Nemabiome metabarcoding reveals differences between gastrointestinal nematode species infecting co-grazed sheep and goats.
Our current understanding of differences in the epidemiology of gastrointestinal nematode (GIN) species in co-grazed sheep and goats is inadequate with reference to the development of sustainable control strategies. The next-generation metabarcoding sequencing method referred to as the 'nemabiome' allows some of these differences to be explored to describe the intensity of co-infecting GIN species. We applied this platform to study sheep and goats that were co-grazed on Guinea grass pasture in northeastern Brazil. Co-grazed goats and sheep were treated with a monepantel anthelmintic, then exposed to the same gastrointestinal nematode species. Overall, there were differences in the prevalence of GIN species identified in the sheep and goats; Trichostrongylus colubriformis and Teladorsagia circumcincta predominated in goat kids, while Haemonchus contortus predominated in adult does, ewes and lambs once burdens became re-established after anthelmintic treatment. Description of the pattern of re-infection following anthelmintic treatment was prevented by the unpredicted poor efficacy of 2.5 mg/kg and 5 mg/kg, respectively, of monepantel against O. columbianum and T. circumcincta in lambs, and T. circumcincta adult does. Differences in drug efficacy between host age and species groups may be important when considering sustainable GIN control strategies for co-grazed animals. The aggregated FECs of the adult does and goat kids representing re-established GIN burdens, were higher than those of the co-grazed adult ewes and lambs. This implies that there are inherent differences in GIN species adaptation to the two naïve small ruminant host species, and shows the need for better understanding of the factors giving rise to this situation associated with exposure to infective larvae and host responses. At the start of the study, the adult does were co-infected with several GIN species, with the highest intensity of T. circumcincta, contrasting with the situation in the adult ewes, in which H. contortus predominated. However, once burdens became re-established after treatment, H. contortus predominated in both adult does and ewes. This demonstrates the potential for host burdens of H. contortus to establish and predominate after anthelmintic treatment when burdens of co-infecting GIN species are low.


Outcomes of male patients attending the symptomatic breast unit: adherence to local and national imaging guidelines and effectiveness of clinical examination and imaging in detecting male breast cancer.
To review outcomes of male patients attending the breast unit, evaluate effectiveness of imaging and examination in detecting breast cancer and review adherence to guidelines for male breast imaging. A retrospective review was undertaken of male patients attending Cambridge Breast Unit from 1 January 2015 to 31 December 2019. Patient electronic records and imaging were reviewed to establish demographics, clinical findings, imaging, biopsy, and pathology outcomes. Of 1,362 male patients attending the breast unit, 1,028 (75%) had imaging performed. Biopsy was performed in 41 men (3%), with 14 cancers diagnosed (1%). Clinical examination showed 42.7% sensitivity, 99.6% specificity, 54.6% positive predictive value (PPV) and 99.4% negative predictive value (NPV) for detection of cancer. Mammogram demonstrated 84.6% sensitivity, 99.4% specificity, 69.8% PPV, and 99.8% NPV for detection of malignancy. Ultrasound demonstrated 78.6% sensitivity, 98.9% specificity, 73.3% PPV and 99.2% NPV for detection of cancer. Forty-one percent of patients <40 years and 51% < 50 years were imaged, who according to local and Royal College of Radiologists (RCR) guidelines did not require imaging based on age and clinical score. Male patients account for a small proportion of referrals to the breast unit but generate significant workload. Imaging protocols, incorporating clinical score and age cut-off at 40 years remains robust for detecting malignancy. Clinician awareness of the imaging protocol, and close liaison with radiologists is essential to minimise additional radiology workload.


Investigating the impact of cognitive biases in radiologists' image interpretation: A scoping review.
Image interpretation is a fundamental aspect of radiology. The treatment and management of patients relies on accurate and timely imaging diagnosis. However, errors in radiological reports can negatively impact on patient health outcomes. These misdiagnoses can be caused by several different errors, but cognitive biases account for 74 % of all image interpretation errors. There are many biases that can impact on a radiologist's perception and cognitive processes. Several recent narrative reviews have discussed these cognitive biases and have offered possible strategies to mitigate their effects. However, these strategies remain untested. Therefore, the purpose of this scoping review is to evaluate the current knowledge on the extent that cognitive biases impact on medical image interpretation. Scopus and Medline Databases were searched using relevant keywords to identify papers published between 2012 and 2022. A subsequent hand search of the narrative reviews was also performed. All studies collected were screened and assessed against the inclusion and exclusion criteria. Twenty-four publications were included and categorised into five main themes: satisfaction of search, availability bias, hindsight bias, framing bias and other biases. From these studies, there were mixed results regarding the impact of cognitive biases, highlighting the need for further investigation in this area. Moreover, the limited and untested debiasing methods offered by a minority of the publications and narrative reviews also suggests the need for further research. The potential of role of artificial intelligence is also highlighted to further assist radiologists in identifying and mitigating these cognitive biases. Cognitive biases can impact radiologists' image interpretation, however the effectiveness of debiasing strategies remain largely untested.


Nrf2 participates in depressive disorders through an anti-inflammatory mechanism.
A causative relationship between inflammation and depression is gradually gaining consistency. Because Nrf2 participates in inflammation, we hypothesized that Nrf2 could play a role in depressive disorders. In this study, we have observed that Nrf2 deletion in mice results in: (i) a depressive-like behavior evaluated as an increase in the immobility time in the tail-suspension test and by a decrease in the grooming time in the splash test, (ii) reduced levels of dopamine and serotonin and increased levels of glutamate in the prefrontal cortex, (iii) altered levels of proteins associated to depression such as VEGF and synaptophysin and (iv) microgliosis. Furthermore, treatment of Nrf2 knockout mice with the anti-inflammatory drug rofecoxib reversed their depressive-like behavior, while induction of Nrf2 by sulforaphane, in an inflammatory model of depression elicited by LPS, afforded antidepressant-like effects. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel antidepressive drugs.


A tale of two lipids: Lipid unsaturation commands ferroptosis sensitivity.
Membrane lipids play important roles in the regulation of cell fate, including the execution of ferroptosis. Ferroptosis is a non-apoptotic cell death mechanism defined by iron-dependent membrane lipid peroxidation. Phospholipids containing polyunsaturated fatty acids (PUFAs) are highly vulnerable to peroxidation and are essential for ferroptosis execution. By contrast, the incorporation of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis. The enzymes and pathways that govern PUFA and MUFA metabolism therefore play a critical role in determining cellular sensitivity to ferroptosis. Here, we review three lipid metabolic processes-fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling-that can govern ferroptosis sensitivity by regulating the balance of PUFAs and MUFAs in membrane phospholipids.


MRI/SPECT-based diagnosis and CT-guided high-intensity focused-ultrasound treatment system in MPTP mouse model of Parkinson's disease.
Single-photon emission computed tomography (SPECT) of dopamine transporters with (99m)Tc-TRODAT-1 has recently been proposed to offer valuable information for the diagnosis of Parkinson's disease (PD). Furthermore, High-intensity focused ultrasound (HIFU) is a newly developed technique in which the energy of ultrasound wave is directed to a focused spot for the purpose treatment of PD. This study presents a diagnosis and image-guided system using HIFU to treat the mouse with PD under a designed stereotactic frame. The system comprises two key components: an automatic atlas-based SPECT/MRI image registration module for diagnosis and a stereotactic CT-guided module for HIFU treatment. The SPECT/MR image registration here is important in the non-invasive examination of the dopamine concentration in vivo. From the experimental results, the image registration module proves to have comparable performance to that derived from manual drawing by experts. In addition, the stereotactic CT-guided module achieved a positioning accuracy to within 2mm on the average, which is acceptable for the purpose of HIFU treatment.


Is Platelet-Rich Plasma a Future Therapy in Pain Management?
Platelet-rich plasma (PRP) has the potential to regenerate tissues and decrease pain through the effects of bioactive molecules and growth factors present in alpha granules. Several PRP preparation systems are available with varying end products, doses of growth factors, and bioactive molecules. This article presents the biology of PRP, the preparation of PRP, and the effects PRP-related growth factors have on tissue healing and repair. Based on available evidence-based literature, the success of PRP therapy depends on the method of preparation and composition of PRP, the patient's medical condition, anatomic location of the injection, and the type of tissue injected.


Hyperlipidaemia in uraemic patients under chronic haemodialysis. Correlation with serum lipoprotein lipase and insulin levels.
Hyperlipidaemia is implicated in vascular complications of uraemic patients on haemodialysis. In this work serum lipids, serum lipoprotein lipase (LPL) and insulin levels were measured in 45 chronic uraemic patients on haemodialysis and 44 healthy volunteers. A significant rise in total lipids (TL), cholesterol and triglycerides (TG) was detected in the haemodialysis patients, but no changes were found in either serum phospholipids or high density lipoprotein cholesterol (HDL-chol.). The rise in TL, TG and cholesterol was positively correlated with the duration of dialysis but not with age or sex. On the other hand, a significant rise was also observed in serum LPL and insulin levels but with no correlation between any of them and the lipid levels. From this study it may be apparent that other factors rather than LPL abnormalities may be implicated in hyperlipidaemia in uraemic patients under haemodialysis.


