Identification of novel sulfur-containing bacterial polyesters: biosynthesis of poly(3-hydroxy-S-propyl-omega-thioalkanoates) containing thioether linkages in the side chains.
This study describes the biosynthesis of novel sulfur-containing polyhydroxyalkanoates (PHAs), which consist exclusively of hydroxypropylthioalkanoic acid containing thioether groups in the side chains. In addition, the utilization of alkylthioalkanoic acids (=thia fatty acids) by various bacteria was investigated. Based on feedings with propylthiooctanoic acid (PTO) or propylthiohexanoic acid, the metabolically engineered PHA-negative mutant PHB(-)4 of Ralstonia eutropha, which harbours plasmid pBBR1::phaC1 expressing the PHA synthase of Pseudomonas mendocina, synthesized two novel poly(3-hydroxy-S-propyl-omega-thioalkanoic) acids [poly(3HPTA)s]. A terpolyester consisting of 3-hydroxypropylthiobutyric acid (3HPTB), 3-hydroxypropylthiohexanoic acid (3HPTHx) and 3-hydroxypropyl- thiooctanoic acid (3HPTO) was synthesized from PTO, whereas a co-polyester of 3HPTB and 3HPTHx was synthesized from propylthiohexanoic acid. Fed-batch fermentation of R. eutropha PHB(-)4(pBBR1::phaC1) on PTO was done on a 26-litre scale, providing a cell density of 7.3 g l(-1), from which 45 g of the novel poly(3HPTB-co-3HPTHx-co-3HPTO) were isolated. The chemical structures of the poly(3HPTA)s were identified by gas chromatography/mass spectrometry, elemental sulfur analysis, partial pyrolysis and detailed mass spectrometric analysis, exhibiting 3HPTB, 3HPTHx and 3HPTO as constituents. These novel, hitherto undescribed, constituents of PHAs were randomly distributed in the co-polyesters.


Modulation of transcriptome and metabolome of tobacco by Arabidopsis transcription factor, AtMYB12, leads to insect resistance.
Flavonoids synthesized by the phenylpropanoid pathway participate in myriad physiological and biochemical processes in plants. Due to the diversity of secondary transformations and the complexity of the regulation of branched pathways, single gene strategies have not been very successful in enhancing the accumulation of targeted molecules. We have expressed an Arabidopsis (Arabidopsis thaliana) transcription factor, AtMYB12, in tobacco (Nicotiana tabacum), which resulted in enhanced expression of genes involved in the phenylpropanoid pathway, leading to severalfold higher accumulation of flavonols. Global gene expression and limited metabolite profiling of leaves in the transgenic lines of tobacco revealed that AtMYB12 regulated a number of pathways, leading to flux availability for the phenylpropanoid pathway in general and flavonol biosynthesis in particular. The tobacco transgenic lines developed resistance against the insect pests Spodoptera litura and Helicoverpa armigera due to enhanced accumulation of rutin. Suppression of flavonol biosynthesis by artificial microRNA reversed insect resistance of the AtMYB12-expressing tobacco plants. Our study suggests that AtMYB12 can be strategically used for developing safer insect pest-resistant transgenic plants.


Characterization of anthocyanins from the fruits of baguaçu (Eugenia umbelliflora Berg).
Anthocyanin pigments in the berries of baguaçu (Eugenia umbelliflora Berg), a tropical fruit from Brazil, were extracted with 0.1% HCl in ethanol, and the crude anthocyanin extract was purified by Amberlite XAD-7 open-column chromatography. Six major anthocyanins were isolated by preparative HPLC, and their chemical structures were identified by spectroscopic methods (TLC, UV-vis, MS, and (1)H NMR). Delphinidin 3-O-beta-glucopyranoside, cyanidin 3-O-beta-glucopyranoside, petunidin 3-O-beta-glucopyranoside, pelargonidin 3-O-beta-glucopyranoside, peonidin 3-O-beta-glucopyranoside, and malvidin 3-O-beta-glucopyranoside were identified. On the basis of chromatographic data the total anthocyanin content was 342 mg/100 g of fresh baguaçu berries. Therefore, the concomitant presence of six anthocyanins in a single plant species makes this product promising as a new pigment source.


