Brain insulin response and peripheral metabolic changes in a Tau transgenic mouse model.
Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aβ oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.


Preformulation Studies of a Liposomal Formulation Containing Sirolimus for the Treatment of Dry Eye Disease.
The aim of this study was to develop and characterize a liposomal product containing sirolimus to be administered subconjunctivally for the treatment of nonresponsive keratoconjunctivitis sicca (KCS) or dry eye. Formulations were prepared using an ethanol injection method and an adaptation of the heating method in pursuance of the most suitable methodology for future industrial production. Liposomes were loaded with either a high dose of 1 mg/mL of sirolimus or a less toxic dose of 0.4 mg/mL. The effects of critical process and formulation parameters were investigated. Liposomes were characterized in terms of size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The formulation was evaluated clinically in dogs with spontaneous KCS. Sterile liposomal dispersions with sizes ranging from 140 to 211 nm, were successfully obtained. High entrapment efficiency of 93%-98% was achieved. The heating method allowed an easier production of liposomes with high entrapment efficiency, to significantly shorten production time and the elimination of the use of alcohol. The poor stability of the obtained liposomes in aqueous dispersion made the inclusion of a lyophilization step necessary to the manufacturing process. In vivo testing of the liposomal sirolimus formulations in the spontaneous KCS dog model have produced promising results, particularly with a sirolimus dose of 1 mg/mL, indicating the need for further development and study of proposed formulations in the treatment of canine KCS. Clinical improvement in tear production in dogs with spontaneous KCS treated with the 1 mg/mL dose product was observed. The heating method allowed easier production of high entrapment efficiency liposomes to significantly shorten production time and the elimination of the use of alcohol. Tear production was increased in dogs administered with the formulation.


Alteration of visual perception prior to microsaccades.
Gaze fixation is an active process, with the incessant occurrence of tiny eye movements, including microsaccades. While the retinal consequences of microsaccades may be presumed minimal because of their minute size, a significant perceptual consequence of these movements can also stem from active extraretinal mechanisms associated with corollaries of their motor generation. Here I show that prior to microsaccade onset, spatial perception is altered in a very specific manner: foveal stimuli are erroneously perceived as more eccentric, whereas peripheral stimuli are rendered more foveal. The mechanism for this perceptual "compression of space" is consistent with a spatially specific gain modulation of visual representations caused by the upcoming eye movements, as is hypothesized to happen for much larger saccades. I then demonstrate that this perimicrosaccadic perceptual alteration has at least one important functional consequence: it mediates visual-performance alterations similar to ones classically attributed to the cognitive process of covert visual attention.


Simulations and theory of power spectral density functions for time-dependent and anharmonic Langevin oscillators.
Simulations and theory are presented for the power spectral density functions (PSDs) of particles in time-dependent and anharmonic potentials, including the effects of a thermal environment leading to damping and fluctuating forces. We investigate three one-dimensional perturbations to the harmonic oscillator of which two are time-dependent changes in the natural frequency of the oscillator, while the other is a time-independent extension of the quadratic potential to include a quartic term. We investigate the effect of these perturbations on two PSDs of the motion that are used in experiments on trapped nano-oscillators. We also derive and numerically test the PSDs for the motion of a spherical nanoparticle in a Paul trap. We found that the simple harmonic Langevin oscillator's PSDs are good approximations for the x and y coordinates' PSDs for small values of the parameter q of the Mathieu equation, but the difference can be more than a factor of two as "q" increases. We also numerically showed that the presence of a permanent electric dipole on the nanosphere can significantly affect the PSDs in the x and y coordinates.


Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus.
Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TF-expressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.


Suppression and treatment of experimental allergic encephalitis in guinea-pigs with the bovine spinal cord protein (BSCP).
Experimental allergic encephalitis (EAE) was suppressed in guinea-pigs that had been sensitized with 50 micrograms of bovine myelin basic protein (MyBP) in Freund's complete adjuvant (FCA) by daily injections of 500 micrograms of the bovine spinal cord protein (BSCP) in saline between day 8 (D 8) and D 23 after sensitization. Injections of 500 micrograms of bovine serum albumin in saline, or saline alone, did not suppress disease. Reversal of clinical disease was achieved with doses of 750 micrograms of BSCP in saline when treatment was begun within a day after the first sign of disease was observed. Six injections of 500 micrograms of BSCP in Freund's incomplete adjuvant (FIA) were required to suppress EAE whether BSCP-FIA injections were begun on D 0 or as late as D 8 when T cells sensitized to MyBP had invaded the central nervous system. When administration of BSCP-FIA was withheld until after disease onset, only three or four injections were needed to reverse clinical signs. BSCP appeared to be as effective quantitatively as MyBP in the suppression or treatment of disease. Because there is no cross-reaction between BSCP and MyBP at the antibody level, the present results raise the possibility that the suppressive activity of BSCP may be due to an amino acid sequence in BSCP and MyBP that is recognized only by T cells. When antigens were injected in FIA at 4 day intervals after sensitization, the onset of disease was delayed up to 5 days. Moreover, even bovine gamma-globulin appeared to have suppressive activity when injected three or four times in FIA. The findings suggest that assessments of the suppressive capacity of an antigen may be inaccurate if the antigen is injected in FIA frequently during the interval between sensitization and onset of disease.


Management of severe spinal cord injury following hyperbaric exposure.
There is an increasing body of evidence that drainage of lumbar cerebrospinal fluid (CSF) improves functional neurological outcome after reperfusion injury to the spinal cord that occasionally follows aortic reconstructive surgery. This beneficial effect is considered owing to lowering of the CSF pressure thereby normalising spinal cord blood flow and reducing the 'secondary' cord injury caused by vascular congestion and cord swelling in the relatively confined spinal canal. Whilst lacking definitive proof, there are convincing randomised controlled trials (RCTs), cohort data and systematic reviews supporting this intervention. The therapeutic window for lumbar CSF drainage requires further elucidation; however, it appears to be days rather than hours post insult. We contend that the same benefit is likely to be achieved following other primary spinal cord injuries that cause cord swelling and elicit the 'secondary' injury. Traditionally the concept of CSF drainage has been considered more applicable to the brain as contained in a 'closed box' by lowering intracranial pressure (ICP) to improve cerebral perfusion pressure (CPP). The control of CPP is intended to limit 'secondary' brain injury and is a key concept of brain injury management. Using microdialysis in the spinal cords of trauma patients, it has been shown that intraspinal pressure (ISP) needs to be kept below 20 mmHg and spinal cord perfusion pressure (SCPP) above 70 mmHg to avoid biochemical evidence of secondary cord damage. Vasopressor have also been used in spinal cord injury to improve perfusion, however complications are common, typically cardiac in nature, and require very careful monitoring; the evidence supporting this approach is notably less convincing. Decompression illness (DCI) of the spinal cord is treated with recompression, hyperbaric oxygen, various medications designed to reduce the inflammatory response and fluid administration to normalise blood pressure and haematocrit. These management protocols are based largely on anecdote and transferred evidence from conventional cord trauma, as the low numbers and sporadic nature of DCI in divers makes RCTs nigh on impossible. Unfortunately even with best management, some patients are left with significant neurological deficit. The 'iceberg phenomenon', occurs when patients with DCI of the cord make a good neurological recovery but actually have profound cord damage as revealed in one case some four years later at post mortem and another example in a diver who developed late functional deterioration due to loss of neuronal reserve. This clinical evidence, together with animal study data, support the notion that even a modest preservation of spinal cord axons is associated with significant improvement in neurological outcome. In the light of the positive level two evidence in the vascular literature that CSF drainage limits 'secondary' injury thereby improving neurological outcome, we propose that centres with appropriate clinical experience consider using lumbar CSF drainage to normalise SCPP, as an adjunct to the conventional treatment of severe spinal cord DCI. Divers with severe spinal cord DCI are generally in the most productive years of their lives and, given the potentially devastating impact of this condition, should be given the benefit of any possible adjuvant treatment that may serve to improve long-term outcome.


Template Instrumentation for "Accurate Constant via Transient Incomplete Separation".
Accurate Constant via Transient Incomplete Separation (ACTIS) is a new method for finding the equilibrium dissociation constant Kd of a protein-small molecule complex based on transient incomplete separation of the complex from the unbound small molecule in a capillary. This separation is caused by differential transverse diffusion of the complex and the small molecule in a pressure-driven flow. The advection-diffusion processes underlying ACTIS can be described by a system of partial differential equations allowing for a virtual ACTIS instrument to be built and ACTIS to be studied in silico. The previous in silico studies show that large variations in the fluidic system geometry do not affect the accuracy of Kd determination, thus, proving that ACTIS is conceptually accurate. The conceptual accuracy does not preclude, however, instrumental inaccuracy caused by run-to-run signal drifts. Here we report on assembling a physical ACTIS instrument with a fluidic system that mimics the virtual one and proving the absence of signal drifts. Furthermore, we confirmed method ruggedness by assembling a second ACTIS instrument and comparing the results of experiments performed with both instruments in parallel. Despite some unintentional differences between the instruments (caused by tolerances in sizes, positions, etc.) and noticeable differences in their respective separagrams, we found that the Kd values determined for identical samples with these instruments were equal. Conclusively, the fluidic system presented here can serve as a template for reliable ACTIS instrumentation.