Microplastics in the edible and inedible tissues of pelagic fishes sold for human consumption in Kerala, India.
Microplastics in commercially important seafood species is an emerging area of food safety concern. While there have been reports of plastic particles in the gastrointestinal tract of several species, presence of microplastics in edible fish tissues has not yet been reported from India. This study examined the presence of microplastics in the edible (muscle and skin) and inedible (gill and viscera) tissues of nine commercially important pelagic fish species from Kerala, India. A total of 163 particles consisting mainly of fragments (58%) were isolated. Out of 270 fishes analysed (n = 30 per species), 41.1% of the fishes had microplastics in their inedible tissues while only 7% of fishes had microplastics in their edible tissues. The quantity of microplastics in inedible tissue was significantly larger in filter feeders than, that in visual predators (p < 0.05). The average abundance of microplastics in edible tissues was 0.07 ± 0.26 items/fish (i.e., 0.005 ± 0.02 items/g) and was 0.53 ± 0.77 items/fish (i.e., 0.054 ± 0.098 items/g) in inedible tissues. The results suggest the possibility of human intake of microplastics by the consumption of pelagic fishes from this region, albeit in small quantities.


Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy.
Because of concerns regarding interactions between midazolam and antiretroviral therapy (ART), alternative sedatives are sometimes used during procedural sedation. Our objective was to compare outcomes in patients on ART who received intravenous (iv) midazolam vs. iv diazepam, a second-line agent, during colonoscopy. We conducted a retrospective analysis of adult HIV-positive patients who underwent colonoscopy over a 3.5-year period. Primary outcomes were sedation duration, nadir systolic blood pressure (SBP), nadir oxygen saturation, abnormal cardiac rhythm, and change in level of consciousness using a standardized scale. We calculated rates of adverse events according to benzodiazepine use and identified risk factors for complications using univariate and multivariate analyses. We identified 136 patients for this analysis: 70 received midazolam-based sedation and 66 received a diazepam-based regimen. There were no significant differences between the two groups with respect to sedation duration (mean 48.0 vs. 45.7 minutes for the midazolam and diazepam groups, respectively; P = 0.68), nadir SBP (mean 97.0 vs. 101.6 mmHg; P = 0.06), nadir oxygen saturation (mean 94.6 vs. 94.8%; P = 0.72) or rate of abnormal cardiac rhythm (11.4 vs. 19.7%; P = 0.18). More patients in the midazolam group experienced a depressed level of consciousness (91% vs. 74% in the diazepam group; P = 0.0075), but no patient required reversal of sedation or became unresponsive. We did not find evidence that patients who received midazolam for procedural sedation had clinical outcomes statistically different from those who received diazepam. These findings should be confirmed in prospective studies or in a randomized controlled trial.


COVID-19 Passport as a Factor Determining the Success of National Vaccination Campaigns: Does It Work? The Case of Lithuania vs. Poland.
As the ongoing COVID-19 pandemic poses a global threat, it is of utmost importance that governments should find effective means of combating vaccine hesitancy and encouraging their citizens to vaccinate. In our article, we compare the vaccination outcomes in the past months in two neighbouring post-communist EU states, Lithuania and Poland. Both introduced COVID-19 certificates, but only the former followed with gradual limitations for those who failed to get vaccinated, beginning with restricted access to restaurants, sports facilities and indoor events, and finally banning residents without a certificate from entering supermarkets or larger shops and using most services. By contrast, in Poland, the certificate remained a tool for international travel only. We show using statistical data that Lithuania's strict policy, regardless of its social implications, led to markedly higher vaccination outcomes in all age groups than those in Poland at the time.


Metastatic Transition of Pancreatic Ductal Cell Adenocarcinoma Is Accompanied by the Emergence of Pro-Invasive Cancer-Associated Fibroblasts.
Cancer-associated fibroblasts (CAFs) are now appreciated as key regulators of cancer metastasis, particularly in cancers with high stromal content, e.g., pancreatic ductal cell carcinoma (PDAC). However, it is not yet well understood if fibroblasts are always primed to be cooperative in PDAC transition to metastasis, if they undergo transformation which ensures their cooperativity, and if such transformations are cancer-driven or intrinsic to fibroblasts. We performed a fibroblast-centric analysis of PDAC cancer, as it transitioned from the primary site to trespass stromal compartment reaching the lymph node using published single-cell RNA sequencing data by Peng et al. We have characterized the change in fibroblast response to cancer from a normal wound healing response in the initial stages to the emergence of subclasses with myofibroblast and inflammatory fibroblasts such as signatures. We have previously posited "Evolved Levels of Invasibility (ELI)", a framework describing the evolution of stromal invasability as a selected phenotype, which explains the large and correlated reduction in stromal invasion by placental trophoblasts and cancer cells in certain mammals. Within PDAC samples, we found large changes in fibroblast subclasses at succeeding stages of PDAC progression, with the emergence of specific subclasses when cancer trespasses stroma to metastasize to proximal lymph nodes (stage IIA to IIB). Surprisingly, we found that the initial metastatic transition is accompanied by downregulation of ELI-predicted pro-resistive genes, and the emergence of a subclass of fibroblasts with ELI-predicted increased invasibility. Interestingly, this trend was also observed in stellate cells. Using a larger cohort of bulk RNAseq data from The Cancer Genome Atlas for PDAC cancers, we confirmed that genes describing this emergent fibroblast subclass are also correlated with lymph node metastasis of cancer cells. Experimental testing of selected genes characterizing pro-resistive and pro-invasive fibroblast clusters confirmed their contribution in regulating stromal invasability as a phenotype. Our data confirm that the complexity of stromal response to cancer is really a function of stage-wise emergence of distinct fibroblast clusters, characterized by distinct gene sets which confer initially a predominantly pro-resistive and then a pro-invasive property to the stroma. Stromal response therefore transitions from being tumor-limiting to a pro-metastatic state, facilitating stromal trespass and the onset of metastasis.


Thyroid papillary cancer elements arising from struma ovarii with benign peritoneal strumosis: Utility of iodine-123 imaging in diagnostics and treatment planning.
In this case of struma ovarii a right-sided ovarian mass contained features of papillary thyroid cancer. Diagnostic iodine-123 revealed multiple foci of extraovarian spread, likely as a manifestation of concomitant peritoneal strumosis. Unilateral oophorectomy, partial peritonectomy, and adjuvant iodine-131 treatment were performed for successful curative treatment. Struma ovarii is a rare form of mature teratoma defined by a predominance of thyroid tissue. Approximately 5% of all ovarian strumae exhibit malignant transformation. Due to their extreme rarity, there has been a lack of consensus concerning uniform diagnostic criteria. Appropriate, risk-stratified treatment strategies also remain widely unelaborated, based only on a small number of cases reported in the literature. We describe the case of a 35-year-old female, who presented after undergoing unilateral oophorectomy for a right-sided ovarian mass. Histological workup revealed a struma ovarii containing papillary thyroid cancer (PTC). Postoperative I-123 scintigraphy with single photon emission computed tomography (SPECT) detected multifocal extra-ovarian spread to the peritoneum, containing likely benign strumosis upon pathological examination. The subsequent treatment strategy involved an ablative concept including total thyroidectomy and subsequent I-131 radioiodine therapy. Throughout a 3-year follow-up, the patient has remained without recurrence with thyroglobulin levels ranging below detection limits. Surgical resection with adjuvant radioiodine therapy is a curative therapeutic strategy in cases of struma ovarii with thyroid-type carcinoma and peritoneal strumosis. Its benefits lay in avoiding more extensive surgery, potentially maintaining fertility, facilitating follow-up, and minimizing the risk of recurrence. Reliable criteria for risk stratification are needed to identify patients who are most likely to benefit from this treatment approach.


Prevalence of selected viral infections among temporarily deferred donors who returned to donate blood: American Red Cross blood donor study.
Health history questions are introduced into the predonation interview to identify blood donors believed to pose a higher risk of infectious diseases to recipients. This study assesses the current impact of some of those questions. Donor deferral and donation data were extracted from a research database of the American Red Cross. The prevalence of hepatitis B surface antigen or antibodies to human immunodeficiency virus, hepatitis C virus, or human T-lymphotropic virus was obtained for different groups of donors who were temporarily deferred in 2000 through 2001 and later returned to donate blood in 2000 through 2003. The results were compared with either first-time or repeat donors in 2000 through 2003, while controlling for differences in sex, age, and year of donation. Of donors temporarily deferred in 2000 through 2001 who had had no donation or deferral during the previous 2 years, only 22.08 percent subsequently returned to donate blood in 2000 through 2003. Donations from returning donors who had been deferred for potential infectious disease risk did not show a higher prevalence for any of the viral markers when those with no donation or deferral during the previous two years were compared with first-time donations, and those with prior donation were compared with repeat donations. Blood donors temporarily deferred in 2000 through 2001 for potential risk of viral infection who later returned to donate blood did not appear to pose a higher risk compared to first-time or repeat donors. The effectiveness of some of the currently used deferral questions in reducing viral risks warrants further study.


Crystal structure of a CoII coordination polymer: catena-poly[[μ-aqua-bis-(μ-2-methyl-propano-ato)-κ2O:O';κ2O:O-cobalt(II)] monohydrate].
In the title cobalt(II) coordination polymer with isobutyrate ligands, {[Co{CH(CH3)2CO2}2(H2O)]·H2O} n , the Co2+ ion is hexa-coordinated in a slightly distorted octa-hedral coordination environment defined by two O atoms from two bridging water mol-ecules and four O atoms from four bridging carboxyl-ate ligands. The carboxyl-ates adopt two different coordination modes, μ-(κ2O:O') and μ-(κ2O:O), forming a one-dimensional polymeric chain extending along [010]. The intra-chain cobalt⋯cobalt separation is 3.2029 (2) Å. The polymeric chains are linked by hydrogen bonds involving the water mol-ecules of solvation, giving a two-dimensional network structure lying parallel to (100).


Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS.
The effect of administration of the antiepileptic drug valproate (VPA), on the composition of the plasma acylcarnitine profile (including free carnitine) was investigated. Plasma samples were obtained from 18 individuals (13 males:5 females; 15-65 y) on long-term treatment with VPA (resulting in plasma levels of 14.6-135.0 mg/L; therapeutic conc.: 40-100 mg/L). Acylcarnitines (AC) in plasma were quantified by electrospray tandem mass spectrometry (ESI-MS/MS). VPA was found to increase the levels (mean +/- SD, microM) of 3-hydroxy-isovalerylcarnitine (0.10 +/- 0.04; controls: 0.02-0.06), C14:2 acylcarnitine (0.11 +/- 0.05; controls: 0.02-0.08), propylglutarylcarnitine (0.06 +/- 0.05; controls: 0.00-0.04), and C18-0H-acylcarnitine (0.09 +/- 0.05; controls: 0.00-0.04). The free carnitine (C) (42.2 +/- 9.0; controls: 22.3-54.9) and the total carnitine (52.3 +/- 10.1; controls: 26.5-73.6) were not significantly altered by VPA. Other AC (C2-C18, monounsaturated and hydroxylated) were all within the control range and especially no increase of C8 (valproyl) carnitine was observed. A positive correlation was found between the ratios [AC] / [C] (p < 0.05) or [long-chain AC (C10-C18)] / [C] (p < 0.09) with the plasma VPA concentration. The unequivocal increase in 3-hydroxy-isovalerylcarnitine is consistent with the increase of 3-hydroxy-isovaleric acid observed in urine of VPA treated patients. This finding suggests an interaction mechanism of VPA with specific enzymes, namely involved in leucine metabolism. Adult patients under VPA monotherapy do not suffer from carnitine deficiency; the effect of the accumulating acylcarnitines is ill-defined.


Evidence in support of the P1/P2 purinoceptor hypothesis in the guinea-pig taenia coli.
1 The relaxations induced by adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine on the carbachol-contracted taenia coli of the guinea-pig have been studied. ATP and ADP produce similar responses which differ in nature and time course from those of AMP and adenosine. 2 Theophylline, at concentrations (25-200 muM) lower than those which produce significant phosphodiesterase inhibition, blocks the effects of AMP and adenosine but fails to antagonize the responses elicited by ATP and ADP. The antagonism of adenosine by theophylline appears to be competitive. 3 Apamin (1-100 nM) blocks the inhibitory effects of ATP and ADP but fails to antagonize the responses to AMP and adenosine. The antagonism by apamin is non-competitive. 4 The results indicate that ATP and adenosine relax the taenia coli by activating different receptors and are consistent with the P1, P2 purinoceptor hypothesis.


[Dynamics of acetylcholinesterase activity in the brain during elaboration and stabilization of defensive conditioned reflexes].
Electro-defensive condtioned reflexes (CR) to light were elaborated in rats in Y-maze in one experimental session and their training was continued during subsequent 20 sessions. Immediately after CR elaboration or the 20th session of its training, AChE activity in the motor and visual cortex and the hippocampus decreased, increasing again in 24 hours. Animals used as active control which received non-paired photic and electric stimuli, exhibited opposite changes of AChE activity.


The practise of breast self-examination over a six-year period following teaching.
The null hypothesis is that there is no difference in the performance of breast self-examination (BSE) with respect to three teaching methodologies. A total of 614 women were randomly assigned to a group receiving content only, one receiving content plus supervised practise on a model with implanted lumps or one receiving content plus instruction on their own breasts. It has been established that all groups increased significantly their frequency of practise and level of confidence (Alcoe SY, Gilbey VJ. McDermot RSR, Wallace DG. The effects of teaching breast self-examination: reported confidence and frequency of practise over a six-year period. Patient Educ Couns 1994; 23: 13-21). This paper considers the steps undertaken during BSE and the changes likely to be noticed through factors labelled Technique, Observation, Inspection and Palpation. The factors have been created from 35 items reflecting multiple aspects of the procedure as reported at four follow-ups. The group wherein teaching involved practise on their own breasts achieved higher scores than the other groups. Scores for Technique and Inspection are better maintained over time than are those for Observation and Palpation.


Lipophilic modification of salirasib modulates the antiproliferative and antimigratory activity.
Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.


The functional roles of lipid rafts in T cell activation, immune diseases and HIV infection and prevention.
The first appearance of lipid rafts, or lipid rafts-like structure, was occasionally observed by cryo-electronic microscopy in 1980s as cavity, such as caveolae. However, the fully understanding of lipid raft was attributed by the studies of T cell activation, virus entry/budding, and other membrane events. During the interaction of T cell and antigen presenting cell, a highly organized structure is formed at the interface of the two cells, where cholesterol and sphingolipids are enriched, and form a liquid ordered phase that facilitates the signaling proteins on and off. Lipid rafts are also involved in virus entry and assembly. In this review, we will discuss cholesterol-sphingolipid floating microdomain, the lipid raft as a unique compartment of the plasma membrane, with biological functions that ensure correct intracellular traffic of proteins and lipids, such as protein-protein interactions by concentrating certain proteins in these microdomains, while excluding others. We also discuss the disruption of lipid rafts is related to different diseases and aging, and we especially exploit the lipid rafts as pharmaceutical targets for anti-virus and anti-inflammation, particularly a new approach to control HIV infection for AIDS prevention and protection by inhibition or disruption of lipid rafts.


Diesel exhaust particles selectively induce both proinflammatory cytokines and mucin production in cornea and conjunctiva human cell lines.
To evaluate the effect of diesel exhaust particles (DEP) on the viability, proliferation, apoptosis, secretion of cytokines (IL-6, IL-8, and TNF-α), and mucin gene transcription (MUC1, MUC5AC, and MUC16) in human epithelial cells of the cornea (HCLE) and conjunctiva (IOBA-NHC). HCLE and IOBA-NHC cells were incubated with DEP (10-500 μg/mL) for 24 hours. Cell proliferation was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were measured by an annexin V-FITC and propidium iodide kit for flow cytometry. Proinflammatory cytokines were determined by an ELISA kit. Mucin gene transcription was quantified by real-time PCR. DEP significantly decreased the viability, proliferation, and secretion of IL-8, but increased the secretion of IL-6 on both HCLE and IOBA-NHC cell lines in a dose-dependent manner. Neither cornea nor conjunctiva cells incubated with DEP released TNF-α. DEP induced a significant increase in the percentage of apoptotic cells in IOBA-NHC, whereas no changes were observed in HCLE. Finally, DEP significantly decreased the transcription levels of MUC1 and MUC16 in HCLE, but increased the transcription levels of MUC1, MUC5AC, and MUC16 in IOBA-NHC. These findings suggest that human corneal and conjunctival epithelial cells incubated with DEP showed cytotoxicity and an inflammatory response mediated by IL-6, not by TNF-α or IL-8. Also, the decrease in mucin expression in the cornea cells might leave exposed areas in the cornea for contact with DEP. Finally, the increase in mucin expression in the conjunctiva cells might be involved at least in the clearance of DEP to protect the ocular epithelium.


Abnormalities of skeletal muscle metabolism during nerve stimulation determined by 31P nuclear magnetic resonance spectroscopy in severe congestive heart failure.
These data confirm the presence of abnormal skeletal muscle metabolic function in patients with chronic heart failure. These changes are independent of patient compliance and central hemodynamic response to conventional exercise, and may explain, in part, the marked decrease in exercise tolerance often observed in patients with chronic severe heart failure. The etiology of these abnormalities of metabolic function and nutritive flow remains uncertain. TNS may prove useful in further elucidation of the peripheral metabolic consequences of chronic heart failure.


Decrease of lysyl hydroxylase 2 activity causes abnormal collagen molecular phenotypes, defective mineralization and compromised mechanical properties of bone.
Lysyl hydroxylase 2 (LH2) is an enzyme that catalyzes the hydroxylation of lysine (Lys) residues in fibrillar collagen telopeptides, a critical post-translational modification for the stability of intermolecular cross-links. Though abnormal LH2 activities have been implicated in various diseases including Bruck syndrome, the molecular basis of the pathologies is still not well understood. Since LH2 null mice die at early embryonic stage, we generated LH2 heterozygous (LH2+/-) mice in which LH2 level is significantly diminished, and characterized collagen and bone phenotypes using femurs. Compared to the wild-type (WT), LH2+/- collagen showed a significant decrease in the ratio of hydroxylysine (Hyl)- to the Lys-aldehyde-derived collagen cross-links without affecting the total number of aldehydes involved in cross-links. Mass spectrometric analysis revealed that, in LH2+/- type I collagen, the extent of hydroxylation of all telopeptidyl Lys residues was significantly decreased. In the helical domain, Lys hydroxylation at the cross-linking sites was either unaffected or slightly lower, but other sites were significantly diminished compared to WT. In LH2+/- femurs, mineral densities of cortical and cancellous bones were significantly decreased and the mechanical properties of cortical bones evaluated by nanoindentation analysis were compromised. When cultured, LH2+/- osteoblasts poorly produced mineralized nodules compared to WT osteoblasts. These data provide insight into the functionality of LH2 in collagen molecular phenotype and its critical role in bone matrix mineralization and mechanical properties.


6,12,18,24-Tetra-meth-oxy-4,10,16,22-tetra-kis-[(meth-oxy-carbon-yl)meth-oxy]-2,8,14,20-tetra-kis-(2-phenyl-eth-yl)resorcin[4]arene.
The title compound, C(76)H(80)O(16), is a macrocyclic structure. This novel resorcin[4]arene derivative has (meth-oxy-carbon-yl)meth-oxy 'head' groups on the upper rim. The compound has a C(2v) 'boat' geometry and there are a range of C-H⋯O contacts in the crystal structure.


The role of miR-150 in normal and malignant hematopoiesis.
MicroRNAs are a class of small non-coding RNAs that have been implicated to mediate gene regulation in virtually all important biological processes. Recently there is accumulating evidence showing that miR-150 has essential regulatory roles in both normal and malignant hematopoiesis and holds great potential as a therapeutic target in treating various types of hematopoietic malignancies. The purpose of this review is to summarize our current knowledge about the expression patterns, biological functions and regulatory mechanisms of miR-150 in normal and malignant hematopoiesis, and to highlight the important questions to be answered in this burgeoning field.


Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.
Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.


Immunohistochemical study on the neuroendocrine system of the digestive tract of turbot, Scophthalmus maximus (L.), infected by Enteromyxum scophthalmi (Myxozoa).
In recent years a new parasite, causing severe losses, has been detected in farmed turbot, Scophthalmus maximus (L.), in Northwestern Spain. Dead fish showed emaciation and cachexia caused by severe necrotizing enteritis, which affected all areas of the digestive tract. The parasite was classified as a myxosporean and named Enteromyxum scophthalmi. This study was designed to assess the response of the turbot neuroendocrine system against E. scophthalmi infection. Immunohistochemical tests were applied to sections of the gastrointestinal tract of uninfected and E. scophthalmi-infected turbot, and the presence of cholecystokinin (CCK-8), serotonin (5-HT), substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) were documented. A higher abundance of both endocrine epithelial cells (ECs) and nerve cell bodies and fibres for CCK-8, 5-HT and SP were recorded in the gastrointestinal tract of infected turbot, whereas VIP-like substance decreased. The results indicate that E. scophthalmi infection in turbot induced changes in the neuroendocrine system, which may cause alterations in gut motility, electrolyte and fluid secretion, and vascular and immune functions.


CD-monitored redox titration of the Rieske Fe-S protein of Rhodobacter sphaeroides: pH dependence of the midpoint potential in isolated bc1 complex and in membranes.
The redox potential of the Rieske Fe-S protein has been investigated using circular dichroism (CD)-spectroscopy. The CD features characteristic of the purified bc1 complex and membranes of Rhodobacter sphaeroides were found in the region between 450 and 550 nm. The difference between reduced and oxidized CD-spectra shows a negative band at about 500 nm with a half of width 30 nm that corresponds to the specific dichroic absorption of the reduced Rieske protein (Fee, J.A. et al. (1984) J. Biol. Chem. 259, 124-133; Degli Esposti, M. et al. (1987) Biochem. J. 241, 285-290; Rich, P.R. and Wiggins, T.E. (1992) Biochem. Soc. Trans. 20, 241S). It was found that the redox potential at pH 7.0 for the Rieske center in the isolated bc1 complex and in chromatophore membranes from the R-26 strain of Rh. sphaeroides is 300 +/- 5 mV. In chromatophores from the BC17C strain of Rh. sphaeroides, the Em value measured for the Rieske iron-sulfur protein (ISP) was higher (315 +/- 5 mV), but the presence of carotenoids made measurement less accurate. The Em varied with pH in the range above pH 7, and the pH dependence was well fit either by one pK at approximately 7.5 in the range of titration, or by two pK values, pK1 = 7.6 and pK2 = 9.8. Similar titrations and pK values were found for the Rieske Fe-S protein in the isolated bc1 complex and membranes from the R-26 strain of Rb. sphaeroides. The results are discussed in the context of the mechanism of quinol oxidation by the bc1 complex, and the role of the iron sulfur protein in formation of a reaction complex at the Qo-site.


Ixabepilone for the treatment of endometrial cancer.
Endometrial cancer (EC) is the most common gynaecological cancer. Despite significant progress in the multimodality treatment approach, the prognosis remains poor for patients with advanced disease. Thus, there is the necessity of more effective strategies. The microtubule-stabilizing agent ixabepilone is the first drug in this new class of agents that has been approved for metastatic breast cancer treatment. Based on empiric data and on the clinical efficacy demonstrated in breast cancer, several clinical trials were proposed to define its role in EC. The aim of this review is to determine whether ixabepilone improved the clinical outcome in patients with locally advanced, recurrent or metastatic EC. Preclinical and clinical studies of ixabepilone in endometrial cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, phase I and II studies registered on clincaltrials.gov, and related abstracts recently presented at major international congresses. Advanced or recurrent EC still represents a challenge and an unmet need in the panorama of gynaecological malignancies. Ixabepilone's future therapeutic role in EC remains ill defined. Nevertheless, despite its limited efficacy in EC, clinicians treating gynaecological tumours should be aware of its main aspects.


Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.
Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.


Effects of a mindfulness based childbirth and parenting program on pregnant women's perceived stress and risk of perinatal depression-Results from a randomized controlled trial.
The aim of this study was to test the efficacy of a Mindfulness-Based Childbirth and Parenting Program (MBCP) in reducing pregnant women's perceived stress and preventing perinatal depression compared to an active control condition. First time pregnant women (n = 197) at risk of perinatal depression were randomized to MBCP or an active control treatment, which consisted of a Lamaze childbirth class. At baseline and post-intervention, participants filled out questionnaires on perceived stress, depressive symptoms, positive states of mind, and five facets of mindfulness. Compared to the active control treatment, MBCP significantly reduced perceived stress (p = 0.038, d = 0.30) and depressive symptoms (p = 0.004, d = 0.42), and increased positive states of mind (p = 0.005, d = 0.41) and self-reported mindfulness (p = 0.039, d = 0.30). Moreover, change in mindfulness possibly mediated the treatment effects of MBCP on stress, depression symptoms, and positive states of mind. The subscales "non-reactivity to inner experience" and "non-judging of experience" seemed to have the strongest mediating effects. The outcomes were self-report questionnaires, the participants were not blinded to treatment condition and the condition was confounded by number of sessions. Our results suggest that MBCP is more effective in decreasing perceived stress and risk of perinatal depression compared to a Lamaze childbirth class. The results also contribute to our understanding of the underlying psychological mechanisms through which the reduction of stress and depression symptoms may operate. Thus, this study increases our knowledge about efficient intervention strategies to prevent perinatal depression and promote mental wellbeing among pregnant women.


Aroma of peas, its constituents and reduction strategies - Effects from breeding to processing.
Peas as an alternative protein source have attracted a great deal of interest from the food industry and consumers in recent years. However, pea proteins usually do not taste neutral and exhibit a distinct flavor, often characterized as "beany". This is usually contrasted by the food industry's desire for sensory neutral protein sources. In this review, we highlight the current state of knowledge about the aroma of peas and its changes along the pea value chain. Possible causes and origins, and approaches to reduce or eliminate the aroma constituents are presented. Fermentative methods were identified as interesting to mitigate undesirable off-flavors. Major potential has also been discussed for breeding, as there appears to be a considerable leverage at this point in the value chain: a reduction of plant-derived flavors, precursors, or substrates involved in off-flavor evolution could prevent the need for expensive removal later.


Carbon Nanotubes as Reinforcement of Cellulose Liquid Crystalline Responsive Networks.
The incorporation of small amount of highly anisotropic nanoparticles into liquid crystalline hydroxypropylcellulose (LC-HPC) matrix improves its response when is exposed to humidity gradients due to an anisotropic increment of order in the structure. Dispersed nanoparticles give rise to faster order/disorder transitions when exposed to moisture as it is qualitatively observed and quantified by stress-time measurements. The presence of carbon nanotubes derives in a improvement of the mechanical properties of LC-HPC thin films.


The seed-specific transcription factor DPBF2 modulates the fatty acid composition in seeds.
Triacylglycerol (TAG), an ester derived from glycerol and three fatty acids (FAs), is synthesized during seed development and controlled by transcriptional regulation. We examined the mechanism regulating the FA composition of developing Arabidopsis thaliana seeds. The seed-specific DC3 PROMOTER-BINDING FACTOR2 (DPBF2) transcription factor was upregulated by LEAFY COTYLEDON2 (LEC2). DPBF2 showed transcriptional activity in yeast and localized to the nucleus in Arabidopsis protoplast cells. The Arabidopsis dpbf2-1 homozygous T-DNA mutant and transgenic lines overexpressing of DPBF2 using a seed-specific phaseolin promoter in wild-type (WT) Arabidopsis and in dpbf2-1 showed similar FA composition profiles in their seeds. Their 18:2 and 20:1 FA contents were higher, but 18:1 and 18:3 contents were lower than that of WT. Transcript levels of FATTY ACID DESATURASE2 (FAD2), FAD3, LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE1 (LPCAT1), LPCAT2, PHOSPHATIDYLCHOLINE DIACYLGLYCEROL CHOLINEPHOSPHOTRANSFERASE (PDCT), and FATTY ACID ELONGASE 1 (FAE1) are increased in DPBF2-overexpressing seeds. Besides, PDCT and FAE1 were upregulated by DPBF2, LEC1-LIKE (L1L), and NUCLEAR FACTOR-YC2 (NF-YC2) transcriptional complex based on tobacco protoplast transcriptional activation assay. These results suggest that DPBF2 effectively modulates the expression of genes encoding FA desaturases, elongase, and acyl-editing enzymes for modifying the unsaturated FA composition in seeds.


Magnetite/graphene oxide nano-composite for enhancement of hydrogen production from gelatinaceous wastewater.
The effect of substrate to inoculum (So/Xo) ratio and supplementation of magnetite/graphene oxide (MGO) nano-composite material on hydrogen production from gelatinaceous wastewater via dark fermentation process was investigated. Results demonstrated that optimum So/Xo ratio of 1.0gCOD/gVSS achieved maximal hydrogen yield (HY) of 79.2±11.9mL H2/gCOD removed. Supplementation of anaerobes with 100mg/L MGO promoted HY up to 112.4±10.5mL H2/gCOD removed. Moreover, the degradation efficiency of carbohydrates, proteins and lipids was improved to 80.8±7.6, 34.4±2.3 and 31.4±2.2%, respectively. Acetate (HAc) and butyrate (HBu) concentrations increased from 102±6.8 to 125.3±6.3 and from 31.1±1.5 to 48.8±3.5mg/gVSS, respectively. However, propionate (HPr) concentration dropped from 35.9±2.7 to 15±1.3mg/gVSS. Hydrogenase enzyme activity increased 9-folds and the anaerobes elongated from ca. 1.8-2.9 to ca. 2.5-5.1μm with MGO addition. Moreover, Proteobacteria, Firmicutes, Clostridia and Bacilli were detected with the batches supplemented with MGO.