Does age worsen sleep-dependent memory consolidation?
Slow wave sleep (SWS) is known to favour episodic memory consolidation. Given that ageing is associated with a reduction in SWS and episodic memory impairment, our aim was to investigate whether memory continues to benefit from sleep in older adults. Episodic memory consolidation was tested in 20 young (22.1 ± 1.7 years) and 20 older volunteers (68.9 ± 5.3 years) who performed a visuospatial two-dimensional object-location task. Retention capacities were evaluated after 12 h of wakefulness or 12 h of sleep. Performances before and after the interval allowed us to calculate a forgetting rate. Sleep architecture was measured by polysomnography (older adults = 410 min; young adults: 467 min). Our results showed that the beneficial effect of sleep on memory consolidation was reduced in older adults compared to young adults. In older adults, sleep did not enhance memory consolidation significantly compared to wakefulness. Sleep prevented young adults from forgetting (-0.10% ± 2.1), while the forgetting rate in older adults was still important after a period of sleep (16.60% ± 4.2; P = 0.05). The sleep architecture of older adults was characterized by a decrease in sleep efficiency (-12%; P < 0.05), in total cycle time (-137 min; P < 0.05), in percentage of total cycle time (-21%; P < 0.05) and in rapid eye movement time (-41 min; P < 0.05) compared to young adults. However, no difference in slow wave sleep was observed (-1%; not significant) and no correlation was found with performance. Age-related changes in sleep parameters may have a negative impact on memory consolidation in older adults.


CRAC channel regulation of innate immune cells in health and disease.
Calcium is a major intracellular signaling messenger in innate immune cells. Similar to other immune cell subsets, the majority of calcium entry into innate immune cells is induced by cell surface receptors that stimulate store-operated calcium entry through calcium-release activated calcium (CRAC) channels. Since the molecular description of the STIM family of calcium sensors and the ORAI family of CRAC channel proteins, the majority of studies support a dominant role for these proteins in calcium signaling in innate cells. In reviewing the literature on CRAC channel function in innate cells, several general themes emerge. All innate cells express multiple members of the STIM and ORAI family members, however the ratio and relative contribution of individual isoforms changes depending on the cell type and activation state of the cell. It is evident that study of functional roles for STIM molecules is clearly ahead of studies of specific ORAI family members in all innate cell types, and that studies of CRAC channels in innate cells are not nearly as advanced as studies in lymphocytes. However, taken together, evidence from both STIM calcium sensors and ORAI channels in innate cells indicates that deficiency of STIM and ORAI proteins tends not to affect the development of any innate cell lineage, but certainly affects their function, in particular activation of the neutrophil oxidase and mast cell activation via IgE receptors. Furthermore, there are clearly hints that therapeutic targeting of CRAC channels in innate cells offers a new approach to various inflammatory and allergic diseases.


Long-term economic benefits attributed to IVF-conceived children: a lifetime tax calculation.
To evaluate whether lifetime future net tax revenues from an in vitro fertilization (IVF)-conceived child are substantial enough to warrant public subsidy relative to the mean IVF treatment costs required to obtain 1 live birth. Mathematical generational accounting model. The model estimates direct financial interactions between the IVF-conceived child and the government during the child's projected lifetime. In the model, we accrue IVF costs required to conceive the child to the government, and then we estimate future net tax revenue to the federal and state governments from this individual, offset by direct financial transfers from the government (eg, child allowances, education, Medicare, and Social Security). We discount lifetime costs and gross tax payments at Treasury Department rates to establish the present value of investing in IVF. We applied US Congressional Budget Office projected changes in tax rates over the course of the model. An IVF-conceived child, average in every respect (eg, future earnings, healthcare consumption, and life expectancy), represents a net positive return to the government. Based on an average employed individual born in 2005, the projected net lifetime tax contribution is US $606,200. Taking into consideration IVF costs and all direct financial interactions, the net present value is US $155,870. Lifetime net taxes paid from a child relative to the child's initial IVF investment represent a 700% net return to the government in discounted US dollars from fully employed individuals. This suggests that removing barriers to IVF would have positive tax benefits for the government, notwithstanding its beneficial effect on overall economic growth.


Guidelines for Diagnosing and Quantifying Noise-Induced Hearing Loss.
This paper makes recommendations for the diagnosis and quantification of noise-induced hearing loss (NIHL) in a medico-legal context. A distinction is made between NIHL produced by: steady broadband noise, as occurs in some factories; more impulsive factory sounds, such as hammering; noise exposure during military service, which can involve very high peak sound levels; and exposure to very intense tones. It is argued that existing diagnostic methods, which were primarily developed to deal with NIHL produced by steady broadband noise, are not adequate for the diagnosis of NIHL produced by different types of exposures. Furthermore, some existing diagnostic methods are based on now-obsolete standards, and make unrealistic assumptions. Diagnostic methods are proposed for each of the types of noise exposure considered. It is recommended that quantification of NIHL for all types of exposures is based on comparison of the measured hearing threshold levels with the age-associated hearing levels (AAHLs) for a non-noise exposed population, as specified in ISO 7029 (2017), usually using the 50th percentile, but using another percentile if there are good reasons for doing so. When audiograms are available both soon after the end of military service and some time afterwards, the most recent audiogram should be used for diagnosis and quantification, since this reflects any effect of the noise exposure on the subsequent progression of hearing loss. It is recommended that the overall NIHL for each ear be quantified as the average NIHL across the frequencies 1, 2, and 4 kHz.