Fixed Combination Antiemetic: A Literature Review on Prevention of Chemotherapy-Induced Nausea and Vomiting Using Netupitant/Palonosetron
Prevention of chemotherapy-induced nausea and vomiting (CINV) can be improved with guideline-consistent use of antiemetics. However, adherence to antiemetic guidelines remains often insufficient. Therefore, new strategies that improve adherence are needed. To review the latest antiemetic guideline recommendations and provide an update on the use of NEPA, a fixed combination antiemetic composed of the neurokinin-1 receptor antagonist (RA) netupitant and the 5-hydroxytryptamine-3 RA palonosetron (Akynzeo®). Analysis of the literature was performed, including guidelines, published literature, congress data on NEPA, and relevant articles on CINV. Nurses are in a unique position to promote guideline-consistent antiemetic prophylaxis and are central in the education of patients and caregivers. Thus, nurses' continuous education on antiemetic treatments is key for the prevention and management of CINV. NEPA offers a simplified antiemetic therapy with the potential to increase guideline adherence.


Factors associated with the inability of children with cerebral palsy to walk at six years: a retrospective study.
The objective of this study was to describe the locomotion level of children with cerebral palsy at six years and to identify the factors associated with the inability to walk. 264 quadriplegic or diplegic children were assessed. Characteristics of the neurological impairment, neuromotor activities, other medical conditions and sociodemographic variables were studied. 47 per cent of the children could not walk at six years. Topography of the impairment, persistence of certain primitive reflexes, inability to retain a sitting position at the time of the initial evaluation and a history of epilepsy were significantly associated with inability to walk. The sensitivity and specificity of the model for classifying the subjects as unable or able to walk at six years were 82 and 93 per cent, respectively.


Clues to the diagnosis of borderline ovarian tumours: An imaging guide.
Borderline Ovarian Tumours (BOTs) are an interesting subset of epithelial neoplasms defined histologically by atypical epithelial proliferation without stromal invasion. These tumours typically affect young women in the reproductive age group and have a good prognosis. Although ultrasonography is the primary screening imaging technique in the evaluation of any suspected adnexal mass, grey-scale and colour Doppler have limited value in characterizing BOTs. Thus, a pelvic magnetic resonance imaging (MRI) is recommended for further characterization on account of its multiplanar capabilities, excellent soft-tissue contrast and high spatial resolution. BOTs histological subtypes display specific features on MRI that are useful in differential diagnosis. However, the final diagnosis and staging of BOTs require pathologic evaluation after surgical excision. Therefore, the purpose of this review is to describe, illustrate and compare the imaging characteristics of the different subtypes of BOTs - serous, mucinous and seromucinous - focusing on MRI, as well as to correlate with pathology findings considering the recent 2020 World Health Organization (WHO) classification, in order to improve the accuracy of preoperative diagnosis and facilitate optimal patient management.


Nanoparticle probes with surface enhanced Raman spectroscopic tags for cellular cancer targeting.
We have developed biocompatible, photostable, and multiplexing-compatible surface-enhanced Raman spectroscopic tagging material (SERS dots) composed of silver nanoparticle-embedded silica spheres and organic Raman labels for cellular cancer targeting in living cells. SERS dots showed linear dependency of Raman signatures on their different amounts, allowing their possibility for the quantification of targets. In addition, the antibody-conjugated SERS dots were successfully applied to the targeting of HER2 and CD10 on cellular membranes and exhibited good specificity. SERS dots demonstrate the potential for high-throughput screening of biomolecules using vibrational information.


DICER1-associated central nervous system sarcoma: A comprehensive clinical and genomic characterization of case series of young adult patients.
DICER1 alterations are associated with intracranial tumors in the pediatric population, including pineoblastoma, pituitary blastoma, and the recently described "primary DICER1-associated CNS sarcoma" (DCS). DCS is an extremely aggressive tumor with a distinct methylation signature and a high frequency of co-occurring mutations. However, little is known about its treatment approach and the genomic changes occurring after exposure to chemoradiotherapy. We collected clinical, histological, and molecular data from eight young adults with DCS. Genomic analysis was performed by Next-generation Sequencing (NGS). Subsequently, an additional germline variants analysis was completed. In addition, an NGS analysis on post-progression tumor tissue or liquid biopsy was performed when available. Multiple clinicopathological characteristics, treatment variables, and survival outcomes were assessed. Median age was 20 years. Most lesions were supratentorial. Histology was classified as fusiform cell sarcomas (50%), undifferentiated (unclassified) sarcoma (37.5%), and chondrosarcoma (12.5%). Germline pathogenic DICER1 variants were present in two patients, 75% of cases had more than one somatic alteration in DICER1, and the most frequent commutation was TP53. Seven patients were treated with surgery, Ifosfamide, Cisplatin, and Etoposide (ICE) chemotherapy and radiotherapy. The objective response was 75%, and the median time to progression (TTP) was 14.5 months. At progression, the most common mutations were in KRAS and NF1. Overall survival was 30.8 months. DCS is an aggressive tumor with limited therapeutic options that requires a comprehensive diagnostic approach, including molecular characterization. Most cases had mutations in TP53, NF1, and PTEN, and most alterations at progression were related to MAPK, RAS and PI3K signaling pathways.


Racial Disparities in Medical Student Membership in the Alpha Omega Alpha Honor Society.
Previous studies have found racial and ethnic inequities in the receipt of academic awards, such as promotions and National Institutes of Health research funding, among academic medical center faculty. Few data exist about similar racial/ethnic disparities at the level of undergraduate medical education. To examine the association between medical student race/ethnicity and induction into the Alpha Omega Alpha (AΩA) honor society. This study analyzed data from the Electronic Residency Application Service, the official service used by US medical students to apply to residency programs. A total of 4655 US medical students from 123 allopathic US medical schools who applied to 12 distinct residency programs associated with one academic health center in the 2014 to 2015 academic year were studied. Membership in the AΩA society among black, white, Hispanic, and Asian medical students. A total of 4655 unique applications were analyzed in the study (median age, 26 years; 2133 women [45.8%]). Overall, self-reported race/ethnicity in our sample was 2605 (56.0%) white (691 [71.5%] of AΩA applicants were white), 276 (5.9%) black (7 [0.7%] AΩA), 186 (4.0%) Hispanic (27 [2.8%] AΩA), and 1170 (25.1%) Asian (168 [17.4%] AΩA). After controlling for US Medical Licensing Examination Step 1 scores, research productivity, community service, leadership activity, and Gold Humanism membership, the study found that black (adjusted odds ratio [aOR], 0.16; 95% CI, 0.07-0.37) and Asian (aOR, 0.52; 95% CI, 0.42-0.65) medical students remained less likely to be AΩA members than white medical students. No statistically significant difference was found in AΩA membership between white and Hispanic medical students (aOR, 0.79; 99% CI, 0.45-1.37) in the adjusted model. Black and Asian medical students were less likely than their white counterparts to be members of AΩA, which may reflect bias in selection. In turn, AΩA membership selection may affect future opportunities for minority medical students.


Idarucizumab for Emergency Reversal of the Anticoagulant Effects of Dabigatran: Final Results of a Japanese Postmarketing Surveillance Study.
Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. This study is registered with ClinicalTrials.gov (NCT02946931).


Corrosion behavior of X65 steel in seawater containing sulfate reducing bacteria under aerobic conditions.
The corrosion behavior of X65 steel was investigated in the seawater inoculated with sulfate reducing bacteria (SRB) under the aerobic environment by electrochemical impedance techniques and immersion tests. The corroded morphologies and the composition of the corrosion products were investigated. The variation of the solution parameters including the bacterium number, the pH value and the soluble iron concentration were also investigated. The results indicated that in the SRB-containing system, the impedance responses presented a depressed semi-circle in the initial period, which then turned into the blocked electrode characteristic during the later immersion. The biofilm, mainly composed of extracellular polymeric substances, Fe(OH)3, γ-FeOOH and α-Fe2O3, formed and degraded with the SRB growth. The soluble iron concentration initially increased, then rapidly decreased and later slowly increased. In the SRB-containing seawater under the aerobic environment, the X65 steel was corroded in the initial immersion. The corrosion became inhibited with the forming of the biofilm during the subsequent immersion. The inhibition efficiency rapidly increased in the logarithmic phase, remained stable in the stationary phase and then decreased in the declination phase. In the corrosion process, the biofilm metabolized by SRB played a key role in the corrosion inhibition of X65 steel.


Localization of the P2Y4 receptor in the guinea pig organ of Corti.
Cochleae of guinea pigs were evaluated for the presence of the metabotropic receptor, P2Y4. Evidence is presented that P2Y4 protein is expressed in the guinea pig cochleae using Western blot analysis. A single protein band of 35 kDa was detected with P2Y4 receptor-specific antibody. The cellular distribution of P2Y4 purinoceptor protein was determined by immunohistochemistry of the whole organ of Corti. Immunoreactive staining for P2Y4 was seen in most cells of the organ of Corti. Staining of Hensen's cells and Deiters' cells, especially the outer Deiters' cells, was more intense than staining of the outer hair cells, inner hair cells, and pillar cells. Staining intensity was greatest at the basal turn and progressively decreased in the upper turns with the apex showing the weakest staining pattern. This is the first demonstration of a metabotropic P2Y receptor in the guinea pig organ of Corti.