The liver in Hodgkin's disease--II. Histopathologic findings.
Histopathologic findings in 459 liver biopsies performed in 308 patients with Hodgkin's disease were reviewed. Typical Hodgkin infiltrates were found in only 11/459 biopsies (2.4%) and infiltrates suspect for Hodgkin's disease in only 8/459 (1.7%), whereas unspecific changes were more common. Lymphocytic infiltration was seen in 47% of the biopsies and focal necrosis in 19%. No correlation could be demonstrated between unspecific changes and clinical characteristics, including prognosis.


In vitro system for studying the efficacy of antiviral agents in preventing the reactivation of latent herpes simplex virus.
Antiviral antibody and interferon did not prevent in vitro reactivation of herpes simplex virus in latently infected sensory ganglia. Phosphonoacetic acid and 9-beta-d-arabinofuranosyladenine blocked reactivation, but this treatment did not eradicate the latent infection.


DNA methylation in peripheral tissues and left-handedness.
Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.


Signs of ancient and modern exon-shuffling are correlated to the distribution of ancient and modern domains along proteins.
Exon-shuffling is an important mechanism accounting for the origin of many new proteins in eukaryotes. However, its role in the creation of proteins in the ancestor of prokaryotes and eukaryotes is still debatable. Excess of symmetric exons is thought to represent evidence for exon-shuffling since the exchange of exons flanked by introns of the same phase does not disrupt the reading frame of the host gene. In this report, we found that there is a significant correlation between symmetric units of shuffling and the age of protein domains. Ancient domains, present in both prokaryotes and eukaryotes, are more frequently bounded by phase 0 introns and their distribution is biased towards the central part of proteins. Modern domains are more frequently bounded by phase 1 introns and are present predominantly at the ends of proteins. We propose a model in which shuffling of ancient domains mainly flanked by phase 0 introns was important in the ancestor of eukaryotes and prokaryotes, during the creation of the central part of proteins. Shuffling of modern domains, predominantly flanked by phase 1 introns, accounted for the origin of the extremities of proteins during eukaryotic evolution.


Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling.
The antidiabetic drug metformin has been associated with reduced colorectal cancer (CRC) risk and improved prognosis of CRC patients. However, the detailed mechanisms underlying such beneficial effects remain unknown. In this study, we aimed to evaluate metformin activity in CRC models and unveil the underlying molecular mechanisms. We showed that metformin inhibits CRC cell proliferation by arresting cells in the G1 phase of the cell cycle and dramatically reduces colony formation of CRC cells. We discovered that metformin causes a robust reduction of MYC protein level. Through the use of luciferase assay and coincubation with either protein synthesis or proteasome inhibitors, we demonstrated that regulation of MYC by metformin is independent of the proteasome and 3' UTR-mediated regulation, but depends on protein synthesis. Data from polysome profiling and ribopuromycylation assays showed that metformin induced widespread inhibition of protein synthesis. Repression of protein synthesis by metformin preferentially affects cell cycle-associated proteins, by altering signaling through the mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E axes. The inhibition of MYC protein synthesis may underlie metformin's beneficial effects on CRC risk and prognosis.


Correlations of selenium and selenoprotein P with asymmetric dimethylarginine and lipid profile in patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular diseases (CVD). Accumulating evidence has suggested that selenium (Se) is of importance for optimal function of the cardiovascular system. This study aimed to investigate the associations of selenium and selenoprotein P (SePP) with asymmetric dimethylarginine (ADMA) and lipid profile in women with PCOS. In this cross-sectional study, 125 females aged 18-45 years diagnosed with PCOS were recruited. An interviewer-administered questionnaire was applied to gather the relevant demographic characteristics, detailed clinical information, and lifestyle habits of participants. Fasting blood samples were obtained to measure biochemical parameters. Serum concentrations of total testosterone, sex hormone-binding globulin (SHBG), ADMA, and lipid profiles as well as anthropometric measurements were assessed across tertiles of serum Se and SePP concentrations. There was a positive correlation between serum Se and SePP concentrations (r = 0.434, p < 0.001). Serum Se level was inversely correlated with ADMA (r = -0.21, p = 0.025) and TG (r = -0.17, p = 0.041) concentrations. There were also inverse correlations between SePP and ADMA (r = -0.34, p < 0.001), TG (r = -0.21, p = 0.019), and oxidized low density lipoprotein (ox-LDL) (r = -0.25, p = 0.007) levels. No significant relationship was found between serum Se and SePP concentrations with total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B100), total testosterone, SHBG, and free androgen index as well as anthropometric parameters (All p > 0.05). The present study found that Se and SePP levels were inversely correlated with ADMA and TG concentrations as well as ox-LDL levels.


Impact of the gut microbiome on mucosal inflammation.
In the past 10 years it has become increasingly apparent that the gut microbiome has profound effects on the immune system to which it is juxtaposed, the mucosal immune system. Here, I explore recent studies in which the effects of the microbiota expand or facilitate anti-inflammatory or regulatory immunological machinery or which favor development of proinflammatory immunological machinery in this system. I then focus on how these opposing processes play out in inflammatory bowel disease (IBD); a disease in which normal immune homeostasis is disturbed and inflammation takes hold.


A molecular genetic study of nif expression in Klebsiella pneumoniae at the level of transcription, translation and nitrogenase activity.
A comprehensive study of nif expression in Klebsiella pneumoniae at the level of transcription, translation and nitrogenase activity during derepression and repression by NH+4 and O2 revealed that (1) transcription and translation rates remained coupled under all conditions; (2) these rates reached a peak during derepression and then decreased to a low level; (3) the transcription profile of nifLA had two peaks; the first was at 1 h before and the second coincided with that of the other operons; and (4) the peaks of nif transcription coincided with a trough in the profile of stringent regulation of RNA synthesis. Our results provide strong evidence that nif-specific repression by NH+4 and O2 occurs exclusively by transcription inhibition and that repression by O2 is independent of transcriptional regulation of the nifLA operon. We have also found evidence which together with the results of previous work shows that O2 repression of nifA mediated transcription involves the nifL gene product.


Potential non-immunoglobulin E-mediated food allergies: comparison of open challenge and double-blind placebo-controlled food challenge.
Comparison of open food challenge (OFC) with double-blind placebo-controlled food challenge (DBPCFC). Prospective sequential randomized challenges. Twenty adults with chronic allergy symptoms and at least 1 positive intradermal food wheal response recorded symptoms during DBPCFC and OFC provoked using organic foods, normal portions, and normal food preparation. Acoustic Rhinometry and biochemical tests were done during DBPCFC. All patients reacted to at least 1 food and to all challenges with the same food, with multiorgan symptoms in the nose, nervous system, throat, and lung. There was a correlation in the type and severity of symptoms (P = 0.015) for OFC and DBPCFC, and both were significantly (P < 0.01) more severe than placebo. Compared with DBPCFC, OFC sensitivity was 66%, and positive predictive value was 89%. This is the first study showing both concordance of OFC and DBPCFC and also that intradermal tests can identify reactive foods that can be verified by DBPCFC. Because most tests for IgE-mediated food allergy were negative, observed reactions were probably non-IgE mediated.


3-Nitropropionic acid (3-NPA), a potent antimycobacterial agent from endophytic fungi: is 3-NPA in some plants produced by endophytes?
3-Nitropropionic acid (3-NPA, 1) was found in extracts of several strains of endophytic fungi. 3-NPA (1) exhibited potent antimycobacterial activity with the minimum inhibition concentration of 3.3 microM, but was inactive against NCI-H187, BC, KB, and Vero cell lines. Endophytes were found to produce high levels of 3-NPA (1), and therefore 3-NPA (1) accumulated in certain plants may be produced by the associated endophytes. 3-NPA (1) may be used as a chemotaxonomic marker for endophytic fungi. The structure of 3-hydroxypropionic acid, a nematicidal agent, should be revised to 3-NPA (1).


The antidromic compound action potential of the hypothalamo-neurohypophysial tract, a tool for assessing posterior pituitary activity in vivo.
A sensitive technique was developed for measuring continuously the summated neural activity of the rat hypothalamo-neurohypophysial tract. Large compound potentials of 4-9 mV peak amplitude were recorded from the fibre tract in response to electrical stimulation of the neurohypophysis. It was estimated that all fibres in the tract were electrically activated and contributed to the compound potential. It was shown that a decrease of peak amplitude could be used as a measure of changes in endogenous neural activity. The decrease in peak amplitude during an increase of endogenous neural activity was due to fatigue and temporal spread of the compound potential, and also to collision of antidromic and orthodromic action potentials. Decrease of the compound potentials was related to the intensity of vaginal distension, haemorrhage and plasma hyperosmolality, and it correlated with neurohypophysial hormone release. This method may usefully complement hormone assays and single cell analysis.


Histopathology and epidemiology of breast cancer in the Padua area.
The histologic epidemiology of all breast cancer cases that had been diagnosed in the Padua area over an 11-year period was studied, and the absolute and relative distribution of breast cancer, location indices according to histologic types, 5-yr distribution and annual age-specific incidences of infiltrating and noninfiltrating cancers, as well as noncancerous disease were calculated. The results suggest that the Padua area should be considered a medium-high risk area along with England and Scandinavia.


