjustable desks (HAD) may promote workplace standing, as long as workers use them on a regular basis. The aim of this study was to investigate (i) how common HAD in German desk-based workers are, and how frequently HADs are used, (ii) to identify sociodemographic, health-related, and psycho-social variables of workday sitting including having a HAD, and (iii) to analyse sociodemographic, health-related, and psycho-social variables of users and non-users of HADs. A cross-sectional sample of 680 participants (51.9% men; 41.0 ± 13.1 years) in a desk-based occupation was interviewed by telephone about their occupational sitting and standing proportions, having and usage of a HAD, and answered questions concerning psycho-social variables of occupational sitting. The proportion of workday sitting was calculated for participants having an HAD (n = 108) and not-having an HAD (n = 573), as well as for regular users of HAD (n = 54), and irregular/non-users of HAD (n = 54). Linear regressions were conducted to calculate associations between socio-demographic, health-related, psychosocial variables and having/not having an HAD, and the proportion of workday sitting. Logistic regressions were executed to examine the association of mentioned variables and participants' usage of HADs. Sixteen percent report that they have an HAD, and 50% of these report regular use of HAD. Having an HAD is not a correlate of the proportion of workday sitting. Further analysis restricted to participants having available a HAD highlights that only the 'perceived advantages of sitting less' was significantly associated with HAD use in the fully adjusted model (OR 1.75 [1.09; 2.81], p < 0.05). The present findings indicate that accompanying behavioral action while providing an HAD is promising to increase the regular usage of HAD. Hence, future research needs to address the specificity of behavioral actions in order to enhance regular HAD use, and needs to give more fundamental insights into these associations.


Anticancer Efficacy of Targeted Shikonin Liposomes Modified with RGD in Breast Cancer Cells.
Shikonin (SHK) has been proven to have a good anti-tumor effect. However, poor water solubility and low bioavailability limit its wide application in clinical practice. In this study, to overcome these drawbacks, RGD-modified shikonin-loaded liposomes (RGD-SSLs-SHK) were successfully prepared. It exhibited excellent physicochemical characteristics including particle size, zeta potential, encapsulation efficiency, and delayed release time. Meanwhile, the targeting activity of the RGD-modified liposomes was demonstrated by flow cytometry and confocal microscopy in the αvβ₃-positive MDA-MB-231 cells. Besides exhibiting greater cytotoxicity in vitro, compared with non-targeted shikonin-loaded liposomes (SSLs-SHK), RGD-SSLs-SHK could also evidently induce apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax. It could also inhibit cell proliferation, migration, invasion, and adhesion by reducing the expression of MMP-9 and the level of NF-κB p65, but did not affect the expression of MMP-2 in the MDA-MB-231 cells. Therefore, these findings indicated that the strategy to use RGD-modified liposomes as carriers for targeted delivery of shikonin is a very promising approach to achieve breast cancer targeted therapy.


Variability control in speech production tasks performed by adults and children.
Eighteen adults and 12 children, ranging from 7 to 11 years of age, participated in a study that investigated their abilities to control the temporal variability of their speech. For both the adults and the children, few substantive differences in performance were observed when considering control data versus findings from an experimental task in which they were specifically instructed to be as consistent as possible in producing various stimuli. Although some subjects did show reduced variability in the experimental condition, there was little evidence that such decreases typically represented more than random effects. In general, the results suggest that when producing multiple repetitions of words and short phrases, adults and 7-11-year-old children are essentially as consistent as they can be, whether specifically attempting to minimize variability or not. The basis for this could be that even in control conditions, subjects may perform at or near optimal levels of consistency across productions.


[New pandemic influenza: what are the risks?].
Influenza pandemics result from the introduction of a new influenza A subtype from the avian reservoir. This reservoir is vast but the introductions are seldom. To be adapted for human infection, they have to undergo major changes. Two mechanisms have been described, allowing this adaptation: direct adaptation after accumulation of mutations, or genetic exchange between human and avian viruses (reassortant virus). Today, we are facing a pandemic threat due to A(H5N1). Already 382 cases have been detected, including 241 death cases. However, this virus is not adapted to man. On the other hand, the large epizootic clusters observed, the cases observed after exposition to infected poultry and the lack of control of the A(H5N1) infection in wild and domestic birds make this virus the best candidate for the next pandemic.


The Role of Blue and Red Light in the Orchestration of Secondary Metabolites, Nutrient Transport and Plant Quality.
Light is a fundamental environmental parameter for plant growth and development because it provides an energy source for carbon fixation during photosynthesis and regulates many other physiological processes through its signaling. In indoor horticultural cultivation systems, sole-source light-emitting diodes (LEDs) have shown great potential for optimizing growth and producing high-quality products. Light is also a regulator of flowering, acting on phytochromes and inducing or inhibiting photoperiodic plants. Plants respond to light quality through several light receptors that can absorb light at different wavelengths. This review summarizes recent progress in our understanding of the role of blue and red light in the modulation of important plant quality traits, nutrient absorption and assimilation, as well as secondary metabolites, and includes the dynamic signaling networks that are orchestrated by blue and red wavelengths with a focus on transcriptional and metabolic reprogramming, plant productivity, and the nutritional quality of products. Moreover, it highlights future lines of research that should increase our knowledge to develop tailored light recipes to shape the plant characteristics and the nutritional and nutraceutical value of horticultural products.


Vitamin K-dependent proteins bind to very low-density lipoproteins.
It has been demonstrated that the surface of large VLDL Sf 100-400 can bind both prothrombin and Factor X(Xa) and that on VLDL Factor Xa can convert prothrombin to thrombin, which degrades apo B and apo E. It has been reported also that the VLDL kinetically supports the conversion of prothrombin to thrombin. The binding of vitamin K-dependent proteins to phospholipid is partially Ca2+-dependent and probably involves their Gla residues. The complex of VLDL, prothrombin, Factor Xa, and Ca2+ lacks only Factor Va, a lipid associating, non-Gla residue containing 330 kd protein, to complete the "prothrombinase complex." Factor V (Va) is found at very low concentrations in the circulation, but is localized on platelets, monocytes, and the endothelium. VLDL can bind both to monocytes and to the endothelium, for example, through both receptor and non-receptor pathways. When carrying this complement of the prothrombinase complex, this subpopulation of VLDL, in the presence of Factor Va on cell surfaces, could conceivably upset the local balance of pro- and anticoagulant activities. Thus, directly or indirectly the increased triglyceride levels, reflected in increased VLDL in patients, may alter this balance, and thereby produce a "hypercoagulable state." This is a simplistic view of the potential role of VLDL in the interplay of cells, coagulation proteins, and the regulatory systems involved in vivo. To realize the degree of complexity that we may need to address, we need only look at the work of Booyse et al in this issue of Seminars, in which they demonstrate that hypertriglyceridemic VLDL, in contrast to normal VLDL, do not support the early release of t-PA from endothelial cells, an antifibrinolytic event.(ABSTRACT TRUNCATED AT 250 WORDS)


Excited-state dynamics of organic dyes at liquid/liquid interfaces.
Liquid/liquid interfaces play a crucial role in numerous areas of science. However, direct spectroscopic access to this thin (~1 nm) region is not possible with conventional optical methods. After a brief review of the most used techniques to perform interfacial optical spectroscopy, we will focus on time-resolved surface second harmonic generation, which allows the measurement of the excited-state dynamics of probe molecules at interfaces. By comparing these dynamics with those measured in bulk solutions, precious information on the properties of the interfacial region can be obtained. To illustrate this, several studies performed in our group will be presented.


Neuropsychological profiles of manganese neurotoxicity.
The etiology of manganese neurotoxicity is heterogenous and includes exposure to welding fumes, chronic liver failure, and chronic total parental nutrition (TPN). We recently reported that cognitive impairment occurs in welders and patients with chronic liver failure who had evidence of manganese neurotoxicity including abnormal magnetic resonance imaging (MRI) basal ganglia T1 hyperintensity. In this study, we compared the neuropsychological profiles of patients with manganese neurotoxicity and basal ganglia T1 hyperintensities from three different etiologies: welding, chronic liver failure, and chronic TPN. Across all three groups, the neuropsychological profiles suggest frontal and subcortical cognitive impairment, with more widespread abnormalities occurring in the non-welding groups.