Embracing complexity in Drosophila cancer models.
Cancer continues to be a leading cause of death worldwide, largely due to metastases and cachexia. It is a complex disease that is commonly associated with a variety of comorbidities. With global increases in ageing populations and obesity, multimorbidity is a rapidly growing clinical issue in the context of cancer. Cancer is also genetically heterogeneous, with a tumour's unique profile determining its incidence of metastasis, degree of cachexia and response to therapeutics. These complexities of human cancer are difficult to replicate in animal models and are, in part, responsible for the failures in translational cancer research. In this Perspective, we highlight the fruit fly, Drosophila melanogaster, as a powerful model organism to investigate multimorbidity and tumour diversity. We also highlight how harnessing these complexities in Drosophila can, potentially, enhance cancer research and advance therapeutic discoveries.


Tumor-induced suppressor of cytokine signaling 3 inhibits toll-like receptor 3 signaling in dendritic cells via binding to tyrosine kinase 2.
The suppressor of cytokine signaling (SOCS) family of negative regulatory proteins is up-regulated in response to several cytokines and pathogen-associated molecular patterns (PAMP) and suppresses cellular signaling responses by binding receptor phosphotyrosine residues. Exposure of bone marrow-derived dendritic cells (BMDC) to 1D8 cells, a murine model of ovarian carcinoma, suppresses their ability to express CD40 and stimulate antigen-specific responses in response to PAMPs and, in particular, to polyinosinic acid:poly-CMP (polyI:C) with the up-regulated SOCS3 transcript and protein levels. The ectopic expression of SOCS3 in both the macrophage cell line RAW264.7 and BMDCs decreased signaling in response to both polyI:C and IFNalpha. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both polyI:C and IFNalpha. Immunoprecipitation and pull-down studies show that SOCS3 binds to the IFNalpha receptor tyrosine kinase 2 (TYK2). Because polyI:C triggers autocrine IFNalpha signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFNalpha. Thus, elevated levels of SOCS3 in tumor-associated DCs may potentially resist the signals induced by Toll-like receptor 3 ligands and type I IFN to decrease DC activation via binding with IFNalpha receptor TYK2.


Research and Analysis on the Localization of a 3-D Single Source in Lossy Medium Using Uniform Circular Array.
In this paper, the methods and analysis for estimating the location of a three-dimensional (3-D) single source buried in lossy medium are presented with uniform circular array (UCA). The mathematical model of the signal in the lossy medium is proposed. Using information in the covariance matrix obtained by the sensors' outputs, equations of the source location (azimuth angle, elevation angle, and range) are obtained. Then, the phase and amplitude of the covariance matrix function are used to process the source localization in the lossy medium. By analyzing the characteristics of the proposed methods and the multiple signal classification (MUSIC) method, the computational complexity and the valid scope of these methods are given. From the results, whether the loss is known or not, we can choose the best method for processing the issues (localization in lossless medium or lossy medium).


Patients with cirrhosis show a relative increase in thrombin generation that is correlated with lower antithrombin levels.
Predicting the risk of bleeding or thrombosis in cirrhotic patients is difficult due to reduced levels and dysregulation of both procoagulant and anticoagulant factors. We utilized thrombin generation and microvesicle analysis to better understand the regulation of haemostasis in cirrhotic patients. We studied 24 patients with cirrhosis vs. 21 healthy controls. Cirrhotic patients had reduced prothrombin activity (40 ± 9 vs. 112 ± 15), protein C activity (36 ± 10 vs. 114 ± 19) and antithrombin activity (43 ± 14 vs. 109 ± 10). Peak thrombin generation was reduced in cirrhotic patients (165 ± 47 vs. 232 ± 101), but the ratio of peak thrombin generation to prothrombin activity was increased in cirrhotic patients (4.2 ± 1.0 vs. 2.1 ± 0.9) indicating a relative increase in thrombin generation in cirrhosis. The termination time ratio was increased in cirrhotic patients (7.2 ± 1.9 vs. 3.1 ± 0.7) and correlated with reduced antithrombin levels, indicating that cirrhotic patients took longer to stop thrombin generation than controls. Cirrhotic patients showed reduced procoagulant microvesicles from platelets (39 500 ± 24 800 vs. 107 700 ± 74 200) and other cells, but levels overlapped with controls. Cirrhotic patients showed a wide range of procoagulant and anticoagulant levels leading to variability in the regulation of thrombin generation. In conclusion, compared with healthy controls, patients with cirrhosis have lower antithrombin levels that lead to slower downregulation of thrombin generation and more overall thrombin being produced for a given procoagulant level in blood, but also low normal levels of procoagulant microvesicles that would slow initiation of thrombin generation. Whether an individual cirrhosis patient is at a greater risk of bleeding vs. thrombosis may depend on their specific imbalance in procoagulants vs. anticoagulants.


A Systematic Review of Breast Reconstruction Options After Mastectomy in Massive Weight Loss Patients.
Given global trends in obesity and bariatric surgeries, there are an increasing number of women presenting for breast reconstruction after massive weight loss. There is a paucity of literature about breast reconstruction after mastectomy in patients with a history of massive weight loss. A literature review revealed 10 articles that discussed outcomes of different reconstruction techniques in patients with massive weight loss. Autologous reconstruction techniques and implant-based reconstruction techniques were assessed to evaluate the advantages, disadvantages, and indications of each approach specific to this unique patient population. This article provides a summary of expected outcomes, including complication profiles. Ultimately, consideration should be given for breast reconstruction of mastectomy defects in patients with a history of massive weight loss, as satisfactory results are demonstrated to be possible. Both autologous reconstruction and implant-based reconstruction present feasible options, although reconstruction in this patient population may be associated with increased need for revisions and a higher complication rate compared with patients without a history of massive weight loss. For this reason, it is imperative to appropriately manage preoperative expectations in patients with a history of massive weight loss.


[Efficacy and safety of arbidol in treatment of naturally acquired influenza].
To evaluate the efficacy and safety of Arbidol in the treatment of naturally acquired influenza. A randomized, double-blinded, placebo controlled trial was conducted. Subjects were enrolled. The inclusion criteria included: aged 18 to 65 years, presented within 36 hours of onset of influenza symptoms; and had documented temperature of 37.8 degrees C or higher during an influenza outbreak in the community. Individuals were randomly divided Arbidol group (200 mg three times daily for 5 days) or placebo group. Totally 232 individuals were recruited and received medication and follow-up. All of them were qualified to be analyzed for safety as intent-to-treat population (ITT) (113 Arbidol, 109 placebo). Twenty-two (9.48%) were during follow-up or refused to continue the trial, and 210 completed as schecule and identified as PP population (102 Arbidol, 108 placebo). Totally 125 individuals were identified as influenza-infected through laboratory test, which was defined as PPi population (59 Arbidol, 66 placebo). In PPi population, the cumulative alleviation proportion of Arbidol group was significantly higher than that of placebo group. The median duration of illness was 72.0 hours (95% confident interval (CI) 66.00-78.00 hours) in Arbidol group and 96.0 hours (95% CI 87.46-104.54 hours) in placebo group. The median area under the curve (AUC) of decreased total score were significantly higher in Arbidol group than in placebo group, which were 780.00 and 684.00 score-hours respectively. For PP population, similar results were seen. Adverse events reported were similar in Arbidol group and in placebo group. The main adverse events were gastrointestial symptoms and increased transaminase. Arbidol was effective and well tolerated in the treatment of early naturally acquired influenza.


Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells.
Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(τ)-alkylation of histidine residues already bearing a N(π)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics.


Aspects of identification and growth during late adolescence and young adulthood.
Psychological growth proceeds through emotional attachment and separation processes. Inhibition of emotional separation in late adolescence can result in delayed psychological differentiation and sometimes identity diffusion. Three cases of analytic psychotherapy are described, in which nonfunctional identifications and idealizations are treated, and delayed maturation resumes through the formation of new, recombinant identifications.


Expressing Anger Is More Dangerous than Feeling Angry when Driving.
Anger is an emotion that drivers often feel and express while driving, and it is believed by researchers to be an important cause of dangerous driving behavior. In this study, the relationships between driving trait anger, driving anger expression, and dangerous driving behaviors were analyzed. The Driving Anger Scale (DAS) was used to measure driving trait anger, whereas the Driving Anger Expression (DAX) Inventory was used to measure expressions of driving anger. A sample of 38 drivers completed the DAS, DAX, and a driving simulation session on a simulator where their driving behaviors were recorded. Correlation analysis showed that the higher scores on the DAS were associated with longer durations of speeding in the simulator. The more participants expressed their anger in verbal and physical ways, the more likely they were to crash the virtual vehicle during the simulation. Regression analyses illustrated the same pattern. The findings suggest that, although trait anger is related to speeding, the passive expression of anger is the real factor underling traffic accidents. This study extends findings about the predictive effects of self-report scales of driving behaviors to behaviors recorded on a simulator. Thus, if in traffic safety propaganda, guiding drivers to use positive ways to cope with driving anger is recommended by our findings.