Sexual behavior and sexual orientation of the female rat after hormonal treatment during various stages of development.
The amount of circulating sex steroids during Postnatal Days 30-90 was varied in normally developed and in androgenized female rats. The influence of these manipulations on sexual behavior and sexual orientation was investigated. Normally developed or neonatally androgenized females were ovariectomized and implanted with estradiol through Postnatal Days 30-90 or sham-implanted. The remaining subjects were left intact during that period. The hormonal condition during Postnatal Days 30-90 significantly affected the behavior of normally developed females, but affected the behavior of neonatally androgenized females only to minor extent. Estrogen implants in normally developed females enhanced masculine sexual responses and induced a female-directed sexual orientation. Feminine sexual responses were unaffected by this treatment. Sham-implanted, normally developed females showed a male-directed sexual orientation and fewer masculine sexual responses than subjects which were left intact during Postnatal Days 30-90. Neonatal androgen treatment in general resulted in elevated levels of masculine Neonatal androgen treatment in general resulted in elevated levels of masculine sexual responses, inhibited feminine sexual behavior, and facilitated a female-directed sexual orientation.


Intraperitoneal transplantation of bioengineered humanized liver grafts supports failing liver in acute condition.
Acute liver failure (ALF) is one of the most devastating fatal conditions which have posed crucial challenges to the clinicians and researchers for identifying permanent cure. Currently liver transplantation has been considered as the only managerial option. However it's wider applicability has been limited owing to non-availability of quality donor organs, cost-intensiveness, surgical hitches, life-long use of immunosuppressive drugs and long-term complications. Since last decades, several liver support systems have been developed for the management of failing liver in acute condition. However, the major limitation has been the lack of natural biological support and long-term survival of the grafts post-transplantation. Repopulation of decellularized xenogeneic organs is one of the emerging technologies for development of humanized neo-organs for demanding regenerative application. However, the earlier reported studies do not fulfil the insistence to provide immunologically tolerable humanized liver grafts for clinical applications. Here we demonstrate an efficient approach to generate transplantable humanized liver grafts which provides long-term support to the failing liver in Acute Liver Failure (ALF) animal models. These bioengineered humanized liver tissue grafts expresses several liver specific transcripts and performed crucial synthetic (albumin production) and detoxification (urea synthesis) functions at comparative level to normal liver. Intraperitoneal transplantation of these humanized liver grafts offered favourable microenvironment to exchange toxic substances across the barrier during ALF condition and provided long-term survival and function of the graft. In summary, the results of present study provide a first proof of concept in pre-clinical ALF animal model for the applicability of these bioengineered humanized livers in the management of failing liver on demand and may be considered as potential bridge to liver transplantation.


Intraocular Pressure after Intravitreal Triesence Injection.
Elevated intraocular pressure (IOP) is a frequent adverse event associated with intravitreal triamcinolone acetate injection. The incidence of elevated IOP with preserved forms of triamcinolone has been studied but the effect of preservative-free formulations has not been clinically evaluated. A retrospective, observational clinical study. For patients undergoing intravitreal injections over the study period, age, sex, history of glaucoma or ocular hypertension were recorded. For each injection, preinjection IOP, maximum IOP (IOPmax), dose, and indication for injection were noted for both eyes. Fourteen patients received 72 injections in 18 eyes. The mean baseline IOP was 15.4 mm Hg; the mean IOPmax was 19.8 mm Hg (P<0.001), occurring 63 days after injection. Outcomes were not significantly different between patients receiving 2 or 4 mg doses. History of glaucoma did not significantly affect IOPmax. Eyes should be monitored for IOP rises after preservative-free triamcinolone acetonide injections.


Assessment of ATM phosphorylation on Ser-1981 induced by DNA topoisomerase I and II inhibitors in relation to Ser-139-histone H2AX phosphorylation, cell cycle phase, and apoptosis.
The ATM kinase regulates cell-cycle checkpoints by phosphorylating multiple proteins, including histone H2AX, CHK1, and CHK2 kinases and p53. ATM is activated through auto- or trans- phosphorylation of Ser-1981 in response to DNA damage, particularly induction of DNA double-strand breaks (DSBs). The aim of the present study was to reveal a possible correlation between activation of ATM vis-à-vis H2AX phosphorylation, cell cycle phase, and apoptosis in cells treated with DNA topoisomerase (topo) I (topotecan; Tpt) or topo2 (mitoxantrone; Mtx) inhibitor. Cultures of HL-60 cells were treated with Tpt or Mtx for various time intervals. ATM or H2AX phosphorylation was detected immunocytochemically, using Ab specific for ATM phosphorylated on Ser-1981 (ATM-S1981(P)) or for H2AX (gammaH2AX) phosphorylated on Ser-139, respectively, concurrent with the analysis of cellular DNA content. Cellular fluorescence was measured by flow cytometry. Untreated cells showed a modest but variable level of labeling with ATM-S1981(P) Ab across the cell cycle, with exception of mitotic cells that were strongly labeled. Exposure of cells to 150 nM Tpt induced ATM phosphorylation concurrent with phosphorylation of H2AX within 10 min; phosphorylation of both proteins was essentially limited to S-phase and was suppressed by caffeine and wortmannin, inhibitors of PI-3-like kinases. Exposure of cells to Mtx also led to ATM and H2AX phosphorylation, which, compared to Tpt, occurred later and was not cell-cycle-phase specific. Apoptosis of HL-60 cells in Tpt or Mtx treated cultures was detected after 2 or 4 h, respectively, and was limited to S-phase cells. The data are consistent with the role of ATM as a mediator of H2AX phosphorylation in response to DNA damage by topo1 (Tpt) or topo 2 (Mtx) inhibitor. The observed cell-cycle-phase related differences in response to Tpt vs Mtx suggest that while the collisions of DNA replication forks with the "cleavable complexes" stabilized by topo1 inhibitor are the primary cause of DSBs induced by Tpt, the collisions of RNA polymerase molecules with the complexes stabilized by the topo2 inhibitor play a major role for induction of DSBs by Mtx. The present report is the first that (i) describes cytometric analysis of ATM activation and (ii) demonstrates activation of the enzyme (kinase) and its consequence (substrate phoshorylation), both in relation to cell-cycle phase and onset of apoptosis within the same cells.


Detection of carcinoma in the post-cystectomy urethral remnant by flow cytometric analysis.
Following radical cystoprostatectomy for bladder cancer patients must be monitored for carcinoma of the urethral remnant. Cytological examination of urethral washings has proved to be a useful alternative to urethroscopy and urethrography. Urethral irrigation specimens also can be evaluated objectively by flow cytometry. In each of 4 patients in whom carcinoma developed in the urethral remnant analysis of urethral irrigation by flow cytometry was positive and comparable to results of urethral irrigation cytology. Flow cytometry is an objective and apparently reliable diagnostic test for malignancy in the urethral remnant.


Cancer cachexia in a mouse model of oxidative stress.
Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation. Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.


Mesectodermal leiomyoma of the ciliary body: report of a case and review of the literature.
Mesectodermal leiomyoma of the ciliary body is a rare benign tumor with double (muscular and neural) differentiation. This neoplasm is considered to originate from the ciliary body smooth muscle, a neural crest derivative. We report a case of mesectodermal leiomyoma of the right eye occurring in a 53-year-old woman, who presented with significant decrease of visual acuity. A malignant melanoma was highly suspected on clinical evaluation, and the globe was enucleated. The tumor measured 1.2cm in greatest dimension, and consisted of spindle and ovoid cells with abundant fibrillary cytoplasmic processes. Immunohistochemical stains revealed positivity for smooth muscle actin, caldesmon, neuron-specific enolase, and CD56 antigen. A review of the 23 cases thus far reported in the literature shows a striking predilection for women, as well as significant difficulties in differentiating this tumor from malignant melanoma on clinical grounds.


Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis.
When infection with Toxoplasma gondii occurs during pregnancy, there is a risk that the parasite will cause severe congenital toxoplasmosis. We developed a method of diagnosing and treating congenital toxoplasmosis in utero. Diagnosis was based on the identification of maternal acute infection, followed by culture of fetal blood and amniotic fluid, testing of fetal blood for toxoplasma-specific IgM and nonspecific measures of infection, and ultrasound examination of the fetal brain. Treatment included the administration of antibiotics to all mothers with confirmed acute infection during pregnancy, with more intensive antibiotic treatment of those who had infected fetuses and who chose to continue the pregnancy. We report a prospective study of 746 documented cases of maternal toxoplasma infection, in which the infants were followed for at least three months. Infection was diagnosed antenatally in 39 of 42 fetuses. Twenty-four of the 39 pregnancies were terminated, and 15 were continued. All the mothers were treated with spiramycin throughout pregnancy; if fetal infection was demonstrated, pyrimethamine and either sulfadoxine or sulfadiazine were added to the regimen. Of the 15 fetuses with congenital toxoplasmosis who were carried to term, all but 2, who had chorioretinitis, remained clinically well during follow-up. We conclude that prenatal diagnosis of congenital toxoplasmosis is practical and that prenatal therapy in women who wish to continue their pregnancies reduces the severity of the manifestations of the disease.


Increased α-tubulin1b expression indicates poor prognosis and resistance to chemotherapy in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. It is important to understand molecular mechanisms of HCC progression and to develop clinically useful biomarkers for the disease. We aimed to investigate the possible involvement of α-tubulin1b (TUBA1B) in HCC pathology. Tissue specimens were obtained from 114 HCC patients during hepatectomy. Immunohistochemistry and western blot analysis were used to detect TUBA1B expression in HCC tissues and cell lines. TUBA1B was knocked down in HCC cells by siRNA transfection. CCK-8 assay and flow cytometry were applied to determine cell proliferation and cell cycle progression, respectively. The efficacy of paclitaxel chemotherapy was evaluated by plate colony formation assay. TUBA1B was higher expressed in HCC tumor tissues than in adjacent nontumor tissues. TUBA1B and Ki-67 expressions were positively related to each other, and both their expressions were significantly associated with histological grade of HCC patients. Univariate and multivariate survival analyses revealed that TUBA1B was a significant predictor for overall survival of HCC patients. TUBA1B expression was increased in HCC cells during the G1- to S-phase transition. TUBA1B knockout in HCC cells inhibited cell proliferation, and attenuated resistance to paclitaxel. Our results indicated that TUBA1B expression was upregulated in HCC tumor tissues and proliferating HCC cells, and an increased TUBA1B expression was associated with poor overall survival and resistance to paclitaxel of HCC patients.