HOX genes in pancreatic development and cancer.
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.


Development and function of innate polyclonal TCRalphabeta+ CD8+ thymocytes.
Innate CD8 T cells are found in mutant mouse models, but whether they are produced in a normal thymus remains controversial. Using the RAG2p-GFP mouse model, we found that ∼10% of TCRαβ(+) CD4(-)CD8(+) thymocytes were innate polyclonal T cells (GFP(+)CD44(hi)). Relative to conventional T cells, innate CD8 thymocytes displayed increased cell surface amounts of B7-H1, CD2, CD5, CD38, IL-2Rβ, and IL-4Rα and downmodulation of TCRβ. Moreover, they overexpressed several transcripts, including T-bet, Id3, Klf2, and, most of all, Eomes. Innate CD8 thymocytes were positively selected, mainly by nonhematopoietic MHCIa(+) cells. They rapidly produced high levels of IFN-γ upon stimulation and readily proliferated in response to IL-2 and IL-4. Furthermore, low numbers of innate CD8 thymocytes were sufficient to help conventional CD8 T cells expand and secrete cytokine following Ag recognition. This helper effect depended on CD44-mediated interactions between innate and conventional CD8 T cells. We concluded that innate TCRαβ(+) CD8 T cells represent a sizeable proportion of normal thymocytes whose development and function differ in many ways from those of conventional CD8 T cells.


Prediction of reversible disulfide based on features from local structural signatures.
Disulfide bonds are traditionally considered to play only structural roles. In recent years, increasing evidence suggests that the disulfide proteome is made up of structural disulfides and reversible disulfides. Unlike structural disulfides, reversible disulfides are usually of important functional roles and may serve as redox switches. Interestingly, only specific disulfide bonds are reversible while others are not. However, whether reversible disulfides can be predicted based on structural information remains largely unknown. In this study, two datasets with both types of disulfides were compiled using independent approaches. By comparison of various features extracted from the local structural signatures, we identified several features that differ significantly between reversible and structural disulfides, including disulfide bond length, along with the number, amino acid composition, secondary structure and physical-chemical properties of surrounding amino acids. A SVM-based classifier was developed for predicting reversible disulfides. RESULTS: By 10-fold cross-validation, the model achieved accuracy of 0.750, sensitivity of 0.352, specificity of 0.953, MCC of 0.405 and AUC of 0.751 using the RevSS_PDB dataset. The robustness was further validated by using RevSS_RedoxDB as independent testing dataset. This model was applied to proteins with known structures in the PDB database. The results show that one third of the predicted reversible disulfide containing proteins are well-known redox enzymes, while the remaining are non-enzyme proteins. Given that reversible disulfides are frequently reported from functionally important non-enzyme proteins such as transcription factors, the predictions may provide valuable candidates of novel reversible disulfides for further experimental investigation. This study provides the first comparative analysis between the reversible and the structural disulfides. Distinct features remarkably different between these two groups of disulfides were identified, and a SVM-based classifier for predicting reversible disulfides was developed accordingly. A web server named RevssPred can be accessed freely from: http://biocomputer.bio.cuhk.edu.hk/RevssPred .


On the effect of 4f electrons on the structural characteristics of lanthanide trihalides: computational and electron diffraction study of dysprosium trichloride.
The molecular and electronic structure of dysprosium trichloride, DyCl(3), was calculated by high-level quantum chemical methods in order to learn about the effect of the partially filled 4f subshell and of the possible spin-orbit coupling on them. High-temperature electron diffraction studies of DyCl(3) were also carried out so that we could compare the computed geometry with the experimental one, after thermal corrections on the latter. Dysprosium monochloride, DyCl, and the dimer of dysprosium trichloride, Dy(2)Cl(6), were also investigated by computation. We found that the electron configuration of the 4f subshell does not influence the geometry of the trichloride monomer molecule as the ground state and first excited state molecules have the same geometry. Nonetheless, taking the 4f electrons into account in the calculation, together with the 5s and 5p electrons, is important in order to get geometrical parameters consistent with the results from experiment. Based on electron diffraction and different levels of computation, the suggested equilibrium bond length (r(e)) of DyCl(3) is 2.443(14) A, while the thermal average distance (r(g)) from electron diffraction is 2.459(11) A. The molecule is trigonal planar in equilibrium. Although the ground electronic state splits due to spin-orbit coupling, the lowering of the total electronic energy is very small (about 0.025 hartree) and the geometrical parameters are not affected. In contrast with the monomeric trichloride molecule, the bond angles of the dimer seem to be different for different electronic states, indicating the influence of the 4f electronic configuration on their structure. We carried out an anharmonic analysis of the out-of-plane vibration of the trichloride monomer and found that the vibration is considerably anharmonic at 39.5 cm(-1), compared with the 30.5 cm(-1) harmonic value.