The Business of Testing.
Theodore Millon was a brilliant man: erudite, thoughtful, confident, deliberate, and curious. He was an integrative thinker. It is widely known how these characteristics manifested themselves in his landmark work in the areas of personality theory, personality development, and personality assessment. What is likely less well known is that he displayed these same characteristics in and to the world of business; in particular, his relationships with those who published and distributed his assessment measures. This article traces those relationships. Various components are explored, ranging from product development to product marketing, from the protection of intellectual property to the development and execution of contracts, from deciding how and when to revise a test to ensuring that his legacy continues long into the future. Although the primary dynamic of these relationships was commercial, the reasons for their success were personal. Common goals, clarity of communication, persistence, respect, and trust allowed these relationships to develop, prosper, evolve, and endure.


A preliminary report of short-term cognitive-behavioral group therapy for inpatients with personality disorders.
A randomized, controlled study evaluated the effectiveness of a cognitive-behavioral therapy group, based on Linehan's dialectical behavior therapy, for inpatients with personality disorders. The treatment, a problem-solving skills group focused on parasuicidality, was compared with a discussion control group. Change was assessed by self-report measures and behavioral observations on the unit. Subjects in both groups improved significantly on most change measures, although no significant between-group differences were found. However, the treatment group patients viewed the intervention as more beneficial to them in their lives outside the hospital. The usefulness of this type of group on a short-term unit is discussed.


[Numerical modeling of shape memory alloy vascular stent's self-expandable progress and "optimized grid" of stent].
Vascular stent is an important medical appliance for angiocardiopathy. Its key deformation process is the expandable progress of stent in the vessel. The important deformation behaviour corresponds to two mechanics targets: deformation and stress. This paper is devoted to the research and development of vascular stent with proprietary intellectual property rights. The design of NiTinol self-expandable stent is optimized by means of finite element software. ANSYS is used to build the finite element simulation model of vascular stent; the molding material is NiTinol shape memory alloy. To cope with the factors that affect the structure of stent, the shape of grid and so on, the self-expanding process of Nitinol stent is simulated through computer. By making a comparison between two kinds of stents with similar grid structure, we present a new concept of "Optimized Grid" of stent.


Simulated high altitude diving experiment for the underwater construction operation.
The simulated dive experiments were conducted at the high altitude of 4500 meters and 5000 meters, for the requirement of diving operation in the lakes at the altitude of 4442 meters for the construction of large-scale hydroelectric power station. The high & low pressure chamber-complex was used, and 15 professional divers participated in the experiment. The divers were stayed at the altitude of 4500 and 5000 meters for 7-9 days. Totally 85 persons-times of dives to the depths of 30-50 meters were operated; they stayed under the water for 30-90 minutes while processing physical activities. During the experiment, we studied the pressurization procedure, decompression table, and physiological functions of the divers. The results indicate that, although the relative pressure differences between the surface and underwater was larger at high altitude than at sea level, the appropriate prolongation of the compression time was able to prevent the difficulty in pressure regulation for the divers to avoid the injury of middle ear. Four tables of the decompression A, B, C and D was calculated with Haldane's theory, and the speed of decompression increased in the order from A to D. The safest procedure was C, and there was no decompression sickness and bubbles in body of the divers. The methods of decompression included underwater stage decompression, surface decompression, oxygen-breathing decompression, and repetitive diving decompression. The surface decompression was the most suitable method for the high altitude, as it could greatly decrease the time in the cold water for the divers. The power spectrum analysis of EEG (electroencephalogram) indicated that, when the divers were exposed to the altitude of 5000 meters, the delta activity in EEG increased, alpha and beta activity decreased. And the delta activity decreased, the alpha and beta activity increased while diving during a dry condition. According to the diving and decompression procedure studied under simulated conditions, 272 person-times of diving training and underwater operations were processed in a high altitude hydroelectric power station at the altitude of 4442 meters, including photographing, video-recording, measuring, and drilling. There were no signs and symptoms of decompression sickness and bubbles.


Prediction of Higher Heating Values in Bio-Oil from Solvothermal Biomass Conversion and Bio-Oil Upgrading Given Discontinuous Experimental Conditions.
Both the conversion of lignocellulosic biomass to bio-oil (BO) and the upgrading of BO have been the targets of many studies. Due to the large diversity and discontinuity seen in terms of reaction conditions, catalysts, solvents, and feedstock properties that have been used, a comparison across different publications is difficult. In this study, machine learning modeling is used for the prediction of final higher heating value (HHV) and ΔHHV for the conversion of lignocellulosic feedstocks to BO, and BO upgrading. The models achieved coefficient of determination (R2) scores ranging from 0.77 to 0.86, and the SHapley Additive exPlanations (SHAP) values were used to obtain model explainability, revealing that only a few experimental parameters are largely responsible for the outcome of the experiments. In particular, process temperature and reaction time were overwhelmingly responsible for the majority of the predictions, for both final HHV and ΔHHV. Elemental composition of the starting feedstock or BO dictated the upper possible HHV value obtained after the experiment, which is in line with what is known from previous methodologies for calculating HHV for fuels. Solvent used, initial moisture concentration in BO, and catalyst active phase showed low predicting power, within the context of the data set used. The results of this study highlight experimental conditions and variables that could be candidates for the creation of minimum reporting guidelines for future studies in such a way that machine learning can be fully harnessed.


Health Care Ergonomics: Contributions of Thomas Waters.
The aim of this study was to assess the contributions of Thomas Waters's work in the field of health care ergonomics and beyond. Waters's research of safe patient handling with a focus on reducing musculoskeletal disorders (MSDs) in health care workers contributed to current studies and prevention strategies. He worked with several groups to share his research and assist in developing safe patient handling guidelines and curriculum for nursing students and health care workers. The citations of articles that were published by Waters in health care ergonomics were evaluated for quality and themes of conclusions. Quality was assessed using the Mixed Methods Appraisal Tool and centrality to original research rating. Themes were documented by the type of population the citing articles were investigating. In total, 266 articles that referenced the top seven cited articles were evaluated. More than 95% of them were rated either medium or high quality. The important themes of these citing articles were as follows: (a) Safe patient handling is effective in reducing MSDs in health care workers. (b) Shift work has negative impact on nurses. (c) There is no safe way to manually lift a patient. (d) Nurse curriculums should contain safe patient handling. The research of Waters has contributed significantly to the health care ergonomics and beyond. His work, in combination with other pioneers in the field, has generated multiple initiatives, such as a standard safe patient-handling curriculum and safe patient-handling programs.


Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia.
In vitro data and pilot data suggest that green tea catechins may possess chemopreventive activity for cervical cancer and precursor lesions. We conducted a randomized, double-blind, placebo-controlled trial of Polyphenon E (decaffeinated and enriched green tea catechin extract) in women with persistent human papillomavirus (HPV) infection and low-grade cervical intraepithelial neoplasia (CIN1) to evaluate the potential of Polyphenon E for cervical cancer prevention. Ninety-eight eligible women were randomized to receive either Polyphenon E (containing 800 mg epigallocatechin gallate) or placebo once daily for 4 months. The primary study outcome was oncogenic HPV clearance and clearance of CIN1. Polyphenon E was shown to be acceptable, safe and well tolerated. There was no difference in the response rate by treatment allocation. Complete response, defined as negative for high-risk HPV and normal histopathology, was noted in 7 (17.1%) and 6 (14.6%) women in the Polyphenon E and placebo arms, respectively. Progression, defined as persistent oncogenic HPV with histopathologic evidence of progression, was more common in the Polyphenon E group than in the placebo group [6 (14.6%) vs. 3 (7.7%)]. Based on the largest randomized placebo-controlled trial of a green tea extract for HPV related cervical disease, we conclude that 4 months of Polyphenon E intervention did not promote the clearance of persistent high-risk HPV and related CIN1. Further studies may be necessary to better delineate the risk factors for persistent HPV infection and biology of the disease to facilitate the evaluation of chemopreventive strategies.


[Hypereosinophilic syndrome--recent developments in diagnosis and treatment].
In case of eosinophilia persisting for more than 6 months a diagnosis of hypereosinophilic syndrome (HES) should be considered if secondary causes of eosinophilia ca be ruled out. Recent studies on the pathogenesis of HES revealed that the syndrome previously coined "idiopathic HES" is comprised of pathogenetically distinct subtypes which are defined by molecular, immunophenotypic or clinical markers. Eosinophilia in HES can be caused by increased production or survival of eosinophils due to cytokines such as interleukin-5 (IL-5) or clonal expansion due to mutations. Distinction of these pathogenetically different subtypes of HES is clinically relevant as new targeted treatment approaches are available for some of these subtypes, such as tyrosine kinase inhibitors for the FIP1L1-PDGFRA-positive myeloproliferativer subtype, immunomodulators such as interferon-alpha or monoclonal antibodies against IL-5 for FIP1L1-PDGFRA-negative patients.


