Short Panicle 3 controls panicle architecture by upregulating APO2/RFL and increasing cytokinin content in rice.
Inflorescence architecture is a major determinant of spikelet numbers per panicle, a key component of grain yield in rice. In this study, Short Panicle 3 (SP3) was identified from a short panicle 3 (sp3) mutant in which T-DNA was inserted in the promoter of SP3, resulting in a knockdown mutation. SP3 encodes a DNA binding with one finger (Dof) transcriptional activator. Quantitative real time (qRT)-PCR and RNA in situ hybridization assays confirmed that SP3 is preferentially expressed in the young rice inflorescence, specifically in the branch primordial regions. SP3 acts as a negative regulator of inflorescence meristem abortion by upregulating APO2/RFL. SP3 both up- and downregulates expression of genes involved in cytokinin biosynthesis and catabolism, respectively. Consequently, cytokinin concentrations are decreased in young sp3 panicles, thereby leading to small panicles having fewer branches and spikelets. Our findings support a model in which SP3 regulates panicle architecture by modulating cytokinin homeostasis. Potential applications to rice breeding, through gene-editing of the SP3 promoter are assessed.


Reuse of constructed wetland effluents for irrigation of energy crops.
The aim of this study was to evaluate biomass production of promising 'no-food' energy crops, Vetiveria zizanoides (L.) Nash, Miscanthus × giganteus Greef et Deu. and Arundo donax (L.), irrigated with low quality water at different evapotranspiration restitutions. Two horizontal subsurface flow (H-SSF) constructed wetland (CW) beds, with different operation life (12 and 6 years), were used to treat secondary municipal wastewaters for crop irrigation. Water chemical, physical and microbiological parameters as well as plant bio-agronomic characters were evaluated. The results confirm the high reliability of CWs for tertiary wastewater treatment given that the H-SSF1 treatment capacity remained largely unchanged after 12 years of operation. Average total suspended solids, chemical oxygen demand and total nitrogen removal for CWs were about 68, 58 and 71%, respectively. The Escherichia coli removal was satisfactory, about 3.3 log unit for both CW beds on average, but caution should be taken as this parameter did not achieve the restrictive Italian law limits for wastewater reuse. The average above-ground dry matter productions were 7 t ha⁻¹ for Vetiveria zizanoides, 24 t ha⁻¹ for Miscanthus × giganteus and 50 t ha⁻¹ for Arundo donax. These results highlight attractive biomass yield by using treated wastewater for irrigation with a complete restitution of evapotranspiration losses.


Protection of UV-induced suppression of skin contact hypersensitivity: a common feature of flavonoids after oral administration?
In this study we investigated the effect of the dietary ingredients fruit and vegetable, green tea phenol extract (GTP) and the specific flavonoid components quercetin and chrysin on the UV-induced suppression of the contact hypersensitivity (CHS) response to picryl chloride (PCl). The SKH-1 mice were fed with test diet from 2 or 4 weeks before and during the UV irradiation (daily, 95 mJ/cm2) and tested for the CHS ear-swelling response 10 weeks after the onset of the irradiation. For the CHS, mice were immunized with PCl by epicutaneous application on nonirradiated sites. Four days after sensitization all mice were challenged on both sides of each ear by topical application of one drop PCl. In addition, from mice fed with the fruit and vegetable mixture the number of Langerhans cells (LC) were scored in the skin and from mice fed with quercetin, quercetin levels in plasma were measured at week 11 after the start of UV irradiation. It was found that fruit and vegetable (19% in the diet), GTP (0.1% and 0.01% in the drinking water), quercetin (1% in the diet) and chrysin (1% and 0.1% in the diet), prevented statistically significantly the UV-induced suppression of CHS to PCl. In the skin of mice fed with fruit and vegetables combined with UV irradiation the number of LC were comparable to the control mice, whereas the number of LC were significantly diminished in mice treated with UV only. This protective effect on the presence of LC in the epidermis after UV irradiation, which was also observed in a previous study with quercetin, may play a role in the prevention of UV-induced immunosuppression by the flavonoids tested. In conclusion, we found protection of flavonoids against UV-induced effects on CHS, which may be a common feature of most flavonoids.


Placental oxygen transport estimated by the hyperoxic placental BOLD MRI response.
Estimating placental oxygen transport capacity is highly desirable, as impaired placental function is associated with fetal growth restriction (FGR) and poor neonatal outcome. In clinical obstetrics, a noninvasive method to estimate the placental oxygen transport is not available, and the current methods focus on fetal well-being rather than on direct assessment of placental function. In this article, we aim to estimate the placental oxygen transport using the hyperoxic placental blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) response. In 21 normal pregnancies and in four cases of severe early onset FGR, placental BOLD MRI was performed in a 1.5 Tesla MRI system (TR:8000 msec, TE:50 msec, Flip angle:90). Placental histological examination was performed in the FGR cases. In normal pregnancies, the average hyperoxic placental BOLD response was 12.6 ± 5.4% (mean ± SD). In the FGR cases, the hyperoxic BOLD response was abnormal only in cases with histological signs of maternal hypoperfusion of the placenta. The hyperoxic placental BOLD response is mainly derived from an increase in the saturation of maternal venous blood. In the normal placenta, the pO2 of the umbilical vein is closely related to the pO2 of the uterine vein. Therefore, the hyperoxic placental BOLD response may reflect the placental oxygen supply to the fetus. In early onset FGR, the placental oxygen transport is reduced mainly because of the maternal hypoperfusion, and in these cases the placental BOLD response might be altered. Thus, the placental BOLD MRI might provide direct noninvasive assessment of placental oxygen transport.


High-dose intravenous immunoglobulin G treatment of myasthenia gravis.
IVIg is a safe and effective adjunctive treatment for myasthenia gravis, but there are no well established guidelines for the use of IVIg in this disease, lacking controlled randomized trials to assess its efficacy in homogeneous group of patients. The main advantages of IVIg are the rapid onset of the effect, the lack of long-term toxicity, and the possibility to reduce the required doses of immunosuppressive drugs. IVIg appears to have a role as an acute treatment in rapidly progressive myasthenia gravis weakness, particularly in situations when therapeutic apheresis is not feasible. In addition, IVIg is safer than plasma exchange (PE) in patients with hypotension or autonomic instability, in children, in patients of older age (>65 years), and in those suffering from sepsis. For these reasons, at present, IVIg are recommended during crises of myasthenia gravis in older patients when PE is contraindicated or not feasible IVIg can be also used as a chronic maintenance therapy when other immunosuppressive treatments have failed or cannot be used. Periodic administration of IVIg on a bimonthly or monthly basis may be able to stabilize chronic, nonresponding patients.


Aortic valve replacement and concomitant mitral valve regurgitation in the elderly: impact on survival and functional outcome.
The impact of mitral regurgitation (MR) on elderly patients (> or = 70 years) undergoing isolated aortic valve replacement (AVR) is not clearly defined. This study investigates the long-term effects of preoperative, moderate MR on survival and functional outcome in elderly AVR patients. A retrospective review identified 408 consecutive elderly patients who underwent isolated AVR from January 1983 to February 2004. The pathologic etiology of MR was determined on preoperative echocardiogram, and patients were stratified into no/mild MR (Group I; n = 338) versus moderate MR (Group II; n = 70). Follow-up was 95.1% complete. Functional outcome was evaluated using the Short Form-12 questionnaire. On univariate analysis, Groups I and II differed in incidence of previous myocardial infarction (13.9% versus 28.6%; P = 0.004), hyperlipidemia (18.7% versus 33.3%; P = 0.009), and congestive heart failure (50.0% versus 70.0%; P = 0.002). On multivariate analysis, moderate MR was an independent risk factor impacting long-term survival (P = 0.04). Actuarial survival at 1, 5, and 10 years for Group I was 93.8%, 73.3%, and 40.1% versus 92.3%, 58.2%, and 14.6% for Group II (P = 0.04). Available postoperative echocardiograms for Group II (n = 37) demonstrated improvement in MR in 81.8% of functional MR patients. However, MR persisted or worsened in 65.4% of patients with intrinsic mitral valve disease (myxomatous, calcific, or ischemic MR). Functional outcomes showed 77% of Group I versus 78.6% of Group II rated their health as good to excellent post-AVR. Moderate MR is an independent risk factor impacting long-term survival in elderly patients undergoing AVR. Therefore, patients with intrinsic mitral valve disease should be considered for concomitant MV surgery.


Youth, family and society: Examining the dynamics of e-cigarette use in Latino college students.
We aimed to document the social factors encouraging and discouraging e-cigarette use amongst Latino college students. Participants were second-generation Latino male college students. We interviewed 20 second-generation Latino male college students, 10 regular smokers and 10 infrequent smokers, at the University of California, Irvine and the University of California, Riverside. Regular and infrequent smokers present similar motivations that either encourage or discourage e-cigarette use. Repeated peer-exposure, skepticism of the harmfulness of recreational use, and disagreement with familial views of substance use encourage e-cigarette use. High costs, weak nicotine euphoria, and evidence of health risks discourage e-cigarette use. Our results suggest that motivations for e-cigarette use in Latino college students are similar to those of young, non-Latinos and that regular and infrequent users may be determined by temporal circumstances and opportunity as opposed to unique social factors. Further research is warranted to comprehensively investigate this phenomenon.


Cardiovascular disease and hypertension.
The cellular and molecular mechanisms whereby hypertension causes vascular and cardiac disease are beginning to be understood. Angiotensin II, perhaps because so many probes to explore its action are available, is emerging as a central pathogenetic factor in the development of both vascular and cardiac hypertrophy. It is clear that this peptide has direct growth effects on vascular smooth muscle cells and cardiocytes as well as indirect effects by stimulating the synthesis of growth factors or potentiating their effects. However, the details of its action need clarification. Abnormalities in endothelium-derived relaxing factor regulation are a new pathogenetic mechanism of hypertension and are also likely to be intimately involved in the development of hypertensive cardiovascular disease. In the clinical arena, converting enzyme inhibitors are emerging as the best antihypertensive agents, and new therapeutic trials and further support to the suspicion that, when in doubt, it is better to treat.