Teaching young children to cross roads safely.
Road safety education is considered essential to teach children to interact with traffic safely. Many programs, however, do not consider the separate component skills of the road-crossing task, the functional and behavioural factors that may put some children at increased risk, and the most beneficial methods to transfer knowledge to improved behaviour in real-world environments. A targeted and practical training program using a simulated road environment has been developed and evaluated amongst primary school children using a randomised controlled trial. Significant reductions in proportion of critically incorrect road-crossing responses were found immediately after training (56%) and one-month post-training (47%) by the case group compared with pre-training responses, and relative to any changes in responses of the control group. The beneficial effects were greater for younger children, females, children with less well developed perceptual, attentional and cognitive skills, and those with little traffic exposure. The effects of the training program on other outcome measures (proportion of missed opportunity responses, decision time and safety rating responses) were less clear but showed some beneficial effects. This paper discusses the use of the simulated training program, a novel and safe way, to improve road crossing decisions. It is suggested that improvements can be made to child pedestrian education by providing tailored and practical programs that target the component skills of road-crossing decisions and improve essential skills through intensive training and feedback on known risk factors.


Mesotherapy for facial skin rejuvenation: a clinical, histologic, and electron microscopic evaluation.
Mesotherapy, as broadly defined, represents a variety of minimally invasive techniques in which medications are directly injected into the skin and underlying tissue in order to improve musculoskeletal, neurologic, and cosmetic conditions. There are few clinical studies evaluating the efficacy and safety of mesotherapy in any form. This study evaluates the histologic and clinical changes associated with one of the simplest formulations of mesotheraphy commonly used for skin rejuvenation. Ten subjects underwent four sessions of mesotherapy involving multiple injections of a multivitamin and hyaluronic acid solution. Treatment was conducted at 4 monthly intervals. All subjects had pre- and post-treatment photographs and skin biopsies. Skin biopsies were evaluated with routine histology, mucin and elastin stains, and electron microscopy. Patient surveys were also evaluated. Evaluation of photographs at 0, 3, and 6 months revealed no significant clinical differences. Light microscopic examination of pre- and posttreatment specimens showed no significant changes. Electron microscopic analysis of collagen fibers measurements did show smaller diameter fibres posttreatment. No significant clinical or histologic changes were observed after multivitamin mesotherapy for skin rejuvenation. Multivitamin and hyaluronic acid solution facial mesotherapy does not appear to provide any significant benefit.


Dyke-Davidoff-Masson syndrome.
Dyke Davidoff Masson syndrome (DDMS) is characterized by seizures, facial asymmetry, contralateral hemiplegia and mental retardation. The characteristic radiologic features are cerebral hemiatrophy with homolateral hypertrophy of the skull and sinuses. We report a case of DDMS in an 18-month-old girl who presented with right sided focal seizures, hemiparesis of the same side, and delayed milestones.


New recommendations for the energy and nutrient supply of dairy cows and heifers in Germany.
In summary, GfE (2001) give not only a view on energy and nutrient requirements, and the official recommendations for supply in Germany established by the Society of Nutrition Physiology, but also a comprehensive literature review on the particular issues. Some gaps of knowledge on requirements of dairy cows and heifers were identified and the need of further research was determined. The derivation of the new recommendations under consideration of physiological aspects has been demonstrated in the paper.


Nurse practitioner and physician communication styles.
No empirical studies of nurse-patient relationships have focused on interpersonal communication and its effects on patient outcomes. In this study, 124 provider-patient interactions of five nurse practitioners (NPs) and four physicians (PHYs) were audiotaped. Communication patterns were examined to determine whether the practitioner's predominant style was informational or controlling and whether style affected patient satisfaction and perceived autonomy support. All providers used predominantly informational styles of communication. Significant differences in communication styles existed between provider groups (F = 5.90, df = 1/8, p =.05) and among individual providers (F = 4.28, df = 8/123, p <.0001). All providers were more controlling in their communication patterns when attempting to make decisions and plan patient care. Examination of communication styles can help NPs develop the skills necessary to provide patient-centered care.


A process evaluation plan for assessing a complex community-based maternal health intervention in Ogun State, Nigeria.
Despite increased investment in community-level maternal health interventions, process evaluations of such interventions are uncommon, and can be instrumental in understanding mediating factors leading to outcomes. In Nigeria, where an unacceptably number of maternal deaths occur (maternal mortality ratio of 814/100,000 livebirths), the Community Level Interventions for Pre-eclampsia (CLIP) study (NCT01911494) aimed to reduce maternal and neonatal mortality and morbidity with a complex intervention of five interrelated components. Building from previous frameworks, we illustrate a methodology to evaluate implementation processes of the complex CLIP intervention, assess mechanisms of impact and identify emerging unintended causal pathways. The study was conducted from 2013-2016 in five Local Government Areas in Ogun State, Nigeria. A six-step approach was developed to evaluate key constructs of context (external factors related to intervention), implementation (fidelity, dose, reach, and adaption) and mechanisms of impact (unintended outcomes and mediating pathways). The steps are: 1) describing the intervention by a logic model, 2) defining acceptable delivery, 3) formulating questions, 4) determining methodology, 5) planning resources in context, lastly, step 6) finalising the plan in consideration with relevant stakeholders. Quantitative data were collected from 32,785 antenatal and postnatal visits at the primary health care level, from 66 community engagement sessions, training assessments of community health workers, and standard health facility questionnaires. Forty-three focus group discussions, 38 in-depth interviews, and 23 structured observations were conducted to capture qualitative data. A total of 103 community engagement reports and 182 suspected pre-eclampsia case reports were purposively collected. Timing of data collection was staggered to understand feedback mechanisms that may have resulted from the delivery of the intervention. Data will be analysed using R and NVivo. Diffusions of innovations and realist evaluation theories will underpin analysis of the interaction between context, mechanisms and outcomes. This comprehensive approach can serve as a guide for researchers and policy makers to plan the evaluation of similar complex health interventions in resource-constrained settings, and to aid in measuring 'effectiveness' of interventions and not just 'efficacy'. This research is a part of the Community Level Interventions for Pre-eclampsia Study, NCT01911494. The trial is registered in Clinicaltrials.gov, the URL is https://clinicaltrials.gov/ct2/show/NCT01911494 The trial was registered on June 28, 2013 and the first participant was enrolled for intervention on March 1, 2014.


Quantitative Evaluation of Twelve Major Components of Sulfur-Fumigated Astragali Radix with Different Durations by UPLC-MS.
In this study, an improved UPLC-MS (Ultra-high performance liquid chromatography-tandem mass spectrometry) method for simultaneously quantifying twelve major components belonging to two chemical types was developed and validated, and was applied to quantitatively compare the quality of sulfur-fumigated Astragali Radix of different durations and of the fresh reference sample. The results showed that the contents of triterpenes astragaloside III and astragaloside IV decreased moderately, while the flavonoids calycosin, formononetin, and 7,2'-dihydroxy-3',4'-dimethoxyisoflavane decreased significantly. The corresponding flavonoid glycosides increased accordingly, which indicated the occurrence of chemical transformation of flavonoids and glycosides in the process of sulfur-fumigation. These transformations were further confirmed by the synthesis of flavonoid glycosides under simulated sulfur-fumigation circumstances. Furthermore, the sulfur-fumigated duration varied in proportion with the contents of compounds 7, 11, and 12. These results suggest that the established method was precise, accurate and sensitive enough for the global quality evaluation of sulfur-fumigated Astragali Radix. Further, sulfur-fumigation not only changes the proportions of bioactive components, but also causes chemical transformation in Astragali Radix.


Toxicokinetics of zinc-oxide nanoparticles and zinc ions in the earthworm Eisenia andrei.
The toxicokinetics of zinc in the earthworm Eisenia andrei was investigated following exposure for 21 days to ionic zinc (ZnCl2) or zinc oxide nanoparticles (ZnO-NPs) in Lufa 2.2 soil, followed by 21 days elimination in clean soil. Two concentrations were tested for both ZnCl2 (250 and 500μg Zn g-1) and ZnO-NPs (500 and 1000μg Zn g-1), corresponding to EC25 and EC50 for effects on reproduction. Based on the measured internal Zn concentrations in the earthworms over time of exposure, the kinetics parameters ka - assimilation rate constant (gsoil g-1body weight day-1) and ke - elimination rate constant (day-1) were estimated using a one-compartment model for either total Zn concentrations in the soil or porewater Zn concentrations. In the ZnCl2 treatments, ka was higher for total Zn concentrations in soil, whereas in the ZnO-NP treatments, ka was higher for porewater Zn concentrations. The value of ke did not differ between the two Zn forms (ZnCl2 vs ZnO-NPs) for either EC50 or EC25 when related to total Zn concentrations in soil, but for EC50, ke related to porewater Zn concentrations was significantly higher for ZnCl2 than for ZnO-NPs. It is concluded that differences in kinetic parameters between treatments were connected with exposure concentrations rather than with the form of Zn. Zinc was efficiently regulated by the earthworms in all treatments: a 2-fold increase in exposure concentration resulted in a less than 2-fold increase in internal concentration, and after transfer to uncontaminated soil the internal Zn concentrations in the earthworms returned to ca 111μgg-1 dw in all treatments.