[The come-back of hypofractionation?].
Hypofractionation (i.e. the use of fewer higher fractional doses than usual) is not a new concept. It had actually been proposed in the early year of Radiotherapy by the German and Austrian specialists. In the seventy's, supported by the - wrong - hypotheses which gave birth to the NSD (Nominal Standard Dose), hypofractionation reappears. The consequential increase of late complications which was observed led the radiation oncologists to give up again using large doses per fraction, except for a few specific situations, such as palliative treatments. We are recently facing a new "come-back" of hypofractionation, in particular for breast and prostate cancers. In the case of breast cancer, the aim is clearly to look for more "convenience" for both the patients and the physicians, proposing shorter irradiation schedules including a lesser number of fractions. Some "modestly" hypofractionated schemes have been proposed and used, without apparently altering the efficacy/toxicity ratio, but these results have been seriously questioned. As for prostate cancer, the situation is different, since in that case new radiobiological data are at the origin of the newly proposed hypofractionation schedules. A number of papers actually strongly suggested that the fractionation sensitivity of prostate cancer could be higher than the one of the tissues responsible for late toxicity (i.e the exact opposite of the classical dogma). Based on those data, several hypofractionated schemes have been proposed, with a few preliminary results looking similar to the ones obtained by the classical schedules. However, no randomised study is available so far, and a few recent radiobiological data are now questioning the new dogma of the high fractionation sensitivity of prostate cancer. For those two - frequent - cancers, it seems therefore that prudence should prevail before altering classical irradiation schedules which have proven their efficacy, while staying open to new concepts and proposing well-designed randomised trials in specific cases.


Cellular cross talk, inflammatory signals, and enhanced microvascular permeability.
Microvascular leakage remains a significant clinical problem for which there is no specific therapeutic available. This Special Topics issue of the journal Microcirculation features reviews pertaining to the cellular and molecular mechanisms that control the integrity of the microvascular barrier. (Meegan et al., Microcirculation, 2017) summarize recent research findings about how neutrophil extracellular traps and how these can cause injury to the microvascular barrier.( Zhang et al. Microcirculation, 2017) highlight the microvascular response to advanced glycation end-products that are formed as part of the pathophysiology of diabetes mellitus. These ongoing investigations are helping to clarify the mechanisms by which endothelial cells receive information and integrate it to generate cellular responses that fine-tune barrier function. Better understanding of these mechanisms is needed for the rational development of therapeutic strategies to reduce excessive microvascular leakage.


Ptychographic phase microscope based on high-speed modulation on the illumination beam.
A type of ptychography-based phase microscope was developed by integrating a spatial light modulator (SLM) into a commercial wide-field light microscope. By displaying a moving pattern on the SLM to change the sample illumination and record the diffraction intensities formed, both the modulus and phase of the transmission function of the sample could be accurately reconstructed with formulas similar to those of common ptychography. Compared with other kinds of phase microscopes, the developed microscope has several advantages, including its simple structure, high immunity to coherent noise, and low requirement for quality optics. In addition, defects in the illumination beam are also removed from the reconstructed image. Further, this microscope's fast data acquisition ability makes it highly suitable for many applications where highly accurate quantitative phase imaging is important, such as in living cells or other fragile biological samples that cannot sustain continuous imaging over a long period of time.


YouTube Videos About Plantar Fasciitis and Calcaneal Spurs Are Insufficient and Poor Quality.
Patients frequently use YouTube to learn about their illness. For this reason, the educational and quality of YouTube videos about various diseases has been investigated. In this study, we aimed to evaluate the accuracy and quality of YouTube videos. A standard query was performed on the YouTube database using the following search terms: Plantar fasciitis, heel spur, and calcaneal spur. For each search term, the top 50 videos determined by YouTube's "relevance" according to its algorithm were evaluated (150 videos in total). After exclusion, 140 videos were included in the study. These videos were watched by 2 observers and the videos were evaluated and scored according to the Global Quality Score (GQS), DISCERN, Journal of the American Medical Association (JAMA), and Plantar Fasciitis and Calcaneal Spurs Specific Score (PFSS) scoring systems. According to the JAMA criteria, 76.42% of the videos and 43.57% of the videos according to the GQS scored 2 points or less. According to DISCERN criteria, 67.15% of the videos were evaluated as very poor/poor. According to the PFSS, 83.5% of the videos were rated as poor or very poor. These findings can be interpreted as the general information content of the videos about plantar fasciitis is insufficient and their reliability and quality are low. As a result, it can be concluded that the quality and reliability of YouTube videos regarding plantar fasciitis are insufficient for patients. Universities/associations prepare videos that provide information about plantar fasciitis to patients, and that these videos are presented on certain platforms can be a solution.


Charge control of the inverse trans-influence.
The synthesis and characterization of uranium(VI) mono(imido) complexes, by the oxidation of corresponding uranium(V) species, are presented. These experimental results, paired with DFT analyses, allow for the comparison of the electronic structure of uranium(VI) mono(oxo) and mono(imido) ligands within a conserved ligand framework and demonstrate that the magnitude of the ground state stabilization derived from the inverse trans-influence (ITI) is governed by the relative charge localization on the multiply bonded atom or group.


Consensus recommendations on holistic care in hereditary ATTR amyloidosis: an international Delphi survey of patient advocates and multidisciplinary healthcare professionals.
Hereditary transthyretin-mediated amyloidosis is a rare, progressive and potentially life-limiting multisystem disease, affecting every aspect of a patient's life. This online international Delphi survey aimed to evolve clinical-patient-led practical guidance, to inspire and encourage a holistic approach to care that is managed in specialist settings by multidisciplinary teams and supported by allied healthcare professionals (HCPs) and patient advocacy groups (PAGs). A 14-member joint patient advocate-HCP primary panel was convened including representation from PAGs and key clinical specialties (neurology, cardiology, internal medicine, physiotherapy, clinical psychology, dietetics and specialist nursing). Guidance evolved on the care provision needed to support seven core goals: early diagnosis and treatment; disease monitoring and organisation of care; maintenance of physical and mental health; family-centred care and caregiver support; patient-doctor dialogue; access to social support and social networking. From June to October 2022, 252 HCPs and 51 PAG representatives from 27 countries were invited to participate in a Delphi survey. Of the 122 respondents who answered at least one survey question, most were HCPs (100, 82%) from specialist centres; the remainder were PAG representatives (22, 18%). Both level of agreement and feasibility in practice of each recommendation was tested by two anonymised online Delphi voting rounds. Based on an a priori threshold for consensus of ≥75% agreement, the clinical-patient community endorsed all but one recommendation. However, only 17/49 (35%) recommendations were identified by most HCPs as a core part of routine care; the remainder (32/49 (65%)) were identified as part of core care by <50% of HCPs respondents, or as largely achievable by 30%-45% of HCPs. By comparison, PAGs recorded lower implementation levels. Further consideration is needed on how to evolve multidisciplinary services (supported by allied HCPs and PAGs) to address the complex needs of those affected by this disease.


Scanning electron microscopy-based approach to understand the mechanism underlying the adhesion of dengue viruses on ceramic hydroxyapatite columns.
Although ceramic hydroxyapatite (HAp) chromatography has been used as an alternative method ultracentrifugation for the production of vaccines, the mechanism of virus separation is still obscure. In order to begin to understand the mechanisms of virus separation, HAp surfaces were observed by scanning electron microscopy after chromatography with dengue viruses. When these processes were performed without elution and with a 10-207 mM sodium phosphate buffer gradient elution, dengue viruses that were adsorbed to HAp were disproportionately located in the columns. However, when eluted with a 10-600 mM sodium phosphate buffer gradient, few viruses were observed on the HAp surface. After incubating the dengue viruses that were adsorbed on HAp beads at 37°C and 2°C, the sphericity of the dengue viruses were reduced with an increase in incubation temperature. These results suggested that dengue virus was adsorbed to the HAp surface by electronic interactions and could be eluted by high-salt concentration buffers, which are commonly used in protein purification. Furthermore, virus fusion was thought to occur with increasing temperature, which implied that virus-HAp adhesion was similar to virus-cell adhesion.


Evaluation of Homogentisic Acid, a Prospective Antibacterial Agent Highlighted by the Suitability of Nitisinone in Alkaptonuria 2 (SONIA 2) Clinical Trial.
Despite urgent warnings about the spread of multidrug-resistant bacteria, the antibiotic development pipeline has remained sparsely populated. Naturally occurring antibacterial compounds may provide novel chemical starting points for antibiotic development programs and should be actively sought out. Evaluation of homogentisic acid (HGA), an intermediate in the tyrosine degradation pathway, showed that the compound had innate activity against Gram-positive and Gram-negative bacteria, which was lost following conversion into the degradation product benzoquinone acetic acid (BQA). Anti-staphylococcal activity of HGA can be attributed to effects on bacterial membranes. Despite an absence of haemolytic activity, the compound was cytotoxic to human HepG2 cells. We conclude that the antibacterial activity and in vitro safety profile of HGA render it more suitable for use as a topical agent or for inclusion in a small-molecule medicinal chemistry program.