The highly conserved spermatophyte cell wall DUF642 protein family: phylogeny and first evidence of interaction with cell wall polysaccharides in vitro.
The evolution of spermatophyte plants involved fundamental changes in cell wall structure and function which resulted from diversification of carbohydrates and proteins. Cell wall proteomic analyses identified a novel family of proteins of yet unknown function, the DUF642 (Domain of Unknown Function 642) proteins. To investigate the evolution of the DUF642 gene family, 154 gene sequences from 24 plant species were analyzed, and phylogenetic inferences were conducted using the Maximum Likelihood and Bayesian Inference methods. Orthologous genes were detected in spermatophyte species and absent in non-seed known plant genomes. Protein sequences shared conserved motifs that defined the signature of the family. Distribution of conserved motifs indicated an ancestral intragenic duplication event. Gene phylogeny documented paleoduplication events originating three or four clades, depending on root position. When based on mid-point rooting, it retrieved four monophyletic clades: A, B, C, and D. A glycosylphosphatidylinositol (GPI)-anchor site and one or two galactose-binding domains-like (GBDLs) could be predicted for some DUF642 proteins. The B, C, and D clades grouped the predicted GPI-anchored proteins. First evidence of in vitro interaction of a DUF642 protein with a cell wall polysaccharide fraction is provided. A competition assay with cellulose prevented this interaction. The degree of diversification and the conservation of the family suggested that DUF642 proteins are key components in seed plant evolution.


Experimental model of focal atrial tachycardia: clinical correlates.
The mechanisms underlying focal atrial tachycardia (AT) are unclear. In 14 pentobarbital anesthetized dogs, a right thoracotomy allowed electrical stimulation (ES) of the anterior right ganglionated plexi (ARGP). After ES was applied to the ARGP at baseline, atropine, 1 mg/cc, was injected into the ARGP and repeat stimulation applied. After a left thoracotomy (n = 8), a similar procedure was followed by atropine injected into the superior left (SL) GP. ES (0.6-3.2 V) applied to the ARGP and SLGP caused an average reduction in sinus rate from 151 ± 14/min to 60 ± 11/min. At ≥4.5 V atrial fibrillation (AF) was induced (duration 48 ± 14 seconds). After injection of atropine into the ARGP or SLGP, ES applied to these GP induced no slowing of the sinus rate. Runs of AT were induced at an average voltage of 10 ± 2 V in 14 experiments (duration ≥4 minutes). AT was localized by ice mapping or by 3D noncontact mapping to the crista terminalis (n = 6), AV junction (n = 2) or a focal site at the left superior pulmonary vein (6). In AT lasting <4 minutes (n = 2), epinephrine injected into the GP significantly increased the AT duration. In 4/4 experiments, sustained AT could be terminated by intravenous esmolol. Atropine injected into the ARGP or SLGP promotes ES-induced AT whose duration is increased by adrenergic agonists and terminated by beta blockade. Presumably cholinergic blockade and accentuated release of adrenergic neurotransmitters provide the AT mechanism. The induced AT was found to be localized at sites similar to those reported clinically.


The replication error phenotype is associated with the development of distant metastases in hormonally treated patients with breast carcinoma.
The positive replication error (RER+) phenotype defines a distinct subgroup of tumors with specific clinical, pathologic, and molecular features that have been documented well in hereditary nonpolyposis colon carcinoma (HNPCC). More recently, this phenotype also has been described in breast carcinoma. To determine the effect of RER phenotype on prognosis in patients with breast carcinoma, the authors examined matched archival tumor and normal tissue from 100 women with Stage I and Stage II breast carcinoma, all of whom were treated with hormonal therapy. Patients had been followed for a minimum of 5 years or until death. Seven microsatellite loci were examined, including hMLH1 (3p22, D3S1611), hMSH2 (2p16, D2S123), NM23-H1 (17q21), TP53-Dint (17p13), TP53-Penta (17p13), APC (5q21, D5S346), and HPC1 (1q24, D1S2883). The RER+ phenotype was defined as the presence of allelic shifts at three of the seven loci examined. Twenty-five percent of patients were classified with the RER+ phenotype based on these criteria. The two groups, women with positive RER status and women with negative RER status, were comparable in terms of other factors that may influence prognosis: age, tumor size, lymph node status, disease stage, and estrogen receptor status. The development of distant metastases to the lung, liver, or brain was correlated significantly with the positive RER phenotype, with a relative risk of 2.625 (95% confidence interval, 1.059-6.057). The presence of high-frequency RER+ may predict for the development of distant metastatic disease in patients with early-stage breast carcinoma who are treated with hormonal therapy.


Structure-Activity Relationships for Some Diamine, Triamine and Schiff Base Derivatives and Their Copper(II) Complexes.
Ethylenediamine (en), putrescine (pu), diethylenetriamine (dien), dipropylenetriamine (dpta), spermidine (spmd) and their Cu(II) compounds as well as the Schiff bases with 2-furaldehyde (dienOO), 2- thiophenecarboxaldehyde (dienSS) and pyrrole-2-carboxaldehyde (dienNN) of dien and that of dpta with 2- thiophenecarboxaldehyde (dptaSS), were prepared and characterised. They were tested against Bacillus substilis, Bacillus cereus, Staphylococcus aureus, Escherichia coli, Proteus vulgaris and Xanthomonas campestris as antibacterial reagents, the highest activity being exhibited by Cu(dptaSS)(NO(3))(2) complex, which acts as antibiotic. In the antiproliferative tests (vs. T(47)D,L(929) and BHK(21/c13) cell lines) the best results were obtained with Cu(dptaSS)(2+) and Cu(dienSS)(2+). Electronic structure calculations gave for dptaSS and dienSS the higher negative charges on the N atoms. The counter-ions (Br(-), NO(3) (-) and SO(4) (2-)) play an important role by modulating the reagent's selectivity versus the bacteria [Gram(+) or Gram(-)], but they have no effect on the antiproliferative activity.


Changes of the spontaneous cytotoxicity of the blood lymphocyte population following local radiation therapy for breast cancer.
The capacity of the blood lymphocyte population to spontaneously lyse K562 and Chang cells In vitro was examined in women who received local radiation therapy (45.0 Gy) for breast cancer. It was observed that cytotoxicity, on a cell-for-cell basis, was significantly reduced against K562 cells at completion of irradiation. This was followed by a recovery to the pretreatment level within 3-4 months and remained relatively constant for approximately 2 yr. The pattern of these changes were reasonably similar to that of the frequency of lymphocytes expressing Fc-receptors for IgG. In contrast, the relative cytotoxicity against Chang cells was unchanged at completion of irradiation. At 3-4 months, however, the relative cytotoxicity was increased above the pretreatment level and remained elevated for at least 2 yr. The results indicate that different effector cells are involved in the spontaneous destruction of K562 and Chang cells.


An in vivo technique for 3-dimensional field mapping in the rodent spinal cord.
The purpose of this investigation was to develop a reliable method for in vivo mapping of small exogenously applied electrical fields in the mammalian spinal cord. Experiments were performed in vitro to validate the technique in addition to recordings made in vivo on normal and spinal cord injured rats. Sine waves of 1.5-50 microA and 0.5-50 Hz were used for stimulation. Field gradients were measured with a lock-in differential amplifier. Glass recording micro-electrodes were used for in vivo experiments. The accuracy of the technique was found to be highly dependent on the waveform of the current and impedance matching between the recording electrodes. Recordings made in vivo demonstrated that measured fields were linearly related to the intensity of stimulation. Field gradients were not influenced by stimulation frequencies of 5-50 Hz. Estimates were made of the influence of the surgical exposure on the measured gradients. Our results demonstrate that small electrical fields can be accurately mapped in vivo and interpolated throughout a broad range of intensities and frequencies.


Study on crystal growth of Ge/Si quantum dots at different Ge deposition by using magnetron sputtering technique.
We investigated the growth and evolution of Si-based Ge quantum dots (Ge/Si QDs) under low Ge deposition (1.2-4.4 nm thick) using magnetron sputtering. The morphology and structure of QDs were analyzed with the help of an atomic force microscope (AFM), scanning electron microscope, transmission electron microscope, Raman, surface energy theory and dynamics theory, the photoelectric properties of QDs were characterized by photoluminescence (PL) spectra. The results showed that the growth mechanism of QDs conformed to Stranski-Krastanow mode, but the typical thickness of the wetting layer was nearly three times higher than those derived from conventional technologies such as molecular beam epitaxy, chemical vapor deposition, solid phase epitaxy and so on. Meanwhile, the shape evolution of QDs was very different from existing reports. The specific internal causes of these novel phenomena were analyzed and confirmed and reported in this paper. In addition, the AFM, Raman, and PL tests all indicated that the QDs grown when 3.4 nm Ge was deposited have the most excellent morphology, structure, and optoelectronic performance. Our work lays a foundation for further exploration of the controllable growth of QDs at high deposition rates, which is a new way to realize the industrialization of QDs used for future devices.


IL-13 in dermal type-2 dendritic cell specialization: From function to therapeutic targeting.
Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.