Influence of degradable starch microspheres on the human nasal mucosa.
The effect of the nasal administration of degradable starch microspheres (DSM) on the mucociliary system and the geometry of the nasal cavities were evaluated in 15 healthy volunteers. The baseline values for mucociliary clearance of the right nasal cavity were determined on two separate days for each subject using the saccharin-dyes test. Acoustic rhinometry was performed before and during the saccharin-dyes test. The patients then started the treatment period and inhaled 10 mg of DSM intranasally once daily in each nostril for 8 days. The saccharin-dyes test was performed 5 min after the deposition of the DSM on day 1 and day 8. The geometry of the nasal cavities was determined before, 7 min after deposition, and after the end of the saccharin test. Both tests were also performed two days after the end of the treatment period. Each subject was examined by means of rhinoscopy on every visit during the investigation. No changes in mucociliary clearance or in the geometry of the nasal cavities were found after repeated administration of starch microspheres. Thus, intranasally-administered degradable starch microspheres did not have an adverse effect on human nasal mucociliary clearance, and the DSM did not cause any congestion or decongestion of the mucosa.


General practice registrars' clinical exposure to dermatological procedures during general practice training: a cross-sectional analysis.
Australian general practitioners (GPs) commonly manage dermatological conditions requiring procedures. GP registrars have limited pre-vocational training exposure to dermatology and find skin problems challenging. We aimed to establish the prevalence, nature and associations of GP registrars' performance of skin procedures. We conducted a cross-sectional analysis from the Registrar Clinical Encounters in Training cohort study. Multivariable logistic regression was used to establish associations of our outcome (skin procedures, both including and excluding cryotherapy). Independent variables included patient and doctor demographics, diagnoses/problems managed and registrars' recourse to in-consultation assistance/information. A total of 1161 registrars provided data on 166,988 consultations, recording 2927 skin procedures (16.7% of all procedures; performed in 1.7% of consultations). Cryotherapy, excision, punch biopsy and shave biopsy were most common. More complex procedures were performed infrequently. Significant associations of performing procedures included rural/remote location (compared to major city), male patients, patient age 65+ (compared to age 15-34) and registrars seeking in-consultation information/assistance. Skin procedures were less likely for Aboriginal patients or those from non-English-speaking backgrounds. For non-cryotherapy procedures, rurality was not significantly associated, but significant differences were found between training regions. In summary, GP registrars perform fewer dermatological procedures compared to established GPs. Findings will inform GP vocational training in skin procedures.


Caloric restriction prevents the development of airway hyperresponsiveness in mice on a high fat diet.
We have previously shown that high fat diet (HFD) for 2 weeks increases airway hyperresponsiveness (AHR) to methacholine challenge in C57BL/6J mice in association with an increase in IL-1β levels in lung tissue. We hypothesize that obesity increases AHR via the IL-1β mechanism, which can be prevented by caloric restriction and IL-1β blockade. In this study, we fed C57BL/6J mice for 8 weeks with several hypercaloric diets, including HFD, HFD supplemented with fructose, high trans-fat diet (HTFD) supplemented with fructose, either ad libitum or restricting their food intake to match body weight to the mice on a chow diet (CD). We also assessed the effect of the IL-1β receptor blocker anakinra. All mice showed the same total respiratory resistance at baseline. All obese mice showed higher AHR at 30 mg/ml of methacholine compared to CD and food restricted groups, regardless of the diet. Obese mice showed significant increases in lung IL-1 β mRNA expression, but not the protein, compared to CD and food restricted mice. Anakinra abolished an increase in AHR. We conclude that obesity leads to the airway hyperresponsiveness preventable by caloric restriction and IL-1β blockade.


Fresh Osteochondral Allograft Transplantation: Is Graft Storage Time Associated With Clinical Outcomes and Graft Survivorship?
Regulatory concerns and the popularity of fresh osteochondral allograft (OCA) transplantation have led to a need for prolonged viable storage of osteochondral grafts. Tissue culture media allow a longer storage time but lead to chondrocyte death within the tissue. The long-term clinical consequence of prolonged storage is unknown. Patients transplanted with OCAs with a shorter storage time would have lower failure rates and better clinical outcomes than those transplanted with OCAs with prolonged storage. Cohort study; Level of evidence, 3. A matched-pair study was performed of 75 patients who received early release grafts (mean storage, 6.3 days [range, 1-14 days]) between 1997 and 2002, matched 1:1 by age, diagnosis, and graft size, with 75 patients who received late release grafts (mean storage time, 20.0 days [range, 16-28 days]) from 2002 to 2008. The mean age was 33.5 years, and the median graft size was 6.3 cm2. All patients had a minimum 2-year follow-up. Evaluations included pain, satisfaction, function, failures, and reoperations. Outcome measures included the modified Merle d'Aubigné-Postel (18-point) scale, International Knee Documentation Committee (IKDC) form, and Knee Society function (KS-F) scale. Clinical failure was defined as revision OCA transplantation or conversion to arthroplasty. Among patients with grafts remaining in situ, the mean follow-up was 11.9 years (range, 2.0-16.8 years) and 7.8 years (range, 2.3-11.1 years) for the early and late release groups, respectively. OCA failure occurred in 25.3% (19/75) of patients in the early release group and 12.0% (9/75) of patients in the late release group ( P = .036). The median time to failure was 3.5 years (range, 1.7-13.8 years) and 2.7 years (range, 0.3-11.1 years) for the early and late release groups, respectively. The 5-year survivorship of OCAs was 85% for the early release group and 90% for the late release group ( P = .321). No differences in postoperative pain and function were noted between the groups. Ninety-one percent of the early release group and 93% of the late release group reported satisfaction with OCA results. The transplantation of OCA tissue with prolonged storage is safe and effective for large osteochondral lesions of the knee and has similar clinical outcomes and satisfaction to the transplantation of early release grafts.


Interpretation and Utility of the Moments of Small-Angle X-Ray Scattering Distributions.
Small angle x-ray scattering has been proven to be a valuable method for accessing structural information below the spatial resolution limit implied by direct imaging. Here, we theoretically derive the relation that links the subpixel differential phase signal provided by the sample to the moments of scattering distributions accessible by refraction sensitive x-ray imaging techniques. As an important special case we explain the scatter or dark-field contrast in terms of the sample's phase signal. Further, we establish that, for binary phase objects, the nth moment scales with the difference of the refractive index decrement to the power of n. Finally, we experimentally demonstrate the utility of the moments by quantitatively determining the particle sizes of a range of powders with a laboratory-based setup.


Evaluation of 6-chloro-N-[3,4-disubstituted-1,3-thiazol-2(3H)-ylidene]-1,3-benzothiazol-2-amine Using Drug Design Concept for Their Targeted Activity Against Colon Cancer Cell Lines HCT-116, HCT15, and HT29.
BACKGROUND Colorectal adenocarcinoma is the second leading cause of cancer-related death in the world. The stage of the disease is related to the survival of the patient, and in early phases surgery is the main modality of treatment. The main aim of modern medicinal chemistry is to synthesize small molecules via drug designing, especially by targeting tumor cells. MATERIAL AND METHODS A new series of 19 compounds containing benzothiazole and thiazole were designed. Molecular docking studies were performed on the designed series of molecules. Compounds showing good binding affinity towards the EGFR receptor were selected for synthetic studies. Characterization of the synthesized compounds was done by FTIR, 1HNMR, Mass and C, H, N, analysis. RESULTS The anticancer evaluation of the synthesized compounds was done at NIC, USA at a single dose against colon cancer cell lines HCT 116, HCT15, and HC 29. The active compounds were further evaluated for the 5-dose testing. Compounds were designed by using docking analysis. To ascertain the interaction of EGFR tyrosine kinase binding, energy calculation was used. CONCLUSIONS The results of the present study indicate that the designed compounds show good activity against colon cancer cell lines, which may be further studied to design new potential molecules.