Emotion regulation and depressive symptoms: Close relationships as social context and influence.
Depression is associated with social dysfunction and maladaptive social environments, but mechanisms through which social relationships affect depressive psychopathology are unclear. We hypothesized that emotion regulation (ER) is such a mechanism, with outcomes of individuals' ER efforts sensitive to the social context, and individuals' ER strategy repertoire and use sensitive to social influence. In Study 1, a longitudinal study of community adults (N = 1,319), associations of individuals' ER strategies with depressive symptoms depended on social connectedness and romantic relationship status (social context hypothesis). Moreover, associations of social connectedness and relationship status with symptoms were accounted for by maladaptive ER concurrently and, for social connectedness, prospectively over 1 year (social influence hypothesis). Study 2a, using a national sample (N = 772), replicated and extended these findings with a broader array of ER strategies, and ruled out alternative explanations regarding social skills and psychological wellbeing. Among participants in romantic relationships (Study 2b; N = 558), intimacy and trust buffered associations of maladaptive ER strategies with symptoms (context), and maladaptive and adaptive ER mediated links between relationship variables and symptoms (influence). Findings suggest that close relationships-and variation in underlying relational processes within relationships-influence the ER strategies people use, and also affect whether individuals' own ER repertoires contribute to depression when deployed. Results elucidate core social mechanisms of ER in terms of both basic processes and depressive psychopathology, suggest ER is a channel through which social factors affect internal functioning and mental health, and inform relationship pathways for clinical intervention.


Marilia caramuru sp. nov. and Marilia paraguassu sp. nov. (Trichoptera: Odontoceridae), two new species from Maranhão State, Northeast Brazil.
Although the world species diversity of Marilia Müller 1880 is not great, knowledge about this group may be underestimated, since several areas are poorly studied, especially in Northeast Region, Brazil. Two new species are described and illustrated here based on specimens collected in Maranhão State, from which the genus has not been reported previously. Despite the similarity of Marilia caramuru sp. nov. with M. elongata Martynov 1912, differences between them are observed especially in segment X and preanal appendages, in addition to details of wing venation. The unique set of spiniform projections on endotheca, and the wrinkled prominence on sternum VIII distinguish Marilia paraguassu sp. nov. from all other species in the genus. The material examined has been deposited in the Coleção Entomológica Professor José Alfredo Pinheiro Dutra, UFRJ, Rio de Janeiro, Brazil, and in the Coleção Zoológica do Maranhão, UEMA, Maranhão, Brazil.


A colorimetric and fluorescent probe for fluoride ions based on 6-acetyl-2-naphthol.
A colorimetric and turn-on fluorescent probe for fluoride ions, tert-butyldimethylsilane 6-acetyl-2-naphtholate, was readily synthesized from 6-acetyl-2-naphthol and tert-butyldimethylchlorosilane (TBSCl). The probe exhibits high sensitivity and good selectivity for fluoride ions in acetonitrile. The inherent mechanism involves the cleavage of the Si-O bond in the probe, which induced yellow color formation and prominent fluorescence enhancement.


Structure, innervation, mechanical properties and reflex activation of a striated sphincter in the vestibule of the cat vagina.
Vaginal constriction might be important for reproduction in mammals, but existing information is both limited and controversial. This paper shows the structure, mechanical properties, innervation and reflex response of a striated sphincter in the vestibule of the cat vagina. A Foley catheter coupled to a pressure transducer detected in the lumen of the vestibule a pressure wave that was induced by stimulation of the external branch of the motor pudendal nerve. The peak pressure of the wave induced by bilateral stimulation (30.6 cm H(2)O) was about double of the peak pressure wave induced unilaterally. The tetanus/twitch amplitude ratio was 4.5. The sphincter that produces the increase in vaginal pressure fatigues slowly. Digital, point-to-point summation of unilateral waves was greater than the wave induced bilaterally. Summation of the pressure wave induced by the separate stimulation of the terminal motor branches was also greater than the wave induced by the entire motor nerve. This might reflect multiple innervation of muscle fibres. Single, controlled probing of the vaginal vestibule induced a reflex discharge in the motor nerve. Repetitive probing (10 Hz) induced a motor nerve post-discharge lasting >1 min. The vaginal sphincter is two-half rings of striated muscle fibres in the wall of the vaginal vestibule; the fibres end freely in the dorsal and ventral midlines. Penetration of the vestibule by the penis might trigger sustained contraction of the vaginal sphincter.


Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy.
Abnormal lipid metabolism associated with diabetes mellitus has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. Oxysterols, oxidation derivatives of cholesterol, are known to be highly cytotoxic. To monitor changes in myocardial oxysterols and to assess the effect of probucol, a lipid lowering agent, on myocardial lipids and oxysterols in diabetic rats. Streptozotocin-induced diabetic rats were divided into two groups; one group was put on a standard diet, and the other a diet containing 1% (weight/weight) probucol for eight weeks. Two oxysterols, 7 beta-hydroxycholesterol and 7-ketocholesterol, were identified in myocardium by capillary gas chromatography. Both 7 beta-hydroxycholesterol and 7-ketocholesterol were significantly increased in diabetic rats (49.9 +/- 9.4 ng/mg dry weight versus 5.8 +/- 1.2 in controls, P < 0.05; and 5.3 +/- 1.2 ng/mg dry weight versus 1.7 +/- 0.1 in controls, P < 0.01, respectively). Probucol reduced not only plasma lipids but also myocardial lipids except for cholesterol and sphingomyelin fractions. However, probucol did not improve insulin deficiency, glucose metabolism or myocardial oxysterol contents. This study demonstrated an increase in oxysterols in the myocardium of diabetic rats, suggesting that oxysterols may play a role in the development of diabetic cardiomyopathy. Probucol did not decrease the myocardial oxysterol content at the dose used in this study, suggesting that the increase in oxysterols may not be attributed to high circulating concentrations of lipids, but rather to disturbed myocardial metabolism due to insulin deficiency.


Shared and unique responses in the microbiome of allopatric lizards reared in a standardized environment.
The gut microbiome can influence host fitness and, consequently, the ecology and evolution of natural populations. Microbiome composition can be driven by environmental exposure but also by the host's genetic background and phenotype. To contrast environmental and genetic effects on the microbiome we leverage preserved specimens of eastern fence lizards from allopatric lineages east and west of the Mississippi River but reared in standardized conditions. Bacterial composition was indistinguishable between lineages but responded significantly to host age-a proxy for environmental exposure. This was accompanied by a continuous decrease in bacterial diversity in both lineages, partially driven by decreasing evenness seen only in western lizards. These findings indicate that longer exposure to a homogeneous habitat may have a depreciating effect on microbiome diversity in eastern fence lizards, a response shared by both lineages. We highlight the importance of such effects when extrapolating patterns from laboratory experiments to the natural world.


Interplanetary magnetic field enhancements and their association with the asteroid 2201 oljato.
Comparison of the times of occurrence of a newly discovered type of disturbance in the interplanetary magnetic field at 0.72 astronomical unit with the passage of the small Venus-crossing asteroid, 2201 Oljato, reveals a possible association, but the source of these disturbances appears to be associated with outgassing material in the Oljato orbit some distance behind the asteroid and not with the asteroid itself. This suggested association can account for one quarter of the total number of events seen in eight Venus years.


Developmental expression of Drosophila melanogaster retrovirus-like transposable elements.
We have determined the pattern of temporal expression of several Drosophila retrovirus-like transposable elements. Some of these elements can be grouped into classes whose members show a similar profile of developmental transcription. The members of the 412 class, which includes 412, mdg1, 17.6 and 3S18, are transcribed mainly in the early larval and pupal stages of development, with small differences among the various members. HMS Beagle and Springer constitute another class where RNA accumulation in the larval stages is higher than in pupae and the adult flies accumulate more RNA than any other stage of development. Finally, the transcription of other elements such as copia, 297 and B104 follows a specific and individual pattern distinct from those described above. These results suggest the existence of evolutionary relationships among different transposable elements in Drosophila and the involvement of different cellular genes in the control of their expression.


Glutamatergic regulation of [3H]-noradrenaline release in the medulla oblongata of normotensive and spontaneously hypertensive rats.
To assess in vitro the role of glutamate receptors in the regulation of noradrenaline release from the medulla oblongata of normotensive and hypertensive rats. The effects of L-glutamate (an endogenous ligand for glutamate receptors), glycine (an allosteric agonist for the N-methyl-D-aspartate type of glutamate receptors) and MK-801 (an antagonist for N-methyl-D-aspartate receptors) on [3H]-noradrenaline release were examined in slices of rat medulla oblongata. L-Glutamate elicited [3H]-noradrenaline release from slices of rat medulla oblongata in magnesium-free medium. Glycine also increased the release of noradrenaline. Moreover, the effect of L-glutamate on noradrenaline release was significantly potentiated by glycine. MK-801 inhibited the increase in noradrenaline release evoked by L-glutamate. In spontaneously hypertensive rats (SHR) the facilitatory effect of L-glutamate on noradrenaline release was significantly more pronounced than in Wistar-Kyoto (WKY) rats. Furthermore, glycine alone and in combination with L-glutamate increased the noradrenaline release to a greater extent in SHR than in WKY rats. The present results show that the excitatory amino acids might increase noradrenaline release from rat medulla oblongata, which was partially dependent on the N-methyl-D-aspartate type of glutamate receptors. The greater effect of L-glutamate and glycine in SHR suggests that these amino acids might be involved in the regulation of noradrenaline release in the medulla oblongata of hypertension.