Preventive Pharmacovigilance: timely and precise prevention of adverse events through person-level patient screening and dose-level product surveillance.
The goal of pharmacovigilance (PV) is to prevent adverse events (AEs) associated with drugs and vaccines. Current PV programs are of a reactive nature and rest entirely on data science, i.e., detecting and analyzing AE data from provider/patient reports, health records and even social media. The ensuing preventive actions are too late for people who have experienced AEs and often overly broad, as responses include entire product withdrawals, batch recalls, or contraindications of subpopulations. To prevent AEs in a timely and precise manner, it is necessary to go beyond data science and incorporate measurement science into PV efforts through person-level patient screening and dose-level product surveillance. Measurement-based PV may be called 'preventive pharmacovigilance', the goal of which is to identify susceptible individuals and defective doses to prevent AEs. A comprehensive PV program should contain both reactive and preventive components by integrating data science and measurement science.


Expression of CD18 on the neutrophils of patients with diabetic retinopathy.
To investigate the expression of CD18 on neutrophils from patients with various stages of diabetic retinopathy (DR) and to determine the possibility of using it as a marker of disease development. Levels of CD18 on neutrophils were measured by flow cytometry in 10 patients with DR stage 1, 14 patients in stages 2-4, 14 patients in stage 5 and 10 non-diabetic healthy subjects (control). Mean channel fluorescence (MCF) of CD18 on neutrophils from the control, stage 1, stages 2-4 and stage 5 groups were 1.36+/-0.17, 2.99+/-1.44, 3.13+/-1.10 and 4.11+/-1.62, respectively. The difference among them was significant (P=0.00). The highest was from the stage 5 group, then stages 2-4 and stage 1. The least was from the control group (trend test, P=0.00). This trend remained after adjusting for confounding variables. This trend was only significant in type 2 when subjects were divided according to diabetic type, even after adjusting for confounding factors. Multiple linear regression against the level of CD18 MCF by stage of DR and covariates revealed a significant and independent association with the stage of DR (beta=0.33; P=0.01). Elevated levels of CD18 on neutrophils were present in each stage of DR in type 2 diabetic patients. The more severe the disease, the higher the level was. CD18 may be a marker of the development of DR in type 2 diabetes.


Monolithic digital patterning of polydimethylsiloxane with successive laser pyrolysis.
The patterning of polydimethylsiloxane (PDMS) into complex two-dimensional (2D) or 3D shapes is a crucial step for diverse applications based on soft lithography. Nevertheless, mould replication that incorporates time-consuming and costly photolithography processes still remains the dominant technology in the field. Here we developed monolithic quasi-3D digital patterning of PDMS using laser pyrolysis. In contrast with conventional burning or laser ablation of transparent PDMS, which yields poor surface properties, our successive laser pyrolysis technique converts PDMS into easily removable silicon carbide via consecutive photothermal pyrolysis guided by a continuous-wave laser. We obtained high-quality 2D or 3D PDMS structures with complex patterning starting from a PDMS monolith in a remarkably low prototyping time (less than one hour). Moreover, we developed distinct microfluidic devices with elaborated channel architectures and a customizable organ-on-a-chip device using this approach, which showcases the potential of the successive laser pyrolysis technique for the fabrication of devices for several technological applications.


Bacteria inactivation at a sub-stoichiometric titanium dioxide reactive electrochemical membrane.
This study investigated the use of a sub-stoichiometric TiO2 reactive electrochemical membrane (REM) for the inactivation of a model Escherichia coli (E. coli) pathogen in chloride-free solutions. The filtration system was operated in dead-end, outside-in filtration model, using the REM as anode and a stainless steel mesh as cathode. A 1-log removal of E. coli was achieved when the electrochemical cell was operated at the open circuit potential, due to a simple bacteria-sieving mechanism. At applied cell potentials of 1.3 and 3.5V neither live nor dead E. coli cells were detected in the permeate stream (detection limit of 1.0 cell mL(-1)), which was attributed to enhanced electrostatic bacteria adsorption at the REM anode. Bacteria inactivation in the retentate solution increased as a function of the applied cell potential, which was attributed to transport of E. coli to the REM and stainless steel cathode surfaces, and direct contact with the local acidic and alkaline environment produced by water oxidation at the anode and cathode, respectively. Clear evidence for an E. coli inactivation mechanism mediated by either direct or indirect oxidation was not found. The low energy requirement of the process (2.0-88Whm(-3)) makes the REM an attractive method for potable water disinfection.


An In-Silico model for evaluating the directional shock vectors in terminating and modulating rotors.
Out-of-hospital cardiac arrest (OHCA) accounts for a majority of mortality worldwide. Survivability from an OHCA highly depends on timely and effective defibrillation. Most of the OHCA cases are due to ventricular fibrillation (VF), a lethal form of cardiac arrhythmia. During VF, previous studies have shown the presence of spatiotemporally organized electrical activities called rotors and that terminating these rotor-like activities could modulate or terminate VF in an in-hospital or research setting. However, such an approach is not feasible for OHCA scenarios. In the case of an OHCA, external defibrillation remains the main therapeutic option despite the low survival rates. In this study, we evaluated whether defibrillation effectiveness in an OHCA scenario could be improved if a shock vector directly targets rotor-like, spatiotemporal electrical activities on the myocardium. Specifically, we hypothesized that the position of defibrillator pads with respect to a rotor's core axis and shock current density could influence the likelihood of rotor termination and thereby result in successful defibrillation. We created a bidomain cardiac model based on porcine heart data using Aliev-Panfilov bidomain equations. We simulated localized rotors, which we attempted to terminate using different defibrillation pad orientations relative to the rotor axis (i.e., perpendicular, parallel, and oblique). In addition, we gradually increased current densities for each defibrillation pad orientation from 4 to 12 A/m2. We repeated the above defibrillation procedure for rotors originating from four different locations on the ventricles. The shock parameters and the outcomes were analyzed using a Generalized Linear Mixed Model (GLMM) with Logistic Regression to link rotor termination with the defibrillation pad orientation and current density. Our results suggest the highest average likelihood of terminating rotors during VF is when defibrillator pads are placed perpendicular to the rotor axis (0.99 ± 0.03), with an average current density of 7.2 A/m2, compared to any other orientation (parallel: 0.76 ± 0.26 and oblique: 0.08 ± 0.12). Our simulations suggest that optimal defibrillator pad orientation, combined with sufficient current density magnitude, could improve the likelihood of rotor termination during VF and thereby improving defibrillation success in OHCA patients.


The historical rationale for operating on cranial fissures.
Cranial fissures are not an indication for surgical intervention. It should be emphasised that the term fissure refers to linear skull fractures as defined in MESH. However, it was the universal term for this injury in the literature which forms the basis of this paper. Nonetheless, for over two millennia, their management was a major reason for opening the skull. The reasons for this deserve analysis, in particular taking into account the available technology and conceptual background. The texts of significant surgical practitioners from Hippocrates to the eighteenth century were examined and analyzed. The need for fissure surgery was based on Hippocrates' teaching. It was considered that extravasated blood would suppurate, and extracranial suppuration could leak inwards through a fracture. Trepanation to facilitate pus drainage and cleansing was considered vital. Avoiding surgical damage to the dura was also emphasized with a preference for operating only when the dura had separated from the cranium. The enlightenment with an increasing reliance on personal observation rather than the teachings of received authority enabled the accumulation of a more rational basis for treatment concerned with the effects of injury on brain function. This culminated in the teachings of Percivall Pott, who despite some minor errors, provided the framework on which modern treatments would develop. Examination of the surgical management of cranial trauma from Hippocrates to the eighteenth century shows that cranial fissures were judged to be of great importance and required active treatment. This treatment was not aimed at improving the healing of the fracture but at avoiding deadly intracranial infection. It is worth noting that this sort of treatment persisted for over two millennia while modern management has only been practiced for just over a century. Who can say how it will change in the next hundred years.


Essential oil from leaves of Conobea scoparioides (Cham. & Schltdl.) Benth. (Plantaginaceae) causes cell death in HepG2 cells and inhibits tumor development in a xenograft model.
Conobea scoparioides (Cham. & Schltdl.) Benth. (syn. Sphaerotheca scoparioides Cham. & Schldtl.) (Plantaginaceae), popularly known as "pataqueira", "vassourinha-do-brejo" and/or "hierba-de-sapo", is a popular medicinal plant used to treat leishmaniasis, pain and beriberi. In addition, inhibition of cell adhesion, antioxidant, cytotoxic and leishmanicidal activities of compounds or fractions of C. scoparioides have been reported. In the present work, chemical constituents and in vitro and in vivo anti-liver cancer potential of essential oil (EO) from leaves of C. scoparioides were investigated using human hepatocellular carcinoma HepG2 cells as a cell model. EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized by GC-MS and GC-FID. The in vitro cytotoxic effect was evaluated on three human cancer cell lines (MCF-7, HepG2 and HCT116) and one human non-cancerous cell line (MRC-5) using the Alamar blue assay. Phosphatidylserine externalization and cell cycle distribution were quantified in HepG2 cells by flow cytometry after 48 h incubation. The effectiveness of EO in anti-liver cancer model was studied with HepG2 cells grafted on C.B. 17 SCID mice. The main constituents of EO were thymol methyl ether (62 %), thymol (16 %) and α-phellandrene (14 %). EO displayed an in vitro cytotoxic effect against all human cancer cell lines and caused externalization of phosphatidylserine and DNA fragmentation in HepG2 cells, suggesting induction of apoptotic-like cell death. In vivo tumor mass inhibition of 36.7 and 55.8 % was observed for treatment with EO at doses of 40 and 80 mg/kg, respectively. These results indicate in vitro and in vivo anti-liver cancer potential of EO from leaves of C. scoparioides.