Controllable Synthesis of ZnO Nanoparticles with Improved Photocatalytic Performance for the Degradation of Rhodamine B under Ultraviolet Light Irradiation.
In this work, two-dimensional (2D) Zn-HMT (Zn(NO3)2(HMT)2(H2O)2]n) nanosheets were synthesized using a facile one-step chemical precipitation in the presence of Zn(NO3)2, hexamine (HMT), and anhydrous ethanol at room temperature. Subsequently, hexagonal Tx-ZnO (Tx-ZnO refers to the zinc oxide (ZnO) nanoparticles) were synthesized by a high-temperature solid-phase method at different temperatures (x = 500, 550, 600, 650, 700, 750, and 800 °C) nanoparticles with different morphologies were synthesized by a high-temperature calcination approach using 2D Zn-HMT nanosheets as precursor. The crystal structure, morphology, specific surface areas, surface and interface properties, optical properties, and charge migration behaviors of the as-synthesized Tx-ZnO nanoparticles were characterized by powder X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), automatic specific surface and aperture analyzer, X-ray photoelectron spectroscopy (XPS), UV-visible spectrophotometer, photoluminescence (PL) spectra, and electrochemical impedance spectroscopy (EIS). The photocatalytic performances and stabilities of the as-synthesized typical Tx-ZnO nanoparticles with various morphologies were evaluated and compared with the commercial ZnO (CM-ZnO) nanoparticle. The T700-ZnO nanoparticle with spherical and irregular morphology exhibited the highest photocatalytic activity (99.12%) for the degradation of Rhodamine B (RhB), compared to T500-ZnO (92.32%), T600-ZnO (90.65%), T800-ZnO (44.04%), and the CM-ZnO (88.38%) nanoparticle, which can be attributed to the cooperative effects of higher crystallinity, bigger crystal size, the strongest separation efficiency, the lowest recombination rate, the fastest charge carrier transfer path, and the highest charge-transfer efficiency. The superior photocatalytic activity illustrated by the T700-ZnO nanoparticle makes it have potential application prospects for the treatment of organic wastewater.


Insects as an alternative protein source for poultry nutrition: a review.
This review summarizes the most relevant scientific literature related to the use of insects as alternative protein sources in poultry diets. The black soldier fly, the housefly, the beetle, mealworms, silkworms, earthworms, crickets, and grasshoppers are in the spotlight because they have been identified as an important future source of sustainable animal proteins for poultry feeding. Insect meals meet poultry requirements in terms of nutritional value, essential amino acid composition, nutrient digestibility, and feed acceptance. Furthermore, they are enriched with antimicrobial peptides and bioactive molecules that can improve global health. Results from poultry studies suggest equivalent or enhanced growth performances and quality of end-products as compared to fish meal and soybean meal. To outline this body of knowledge, this article states established threads of research about the nutrient profiles and the digestibility of insect meals, their subsequent effects on the growth and laying performances of poultry as well as the quality of meat, carcass, and eggs. To fully exploit insect-derived products, the effects of insect bioactive molecules (antimicrobial peptides, fatty acids, and polysaccharides) were addressed. Furthermore, as edible insects are likely to take a meaningful position in the feed and food chain, the safety of their derived products needs to be ensured. Some insights into the current knowledge on the prevalence of pathogens and contaminants in edible insects were highlighted. Finally, the effect of insect farming and processing treatment on the nutritive value of insect larvae was discussed. Our overview reveals that using insects can potentially solve problems related to reliance on other food sources, without altering the growth performances and the quality of meat and eggs.


Neurological complications of alcohol and misuse of drugs.
The nature of many of the symptoms associated with substance and alcohol use means that patients often present to neurologists. The frequently catastrophic consequences of overlooking these patients makes this an important cause to identify. Here I will discuss various acute and non-acute substance misuse associated presentations, with particular emphasis on the neurology. As neurological sequelae are particularly common in alcohol use, there will be an emphasis on this drug while other substances are included when relevant, extending to the recently notorious 'legal highs'. I hope this review will increase vigilance to the possibility of substance use disorder, and persuade neurologists that they have a role in the detection and treatment of these conditions.


Genetic and metabolic engineering in diatoms.
Diatoms have attracted considerable attention due to their success in diverse environmental conditions, which probably is a consequence of their complex origins. Studies of their metabolism will provide insight into their adaptation capacity and are a prerequisite for metabolic engineering. Several years of investigation have led to the development of the genome engineering tools required for such studies, and a profusion of appropriate tools is now available for exploring and exploiting the metabolism of these organisms. Diatoms are highly prized in industrial biotechnology, due to both their richness in natural lipids and carotenoids and their ability to produce recombinant proteins, of considerable value in diverse markets. This review provides an overview of recent advances in genetic engineering methods for diatoms, from the development of gene expression cassettes and gene delivery methods, to cutting-edge genome-editing technologies. It also highlights the contributions of these rapid developments to both basic and applied research: they have improved our understanding of key physiological processes; and they have made it possible to modify the natural metabolism to favour the production of specific compounds or to produce new compounds for green chemistry and pharmaceutical applications.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.


A soft X-ray (80-1500 eV) grazing-incidence monochromator with varied-line-spacing plane gratings at PF-BL-11A.
The design and performance of a new soft X-ray beamline BL-11A at the Photon Factory (PF) are presented. A Hettrick-type grazing-incidence monochromator equipped with three varied-line-spacing plane gratings was designed and constructed at a bending-magnet source of the PF 2.5 GeV storage ring. An 800 lines mm(-1) laminar grating produced by aspheric-wavefront holographic recording optics, as well as a mechanically ruled blazed one, were tested. A resolving power of more than 4500 was achieved at 400 eV with either grating, and approximately 10(10) photons s(-1) are available at a resolving power of 2000. High photon flux enables low-concentration samples, such as surface adsorbates, to be studied. A simple scanning mechanism for a wide energy range is quite useful for EXAFS measurements on light elements such as C, N and O.


Maternal atopic conditions and autism spectrum disorder: a systematic review.
Autism spectrum disorder (ASD) is a disabling neurodevelopmental condition with complex etiology. Emerging evidence has pointed to maternal atopy as a possible risk factor. It is hypothesized that maternal atopic disease during pregnancy can lead to increased levels of inflammatory cytokines in fetal circulation via placental transfer or increased production. These cytokines can then pass through the immature blood-brain barrier, causing aberrant neurodevelopment via mechanisms including premature microglial activation. The objective of this study is to systematically review observational studies that investigate whether a maternal history of atopic disease (asthma, allergy, or eczema/atopic dermatitis) is associated with a diagnosis of ASD in offspring. A search was conducted in Ovid MEDLINE, PsycINFO, and Embase databases for relevant articles up to November 2021; this was later updated in January 2022. Observational studies published in peer-reviewed journals were included. Data were synthesized and qualitatively analyzed according to the specific atopic condition. Quality assessment was done using the Newcastle-Ottawa Scale. Nine articles were identified, with all including asthma as an exposure, alongside four each for allergy and eczema. Findings were inconsistent regarding the association between a maternal diagnosis of either asthma, allergy, or eczema, and ASD in offspring, with variations in methodology contributing to the inconclusiveness. More consistent associations were demonstrated regarding maternal asthma that was treated or diagnosed during pregnancy. Evidence suggests that symptomatic maternal asthma during pregnancy could be associated with ASD in offspring, underscoring the importance of effective management of atopic conditions during pregnancy. Further research is needed, particularly longitudinal studies that use gold-standard assessment tools and correlate clinical outcomes with laboratory and treatment data.PROSPERO Registration Number and Date: CRD42018116656, 26.11.2018.