Xenon contrast CT-CBF measurements in high-intensity foci on T2-weighted MR images in centrum semiovale of asymptomatic individuals.
White matter lesions (WMLs) on T2-weighted MR images occurring in the centrum semiovale of normal individuals are a subject of great clinical interest. We therefore investigated regional cerebral blood flow (rCBF) of the centrum semiovale among neurologically normal individuals. One hundred thirty-five neurologically normal subjects were divided into four grades of WML on the basis of their MR images. rCBF values in the centrum semiovale were measured by xenon contrast CT methods. Advanced age and associated hypertension were significant risk factors for higher grade WMLs. Centrum semiovale rCBF values on the left side were 24.27 +/- 2.60 mL.100 g-1.min-1 in grade 0, 23.52 +/- 2.78 in grade I, 19.35 +/- 2.81 in grade II, 15.82 +/- 2.05 in grade III, and 11.31 +/- 2.56 in grade IV. Differences were significant between grades (P < .005 between grade 0 and grades II, III, and IV; between grade II and grades III and IV; and between grades III and IV). Patients with hypertension had lower rCBF values than those without in grades 0, I, II, and III, with significant difference in grade I (P < .005). Age-matched studies between patients 61 to 70 years old confirmed a significant difference between WML grades. WMLs in centrum semiovale are associated with greater age, hypertension, and reduced rCBF values.


Progressive Applications of Hyperbranched Polymer Based on Diarylamine: Antimicrobial, Anti-Biofilm and Anti-Aerobic Corrosion.
New generations of hyperbranched aramids were synthesized from diarylamine and methyl acrylate using an AB2 monomer approach in a straightforward one-pot preparation. The chemical structure of hyperbranched Phenylenediamine/Methyl Acrylate HB(PDMA was confirmed by Fourier Transform Infrared (FTIR) and Nuclear Magnetic Resonance (1HNMR) spectroscopy. In addition, the particle's size and distribution were recorded using Dynamic Light Scattering (DLS). Moreover, the synthesized HB(PDMA)s displayed broad-spectrum antimicrobial activities against Gram-positive and Gram-negative bacteria as well as yeast strains and anti-biofilm activity where the highest activity was attributed to HB(PDMA)G4 at the lowest Minimum Inhibitory, Minimum Bactericidal, and Fungicidal Concentrations (MIC, MBC, and MFC, respectively). Furthermore, the HB(PDMA)s expressed anti-bacterial activity against isolated Pseudomonas sp. (R301) at a salinity of 35,000 ppm (NaCl). In addition, they revealed different corrosion inhibition efficiencies at the cultivated medium salinity at the estimated minimum bactericidal concentrations. The highest metal corrosion inhibition efficiencies were 59.5 and 94.3% for HB(PDMA)G4 at the Minimum Bactericidal Concentrations (MBCs) and two times Minimum Bactericidal Concentrations (2XMBCs), respectively, in comparison to both negative and positive controls.


Patterns of alcohol abuse and family stability.
Male alcoholics and their spouses participating in an ongoing family interaction study were assessed as to drinking patterns, psychiatric symptoms, and marital satisfaction. Analyses of these data indicated that high alcohol consumption was associated with high satisfaction and reduced symptomatology in the spouses of steady but not binge drinkers. Findings are discussed in terms of Steinglass' suggestion that alcohol can have "adaptive" consequences for the marriage and family life of alcoholics.


Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy.
Over the last decade, there has been increasing evidence that hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is a hallmark of malformations of cortical development such as focal cortical dysplasia (FCD) or hemimegalencephaly. The mTOR pathway governs protein and lipid synthesis, cell growth and proliferation as well as metabolism and autophagy. The molecular genetic aetiology of mTOR hyperactivation has only been recently clarified. This article will review the current and still evolving genetic advances in the elucidation of the molecular basis of FCD. Activating somatic mutations in the MTOR gene are to date the most frequent mutations found in FCD brain specimens.


Systemic effect of human growth hormone after intramuscular injection of a single dose of a muscle-specific gene medicine.
A muscle-specific gene medicine is described that provides for long-term secretion of biologically active human growth hormone (hGH) from skeletal muscle into the systemic circulation. The hGH gene medicine is composed of a muscle-specific hGH plasmid expression system complexed with a protective, interactive, non-condensing (PINC) delivery system. The muscle-specific gene expression system, pSK-hGH-GH, was constructed by linking the promoter/enhancer regions of chicken skeletal alpha-actin to hGH gene. C2C12 myoblast transfection with pSK-hGH-GH resulted in the synthesis of hGH in a muscle-specific manner. Direct injection into rat tibialis cranialis muscle of pSK-hGH-GH complexed with a polymeric PINC delivery system, polyvinylpyrrolidone (PVP), produced hGH levels in muscle that were 10- to 15-fold higher compared with plasmid formulated in saline at 14 days post-injection. Intratracheal instillation in rat lung of pSK-hGH-GH did not produce significantly detectable levels of hGH. In hypophysectomized rats, a single intramuscular dose of the pSK-hGH-GH/PVP complex resulted in hGH expression and a subsequent increase in serum levels of rat IGF-I and growth. hGH expression and effects on rat serum IGF-I levels were detectable up to 28 days after injection of formulated plasmid and effects on growth were detectable unto 21 days. Anti-hGH antibodies were detectable in serum at 14 days post-injection, reached a plateau at 21 days, and remained elevated through the study period. Cyclosporin treatment of the pSK-hGH-GH/PVP-injected animals completely inhibited the antibody response and resulted in increased hGH expression.


Apolipoprotein B: a novel mechanism for deriving two proteins from one gene.
Evidence from antibody and peptide mapping, protein sequencing and amino acid composition studies suggests that intestinal apo-B48 is colinear with the amino terminal half of hepatic apo-B100. To investigate the mechanism of apo-B48 production we examined cDNA clones from human and rabbit small intestine. All clones contained a single C----T base difference from the hepatic sequence resulting in a translational stop at codon 2153. Amplification by the polymerase chain reaction of cDNA from human and rabbit small intestine, rabbit liver and the human hepatoma cell line HepG2 showed that the stop codon was only present in intestinal mRNA. Enterocyte genomic DNA did not contain the stop codon. We suggest that a co- or post-transcriptional C----U change may result in the production of apo-B48, which represents the amino terminal 2152 amino acids of apo-B100. This is the first example of tissue specific modification of a single mRNA nucleotide resulting in two different proteins from the same primary transcript.


Pulmonary Artery Banding for Children With Dilated Cardiomyopathy: US Experience.
Pulmonary artery band placement is a recently described therapeutic strategy for dilated cardiomyopathy with preserved right ventricular function, originally reported from Germany.1 We present the results of the multicenter retrospective study of pulmonary artery band experience in the United States, with comparison to the German experience. Five centers contributed a total 14 patients (median age 5 months, interquartile range 3.5-10). Mechanical ventilation was required in 9/12 (75%) patients and inotropes were used in 13/14 (93%) patients preoperatively. Ultimately, 4 (29%) patients experienced cardiac recovery, 8 (57%) were bridged to cardiac transplantation (6 with ventricular assist device placement), and 2 (14%) died. Although both the US and Germany series demonstrated high prevalence of achieving patients' individual target (either cardiac recovery or transplant), the mode of success was different (recovery rate: <1/3 in the United States and >2/3 in Germany). Lower recovery rate may be a reflection of sicker preoperative status, and thereby a more advanced stage of heart failure (preoperative intubation: >2/3 in the United States vs <1/3 in Germany). Further studies would be warranted to gain more insight into patient selection as well as optimal timing for the intervention.


Patterns of Relapse in Squamous Cell Carcinoma of the Tonsil - Unilateral vs. Bilateral Radiation in the HPV-Era.
In the pre-human papillomavirus (HPV) era, unilateral radiation therapy (URT) for tonsil cancer was associated with low contralateral failure rates and had less toxicity than bilateral radiation therapy (BRT). This study explores the validity of URT in HPV-positive tonsil cancers. Tonsil squamous cell carcinomas (SCC) treated (typically with 70 Gy radiation and Cisplatin-based chemotherapy) between 2001 and 2007 were reviewed. Retrospective p16 immunohistochemistry staining was undertaken. Baseline, treatment, and response data were collected. Of 182 patients, 78% were p16-positive, were younger (predominantly male), mostly former or non-smokers, and had a more advanced nodal stage. With a median follow-up of 68 months, contralateral recurrence (CLR) rates were low (3.5% p16-positive versus 2.5% p16-negative, p=0.63). Overall survival (OS) was 74% for p16-positive versus 54% for p16-negative subjects (p=0.01), but all other outcomes were similar. Analysis amongst only p16-positive subjects revealed URT was delivered to 37%, with CLR rates of 7.5% versus 1.1% for those treated with BRT, p=0.05. Of the four p16-positive subjects treated with URT who developed contralateral recurrences, three were managed with neck dissection (two disease-free and one died of lung metastases) and one received palliative radiation to the neck and distant metastatic site. All disease control and survival outcomes were similar between those treated with URT versus BRT. While CLRs remain rare overall, there appears to be a slightly increased rate among HPV-positive subjects treated with URT. However, overall outcomes do not appear to be impacted, suggesting that URT remains a reasonable approach in HPV-positive subjects.


24-hour profile of serum sclerostin and its association with bone biomarkers in men.
The osteocyte's role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men. The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20-65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04). Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.