The impact of micronized progesterone on the endometrium: a systematic review.
Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel's recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3-5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.


Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter.
Activated macrophages play an important role in the pathogenesis of acute ischemic syndromes. It has been postulated that detection of heat released by activated inflammatory cells of atherosclerotic plaques may predict plaque rupture and thrombosis. Previous ex vivo studies have shown that there is thermal heterogeneity in human carotid atherosclerotic plaques. To measure the temperature of human arteries in vivo, we developed a catheter-based technique. Ninety patients (45 with normal coronary arteries, 15 with stable angina [SA], 15 with unstable angina [UA], and 15 with acute myocardial infarction [AMI]) were studied. The thermistor of the thermography catheter has a temperature accuracy of 0.05 degrees C, a time constant of 300 ms, and a spatial resolution of 0.5 mm. Temperature was constant within the arteries of the control subjects, whereas most atherosclerotic plaques showed higher temperature compared with healthy vessel wall. Temperature differences between atherosclerotic plaque and healthy vessel wall increased progressively from SA to AMI patients (difference of plaque temperature from background temperature, 0. 106+/-0.110 degrees C in SA, 0.683+/-0.347 degrees C in UA, and 1. 472+/-0.691 degrees C in AMI). Heterogeneity within the plaque was shown in 20%, 40%, and 67% of the patients with SA, UA, and AMI, respectively, whereas no heterogeneity was shown in the control subjects. Thermal heterogeneity within human atherosclerotic coronary arteries was shown in vivo by use of a special thermography catheter. This heterogeneity is larger in UA and AMI, suggesting that it may be related to the pathogenesis.


Duodenal gangliocytic paraganglioma: A rare cause for gastrointestinal polyp.
Duodenal gangliocytic paragangliomas are rare neoplasms often arising in the duodenum in close proximity to the ampulla of Vater. These neoplasms are considered to have a benign behavior with lymph node metastases being a rare phenomenon and distant metastases even more so. Although a standardized treatment has not been determined, a margin-free tumor resection seems to be the best treatment modality. We report herein the case of a 36-year-old female who presented with abdominal pain and was found to have a polyp in the second part of duodenum which was excised endoscopically. Histopathology and immunohistochemistry revealed characteristic features of this rare tumor.


Leukocyte mean corpuscular volume in the differential diagnosis of acute leukemias.
The leukocyte mean corpuscular volume was measured in 61 cases of acute leukemia. The volume of blast cells allows a clear distinction between lymphoblastic and other varieties of acute leukemia. There seems to be good correlation between patients' age, leukocyte corpuscular volume, cytological and cytochemical findings. Furthermore, myeloblastic leukemias.Leukemic cells can be characterized by their volume, which is close to that of normal cells of the same line. This observation supports the clonal theory of their origin and concurs with the classical nomenclature which separates them into lymphoblastic, myeloblastic and monoblastic types.


An extensive log-file analysis of step-and-shoot intensity modulated radiation therapy segment delivery errors.
We present a study to evaluate the monitor unit (MU), dosimetric, and leaf-motion errors found in the delivery of 91 step-and-shoot IMRT treatment plans performed at three nominal dose rates using a dual modality high energy Linac (Varian 2100 C/D, Varian Medical Systems Inc., Palo Alto, CA) equipped with a 120-leaf multileaf collimator (MLC). The analysis was performed by studying log files generated by the MLC controller system. Recent studies by our group have validated that the automatically generated MLC log files accurately record the actual system delivery. A total of 635 beams were delivered at three nominal dose rates: 100, 300, and 600 MU/min. The log files were manually retrieved and analysis software was developed to extract the recorded MU delivery and leaf positions for each segment. Our analysis revealed that the magnitude of segment MU errors were independent of the planned segment MUs. Segment MU errors were found to increase with dose rate having maximum errors per segment of +/-1.8 MU at 600 MU/min, +/-0.8 MU at 300 MU/min, and +/-0.5 MU at 100 MU/min. The total absolute MU error in each plan was observed to increase with the number of plan segments, with the trend increasing more rapidly for higher dose rates. Three dimensional dose distributions were recomputed based on the observed segment MU errors for three plans with large cumulative absolute MU errors. Comparison with the original treatment plans indicated no clinically significant consequences due to these errors. In addition, approximately 80% of the total segment deliveries reported at least one collimator leaf moving at least 1 mm (projected at isocenter) during segment delivery. Such errors occur near the end of segment delivery and have been previously observed by our group using a fast video-based electronic portal imaging device. At 600 MU/min, between 5% and 23% of the plan MUs were delivered during leaf motion that had exceeded a 1 mm position tolerance. These leaf motion errors were not included in the treatment plan recalculations performed in this study.


MicroRNAs in Irritable Bowel Syndrome: a Systematic Review.
Irritable bowel syndrome (IBS), a common gastrointestinal disorder, was reported to contribute to abdominal pain, decrease the quality of life and work productivity of affected individuals, and lead to cachexia and frailty. However, molecules that regulate irritable bowel syndrome have not been fully clarified. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit the translation of target messenger RNAs. Previous studies have shown that miRNAs have critical roles in the regulation of the pathogenicity of irritable bowel syndrome. Therefore, this systematic review focused on miRNAs that regulate irritable bowel syndrome. PubMed and Web of Science were searched to retrieve reference lists of eligible articles and related reviews. Original articles and reviews that reported the utility of miRNAs as potential biomarkers or targets for specific therapies of IBS that were published in English from 2004 to 2021 were included. Among 78 identified studies, 22 eligible studies were included in this systematic review. These results suggest that miRNAs are potential biomarkers and targets of gene therapy for IBS. Further studies including clinical studies will be necessary to confirm the utility of miRNAs as biomarkers and targets for the gene therapy of IBS.


[Chemical characterisation of structural components of Rahnella aquatilis lipopolysaccharides].
The studies of lipopolysaccharides (LPS) of eight Rahnella aquatilis strains, isolated from different sources have shown that they contain both S- and R-types of molecules. This fact is evidenced by the presence of high-molecular fraction of O-specific polysaccharides (O-PS) and low-molecular fraction of core oligosaccharides. The predominant monosaccharides of core oligosaccharides were glucose, galactose. The presence of only one high-molecular fraction O-PS was a characteristic feature of all investigated strains. The predominant monosaccharides of O-PS were galactose, glucose, mannose, rhamnose and fucose. 3-hydroxytetradecanoic (48.9-93.1%), dodecanoic (2.9-12.1%), tetradecanoic (4.1-25.3%) and hexadecanoic (2.8-15.3%) acids have been obtained in lipids A of LPS depending on the strain. The presence in lipid A of R. aquatilis of only 3-hydroxytetradecanoic acid which is characteristic of Enterobacteriaceae proves the correct ascribing of the isolated strains to this family.


Cytoplasmic transfer of the mitogenic response to platelet-derived growth factor.
BALB/c 3T3 mouse cells exposed briefly to platelet-derived growth factor (PDGF) become "competent" to replicate their DNA and divide. When cells are treated with PDGF and then fused to untreated cells, the resulting heterokaryons become competent to replicate their DNA. Cytoplasts derived from PDGF-treated cells are also able to transfer the growth response to untreated cells. After cytoplasmic transfer to another cell, the strength of the PDGF-induced mitogenic signal is attenuated by a factor roughly proportional to the increase in total cytoplasmic volume. When RNA synthesis is blocked during PDGF treatment, cells do not acquire the capacity to transfer the PDGF growth signal to untreated cells. By contrast, exposure to cycloheximide during PDGF treatment has no effect. These observations suggest that cytoplasmic transfer of the growth response to PDGF (competence) is mediated by a PDGF-induced stable RNA rather than by PDGF itself or a PDGF--receptor complex. The onset of DNA synthesis in PDGF--control heterokaryons occurs a minimum of 11 hr after cell fusion. Thus the substance that is transferred in these cell fusions is not directly involved in DNA synthesis; rather, it seems to trigger a sequence of events culminating in DNA synthesis.


Regulation of wound healing from a connective tissue perspective.
Tissue injury resulting in irreversible tissue loss initiates the repair process. The restoration of dermal loss is by scarring, where a new cell population resides in a new connective tissue matrix. The chemical composition of a scar is similar to normal dermis, but the organization of that tissue is altered. The inability of the organism to reassemble collagen into a normal dermal pattern is an attribute of a scar, but in most cases it restores normal function. With impaired scarring, wound dehiscence or chronic wounds arise, whereas the overproduction of scar tissue results in keloid or hypertrophic scarring. In both situations a catastrophic end point occurs. The volume of scar tissue deposited, as well as its organization, is critical for determining the scar's integrity, stability, and restoration of function. The maturation of scar depends on the character of its resident cell populations, the quality of deposited connective tissue, and the interactions between those components. In this Perspective article, the focus will be on the repair process in terms of collagen fiber organization. As our knowledge of cell-cell and cell-matrix interactions in the repair process increases, we may be able to direct the pattern of scar collagen fibers to resemble that of dermis and thereby provide better wound care to the patient of the future.


Spatial distribution of reniform nematode in cotton as influenced by soil texture and crop rotations.
Reniform nematode (RN) is an important pest in cotton production. Knowledge of the distribution patterns of RN is essential for selecting sampling strategies and for site-specific management. A 3-year study was conducted in two fields in South Carolina with the purpose of characterizing the distribution of RN using a fine-scale sampling scheme in plots representing different soil textures (field 1), and using a large-scale arbitrary sampling scheme (field 2). Horizontal distribution data showed an aggregated pattern of RN densities at planting and after harvest in both fields each year, with patches ranging from 8 to 12 m. However, a significant neighborhood structure was only detected when suitable hosts (cotton and soybean) were planted. Correlations between RN densities and percent sand and silt were detected, showing nematode densities peaked when sand content was around 60% and declined when sand content increased above 60 to 65%. When fewer samples were taken in the field with more uniform sand content, percentage of sand was a less reliable predictor of RN densities. Vertical sampling showed the highest numbers of RN were found at 15 to 30 cm deep after cotton, but were deeper after a nonhost crop. Understanding distribution patterns of RN within a field may improve the effectiveness of management practices.