Epithelioid melanocytic nevus with tubule and pseudoacini formation.
A 26-year-old female presented with a 7 mm irritated pink-red papule on the left posterior shoulder. A shave biopsy revealed a dermal proliferation of epithelioid cells arranged in small nests with central lumen-like structures resembling glands set in a densely sclerotic stroma. S100 and Melanoma antigen recognized by T cells 1 (MART-1) immunohistochemical positivity confirmed a dermal melanocytic neoplasm. Pan-cytokeratin and cytokeratin 7 were negative within the nests ruling out an adnexal neoplasm or metastatic adenocarcinoma. A Spitz nevus variant characterized by the presence of focal tubular structures (tubular epithelioid cell nevus) has rarely been described in the literature and is of uncertain biological significance. Similar structures have also been observed in Clark/dysplastic nevi and melanoma. Glandular differentiation is seen in a wide variety of benign and malignant epithelial neoplasms; however, melanocytes are not known to be capable of forming true glands. The exact mechanism and significance of this phenomenon are currently unknown. Certain postulations include central melanocyte apoptosis, autocrine or paracrine factor secretion or retraction artifact caused by tissue fixation. This distinctive finding is important to recognize in order to avoid misdiagnosis as a glandular neoplasm.


Coronary flow velocity reserve by echocardiography: feasibility, reproducibility and agreement with PET in overweight and obese patients with stable and revascularized coronary artery disease.
Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography of the LAD is used to assess microvascular function but validation studies in clinical settings are lacking. We aimed to assess feasibility, reproducibility and agreement with myocardial flow reserve (MFR) measured by PET in overweight and obese patients. Participants with revascularized coronary artery disease were examined by CFVR. Subgroups were examined by repeated CFVR (reproducibility) or Rubidium-82-PET (agreement). To account for time variation, results were computed for scans performed within a week (1-week) and for all scans regardless of time gap (total) and to account for scar tissue for patients with and without previous myocardial infarction (MI). Eighty-six patients with median BMI 30.9 (IQR 29.4-32.9) kg × m(-2) and CFVR 2.29 (1.90-2.63) were included. CFVR was feasible in 83 (97 %) using a contrast agent in 14 %. For reproducibility overall (n = 21) limits of agreement (LOA) were (-0.75;0.71), within-subjects coefficient of variation (CV) 11 %, and reliability 0.84. For reproducibility within 1-week (n = 13) LOA were (-0.33;0.25), within-subjects CV 5 %, and reliability 0.97. Agreement with MFR of the LAD territory (n = 35) was without significant bias and overall LOA were (-1.40;1.46). Agreement was best for examinations performed within 1-week of participants without MI of the LAD-territory (n = 12); LOA = (-0.68;0.88). CFVR was highly feasible with a good reproducibility on par with other contemporary measures applied in cardiology. Agreement with MFR was acceptable, though discrepancy related to prior MI has to be considered. CFVR of LAD is a valid tool in overweight and obese patients.


Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function.
Whereas cell cycle arrest, apoptosis, and senescence are traditionally thought of as the major functions of the tumor suppressor p53, recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Here, we identify glutaminase 2 (GLS2) as a previously uncharacterized p53 target gene to mediate these two functions of the p53 protein. GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate. p53 increases the GLS2 expression under both nonstressed and stressed conditions. GLS2 regulates cellular energy metabolism by increasing production of glutamate and alpha-ketoglutarate, which in turn results in enhanced mitochondrial respiration and ATP generation. Furthermore, GLS2 regulates antioxidant defense function in cells by increasing reduced glutathione (GSH) levels and decreasing ROS levels, which in turn protects cells from oxidative stress (e.g., H(2)O(2))-induced apoptosis. Consistent with these functions of GLS2, the activation of p53 increases the levels of glutamate and alpha-ketoglutarate, mitochondrial respiration rate, and GSH levels and decreases reactive oxygen species (ROS) levels in cells. Furthermore, GLS2 expression is lost or greatly decreased in hepatocellular carcinomas and the overexpression of GLS2 greatly reduced tumor cell colony formation. These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53's role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression.


Stimulation of the respiratory burst of murine peritoneal inflammatory neutrophils by conjugation with tumor cells.
Murine peritoneal neutrophils (PMNs), elicited by i.p. injection of formalin-killed Corynebacteria parvum, spontaneously lyse teratocarcinoma targets through the secretion of reactive oxygen intermediates. Examination of effector-target interactions at the single cell level revealed that PMNs conjugated to tumor cells were 3-fold more frequently stained by nitroblue tetrazolium compared to nonconjugating PMNs suggesting that tumor targets stimulated a potent tumor-lytic respiratory burst. This notion was confirmed by the detection of superoxide and hydrogen peroxide generation from PMNs as well as a luminol-dependent chemiluminescent response following conjugation with viable tumor targets. Generation of superoxide was dependent upon the presence of dihydrocytochalasin B. In addition to teratocarcinoma cells, comparable stimulation was achieved by conjugation with YAC and P815 targets but not thymocytes. Reactive oxygen intermediate release was also achieved by mixing peritoneal PMNs with heat-killed tumor cells. In contrast to bacteria-induced effectors, PMNs elicited by i.p. injection of thioglycollate were incapable of responding following conjugation with tumor targets although they were competent for reactive oxygen intermediate release when stimulated by phorbol myristate acetate. Teratocarcinoma targets were sensitive to concentrations of H2O2 that could be achieved by PMNs following contact. These data indicate that Corynebacteria-elicited inflammatory PMNs lyse their bound tumor targets by a mechanism similar to a stimulus-secretion model.


Teaching the behavioural sciences to medical students: some observations on Australia.
Despite a climate generally favourable to the teaching of the behavioural sciences, many Australian medical school programmes seem to be hampered by the lack of trained faculty teachers and demographic and epidemiological data. Consequently, they teach what is feasible rather than what is relevant. The persistence of this trend will inhibit programme modification toward greater relevance.


Regulatory signals for intestinal amino acid transporters and peptidases.
Dietary protein ultimately regulates many processes involved in protein digestion, but it is often unclear whether proteins themselves, peptides, or amino acids (AAs) are the proximate regulatory signal. Hence we compared several processes involved in protein digestion in mice adapted to one of three rations, identical except for containing 54% of either casein, a partial hydrolysate of casein, or a free AA mixture simulating a complete hydrolysate of casein. We measured brush-border uptakes of seven AAs that variously serve as substrates for four AA transporters, and brush-border and cytosolic activities of four peptidases. The three rations yielded essentially the same AA uptake rates. Peptidase activities tended to be lower on the AA ration than on the protein ration. In other studies, all three rations yielded the same rates of brush-border peptide uptake; protein is only modestly more effective than AAs at inducing synthesis of pancreatic proteases; and, depending on the animal species, protein is either much less or much more effective than AAs at stimulating release of cholecystokinin and hence of pancreatic enzymes. Thus the regulators of each process involved in protein digestion are not necessarily that process's substrate. We call attention to other cases in which the functional significance of regulatory signals remains to be understood.


[Spontaneous splenic rupture due to splenic metastasis of lung cancer].
We report the case of a patient who underwent splenectomy for spontaneous rupture of the spleen due to splenic metastasis. Pathologic examination revealed diffuse infiltration by carcinoma. Chest X-ray revealed a right lung superior lobe tumor, related to poorly differentiated carcinoma. Total splenectomy is a good option for diagnosis and treatment of splenic metastases.


THE DISTRIBUTION OF POSTMATING REPRODUCTIVE ISOLATING GENES IN POPULATIONS OF THE YELLOW MONKEY FLOWER, MIMULUS GUTTATUS.
Postmating reproductive isolating barriers are generally believed to arise as the chance by-product of genetic differentiation. The classical view is that these barriers normally involve differentiation at many loci, and therefore require long periods of allopatric isolation. The formal genetics of, and the distribution of genes responsible for, such barriers are known in very few cases. This paper examines the distribution of the genes responsible for two different postmating barriers in 18 populations of the yellow monkey flower, Mimulus guttatus. The genetic relatedness of the populations was measured by a morphometrical analysis. Widespread polymorphism was found for three of the four components of the two genetic systems responsible for the two barriers, with at least 13 populations possessing genes for one or both of the barriers. In one system (the C7/U8 system; Christie and Macnair, 1984), the distribution of the two component genes was correlated with the morphometrical similarity and geographical location of the populations. This pattern could be produced by a historical association or by an adaptive response. In the other system (the Cerig/C10 system; Macnair and Christie, 1983), the genes were more widely dispersed, and there was no obvious morphometrical or geographical association. Populations possessing the complementary factors causing partial reproductive isolation are not always widely separated geographically. These results indicate that the spread of postmating reproductive isolating genes through drift, selection, or hitchhiking could readily cause reproductive isolation to evolve in this species.>.