Cancers in Australia in 2010 attributable to modifiable factors: summary and conclusions.
To estimate the numbers and proportions of cancers occurring in Australia in 2010 attributable to modifiable causal factors. We estimated the population attributable fraction (PAF) of cancers associated with exposure to 13 causal factors using standard formulae incorporating exposure prevalence and relative risk data. We also calculated the potential impact of changing exposure to some factors. A total of 32% of all cancers diagnosed in Australia in 2010 (excluding keratinocyte cancers) were attributable to the 13 factors assessed (men 33%; women 31%). Leading factors were tobacco smoke (PAF all cancers: 13.4%), solar radiation (6.2%), inadequate diet (6.1%) and overweight/obesity (3.4%). Factors conferring highest PAFs differed by sex: highest PAFs for men were tobacco smoke (15.8%), solar radiation (7.1%) and alcohol (3.0%); while highest PAFs for women were tobacco smoke (10.1%), solar radiation (5.0%) and overweight/obesity (4.5%). Sites with the highest counts of potentially preventable cancers were lung (8,569), colorectal (7,404), melanoma of the skin (7,220) and breast (3,233). At least one in three cancers in Australia is attributable to exposure to known modifiable factors. Up to 37,000 cancers could be prevented in Australia each year if the population avoided exposure to 13 common factors known or strongly suspected to cause cancer.


The use of invertebrates to detect small-scale habitat heterogeneity and its application to restoration practices.
Recent conceptual and technological solutions to biodiversity assessment allow large numbers of invertebrate specimens to be processed rapidly and provide researchers and practitioners with a unique tool for characterizing habitats. One application of these advances is the ability to detect and monitor small-scale habitat heterogeneity and so provide a measure of ecosystem restoration. This case study presents a test of the efficacy of using invertebrates to assess and monitor ecological restoration following bush regeneration. Eight contiguous habitat patches within a suburb of northern Sydney, Australia, were selected to represent areas that had undergone different bush regeneration techniques. A nearby and relatively undisturbed area of bushland was also sampled. A total of 57,806 ground-active invertebrate specimens from 35 different orders were collected in pitfall traps. 1,246 ant (Formicidae) specimens were further sorted into 46 ant morphospecies from 20 genera. Analyses of the three taxonomic data sets, including two different data transformations, demonstrated that: (i) invertebrate communities successfully characterized different sites, providing a high degree of differentiation among sites; (ii) ordinations of the sites allowed visual assessment of the impact of each management technique on the habitat relative to undisturbed habitats; and (iii) characterization of sites could be achieved using abundance classes or binary counts of ant morphospecies, representing potential cost and time savings. The project duration was a total of three person weeks and cost less than US$3,000 (1999 prices) to complete. Measurement of invertebrate assemblages will provide a tool for both rapid assessment of management decisions and a means by which to implement adaptive management and restoration.


Gold, palladium, and gold-palladium alloy nanoshells on silica nanoparticle cores.
The synthesis of gold, palladium, and gold-palladium alloy nanoshells (approximately 15-20 nm thickness) was accomplished by the reduction of gold and palladium ions onto dielectric silica core particles (approximately 100 nm in diameter) seeded with small gold nanoparticles (approximately 2-3 nm in diameter). The size, morphology, elemental composition, and optical properties of the nanoshells were characterized using field-emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, and ultraviolet-visible spectroscopy. The results demonstrate the successful growth of gold, palladium, and gold-palladium alloy nanoshells, where the optical properties systematically vary with the relative content of gold and palladium. The alloy nanoshells are being prepared for use in applications that stand to benefit from photoenhanced catalysis.


Dissecting the human protein-protein interaction network via phylogenetic decomposition.
The protein-protein interaction (PPI) network offers a conceptual framework for better understanding the functional organization of the proteome. However, the intricacy of network complexity complicates comprehensive analysis. Here, we adopted a phylogenic grouping method combined with force-directed graph simulation to decompose the human PPI network in a multi-dimensional manner. This network model enabled us to associate the network topological properties with evolutionary and biological implications. First, we found that ancient proteins occupy the core of the network, whereas young proteins tend to reside on the periphery. Second, the presence of age homophily suggests a possible selection pressure may have acted on the duplication and divergence process during the PPI network evolution. Lastly, functional analysis revealed that each age group possesses high specificity of enriched biological processes and pathway engagements, which could correspond to their evolutionary roles in eukaryotic cells. More interestingly, the network landscape closely coincides with the subcellular localization of proteins. Together, these findings suggest the potential of using conceptual frameworks to mimic the true functional organization in a living cell.


Molecular adaptation to high pressure in cytochrome P450 1A and aryl hydrocarbon receptor systems of the deep-sea fish Coryphaenoides armatus.
Limited knowledge of the molecular evolution of deep-sea fish proteomes so far suggests that a few widespread residue substitutions in cytosolic proteins binding hydrophilic ligands contribute to resistance to the effects of high hydrostatic pressure (HP). Structure-function studies with additional protein systems, including membrane bound proteins, are essential to provide a more general picture of adaptation in these extremophiles. We explored molecular features of HP adaptation in proteins binding hydrophobic ligands, either in lipid bilayers (cytochrome P450 1A - CYP1A) or in the cytosol (the aryl hydrocarbon receptor - AHR), and their partners P450 oxidoreductase (POR) and AHR nuclear translocator (ARNT), respectively. Cloning studies identified the full-length coding sequence of AHR, CYP1A and POR, and a partial sequence of ARNT from Coryphaenoides armatus, an abyssal gadiform fish thriving down to 5000m depth. Inferred protein sequences were aligned with many non-deep-sea homologs to identify unique amino acid substitutions of possible relevance in HP adaptation. Positionally unique substitutions of various physicochemical properties were found in all four proteins, usually at sites of strong-to-absolute residue conservation. Some were in domains deemed important for protein-protein interaction or ligand binding. In addition, some involved removal or addition of beta-branched residues; local modifications of beta-branched residue patterns could be important to HP adaptation. In silico predictions further suggested that some unique substitutions might substantially modulate the flexibility of the polypeptide segment in which they are found. Repetitive motifs unique to the abyssal fish AHR were predicted to be rich in glycosylation sites, suggesting that post-translational changes could be involved in adaptation as well. Recombinant CYP1A and AHR showed functional properties (spectral characteristics, catalytic activity and ligand binding) that demonstrate proper folding at 1atm, indicating that they could be used as deep-sea fish protein models to further evaluate protein function under pressure. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone".


Retrospective evaluation of the incidence and prognostic significance of spontaneous echocardiographic contrast in relation to cardiac disease and congestive heart failure in cats: 725 cases (2006-2011).
To determine whether the presence of spontaneous echocardiographic contrast (SEC) in cats with cardiomyopathy is associated with increased mortality. To establish whether specific types of cardiomyopathy are more often associated with SEC in an attempt to provide a risk-stratification scheme for cats with increased risk of thromboembolic events. Retrospective study 2006-2011. Tertiary referral and teaching hospital. Seven hundred twenty-five client-owned cats undergoing echocardiographic evaluation. Patient characteristics, including age, breed, clinical signs, type of cardiovascular disease, presence of SEC, and survival time were recorded. Thyroxine, HCT, and blood pressure were recorded when available. Among cats diagnosed with cardiac abnormalities based on echocardiographic findings, those with SEC were at significantly increased risk of death as compared to those without SEC. Cats with dilated cardiomyopathy, unclassified cardiomyopathy, and hypertrophic cardiomyopathy were significantly more likely to have SEC compared to cats with other types of cardiac disease. Cats with cardiomyopathy and SEC have an increased risk of death compared to cats without SEC, although other previously identified factors such as the presence of congestive heart failure and increased left atrium to aorta ratio remain important determinants of mortality. Cats with hypertrophic cardiomyopathy, unclassified cardiomyopathy, and dilated cardiomyopathy may benefit from anticoagulant therapy due to the increased risk of SEC in these subpopulations.


Phytochemistry and Antioxidant Activity of Aerial Parts of Phagnalon sordidum L.
One new natural monoterpene, 5-O-β-d-glucopyranosyl-2-hydroxy-p-cymene (1: ), and 11 known compounds were isolated through a biologically oriented approach from the aerial parts of Phagnalon sordidum L. The most active extract and fractions were selected using 3 complementary antioxidant activity assays. Results and the different methods were compared by relative antioxidant capacity index. In addition, the most active extract of P. sordidum was subjected to liquid chromatography coupled with electrospray ionization hybrid linear ion trap quadrupole Orbitrap mass spectrometry to quantify secondary metabolites. Antioxidant activities of ethyl acetate extract, and purified 3,4-dihydroxyacetophenone (3: ) and nebrodenside A (7: ) were demonstrated by in vitro cell free model assays, and their protective effect against H2O2-induced oxidative stress in a HepG2 (human hepatocellular carcinoma) cell line was established.


Eight rules for improving the quality of papers on the antimicrobial susceptibility of bacteria isolated from aquatic animals.
The methods for antimicrobial susceptibility testing of bacteria, although relatively simple, are not robust. As a consequence, if the data generated in such tests are to be commensurate, all susceptibility tests must be performed using standard protocols. A review of the published literature of antimicrobial susceptibility testing of bacteria from aquatic animals revealed a frequent occurrence of significant errors, particularly with regard to testing methodology, quality control and the use of appropriate interpretive criteria in the performance and reporting of susceptibility tests. This opinion piece provides a set of rules that, if followed, would help authors to avoid these frequently detected shortcomings.