Electrochemically Driven Hydrogen Atom Transfer Catalysis: A Tool for C(sp3)/Si-H Functionalization and Hydrofunctionalization of Alkenes.
Electrochemically driven hydrogen atom transfer (HAT) catalysis provides a complementary approach for the transformation of redox-inactive substrates that would be inaccessible to conventional electron transfer (ET) catalysis. Moreover, electrochemically driven HAT catalysis could promote organic transformations with either hydrogen atom abstraction or donation as the key step. It provides a versatile and effective tool for the direct functionalization of C(sp3)-H/Si-H bonds and the hydrofunctionalization of alkenes. Despite these attractive properties, electrochemically driven HAT catalysis has been largely overlooked due to the lack of understanding of both the catalytic mechanism and how catalyst selection should occur. In this Review, we give an overview of the HAT catalysis applications in the direct C(sp3)-H/Si-H functionalization and hydrofunctionalization of alkenes. The mechanistic pathways, physical properties of the HAT mediators, and state-of-the-art examples are described and discussed.


Sodium Channels and Venom Peptide Pharmacology.
Venomous animals including cone snails, spiders, scorpions, anemones, and snakes have evolved a myriad of components in their venoms that target the opening and/or closing of voltage-gated sodium channels to cause devastating effects on the neuromuscular systems of predators and prey. These venom peptides, through design and serendipity, have not only contributed significantly to our understanding of sodium channel pharmacology and structure, but they also represent some of the most phyla- and isoform-selective molecules that are useful as valuable tool compounds and drug leads. Here, we review our understanding of the basic function of mammalian voltage-gated sodium channel isoforms as well as the pharmacology of venom peptides that act at these key transmembrane proteins.


In Vivo Imaging of Transgenic Gene Expression in Individual Retinal Progenitors in Chimeric Zebrafish Embryos to Study Cell Nonautonomous Influences.
The genetic and technical strengths have made the zebrafish vertebrate a key model organism in which the consequences of gene manipulations can be traced in vivo throughout the rapid developmental period. Multiple processes can be studied including cell proliferation, gene expression, cell migration and morphogenesis. Importantly, the generation of chimeras through transplantations can be easily performed, allowing mosaic labeling and tracking of individual cells under the influence of the host environment. For example, by combining functional gene manipulations of the host embryo (e.g., through morpholino microinjection) and live imaging, the effects of extrinsic, cell nonautonomous signals (provided by the genetically modified environment) on individual transplanted donor cells can be assessed. Here we demonstrate how this approach is used to compare the onset of fluorescent transgene expression as a proxy for the timing of cell fate determination in different genetic host environments. In this article, we provide the protocol for microinjecting zebrafish embryos to mark donor cells and to cause gene knockdown in host embryos, a description of the transplantation technique used to generate chimeric embryos, and the protocol for preparing and running in vivo time-lapse confocal imaging of multiple embryos. In particular, performing multiposition imaging is crucial when comparing timing of events such as the onset of gene expression. This requires data collection from multiple control and experimental embryos processed simultaneously. Such an approach can easily be extended for studies of extrinsic influences in any organ or tissue of choice accessible to live imaging, provided that transplantations can be targeted easily according to established embryonic fate maps.


Immediate allergic reactions to betalactams: facts and controversies.
To analyse the available data in the field of immediate allergic reactions to beta-lactams, with particular emphasis on more recent studies, and to comment on the future role of this group of antibiotics. The world of beta-lactams has become more complex than initially thought, due to the increased number of chemical structures available, the wide variety of indications for their use in treating different infectious diseases, and possibly also due to the interaction of other as yet undetermined factors. Benzyl penicillin, the original inducer of allergic reactions, has now largely been replaced by amoxicillin and, to a lesser extent, by cephalosporins in inducing IgE-mediated allergic reactions. These structures often share extensive cross-reactivity, eliciting clinical reactions to many compounds, especially amongst penicillins. In other circumstances selective responses are observed which are restricted to one group or one single compound, as occurs in the group of cephalosporins. The application of new determinants for skin testing and the use of adapted in-vitro studies have enabled these findings to be confirmed in detail. Results indicate that evaluation of immediate reactions to beta-lactams requires the use of several determinants for both in-vitro and in-vivo testing, and which must reflect the relevant drug involved in eliciting the response. This tendency will be strengthened in the future if use of benzyl penicillin continues to decrease as a drug to which populations are exposed.


Advances in immunotoxins.
The field of immunotoxins is continuing to grow, as shown by the increase in attendance (175 vs. 145) and abstracts (110 vs. 60) at the symposium. Advances in the molecular biology of the toxins and clinical applications were notable at this meeting. The next 2 years should see better definition of the mechanism of action of peptide toxins as well as improvements in the design of targeted toxins for potential therapy of a wide variety of human diseases.


Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review.
Orthostatic hypotension is a frequent cause of falls and syncope, impairing quality of life. It is an independent risk factor of mortality and a common cause of hospitalizations, which exponentially increases in the geriatric population. We present a management plan based on a systematic literature review and understanding of the underlying pathophysiology and relevant clinical pharmacology. Initial treatment measures include removing offending medications and avoiding large meals. Clinical assessment of the patients' residual sympathetic tone can aid in the selection of initial therapy between norepinephrine "enhancers" or "replacers." Role of splanchnic venous pooling is overlooked, and applying abdominal binders to improve venous return may be effective. The treatment goal is not normalizing upright blood pressure but increasing it above the cerebral autoregulation threshold required to improve symptoms. Hypertension is the most common associated comorbidity, and confining patients to bed while using pressor agents only increases supine blood pressure, leading to worsening pressure diuresis and orthostatic hypotension. Avoiding bedrest deconditioning and using pressors as part of an orthostatic rehab program are crucial in reducing hospital stay.


A simple liquid extraction for simultaneous determination of 12 opioid ligands in plasma by LC-MS/MS.
Opioids are commonly used as analgesics to relieve chronic pain and have high abuse potential. Due to their strong potency and trace concentration in plasma, a robust analytical method is necessary for quantification in forensic and pharmacology fields. Hence, this study developed and validated a simple, rapid, and robust method for the simultaneous determination of 12 opioids and metabolites which were available legally by prescription or abused for non-medical purposes, in plasma samples by simple liquid extraction and high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). We compared the extraction recovery of our sample pre-treatment to two other sample pre-treatments (namely QuEChERS and simplified QuEChERS) and showed that the method used in our study gave the highest recoveries. The method validation followed the European Medicines Agency guidelines, including selectivity, carryover, accuracy and precision, dilution integrity, matrix effect and freeze/thaw stability. This method's accuracy ranged from 85% to 115% with a precision less than 15%, within the acceptable range of the validation protocol. The lower limit of quantification of the method ranged between 0.05 μg L-1 and 0.38 μg L-1 among 12 opioids/metabolites. Stability was assessed, with all opioids observed as relatively stable at 0.5 μg L-1 and 5 μg L-1 levels under -20 °C and 25 °C storage conditions. In summary, the developed method has the potential to achieve simultaneous analysis for monitoring opioids in forensic and pain management regimens using a simple sample pre-treatment.


Biological Processes for Hydrogen Production.
Methane is produced usually from organic waste in a straightforward anaerobic digestion process. However, hydrogen production is technically more challenging as more stages are needed to convert all biomass to hydrogen because of thermodynamic constraints. Nevertheless, the benefit of hydrogen is that it can be produced, both biologically and thermochemically, in more than one way from either organic compounds or water. Research in biological hydrogen production is booming, as reflected by the myriad of recently published reviews on the topic. This overview is written from the perspective of how to transfer as much energy as possible from the feedstock into the gaseous products hydrogen, and to a lesser extent, methane. The status and remaining challenges of all the biological processes are concisely discussed.


Detecting glaucomatous wedge shaped defects in polarimetric images.
Wedge shaped defects of the retinal nerve fiber layer (RNFL) may occur in glaucoma. Currently, automatic detection of wedge shaped defects in Scanning Laser Polarimetry (SLP) images of the RNFL is not available. An automatic classification is currently based only on global parameters, thereby ignoring important local information. Our method works by a modified dynamic programming technique that searches for locally strong edges with a preference for straight edges. These edges are initially classified based on their strength and next combined into wedge shaped defects. Our method yields a sensitivity of 73% and a specificity of 90% on a limited set of 65 images.


Strategies Resident-Physicians Use to Manage Sleep Loss and Fatigue.
Our purpose is to examine strategies or countermeasures resident-physicians used in dealing with the effects of sleep loss and fatigue during residency training. A total of 149 residents across five sites and six specialty areas were recruited for the study. Focus groups consisted of an average of 7 individuals in the same year of training and residency program, and included 60 interns and 89 senior residents. Trained moderators conducted focus groups using a semi-structured discussion guide. Transcripts were analyzed using the grounded theory tradition. The range of strategies adopted was: Chemical, Dietary, Sleep Management, Behavioral, and Cognitive. Residents exhibited a trial-and-error approach to identifying management strategies. None mentioned searching the scientific literature or consulting local sleep medicine experts. Residents relied on putative countermeasures even when they were aware of their negative effects. Our results document the need to educate resident physicians on self-care strategies during residency training.