An in vivo evaluation of the diagnostic quality ultra-speed versus insight intraoral dental film.
Twelve sets of FMS (full mouth survey) radiographs were taken by California licensed radiology technicians. Ten of the sets of FMS radiographs were taken using Ultra-Speed "D" film on the left side of the patient and Insight "F" speed film on the right side of the patient. The remaining two sets of films were taken using Insight Film on both sides of the patient to act as a control. Ten faculty members of the Diagnostic Department were asked to evaluate the twelve sets of FMS radiographs and report whether they had a preference for the right side, left side, or no preference. Criteria for preference were diagnostic ability and clarity of the films. The results of the study showed a preference for the right side (65.7%), which was imaged with Insight Film, compared to the left side (34.3%), which was imaged with Ultra-Speed Film.


Applications and implications of neutral versus non-neutral markers in molecular ecology.
The field of molecular ecology has expanded enormously in the past two decades, largely because of the growing ease with which neutral molecular genetic data can be obtained from virtually any taxonomic group. However, there is also a growing awareness that neutral molecular data can provide only partial insight into parameters such as genetic diversity, local adaptation, evolutionary potential, effective population size, and taxonomic designations. Here we review some of the applications of neutral versus adaptive markers in molecular ecology, discuss some of the advantages that can be obtained by supplementing studies of molecular ecology with data from non-neutral molecular markers, and summarize new methods that are enabling researchers to generate data from genes that are under selection.


Cholinesterase characterization of two autochthonous species of Ria de Aveiro (Diopatra neapolitana and Solen marginatus) and comparison of sensitivities towards a series of common contaminants.
Biomonitoring of chemical contamination requires the use of well-established and validated tools, including biochemical markers that can be potentially affected by exposure to important environmental toxicants. Cholinesterases (ChEs) are present in a large number of species and have been successfully used for decades to discriminate the environmental presence of specific groups of pollutants. The success of cholinesterase inhibition has been due to their usefulness as a biomarker to address the presence of organophosphate (OP) and carbamate (CB) pesticides. However, its use in ecotoxicology has not been limited to such chemicals, and several other putative classes of contaminants have been implicated in cholinesterasic impairment. Nevertheless, the use of cholinesterases as a monitoring tool requires its full characterization in species to be used as test organisms. This study analyzed and differentiated the various cholinesterase forms present in two autochthonous organisms from the Ria de Aveiro (Portugal) area, namely the polychaete Diopatra neapolitana and the bivalve Solen marginatus, to be used in subsequent monitoring studies. In addition, this study also validated the putative use of the now characterized cholinesterasic forms by analyzing the in vitro effects of common anthropogenic contaminants, such as detergents, pesticides, and metals. The predominant cholinesterasic form found in tissues of D. neapolitana was acetylcholinesterase, while homogenates of S. marginatus were shown to possess an atypical cholinesterasic form, with a marked preference for propionylthiocholine. Cholinesterases from D. neapolitana were generally non-responsive towards the majority of the selected chemicals. On the contrary, strong inhibitory effects were reported for ChEs of S. marginatus following exposure to the selected pesticides.


An analytical study, anti-inflammatory and analgesic effects of Harpagophytum procumbens and Harpagophytum zeyheri.
The iridoids of Harpagophytum procumbens and Harpagophytum zeyheri were studied by CLHP. Harpagoside is the main iridoid for both drugs whereas 8-p-coumaroylharpagide is a representative iridoid of Harpagophytum zeyheri only. The ratio harpagoside/8-p-coumaroylharpagide can be used to distinguish chemically both species. For commercial dried aqueous extracts this ratio is intermediate because they are probably prepared from a mixture of H. procumbens and H. zeyheri drugs. The aqueous extracts of both drugs show similar analgesic and anti-inflammatory properties. Harpagophytum procumbens and Harpagophytum zeyheri should be accepted as sources for the drug Harpagophyti radix.


Structure and flexibility of the extracellular region of the PirB receptor.
Murine paired immunoglobulin receptor B (PirB) and its human ortholog leukocyte immunoglobulin-like receptor B2 (LILRB2) are widely expressed inhibitory receptors that interact with a diverse set of extracellular ligands and exert functions ranging from down-regulation of immune responses to inhibition of neuronal growth. However, structural information that could shed light on how PirB interacts with its ligands is lacking. Here, we report crystal structures of the PirB ectodomain; the first full ectodomain structure for a LILR family member, at 3.3-4.5 Å resolution. The structures reveal that PirB's six Ig-like domains are arranged at acute angles, similar to the structures of leukocyte immunoglobulin-like receptor (LILR) and killer-cell immunoglobulin-like receptor (KIR). We observe that this regular arrangement is followed throughout the ectodomain, resulting in an extended zigzag conformation. In two out of the five structures reported here, the repeating zigzag is broken by the first domain that can adopt two alternative orientations. Quantitative binding experiments revealed a 9 μm dissociation constant for PirB-myelin-associated glycoprotein (MAG) ectodomain interactions. Taken together, these structural findings and the observed PirB-MAG interactions are compatible with a model for intercellular signaling in which the PirB extracellular domains, which point away from the cell surface, enable interaction with ligands in trans.


Characterization and scoring of skin changes in severe acute malnutrition in children between 6 months and 5 years of age.
Severe acute malnutrition is a life-threatening condition. It can be associated with severe skin changes, first properly described by Williams in 1933. The aetiology of these skin changes is still unknown and their character has never been systematically described in dermatological terms. The skin changes have been shown to be a predictor of mortality in hospital care. Systematic investigations on the character of the skin changes that have effect on prognosis, are needed to investigate which of the skin changes that are relevant to improve treatment. Our main objective was to identify the skin changes characteristic of children with severe acute malnutrition and to develop a clinical score that describes the morphology and severity in dermatological terms. We also investigated if any of the different skin changes were connected to prognosis. At Mulago Hospital, Mwanamugimu (Department of Paediatrics and Child Health), Uganda, 120 children were included over a period of six months and observed when treated for severe acute malnutrition. Skin changes were registered through clinical examination and photo documentation and associated to prognosis using Cox and logistic regression analysis. Skin manifestations were characterized by five objective skin signs: telogenic effluvium, pigmentary changes (hyper- and hypo-pigmentation), ichthyosiform skin changes, lichenoid skin changes and bullae-erosion-desquamation. The skin changes could be registered in a systematic manner using our simple clinical score. Lichenoid skin changes were a significant predictor of death and allowed improved accuracy of prediction of mortality. The clinical score is simple and practical. A standardized way to register and score the skin changes, will allow a more unified way of reporting results in future studies. The standardization of observations, obtained through the proposed scoring system, will enable comparison of study results in the future.


Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats.
Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder.


Using Systolic Local Mechanical Load to Predict Fiber Orientation in Ventricles.
A simple rule adopted for myofiber reorientation in the ventricles is pursued by taking the microscopic branching network of myocytes into account. The macroscopic active tension generated on the microscopic branching structure is modeled by a multidirectional active stress tensor, which is defined as a function of the strains in the branching directions. In our reorientation algorithm, the principal direction of the branching network is updated so that it turns in the direction of greater active tension in the isovolumetric systole. Updates are performed step-by-step after the mechanical equilibrium has been attained with the current fiber structure. Starting from a nearly flat distribution of the principal fiber orientation along the circumferential direction, the reoriented fiber helix angles range from 70 to 40° at epicardium and from 60 to 80° at endocardium, in agreement with experimental observations. The helical ventricular myocardial band of Torrent-Guasp's model and the apical spiral structure of Rushmer's model are also reconstructed by our algorithm. Applying our algorithm to the infarcted ventricle model, the fiber structure near the infarcted site is remodeled so that the helix angle becomes steeper with respect to the circumferential direction near the epicardial surface. Based on our numerical analysis, we draw the following conclusions. (i) The multidirectional active tension based on the microscopic branching network is potentially used to seek tighter connection with neighboring aggregates. (ii) The thickening and thinning transitions in response to active tension in each myocyte allow the macroscopic principal fiber orientation of the microscopic branching network to move toward the direction of greater active tension. (iii) The force-velocity relationship is the key factor in transferring the fiber shortening strain to the magnitude of active tensions used in the myofiber reorientation. (iv) The algorithm naturally leads to homogeneity in the macroscopic active tension and the fiber shortening strain, and results in near-optimal pumping performance. (v) However, the reorientation mechanism may degrade the pumping performance if there is severely inhomogeneous contractility resulting from infarction. Our goal is to provide a tool to predict the fiber architecture of various heart disease patients for numerical simulations of their treatment plans.