Amifostine treatment in patients with myelodysplastic syndrome.
Myelodysplastic syndrome (MDS) is a clonal disorder that is characterized by peripheral cytopenia and the induction of apoptosis is thought to be partially responsible for pathological haematopoiesis in MDS. Amifostine is a cytoprotective and antioxidant agent, and it may prolong the survival of progenitor cells in MDS by delaying apoptosis. The study has been carried out with 9 MDS cases. Four of them were diagnosed as refractory anemia (MDS-RA), two as refractory anemia with ring sideroblasts (MDS-RARS) and the remaining three as refractory anemia with excess blasts (MDS-RAEB) according to the French-American-British (FAB) classification. Amifostine was given in a dose of 400 mg/m2, as an IV infusion administered in 5-6 minutes, three times a week for 4 consecutive weeks. Three of the cases (33.3%), two with MDS RARS and one with MDSRA, showed a significant improvement in the number of total leukocyte, neutrophil and reticulocyte counts and a decrease in the requirement of erithrocyte transfusions. In clinically responsive cases, all hematological parameters returned back to pre-treatment values two weeks after the cessation of therapy. We conclude that Amifostine can be used in a selected group of patients with MDS-RA and MDS-RARS.


Effects of cadmium and zinc on tissue levels of metallothionein.
Although the induced synthesis of metallothionein (MT) after exposure to certain metals has been known for some time, there is little information on the quantitation of MT in various tissues. In this study, tissue MT concentrations were measured by a modified Cd-saturation method in tissues of adult male rats after injection of different metal salts. There were differences in tissue levels of MT, depending on the injected metals. Of all the metals studied, Cd2+ was the most effective element in increasing MT concentrations in liver, kidney, pancreas and small intestine. The highest increase in tissue MT concentration after CdCl2 injection was found in the liver, while the pancreas contained the highest MT level after ZnSO4 injection. Co and Ni salts increased MT levels in both liver and kidney, while Mn and Ca increased MT levels only in liver. A direct correlation between tissue MT levels and Cd or Zn concentration was observed in most of the tissues after injection of CdCl2 or ZnSO4. Although there was no positive relationship between tissue levels of MT and tissue Mn and Ni concentrations, the increase in hepatic Zn after injection of these metals was related to hepatic MT levels. The tissue distribution of injected Cd2+ in control adult rats and Zn-deficient rats was similar. However, there was no increase in pancreatic MT levels in Zn-deficient rats after injection of CdCl2. The high concentration of MT in pancreas after ZnSO4 injection in adult rats and the inability of the pancreas to synthesize MT in Zn-deficient rats suggest that the induction of pancreatic MT synthesis is sensitive to Zn status.(ABSTRACT TRUNCATED AT 250 WORDS)


Practice Patterns and Outcomes of Novel Targeted Agents for the Treatment of ERBB2-Positive Metastatic Breast Cancer.
Clinical trials have shown that the addition of pertuzumab to trastuzumab-based chemotherapy for first-line treatment of ERBB2-positive metastatic breast cancer is associated with considerable improvement in overall survival (OS). In the second-line setting, trastuzumab emtansine (T-DM1) improves OS compared with capecitabine/lapatinib in patients previously treated with trastuzumab-based chemotherapy. However, there are few data describing long-term real-world outcomes with these agents. To describe practice patterns and outcomes associated with pertuzumab and T-DM1 in routine clinical practice. This population-based retrospective cohort study used the Ontario Cancer Registry linked to electronic treatment databases to identify all patients treated with pertuzumab and T-DM1 following reimbursement approval in Ontario, Canada, which has a single-payer public health system. Participants included women with stage IV ERBB2-positive metastatic breast cancer receiving treatment with pertuzumab for first-line metastatic indication from December 2013 through December 2017, and those treated with T-DM1 from May 2014 through December 2017. Pertuzumab and T-DM1 cohorts were analyzed separately. Data were analyzed December 2019 to December 2020. Treatment with pertuzumab or T-DM1. The primary outcome was OS, determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. The median (interquartile range [IQR]) age of the 795 women who received pertuzumab and 506 women who received T-DM1 was 57 (49-67) and 56 (48-66) years, respectively. Among the cohort of patients who received pertuzumab, the median (IQR) OS and time on treatment was 43 (16.2-unavailable) and 14 (6.0-26.2) months, respectively. In the T-DM1 cohort, the proportion of pertuzumab-naive patients decreased over time from 68 of 91 [74.7%] in 2014 to 16 of 89 [18.0%] in 2017 (P < .001). The median (IQR) OS and time on treatment was 15 (6.7-27.7) and 4 (1.4-9.0) months, respectively. Median OS was shorter for patients with prior pertuzumab treatment than in the pertuzumab-naive subgroup (12 vs 19 months; adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = .004). In this population-based cohort study, the survival of patients treated with pertuzumab and T-DM1 in routine practice appeared inferior to results from pivotal clinical trials. Differences in outcome likely reflect differences in patient population and previous lines of therapy in routine practice. Further work is needed to understand the effectiveness of T-DM1 after pertuzumab exposure.


Artificial Intelligence Inheriting the Historical Crisis in Psychology: An Epistemological and Methodological Investigation of Challenges and Alternatives.
By following the arguments developed by Vygotsky and employing the cultural-historical activity theory (CHAT) in addition to dialectical logic, this paper attempts to investigate the interaction between psychology and artificial intelligence (AI) to confront the epistemological and methodological challenges encountered in AI research. The paper proposes that AI is facing an epistemological and methodological crisis inherited from psychology based on dualist ontology. The roots of this crisis lie in the duality between rationalism and objectivism or in the mind-body rupture that has governed the production of scientific thought and the proliferation of approaches. In addition, by highlighting the sociohistorical conditions of AI, this paper investigates the historical characteristics of the shift of the crisis from psychology to AI. Additionally, we examine the epistemological and methodological roots of the main challenges encountered in AI research by noting that empiricism is the dominant tendency in the field. Empiricism gives rise to methodological and practical challenges, including challenges related to the emergence of meaning, abstraction, generalization, the emergence of symbols, concept formation, functional reflection of reality, and the emergence of higher psychological functions. Furthermore, through discussing attempts to formalize dialectical logic, the paper, based on contradiction formation, proposes a qualitative epistemological, methodological, and formal alternative by using a preliminary algorithmic model that grasps the formation of meaning as an essential ability for the qualitative reflection of reality and the emergence of other mental functions.


Isolation, Characterization, and Antiproliferative Activities of Eudesmanolide Derivatives from the Flowers of Inula japonica.
Inula japonica belongs to the family Asteraceae, and its flowers have been used as dietary supplements and health tea in China. The study aimed to identify the bioactive components with the antiproliferative property. Ten 1,10-seco-eudesmanolide derivatives, including four new compounds (1-4), were isolated from the flowers of I. japonica. Their structures were established on the basis of the interpretation of spectroscopic data and electronic circular dichroism (ECD) calculations. All of these isolates were evaluated for their antiproliferative activities against MCF-7 and MDA-MB-231 human breast cancer cells. Compound 4 possessed the most potent effects, with the IC50 values of 0.20 ± 0.04 and 6.22 ± 1.30 μM against MCF-7 and MDA-MB-231 cells, respectively. The present investigation indicated that eudesmanolide derivatives from the flowers of I. japonica, especially compound 4, might be used as potential antitumor chemotherapy agent candidates.


Linking plant nutritional status to plant-microbe interactions.
Plants have developed a wide-range of adaptations to overcome nutrient limitation, including changes to the quantity and composition of carbon-containing compounds released by roots. Root-associated bacteria are largely influenced by these compounds which can be perceived as signals or substrates. Here, we evaluate the effect of root exudates collected from maize plants grown under nitrogen (N), phosphate (P), iron (Fe) and potassium (K) deficiencies on the transcriptome of the plant growth promoting rhizobacterium (PGPR) Bacillus amyloliquefaciens FZB42. The largest shifts in gene expression patterns were observed in cells exposed to exudates from N-, followed by P-deficient plants. Exudates from N-deprived maize triggered a general stress response in FZB42 in the exponential growth phase, which was evidenced by the suppression of numerous genes involved in protein synthesis. Exudates from P-deficient plants induced bacterial genes involved in chemotaxis and motility whilst exudates released by Fe and K deficient plants did not cause dramatic changes in the bacterial transcriptome during exponential growth phase. Global transcriptional changes in bacteria elicited by nutrient deficient maize exudates were significantly correlated with concentrations of the amino acids aspartate, valine and glutamate in root exudates suggesting that transcriptional profiling of FZB42 associated with metabolomics of N, P, Fe and K-deficient maize root exudates is a powerful approach to better understand plant-microbe interactions under conditions of nutritional stress.


Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.
Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.


Clinical puzzle: Barrett's oesophagus.
The incidence of oesophageal adenocarcinoma has increased dramatically in the Western world over the past two decades. Owing to its dismal 5-year prognosis in advanced stages, early diagnosis is required in order to improve survival rates. Barrett's oesophagus (Barrett's) has been recognised as a pre-cancerous condition generally associated with chronic and severe gastro-oesophageal reflux disease (GORD). Barrett's is defined as the substitution of the normal stratified squamous epithelium of the oesophagus with a columnar cell lining with intestinal-type differentiation; a phenomenon commonly referred to as intestinal metaplasia. Clinical challenges include finding cost-effective ways to identify patients with Barrett's, stratifying them according to their cancer risk and improving the diagnostic potential of endoscopic sampling. Research has generally focused on identifying tissue biomarkers to predict cancer risk in these patients. The oesophagus is easily accessible, making it possible to work with human samples, but most studies have been retrospective and underpowered. Endoscopic surveillance programmes are problematic due to sampling bias and the subjective grading of dysplasia. The lack of an animal model has hampered studies to elucidate markers of the transition from Barrett's to cancer and to test potential therapeutics. However, a number of in vitro model systems are ripe for further development into more physiologically complete systems.


[Hydropneumatic dilatation of the ureter: A technical option in ureteropyeloplasty].
The pyeloureteric junction (UP) is the site of obstruction commonest in the upper tract urinary. Several surgical techniques exist and the main complication is the stricture by the disproportion between both ends. The hydropneumatic dilatation of the ureteric would increase of the 5:1 to 2:1 the light of the ureter, improving technically anastomosis and reducing complications. They studied 27 patients with diagnose of Estenosis UP in the Paediatric Urologist Service of CMN 20 of November of the ISSSTE, being made dismembered Pyeloplasty pyeloureteric in all, introducing Fogarty catheter in the Ureter carrying out the hydropneumatic dilatation of the same one, introduction of catheter double J in ureter and in the last patient without this, previous one to the anastomosis. All had a pursuit of 6 months. Of the 27 patients, 21 masculine ones (77.78%), 6 feminine ones (22.22%), of the right side 10 (37.04%), left 14 (51.85%) and bilateral 3 (11.11%). In the 27 studied patients postoperating complications did not appear. To all the patients I am made the dilatation to them hydropneumatics of the Ureter during UP plasty, did not present/display postoperating complications, the anastomosis is carried out with greater technical facility since the light of the Ureteric increase from 5:1 in 2:1, and in I complete case without ferulization of the Ureter, I do not present/display complications. DOSCUSSION: The hydropneumatics dilatation of the Ureter is a technical option in the Surgical handling of stricture UP, facilitating the anastomosis, diminishing the postoperating complications, making the ferulization do withoutible of the Ureter.


Muscle oxygen supply during cold face immersion in breath-hold divers and controls.
The human diving reflex is characterized by bradycardia, decreased cardiac output, and peripheral vasoconstriction, and has an oxygen-conserving effect both at rest and during exercise. However, the resultant time course and extent of muscle desaturation is unknown. We used near-infrared spectroscopy to continuously measure the decrease in tissue oxygen saturation (StO2) in the calf muscle during a series of breath-holds. Subjects were seven trained divers (TD) and eight untrained controls (UC). Other measured variables included arterial blood pressure, heart rate, and arterial oxygen saturation (SaO2). Each subject performed five maximal apneas during face immersion in cold water with 2-min recovery intervals between breath-holds. On average, total apnea time for TD was significantly longer than for UC (772.6 +/- 40.9 s vs. 499.1 +/- 118.2 s, respectively). Further, TD had a more pronounced decrease in StO2 than UC (70.6 +/- 15.3% for TD vs. 87.9 +/- 6.1% UC for the fifth and longest apnea). When values for the two groups were compared at the mean breakpoint time for UC, there was no difference in StO2 and SaO2 remained at baseline. By contrast, at the same time point in all five apneas, UC experienced simultaneous, significantly larger reductions in SaO2 and StO2. These data indicate that TD have an attenuated diving reflex compared with UC at the same breath-hold times (the breakpoint for UC). In addition, muscle desaturation occurs earlier than arterial desaturation in both groups; the fact that this effect was less pronounced in TD suggests a training effect. This study provides further evidence for the oxygen-conserving effect of the human diving reflex in maintaining the oxygen supply of vital organs.


Airway injury resulting from repeated endotracheal intubation: Possible prevention strategies.
To characterize physical and inflammatory injury that may result from repeated intubation, independent of positive-pressure ventilation; and to determine whether corticosteroids can attenuate injury and or inflammation that may result from repeated intubation. A 4-hr animal protocol. All work was done in the animal laboratory at the Alfred I. DuPont Hospital for Children. Neonatal piglets (2-8 days old; 2.5 ± 0.4 kg) were intubated and randomized to four groups (n = 8 each) to be followed over 4 hrs. Groups were control (not reintubated), injured (reintubated every 0.5 hr), intratracheal pretreatment with 1 mg of nebulized budesonide (intratracheal pretreated), or intravenous pretreatment with 0.3 mg/kg of dexamethasone (intravenous pretreated). Each pig was sedated for the duration of study and had a 3.5F catheter inserted in the femoral artery for blood sampling and blood pressure measurement every hour. After 4 hrs, each pig was killed, and tissue was harvested for histology and interleukin-6 assays. Laryngeal tissue interleukin-6 content was greater in the injured group compared with the control group (p < .05). In the intratracheal pretreated group, the interleukin-6 content of laryngeal tissue was greater compared with the control group (p < .05), whereas the intravenous pretreated group was not different from the control group. The reintubation injury resulted in plasma interleukin-6 levels that, compared with control, were greater in the injured and intratracheal pretreated groups (p < .05). Quantitative histology showed that the degree of tracheal injury was higher in injured and intratracheal pretreated groups compared with the control group (p < .05). Repeated intubation alone results in significant tracheal trauma and systemic inflammation. Intravenous but not inhaled steroids attenuated the injury.


Logistic and technical considerations in the treatment of the wounded heart.
As improvements in the prehospital care of traumatically injured patients have paralleled advancements in cardiovascular surgery, changing concepts in the management of the patient with blunt and penetrating injuries of the heart have occurred. More critically injured patients now arrive at a hospital facility still alive than in former years. Between 1951 and 1974, 350 patients with heart injuries were treated at Harris County Hospital District facilities. Gunshot wounds now predominate, compared with stab wounds in former years. Thirteen patients had rupture of the heart secondary to blunt trauma. Patients arriving with cardiac arrest and cerebral signs of preterminal activity had a 67% survival rate when cardiorraphy was performed in the Trauma Center. In the last four years, 50 patients without cardiac arrest, but frequently with pericardiocentesis as a preoperative adjunct, had an 87% survival rate.


Antifouling Properties of Amine-Oxide-Containing Zwitterionic Polymers.
Biofouling due to nonspecific proteins or cells on the material surfaces is a major challenge in a range of applications such as biosensors, medical devices, and implants. Even though poly(ethylene glycol) (PEG) has become the most widely used stealth material in medical and pharmaceutical products, the number of reported cases of PEG-triggered rare allergic responses continues to increase in the past decades. Herein, a new type of antifouling material poly(amine oxide) (PAO) has been evaluated as an alternative to overcome nonspecific foulant adsorption and impart comparable biocompatibility. Alkyl-substituted PAO containing diethyl, dibutyl, and dihexyl substituents are prepared, and their solution properties are studied. Photoreactive copolymers containing benzophenone as the photo-cross-linker are prepared by reversible addition-fragmentation chain-transfer polymerization and fully characterized by gel permeation chromatography and dynamic light scattering. Then, these water-soluble polymers are anchored onto a silicon wafer with the aid of UV irradiation. By evaluating the fouling resistance properties of these modified surfaces against various types of foulants, protein adsorption and bacterial attachment assays show that the cross-linked PAO-modified surface can efficiently inhibit biofouling. Furthermore, human blood cell adhesion experiments demonstrate that our PAO polymer could be used as a novel surface modifier for biomedical devices.


A functional magnetic resonance imaging study of emotional Stroop in euthymic bipolar disorder.
Bipolar disorder is regarded as a disorder of mood and initial studies have focused on structural abnormalities in limbic networks, known to subserve mood. More recently, functional imaging studies allude to affect processing deficits, which may involve frontostriatal networks. This study sought to explore disturbances in networks involved in the processing of negative affect in euthymic bipolar patients. We used simultaneous functional magnetic resonance imaging and galvanic skin responsivity to explore disturbances in these networks. When processing negative affect, controls recruited a distributed subcortical-prefrontal network. In contrast, patients could only activate a subcortical network that included the amygdala and hippocampus. This study provides evidence for a disconnection in the transfer of information within frontostriatal networks in bipolar disorder.


Magnetism in Nonplanar Zigzag Edge Termini of Graphene Nanoribbons.
Graphene nanoribbons (GNRs) and nanographenes synthesized by on-surface reactions using tailor-made molecular precursors offer an ideal playground for a study of magnetism towards nano-spintronics. Although the zigzag edge of GNRs has been known to host magnetism, the underlying metal substrates usually veil the edge-induced Kondo effect. Here, we report the on-surface synthesis of unprecedented, π-extended 7-armchair GNRs using 7-bromo-12-(10-bromoanthracen-9-yl)tetraphene as the precursor. Characterization by scanning tunneling microscopy/spectroscopy revealed unique rearrangement reactions leading to pentagon- or pentagon/heptagon-incorporated, nonplanar zigzag termini, which demonstrated Kondo resonances even on bare Au(111). Density functional theory calculations indicate that the nonplanar structure significantly reduces the interaction between the zigzag terminus and the Au(111) surface, leading to a recovery of the spin localization of the zigzag edge. Such a distortion of planar GNR structures offers a degree of freedom to control the magnetism on metal substrates.


The essential role of inflammation and induced gene expression in the pathogenic pathway of Alzheimer's disease.
Alzheimer's disease is among the most common diseases of advanced age affecting almost one out of ten individuals who survive beyond the age of 65 years, and an another 10% for each additional decade of the life-span. The prognosis of the disease is an inexorable decline of mental functions leading to complete dependence on caretakers in the late stages of the disease. Alzheimer's disease will become a steadily increasing financial health-care problem in the industrialized world with the increasing longevity and ageing of the population. To-date there are no effective therapeutics. However, during the last years promising findings suggest that anti-inflammatory treatment strategies might be efficient. Here, we will review the experimental and epidemiological findings which support the idea that inflammatory mechanisms play an important role in Alzheimer's disease pathogenesis. The review of the experimental findings will be focussed on the amyloid-associated proteins, alpha1-antichymotrypsin and apolipoprotein E, as well as the major cytokines. In addition, the epidemiological studies on non-steroidal anti-inflammatory drugs and traumatic head injury will be summarized. We hypothesize a pathogenic model for Alzheimer's disease in which the expression of amyloid-associated proteins/pathological chaperones, induced by inflammatory cytokines, plays an essential role in accelerating the disease progress, and suggest potential targets for drug discovery based on such a model.


Complexity in language acquisition.
Learning theory has frequently been applied to language acquisition, but discussion has largely focused on information theoretic problems-in particular on the absence of direct negative evidence. Such arguments typically neglect the probabilistic nature of cognition and learning in general. We argue first that these arguments, and analyses based on them, suffer from a major flaw: they systematically conflate the hypothesis class and the learnable concept class. As a result, they do not allow one to draw significant conclusions about the learner. Second, we claim that the real problem for language learning is the computational complexity of constructing a hypothesis from input data. Studying this problem allows for a more direct approach to the object of study--the language acquisition device-rather than the learnable class of languages, which is epiphenomenal and possibly hard to characterize. The learnability results informed by complexity studies are much more insightful. They strongly suggest that target grammars need to be objective, in the sense that the primitive elements of these grammars are based on objectively definable properties of the language itself. These considerations support the view that language acquisition proceeds primarily through data-driven learning of some form.