Goethite Formed in the Periplasmic Space of Pseudomonas sp. JM-7 during Fe Cycling Enhances Its Denitrification in Water.
Denitrification-driven Fe(II) oxidation is an important microbial metabolism that connects iron and nitrogen cycling in the environment. The formation of Fe(III) minerals in the periplasmic space has a significant effect on microbial metabolism and electron transfer, but direct evidence of iron ions entering the periplasm and resulting in periplasmic mineral precipitation and electron conduction properties has yet to be conclusively determined. Here, we investigated the pathways and amounts of iron, with different valence states and morphologies, entering the periplasmic space of the denitrifier Pseudomonas sp. JM-7 (P. JM-7), and the possible effects on the electron transfer and the denitrifying ability. When consistently provided with Fe(II) ions (from siderite (FeCO3)), the dissolved Fe(II) ions entered the periplasmic space and were oxidized to Fe(III), leading to the formation of a 25 nm thick crystalline goethite crust, which functioned as a semiconductor, accelerating the transfer of electrons from the intracellular to the extracellular matrix. This consequently doubled the denitrification rate and increased the electron transport capacity by 4-30 times (0.015-0.04 μA). However, as the Fe(II) concentration further increased to above 4 mM, the Fe(II) ions tended to preferentially nucleate, oxidize, and crystallize on the outer surface of P. JM-7, leading to the formation of a densely crystallized goethite layer, which significantly slowed down the metabolism of P. JM-7. In contrast to the Fe(II) conditions, regardless of the initial concentration of Fe(III), it was challenging for Fe(III) ions to form goethite in the periplasmic space. This work has shed light on the likely effects of iron on environmental microorganisms, improved our understanding of globally significant iron and nitrogen geochemical cycles in water, and expanded our ability to study and control these important processes.


Antibacterial and antidiarrhoeal effects of alkaloids of Holarrhena antidysenterica WALL.
The alkaloids from the ethanolic extract of H. antidysenterica seeds were evaluated for their antibacterial activity against clinical isolates of enteropathogenic Escherichia coli (EPEC) in vitro, and their antidiarrhoeal activity on castor oil-induced diarrhoea in rats, in vivo. The plasmid DNA, whole cell lysate and outer membrane protein profile of a clinical isolate of EPEC was determined in presence of alkaloids of H. antidysenterica. The disc diffusion and agar well diffusion methods were used to evaluate the antibacterial efficacy. The alkaloids showed strong antibacterial activity against EPEC strains. In castor oil-induced diarrhoea, alkaloids reduced the diarrhoea with decrease in the number of wet faeces in pretreated rats at a dose of 200-800 mg/kg. The loss of plasmid DNA and suppression of high molecular weight proteins were observed on alkaloids treatment. Taking into account the multiple antibiotic resistance of EPEC, the results suggest usefulness of alkaloids of H. antidysenterica seeds as antibacterial and antidiarrhoeal agents.


Detection of vimentin-specific autoreactive CD8+ T cells in cardiac transplant patients.
Evidence is emerging that autoimmunity can play a role in allograft rejection. Reports have described the presence of autoantibodies in transplant patients and CD4+ autoreactive T cells in rodent models of allograft rejection. The objective of this study was to seek evidence of CD8+ T-cell-mediated autoimmunity in the transplant setting. The author have previously observed autoimmunity to the non-polymorphic cytoskeletal protein vimentin in cardia transplant patients. In this study, vimentin antibody positive patients were screened for the presence of vimentin-specific self-major histocompatibility complex class I-restricted CD8+ T cells. Two peptide sequences from vimentin that bound HLA-A*0201 were identified and fluorochrome-labeled A*0201 tetramers with each peptide were constructed to screen for vimentin-specific T cells. Tetramer-binding CD8+ T cells were detected in peripheral blood lymphocytes from two of six patients after expansion by in vitro stimulation with peptide. Tetramer-binding T cells produced interferon-gamma in an antigen-specific fashion. No autoreactive T cells specific for vimentin were detected after peptide stimulation of T cells from eight healthy A*0201-positive volunteers. This finding is the first evidence of CD8+ T-cell-mediated autoimmunity in human transplant patients.


A concept to collect neutron and x-ray images on the same line of sight at NIF.
Neutron and x-ray images are collected at the National Ignition Facility (NIF) to measure the size and shape of inertial confinement fusion implosions. The x-ray images provide a measure of the size and shape of the hot region of the deuterium-tritium fuel while the neutron images provide a measure of the size and shape of the burning plasma. Although these two types of images are collected simultaneously, they are not collected along the same line of sight (LOS). One 14 MeV neutron image is collected on the NIF equator, and two x-ray images are collected along the polar axis and nearly perpendicular to the neutron imaging line of sight on the equator. Both measurements use pinhole apertures to form the images, but existing x-ray imaging provides time-resolved measurements while the neutron images are time-integrated. Detailed comparisons of the x-ray and neutron images can provide information on the fuel assembly, but these studies have been limited because the implosions are not azimuthally symmetric and the images are collected along different LOS. We have developed a conceptual design of a time-integrated x-ray imaging system that could be added to the existing neutron imaging LOS. This new system would allow these detailed studies, providing important information on the fuel assembly of future implosions. Here we present this conceptual design and the expected performance characteristics.


Bed-side blind insertion of peritoneal dialysis catheters.
Access to the peritoneal cavity is an essential factor for successful peritoneal dialysis. The technique of catheter insertion can influence technique success and patient satisfaction. As compared to conventional surgical laparotomy, a bedside blind insertion technique under local anaesthesia has logistical advantages for the patient, the hospital and the community. This study compares outcomes of both methods in a single centre. A retrograde analysis of a prospectively collected database on all catheters implanted at the University hospital Ghent between 1/1/1998 and 31/5/2002 was carried out. During this period, catheters were implanted either by conventional laparotomy (CL) or by a bedside blind insertion technique (BI) under local anaesthesia.


Head growth in fetuses with isolated congenital heart defects: lack of influence of aortic arch flow and ascending aorta oxygen saturation.
Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters. Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth. Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18)). Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Advances in spotted microarray resources for expression profiling.
The new millennium has ushered in a new era in human biology. The elucidation of the human genome sequence, together with those of model organisms, provides us with an unprecedented insight into the makeup of our genetic blueprint. The challenge now is to figure out how all the constituent pieces fit together to form the whole picture, and the consequences of what happens when the process goes awry. One experimental tool that has the potential to provide enormous insights into this complex process is expression profiling using microarrays. The past few years have seen a considerable growth in the availability and use of microarrays. Fuelled in part by the many genome projects currently underway, there has been a large increase in the number of organisms for which microarray reagents are available from both commercial and academic sources. In addition to the increasing number of genome-wide probe sets that are available, a significant amount of attention has been focussed on generating more targeted probe sets that focus in on specific pathways or biological processes. Finally, the microarray field is starting to see a shift away from the use of cDNAs or polymerase chain reaction (PCR) products as probes towards the use of 50-70mer oligonucleotide probes with all of the potential advantages that they offer. The aim of this review is to provide an overview of what is currently available in terms of spotted microarray reagents both with respect to pre-made arrays and to probe sets available for arraying.


Assessing Individuals Attending the Family Medicine Clinic for Periodic Health Examinations in Screening of Diabetes Mellitus.
This study aims to evaluate the presence and risk of diabetes mellitus (DM) and the factors affecting the risk in those who visited the family medicine outpatient clinic. The present study included adult patients who presented to the outpatient clinic for periodic health examination between February 4, 2022, and April 4, 2022, and who had no known history of DM and were eligible for screening. Anthropometric measurements of the participants were made and their clinical and familial histories were taken in relation to DM. HbA1c and fasting blood glucose (FBG) tests were conducted for each participant. A total of 125 participants, 87 (69.6%) women and 38 (30.4%) men, were included in the study, and five (4%) participants had diabetes. The analysis of the independent risk factors associated with diabetes by multivariate logistic regression analysis revealed that the presence of DM in the family increased the risk of having HbA1c ≥ 5.7% (OR: 3.441; 95% CI: 1.381-8,574; p=0.008). Among women, the waist circumference being > 95 cm was determined as a discriminating factor for HbA1c ≥ 5.7% (sensitivity: 61.54% and specificity: 68.85%). Accurate patient-centered risk assessments by family physicians can lead to positive lifestyle modifications in patients. For this purpose, family physicians should evaluate the patients for diabetes and its associated risk factors and encourage them to take measures in order to prevent diabetes.


Nucleic-acid recognition interfaces: how the greater ability of RNA duplexes to bend towards the surface influences electrochemical sensor performance.
The influence of RNA versus DNA on the performance of electrochemical biosensors where redox-labelled nucleic acid duplexes bend towards the electrode surface has been assessed. Faster electron transfer was observed for duplexes containing RNA, suggesting duplexes with RNA are more flexible. These data are of particular importance for microRNA biosensors.


Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.
In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.


Randomized controlled versus naturalistic studies: a new research agenda.
The present article addresses the question of what kind of evidence is required to demonstrate that a method of psychotherapy works. Referring to recent conceptualizations of the logical structure of scientific theories, that is, the structuralistic view of theories, the author shows that randomized controlled studies (RCTs) and naturalistic studies (effectiveness studies) refer to different domains of intended applications (laboratory vs. field). This view has several important implications: (1) RCTs and naturalistic studies do not differ concerning their internal and external validity; (2) naturalistic studies do not necessarily provide lower-level evidence than RCTs; (3) evidence from RCTs cannot be transferred to psychotherapeutic practice in the field; (4) naturalistic studies are required to demonstrate that a form of therapy works in the field; (5) The proposed catalogues for levels of evidence focus on RCTs; thus, they cannot be applied to the question if a therapy works in the field; (6) It is necessary to define separate criteria for levels of evidence of naturalistic studies; and (7) a new research agenda for naturalistic studies can be derived, which is analogous to that of efficacy studies. In this article, a proposal is made to define levels of evidence of naturalistic studies. A gold standard for naturalistic studies is proposed.


Exploring Political Mistrust in Pandemic Risk Communication: Mixed-Method Study Using Social Media Data Analysis.
This research extends prior studies by the Finnish Institute for Health and Welfare on pandemic-related risk perception, concentrating on the role of trust in health authorities and its impact on public health outcomes. The paper aims to investigate variations in trust levels over time and across social media platforms, as well as to further explore 12 subcategories of political mistrust. It seeks to understand the dynamics of political trust, including mistrust accumulation, fluctuations over time, and changes in topic relevance. Additionally, the study aims to compare qualitative research findings with those obtained through computational methods. Data were gathered from a large-scale data set consisting of 13,629 Twitter and Facebook posts from 2020 to 2023 related to COVID-19. For analysis, a fine-tuned FinBERT model with an 80% accuracy rate was used for predicting political mistrust. The BERTopic model was also used for superior topic modeling performance. Our preliminary analysis identifies 43 mistrust-related topics categorized into 9 major themes. The most salient topics include COVID-19 mortality, coping strategies, polymerase chain reaction testing, and vaccine efficacy. Discourse related to mistrust in authority is associated with perceptions of disease severity, willingness to adopt health measures, and information-seeking behavior. Our findings highlight that the distinct user engagement mechanisms and platform features of Facebook and Twitter contributed to varying patterns of mistrust and susceptibility to misinformation during the pandemic. The study highlights the effectiveness of computational methods like natural language processing in managing large-scale engagement and misinformation. It underscores the critical role of trust in health authorities for effective risk communication and public compliance. The findings also emphasize the necessity for transparent communication from authorities, concluding that a holistic approach to public health communication is integral for managing health crises effectively.


Time-domain impedance boundary condition modeling with the discontinuous Galerkin method for room acoustics simulations.
The time-domain nodal discontinuous Galerkin (TD-DG) method is emerging as a potential wave-based method for three-dimensional (3D) room acoustics modeling, where high-order accuracy in the low frequency range, geometrical flexibility, and accurate modeling of boundary conditions are of critical importance. This paper presents a formulation of broadband time-domain impedance boundary conditions (TDIBCs) of locally-reacting surfaces in the framework of the TD-DG method. The formulation is based on the approximation of the plane-wave reflection coefficient at normal incidence in the frequency domain using a sum of template rational functions, which can be directly transformed to the time-domain. The coupling of the TDIBCs with the discontinuous Galerkin discretization is achieved through the characteristic waves of the upwind flux along the boundary, where a series of first-order auxiliary differential equations is time-integrated in a high-order way. To verify the performance of the formulation, various numerical tests of single reflection scenarios are shown to demonstrate the cost efficiency and memory-efficiency of high-order basis functions, among which a 3D application to an impedance boundary of rigidly backed glass-wool baffle for room acoustic purposes is presented.


Syntheses, characterizations and properties of [Mo2O2S2]-based oxothiomolybdenum wheels incorporating bisphosphonate ligands.
We report the syntheses and characterizations of the first polyoxothiometalate complexes isolated from the reaction of the oxothiocationic [Mo(V)(2)O(2)S(2)](2+) precursor and bisphosphonate ligands H(2)O(3)PCR(OH)PO(3)H(2) (R = C(4)H(5)N(2), zoledronic acid; R = C(3)H(6)NH(2), alendronic acid). [(Mo(2)O(2)S(2)(H(2)O))(4)(O(3)PC(O)(C(4)H(6)N(2))PO(3))(4)](8-) (Mo(8)S(8)(Zol)(4)) and [(Mo(2)O(2)S(2)(H(2)O))(4)(O(3)PC(O)(C(3)H(6)NH(3))PO(3))(4)](8-) (Mo(8)S(8)(Ale)(4)) contain four Mo(V) dimers connected via bisphosphonate ligands. These compounds offer a unique opportunity to compare the structures and properties of cyclic compounds obtained with [Mo(2)O(2)S(2)](2+) and with [Mo(2)O(4)](2+). The oxothio compounds appear less stable in solution than the oxo analogue, confirming the higher lability and versatility of [Mo(2)O(2)S(2)]-based compounds compared to [Mo(2)O(4)]-based POMs. Multinuclear and multidimensional solid-state NMR studies were carried out to complement X-ray diffraction analysis. Information on short-range interactions, dynamic behaviors, and local disorder within the crystalline materials are therefore reported. Furthermore, the electrocatalytic properties of Mo(8)S(8)(Ale)(4) and of the analogous [(Mo(2)O(4)(H(2)O))(4)(O(3)PC(O)(C(3)H(6)NH(3))PO(3))(4)](8-) (Mo(8)O(8)(Ale)(4)) immobilized onto the surface of a glassy carbon electrode were studied, thus evidencing the ability of [Mo(2)O(2)S(2)]-based cycles to promote the reduction of protons into hydrogen, whereas the oxo analogue appeared inactive.


Condensin restructures chromosomes in preparation for meiotic divisions.
The production of haploid gametes from diploid germ cells requires two rounds of meiotic chromosome segregation after one round of replication. Accurate meiotic chromosome segregation involves the remodeling of each pair of homologous chromosomes around the site of crossover into a highly condensed and ordered structure. We showed that condensin, the protein complex needed for mitotic chromosome compaction, restructures chromosomes during meiosis in Caenorhabditis elegans. In particular, condensin promotes both meiotic chromosome condensation after crossover recombination and the remodeling of sister chromatids. Condensin helps resolve cohesin-independent linkages between sister chromatids and alleviates recombination-independent linkages between homologues. The safeguarding of chromosome resolution by condensin permits chromosome segregation and is crucial for the formation of discrete, individualized bivalent chromosomes.


[C-reactive protein: general review and role in the study of infections].
Known since 1930, C-reactive protein is, as serum amyloid P component its similar, part of acute phase response proteins. Its principals properties are short half-life (6-8 h), great (within 6 hours) and high (X500) rate after injury. It activates the classical complement pathway, leading further to bacterial opsonization. Different biological methods for measurement are described: both nephelometric laser method, most sensible, and agglutination-latex method, most simple and quickest, are chosen. Studies showed us that CRP value is interesting for diagnosis of bacterial infections: among them neonates infections, peri-partum infections, meningitis, pyelonephritis, pancreatitis or peritonitis. CRP value determination seems to be useful also to hold on with patients who keep infectious peril, as in post chirurgical following, neutropenic induced patients. It seemed to be no use for CRP measurement in grafts following. Its rate in inflammatory diseases or myocardial infarcts is just mentioned. The author precognize more determinations of CRP: in emergency laboratories for diagnosis of bacterial infections (agglutination latex method) and in "routine" to follow up the infectious peril.