The utility of postoperative radiotherapy in intermediate-risk oral squamous cell carcinoma.
The effectiveness of postoperative radiotherapy (PORT) in improving outcomes remains debatable for oral squamous cell carcinoma (OSCC) patients with pathological intermediate-risk factors (IRFs) after surgery. A retrospective analysis was conducted on 432 intermediate-risk OSCC patients defined by histological reporting of close margin (<5mm), early nodal disease (pN1), depth of invasion/tumour thickness ≥5mm, perineural invasion, and/or lymphovascular invasion. Outcomes measured were disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). PORT was associated with an improvement in 5-year DFS on univariable analysis (80% vs 71%; P=0.044), but this did not remain significant on multivariable analysis. PORT was not associated with differences in DSS or OS. The surgical salvage rate was similar in the PORT and surgery-only groups (41% vs 47%; P=0.972). Perineural invasion was found to be an independent predictor of inferior DSS (hazard ratio (HR) 2.19), DFS (HR 1.89), and OS (HR 1.97). Significantly worse outcomes were observed for patients with ≥4 concurrent IRFs. The application of PORT was associated with lower rates of recurrence, but the benefit was less apparent on mortality. Patients with perineural invasion and multiple concurrent IRFs were found to be at greatest risk, representing a subset of intermediate-risk OSCC patients who may benefit from PORT.


Synthetic signal peptides specifically recognize SecA and stimulate ATPase activity in the absence of preprotein.
Although it is known that virtually all exported proteins require a signal peptide, it is not clearly understood how the signal peptide interfaces with the translocation machinery to achieve transport. In this study we document a direct interaction between the signal peptide and SecA, a primary component of the translocase in Escherichia coli, and show that the signal peptide itself can stimulate SecA-lipid ATPase activity. Using synthetic signal peptides corresponding to the wild type alkaline phosphatase signal sequence and two model sequences, we find that the extent of stimulation of SecA ATPase activity by the different peptides parallels the hierarchy of results found for in vivo function (Izard, J. W., Doughty, M. B., and Kendall, D. A. (1995) Biochemistry 34, 9904-9912). The peptide-induced activity requires a lipid to protein molar ratio of at least 300:1 and liposomes enriched in negatively charged phospholipids. Furthermore, specific binding of the signal peptide to SecA was demonstrated using chemical cross-linking and competition with unlabeled peptides.


Graphene-supporting films and low-voltage STEM in SEM toward imaging nanobio materials without staining: Observation of insulin amyloid fibrils.
Utilization of graphene-supporting films and low-voltage scanning transmission electron microscopy (LV-STEM) in scanning electron microscopy (SEM) is shown to be an effective means of observing unstained nanobio materials. Insulin amyloid fibrils, which are implicated as a cause of type II diabetes, are formed in vitro and observed without staining at room temperature. An in-lens cold field-emission SEM, equipped with an additional homemade STEM detector, provides dark field (DF)-STEM images in the low energy range of 5-30keV, together with secondary electron (SE) images. Analysis based on Lenz's theory is used to interpret the experimental results. Graphene films, where the fibrils are deposited, reduce the background level of the STEM images compared with instances when conventional amorphous carbon films are used. Using 30keV, which is lower than that for conventional TEM (100-300keV), together with low detection angles (15-55mrad) enhances the signals from the fibrils. These factors improve image quality, which enables observation of thin fibrils with widths of 7-8nm. STEM imaging clearly reveals a twisted-ribbon structure of a fibril, and SE imaging shows an emphasized striped pattern of the fibril. The LV-STEM in SEM enables acquisition of two types of images of an identical fibril in a single instrument, which is useful for understanding the structure. This study expands the application of SEM to other systems of interest, which is beneficial to a large number of users. The method in this study can be applied to the observation of various nanobio materials and analysis of their native structures, thus contributing to research in materials and life sciences.


Immunohistochemistry Applied to Breast Cytological Material.
Fine-needle aspiration biopsies (FNABs) of the breast are minimally invasive procedures enabling the diagnosis of suspicious breast lesions. Unfortunately, they are often perceived as inferior to core-needle biopsies, namely because they are supposedly unable to differentiate between high-grade ductal carcinoma in situ and invasive carcinoma or provide material for ancillary testing. Several studies have shown, however, that FNAB samples, when handled properly, are indeed capable of providing sufficient and adequate material for ancillary testing, namely immunocytochemistry (ICC). We reviewed the published literature regarding the use of ICC for both diagnostic and theranostic uses in the different types of cytological samples obtained from FNABs of the breast, including smears, liquid-based cytology samples, and cellblocks. We found that p63 and 34βE12 show promise in aiding in the differential diagnosis between in situ and invasive lesions and that most other diagnostic markers may be used as in tissue. Regarding theranostic ICC markers, results vary between publications, but with care, these can successfully be performed in cytological samples. Air-dried smears should be avoided, and cellblocks are overall more versatile than cytology slides, enabling the evaluation of not only hormonal receptors and HER2 by ICC, but also of Ki-67. Particular attention should be paid to fixation and antigen retrieval procedures in all cases. We recommend that laboratories without experience perform short validation runs before adopting these techniques into clinical practice.


Dipylidium caninum infection.
Dipylidium caninum is a cestode that requires from the participation of an arthropod in its life cycle. This parasitosis occurs in dogs and cats, and occasionally in human beings. Human cases of D caninum infection have been reported in Europe, Philippines, China, Japan, Latin America and the United States; mostly children, one third of them being infants under 6 months old. The diagnosis of this disease is done by the parasitological study of the feces, observing the characteristics of the gravid proglottids. The treatment is performed by administering broad-spectrum anthelmintics. The authors report a case of a rare infection in a Mexican child.


Alternate gram staining technique using a fluorescent lectin.
Fluorescence-labeled wheat germ agglutinin binds specifically to N-acetylglucosamine in the outer peptidoglycan layer of gram-positive bacteria. The peptidoglycan layer of gram-negative bacteria is covered by a membrane and is not labeled by the lectin. By exploiting this phenomenon, an alternative Gram staining technique has been developed.


[Legal recognition of transsexuality in Chile through the judicial procedure for name change].
Do transsexual people in Chile have a right to have their gender identity or their sex reassignment legally recognized? The absence of any legislation on gender identity or transsexualism could lead us to believe that it is not the case. However, a quantitative review of decisions issued by Chilean courts during the last years on name-and sex-change requests filed by transsexual people reveals that most of these courts have accepted these requests. From the perspective of the well-being of transsexual people, this is a positive result. However, the fact that a few rejections exist reminds us of the need to enact an explicit legislation in this issue. Lastly, a qualitative analysis of those decisions suggests that the traditional reluctance of courts to interpret the law in a creative way has been overcome in these cases by the use of knowledge and discourses belonging to healthcare sciences. This is an example of an epistemological complementariness between medicine and law.


Miniaturized electrochemical detector as a tool for detection of DNA amplified by PCR.
This paper reports on the analysis of specific sequence of Phage Lambda DNA amplified by PCR. Agarose gel electrophoresis, gel electrophoresis on chip and stationary electrochemical instrument were employed for detection of amplicons obtained after 2, 4, 6, 8, 10, 15, 20, 25, 30 and 35 cycles. In the case of agarose gel electrophoresis the lowest detectable amount of DNA was obtained after 15 PCR cycles. Gel electrophoresis on chip offers higher sensitivity because the lowest detectable amount of amplicons by this technique was obtained after eight PCR cycles. Further we employed square wave voltammetry and various working electrodes (hanging mercury drop electrode, screen-printed carbon electrode and carbon-nanotube-based screen-printed electrodes) to detect amplicons. Amplicons obtained even after two cycles were detectable at all electrodes. To improve the selectivity of electrochemical detection carbon nanoelectrodes were off-line coupled with gel electrophoresis. Into the agarose gel the electrodes were placed. Further the amplicons were loaded into agarose gel wells. DNA migrating to the detection place was electrochemically analyzed. Amplicons obtained after two cycles were detectable by this hyphenated technique.


Immunoglobulin G is associated with surfactant protein A aggregate isolated from patients with pulmonary alveolar proteinosis.
We have previously shown that the purified preparation of surfactant protein A (SP-A) isolated from patients with pulmonary alveolar proteinosis (PAP) contains a very small amount of immunoglobulin G (IgG). We have recently found that there exists an abnormal multimerized form (alveolar proteinosis protein-I, APP-I) in SP-As isolated from patients with PAP in addition to normal-sized octadecameric APP-II. We examined which of the populations of APP that IgG is associated with. The APP was purified by mannose-affinity column followed by gelfiltration over Bio Gel A5m after the delipidation with 1-butanol. Analysis by gel filtration over Bio Gel A15m showed two elution peaks of APP-I and APP-II. When the fractions eluted from the Bio Gel A15m column were coated onto microtiter wells and reacted with HRP-labeled antihuman IgG, the elution peak of IgG was superimposed on that of APP-I but not on that of APP-II. The immunoblotting analysis also revealed that a very small amount of IgG, which could not be detected by staining with Coomassie blue or amido black, was associated with APP-I but not with APP-II or normal SP-A. APP-I bound to nonimmune IgG coated onto microtiter wells in a concentration-dependent manner, whereas APP-II, normal human SP-A, and rat SP-A exhibited almost no binding to IgG. The results indicate an unusual property of SP-A during the diseased state.


[Azygos Arch Preserving Thoracoscopic Esophagectomy for Less Invasiveness].
We reported the technique ofthoracoscopic esophagectomy with preservation ofazygos arch for less invasivenesss. Among thoracoscopic esophagectomy, this retchnique indicated for the patients with the tumor located at middle or lower thoracic and don't reach adventitia. Twenty-eight patients was performed this procedure and azygos arch were preserved in all cases. None the cases were converted conventional thoracotomy. The operation time was 133.5 minutes(median), and estimated blood loss was 30 mL(median)in thoracic procedure. As for thoracoscopic esophagectomy, could preserved respiratory function, further less surgical stress can obtain this technique.


Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curaçao Extrapyramidal Syndromes Study III.
The authors examined the association between three lifetime medication variables (cumulative amount of neuroleptics, number of interruptions in neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence and severity of tardive dyskinesia. The study was conducted in the only psychiatric hospital of a well-defined catchment area (the Netherlands Antilles). For all patients who had a history of taking neuroleptics for at least 3 months and were currently using neuroleptics (N = 133, mean age = 51.5 years), the presence and severity of tardive dyskinesia were measured with the Abnormal Involuntary Movement Scale. Of the three lifetime medication variables, only the number of neuroleptic interruptions was significantly related to tardive dyskinesia. The risk of tardive dyskinesia was three times as great for patients with more than two neuroleptic interruptions as for patients with two or fewer interruptions. This finding supports the schizophrenia protocol of long-term neuroleptic treatment rather than targeted or intermittent neuroleptic treatment.


Chukfuransins A-D, four new phragmalin limonoids with β-furan ring involved in skeleton reconstruction from Chukrasia tabularis.
Four new phragmalin limonoids (chukfuransins A-D) were isolated from the twigs and leaves of Chukrasia tabularis. Chukfuransins A (1) and B (2) feature a unique C-15/C-20 linkage proposed to be built by a biogenetic pathway involving Michael addition. Chukfuransins C (3) and D (4) feature the C-15/C-21 linkage. Their structures and absolute configurations were established by NMR techniques and X-ray crystallographic analysis.


beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium- and G-protein-dependent.
The proinflammatory cytokine, interleukin-1 (IL-1) is elevated in the Alzheimer's disease (AD) brain. Studies from our laboratory have demonstrated that beta-amyloid (A beta) 1-42, fibrillar A beta 1-40 and A beta 25-35 induce the release of IL-1 beta from activated THP-1 cells, a human monocyte cell line. A beta also is chemotactic for primary rodent microglia and peritoneal macrophages. We hypothesize that A beta is a chemokine and induces these responses by interaction with chemotactic receptors. If this is true, then these A beta-induced responses should be calcium-dependent and require activation of pertussis toxin-sensitive G-proteins. To test this hypothesis, THP-1 cells were grown in culture with lipopolysaccharide (LPS) and incubated with A beta 1-42 (5 muM) in the presence and absence of a calcium chelator, an inhibitor of intracellular calcium mobilization, a calcium channel blocker, or pertussis toxin, a bacterial endotoxin which uncouples G proteins from receptors by catalyzing the ADP ribosylation of cysteine near the carboxy-terminus of the alpha subunit. The media was collected and IL-1 beta present in the media was measured using an ELISA. Treatment of LPS-activated THP-1 cells with A beta 1-42 significantly elevated IL-1 beta released into the media as previously shown. Addition or ethylene glycol-bis (beta-aminothyl ether) N,N,N'N'-tetraacetic acid (EGTA) (0.5 mM), a calcium chelator, to the media blocked A beta-induced IL-1 beta release, but had no effect on LPS-activated THP-1 cell release of IL-1 beta. The presence of 3,4,5-trimethoxybenzoic acid 8-(diethyl amino)-octyl ester (TMB-8), an inhibitor of intracellular calcium mobilization, as well as nickel chloride, a non-specific calcium channel blocker, in the media also inhibited A beta-induced IL-1 release from LPS-activated THP-1 cells. IL- 1 beta release from activated THP-1 monocytes incubated with TMB-8 and nickel chloride without A beta remained at baseline values. Pretreatment of THP-1 monocytes with pertussis toxin for 4 h, followed by LPS activation and incubation with A beta, antagonized the release of IL-1 beta from these cells, but did not alter IL-1 beta release from activated THP-1 monocytes. These data suggest that A beta-induced IL-1 beta release from these cells is calcium-dependent and requires the activation of specific G-proteins. These findings are consistent with known second messengers that are activated following stimulation of chemotactic receptors.


Messenger RNA for cataractous lens proteins are also present on normal lens polyribosomes.
We have previously described an experimental model in vivo where cataract is induced by injection of the antimitotic bleomycin in the newborn rat. The first opacity of the lens appears 12--15 days after the injection of the drug concomitantly with a group of precise biochemical modifications among the soluble crystallins. These modifications are mainly the accumulation of two additional low-molecular-weight beta crystallin subunits (beta L subunits) and of several smaller alpha-crystallin polypeptides. Messenger RNA isolated from normal and cataractous lenses was assayed for translation in a cell-free wheat germ extract. Analysis of the translation products by one-dimensional and two-dimensional gel electrophoresis indicated that the messenger RNAs coding for the two beta L subunits are also present on normal lens polyribosomes. Purification and subsequent analysis by peptide mapping of the cataractous Beta L subunits suggest that they are precursor polypeptides of the normal low-molecular-weight beta-crystallins, which are no longer processed after translation and therefore accumulate in the pathological lens cell. On the other hand, in the translation of the cataractous mRNA in vitro, only the normal alpha chains are detected. These cataractous alpha-crystallins are therefore post-translational degradation products of the normal alpha polypeptides. This phenomenon seems similar to the one observed in the senescent lens. The possible involvement of these modifications in the etiology of this experimental cataract is discussed further.


The Risk of Acute Kidney Injury from Fluid Restriction and Hydroxyethyl Starch in Thoracic Surgery.
Fluid is restricted in thoracic surgery to reduce acute lung injury, and hydroxyethyl starches (HES) are often administered to reduce fluid amount. This strategy may contribute to the development of acute kidney injury (AKI). We evaluated the incidence, risk factors, and prognosis of AKI in thoracic surgery. We especially focused on whether fluid restriction/HES administration increased AKI. This is a retrospective study of patients undergoing thoracic surgery in a tertiary care academic center. Postoperative AKI was diagnosed within 72 hours after surgery based on the Acute Kidney Injury Network criteria. Demographic, intraoperative, and postoperative data were compared between non-AKI and AKI groups. Logistic regression was used to model the association between risk factors and AKI. Final analysis included 1442 patients. Of these, 74 patients developed AKI (5.1%). Crystalloid restriction (≤3 mL·kg·h) was unrelated to AKI, regardless of preoperative renal functions (odds ratio [OR], 0.5; 95% confidence interval [CI] 0.2-1.4). AKI occurred more often when HES were administered to the patients with decreased renal function (OR, 7.6; 95% CI, 1.5-58.1) or having >2 risk factors with normal renal function (OR, 7.2; 95% CI, 3.6-14.1). Multivariate analysis revealed several risk factors: angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, open thoracotomy, pneumonectomy/esophagectomy, diabetes mellitus, cerebrovascular disease, low albumin level, and decreased renal function. Fluid restriction neither increased nor was a risk factor for AKI. HES should be administered with caution in high-risk patients undergoing thoracic surgery.


Microscopic fields in liquid dielectrics.
We present the results of an analytical theory and numerical simulations of microscopic fields in dipolar liquids. Fields within empty spherical cavities (cavity field) and within cavities with a probe dipole (directing field) and the field induced by a probe dipole in the surrounding liquid (reaction field) are considered. Instead of demanding the field produced by a liquid dielectric in a large-scale cavity to coincide with the field of Maxwell's dielectric, we continuously increase the cavity size to reach the limit of a mesoscopic dimension and establish the continuum limit from the bottom up. Both simulations and analytical theory suggest that the commonly applied Onsager formula for the reaction field is approached from below, with increasing cavity size, by the microscopic solution. On the contrary, the cavity and directing fields do not converge to the limit of Maxwell's dielectric. The origin of the disagreement between the standard electrostatics and the results obtained from microscopic models is traced back to the failure of the former to account properly for the transverse correlations between dipoles in molecular liquids. A new continuum equation is derived for the cavity field and supported by numerical simulations. Experimental tests of the theoretical results are suggested.


Searching for recursive causal structures in multivariate quantitative genetics mixed models.
Biology is characterized by complex interactions between phenotypes, such as recursive and simultaneous relationships between substrates and enzymes in biochemical systems. Structural equation models (SEMs) can be used to study such relationships in multivariate analyses, e.g., with multiple traits in a quantitative genetics context. Nonetheless, the number of different recursive causal structures that can be used for fitting a SEM to multivariate data can be huge, even when only a few traits are considered. In recent applications of SEMs in mixed-model quantitative genetics settings, causal structures were preselected on the basis of prior biological knowledge alone. Therefore, the wide range of possible causal structures has not been properly explored. Alternatively, causal structure spaces can be explored using algorithms that, using data-driven evidence, can search for structures that are compatible with the joint distribution of the variables under study. However, the search cannot be performed directly on the joint distribution of the phenotypes as it is possibly confounded by genetic covariance among traits. In this article we propose to search for recursive causal structures among phenotypes using the inductive causation (IC) algorithm after adjusting the data for genetic effects. A standard multiple-trait model is fitted using Bayesian methods to obtain a posterior covariance matrix of phenotypes conditional to unobservable additive genetic effects, which is then used as input for the IC algorithm. As an illustrative example, the proposed methodology was applied to simulated data related to multiple traits measured on a set of inbred lines.


Effects of atenolol as add-on therapy to fosinopril in heart failure.
Several trials have demonstrated functional benefit with beta-blockers in patients with chronic heart failure. The aim of this observational study was to investigate if additional beneficial effects can be obtained from beta-blockade in a heart failure population that is already receiving high-dose ACE-inhibitor therapy. Atenolol is a long-acting cardioselective beta-blocking agent and is devoid of additional vasodilatory properties. Twenty-five male patients with class II or III heart failure and background therapy of digitalis, furosemide and 20 mg fosinopril per day were treated with 40 mg fosinopril per day and additional 75 mg atenolol per day (beta-blocker group) or with 40 mg fosinopril per day alone (control group). At the end of one year, changes in left ventricular function, exercise parameters and plasma neurohumoral variables reflecting vasoconstriction (noradrenaline, big endothelin) were measured and compared in the two treatment groups. Nineteen patients completed the study. Drop-outs were due to death (4 patients) and non-compliance (2 patients) with no significant difference between the groups. There was a beta-blocker related improvement in left ventricular ejection fraction (p < 0.05 between groups) and an increase in peak oxygen consumption in the control group only (p < 0.05 between groups). Thus, in a heart failure population receiving high-dose ACE inhibitor background therapy beta-blockade with atenolol produced additional benefit by reversing left ventricular dysfunction.


Ceramic Robocasting: Recent Achievements, Potential, and Future Developments.
Additive manufacturing (AM) of ceramic materials has attracted tremendous attention in recent years, due to its potential to fabricate suitable advanced ceramic structures for various engineering applications. Robocasting, a subset of ceramic AM, is an ideal technique for constructing fine and dense ceramic structures with geometrically complex morphology. With the freedom and convenience to deposit various materials within any 3D spatial position, ceramic robocasting opens up unlimited opportunities, which are otherwise hardly attainable from other AM techniques. Here, a summary of the recent progress on the fabrication of single and multi-ceramic structures by robocasting is provided, as well as the prospects of achieving shapeable ceramic structures. The current challenges in ceramic robocasting and an outlook on its development, especially toward the fabrication of self-shaping ceramic structures, are also discussed.


Label-free imaging of amyloids using their intrinsic linear and nonlinear optical properties.
The optical properties of amyloid fibers are often distinct from those of the source protein in its non-fibrillar form. These differences can be utilized for label-free imaging or characterization of such structures, which is particularly important for understanding amyloid fiber related diseases such as Alzheimer's and Parkinson's disease. We demonstrate that two amyloid forming proteins, insulin and β-lactoglobulin (β-LG), show intrinsic fluorescence with emission spectra that are dependent on the excitation wavelength. Additionally, a new fluorescence peak at about 430 nm emerges for β-LG in its amyloid state. The shift in emission wavelength is related to the red edge excitation shift (REES), whereas the additional fluorescence peak is likely associated with charge delocalization along the fiber backbone. Furthermore, the spherulitic amyloid plaque-like superstructures formed from the respective proteins were imaged label-free with confocal fluorescence, multiphoton excitation fluorescence (MPEF), and second-harmonic generation (SHG) microscopy. The latter two techniques in particular yield images with a high contrast between the amyloid fiber regions and the core of amorphously structured protein. Strong multiphoton absorption (MPA) for the amyloid fibers is a likely contributor to the observed contrast in the MPEF images. The crystalline fibrillar region provides even higher contrast in the SHG images, due to the inherently ordered non-centrosymmetric structure of the fibers together with their non-isotropic arrangement. Finally, we show that MPEF from the insulin spherulites exhibits a spectral dependence on the excitation wavelength. This behavior is consistent with the REES phenomenon, which we hypothesize is the origin of this observation. The presented results suggest that amyloid deposits can be identified and structurally characterized based on their intrinsic optical properties, which is important for probe-less and label-free identification and characterization of amyloid fibers in vitro and in complex biological samples.


Chameleon: Dynamic Color Mapping for Multi-Scale Structural Biology Models.
Visualization of structural biology data uses color to categorize or separate dense structures into particular semantic units. In multiscale models of viruses or bacteria, there are atoms on the finest level of detail, then amino-acids, secondary structures, macromolecules, up to the compartment level and, in all these levels, elements can be visually distinguished by color. However, currently only single scale coloring schemes are utilized that show information for one particular scale only. We present a novel technology which adaptively, based on the current scale level, adjusts the color scheme to depict or distinguish the currently best visible structural information. We treat the color as a visual resource that is distributed given a particular demand. The changes of the color scheme are seamlessly interpolated between the color scheme from the previous views into a given new one. With such dynamic multi-scale color mapping we ensure that the viewer is able to distinguish structural detail that is shown on any given scale. This technique has been tested by users with an expertise in structural biology and has been overall well received.


Role of janus kinase inhibitors in the treatment of alopecia areata.
Alopecia areata (AA) is a common hair loss disorder worldwide with characteristic exclamation mark hairs. Although AA is self-limited, it can last for several months or even years in some patients. Currently, there is no US Food and Drug Administration-approved treatment for AA. Many off-label treatments are available but with limited efficacy. Through a better understanding of molecular biology, many targeted therapies have emerged as new alternatives for various autoimmune diseases. Various janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins form signaling pathways, which transmit extracellular cytokine signals to the nucleus and induce DNA transcriptions. By inhibiting JAK, T-cell-mediated inflammatory responses are suppressed. Increasing evidence suggests that JAK inhibitors (JAKis) are effective in the treatment of many autoimmune diseases, including AA. Among these, several studies on tofacitinib, ruxolitinib, and baricitinib in AA had been published, demonstrating promising outcomes of these agents. Unlike oral formulations, efficacy of topical forms of tofacitinib and ruxolitinib reported in these studies is still unsatisfactory and requires improvement. This review aims to summarize evidence of the efficacy and safety of JAKis in the treatment of AA.


HLA-DQ: Celiac disease vs inflammatory bowel disease.
To determine the genetic predisposition to celiac disease (CeD) in inflammatory bowel disease (IBD) patients by quantifying the frequency of CeD-related human leucocyte antigen (HLA) (HLA-CeD: HLA-DQ2 and -DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease. We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors. 1034 subjects were analyzed: 457 IBD [207 ulcerative coliti (UC) and 250 Crohn's disease (CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD (P = 0.0852). HLA-DQ2 was less frequent in UC patients (P = 0.0287), and HLA-DQ8 in CD (P = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls (P = 0.001) and UC patients (etiological fraction = 15%). HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.


Characterization of the Key Aroma Volatile Compounds in Cranberry (Vaccinium macrocarpon Ait.) Using Gas Chromatography-Olfactometry (GC-O) and Odor Activity Value (OAV).
The volatile compounds of cranberries obtained from four cultivars (Early Black, Y1; Howes, Y2; Searles, Y3; and McFarlin, Y4) were analyzed by gas chromatography-olfactometry (GC-O), gas chromatography-mass spectrometry (GC-MS), and GC-flame photometric detection (FPD). The result presented that a total of thirty-three, thirty-four, thirty-four, and thirty-six odor-active compounds were identified by GC-O in the Y1, Y2, Y3, and Y4, respectively. In addition, twenty-two, twenty-two, thirty, and twenty-seven quantified compounds were demonstrated as important odorants according to odor activity values (OAVs > 1). Among these compounds, hexanal (OAV: 27-60), pentanal (OAV: 31-51), (E)-2-heptenal (OAV: 17-66), (E)-2-hexenal (OAV: 18-63), (E)-2-octenal (OAV: 10-28), (E)-2-nonenal (OAV: 8-77), ethyl 2-methylbutyrate (OAV: 10-33), β-ionone (OAV: 8-73), 2-methylbutyric acid (OAV: 18-37), and octanal (OAV: 4-24) contributed greatly to the aroma of cranberry. Partial least-squares regression (PLSR) was used to process the mean data accumulated from sensory evaluation by the panelists, odor-active aroma compounds (OAVs > 1), and samples. Sample Y3 was highly correlated with the sensory descriptors "floral" and "fruity". Sample Y4 was greatly related to the sensory descriptors "mellow" and "green and grass". Finally, an aroma reconstitution (Model A) was prepared by mixing the odor-active aroma compounds (OAVs > 1) based on their measured concentrations in the Y1 sample, indicating that the aroma profile of the reconstitution was pretty similar to that of the original sample.


Porcine Plasmacytoid Dendritic Cells Are Unique in Their Expression of a Functional NKp46 Receptor.
The activating receptor NKp46 shows a unique expression pattern on porcine leukocytes. We showed already that in swine not all NK cells express NKp46 and that CD3+NKp46+ lymphocytes form a T-cell subset with unique functional properties. Here we demonstrate the expression of NKp46 on CD4highCD14-CD172a+ porcine plasmacytoid dendritic cells (pDCs). Multicolor flow cytometry analyses revealed that the vast majority of porcine pDCs (94.2% ± 4) express NKp46 ex vivo and have an increased expression on the single-cell level compared to NK cells. FSC/SSChighCD4highNKp46+ cells produced high levels of IFN-α after CpG ODN 2216 stimulation, a hallmark of pDC function. Following receptor triggering with plate-bound monoclonal antibodies against NKp46, phosphorylation of signaling molecules downstream of NKp46 was analyzed in pDCs and NK cells. Comparable to NK cells, NKp46 triggering led to an upregulation of the phosphorylated ribosomal protein S6 (pS6) in pDCs, indicating an active signaling pathway of NKp46 in porcine pDCs. Nevertheless, a defined effector function of the NK-associated receptor on porcine pDCs could not be demonstrated yet. NKp46-mediated cytotoxicity, as shown for NK cells, does not seem to occur, as NKp46+ pDCs did not express perforin. Yet, NKp46 triggering seems to contribute to cytokine production in porcine pDCs, as induction of TNF-α was observed in a small pDC subset after NKp46 cross-linking. To our knowledge, this is the first report on NKp46 expression on pDCs in a mammalian species, showing that this receptor contributes to pDC activation and function.


Pattern recognition in nucleic acid sequences. II. An efficient method for finding locally stable secondary structures.
We present a method for calculating all possible single hairpin loop secondary structures in a nucleic acid sequence by the order of N2 operations where N is the total number of bases. Each structure may contain any number of bulges and internal loops. Most natural sequences are found to be indistinguishable from random sequences in the potential of forming secondary structures, which is defined by the frequency of possible secondary structures calculated by the method. There is a strong correlation between the higher G+C content and the higher structure forming potential. Interestingly, the removal of intervening sequences in mRNAs is almost always accompanied by an increase in the G+C content, which may suggest an involvement of structural stabilization in the mRNA maturation.