Recent Advances in Pediatric Medulloblastoma.
Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma. The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors.


Perfluorinated compounds in blood of Caretta caretta from the Mediterranean Sea.
Perfluorinated compounds (PFCs), widely used for their hydro-oil repellent properties, are almost non-degradable in the environment; there is scientific evidence that indicate bioaccumulation. They represent a threat to many organisms, because they are toxic and are endocrine disruptors. Scientific studies have demonstrated the presence of PFCs in blood and liver samples of fish, turtles, birds and mammals of marine ecosystems in different geographical areas. The aim of this study was to determine the distribution of PFOS and PFOA in blood samples of the marine turtle Caretta caretta, using a minimally invasive sampling procedure. 49 blood samples of marine turtle, taken from several Italian marine turtle rescue centers, were analyzed. While PFOA was never detected, measurable concentrations of PFOS were found in 15 blood samples; the values show a range from 1.14 ng/g to 28.51 ng/g (wet wt.). No differences between groups of samples taken from different areas were found.


Efficacy of motivational interviewing for smoking cessation: a systematic review and meta-analysis.
A systematic review and meta-analysis to investigate the efficacy of interventions incorporating motivational interviewing for smoking cessation and identify correlates of treatment effects. Medline/PubMed, PsycInfo and other sources including grey literature. Title/abstract search terms were motivational interview* OR motivational enhancement AND smok*, cigarette*, tobacco, OR nicotine. Randomised trials reporting number of smokers abstinent at follow up were eligible. Data were independently coded by the first and third authors. We coded for a variety of study, participant, and intervention related variables. A random effects logistic regression with both a random intercept and a random slope for the treatment effect. 31 smoking cessation research trials were selected for the study: eight comprised adolescent samples, eight comprised adults with chronic physical or mental illness, five comprised pregnant/postpartum women and 10 comprised other adult samples. Analysis of the trials (9485 individual participants) showed an overall OR comparing likelihood of abstinence in the motivational interviewing (MI) versus control condition of OR 1.45 (95% CI 1.14 to 1.83). Additional potential correlates of treatment effects such as study, sample, and intervention characteristics were examined. This is the most comprehensive review of MI for smoking cessation conducted to date. These findings suggest that current MI smoking cessation approaches can be effective for adolescents and adults. However, comparative efficacy trials could be useful.


Net pressure gradients in aortic prosthetic valves can be estimated by Doppler.
In aortic prosthetic valves, both the Doppler-estimated gradients and orifice areas are misleading in the assessment of hemodynamic performance. The parameter of major interest is the net pressure gradient after pressure recovery (PR). We, therefore, investigated, in vitro, our ability to predict the net pressure gradient and applied the formulas in a representative patient population with 2 different valve designs. We studied the St Jude Medical (SJM) standard valve (size 19-27) and SJM Biocor (size 21-27) in an in vitro steady-flow model with simultaneous Doppler-estimated pressure and catheter pressure measurements. Using echocardiography, we also studied patients who received the SJM (n = 66) and SJM Biocor (n = 45). In the SJM, we observed PR both within the prosthesis and aorta, whereas in the SJM Biocor, PR was only present in the aorta. We estimated the PR within the valve and within the aorta separately from echocardiographic in vitro data, combining a regression equation (valve) with an equation on the basis of fluid mechanics theory (aorta). The difference between estimated and catheter-obtained net gradients (mean +/- SD) was 0.6 +/- 1.6 mm Hg in the SJM and -0.2 +/- 1.9 mm Hg in the SJM Biocor. When these equations were applied in vivo, we found that PR had an overall value of 57 +/- 7% of the peak Doppler gradient in the SJM and 33 +/- 9% in the SJM Biocor. The in vitro results indicate that it is possible to predict the net pressure gradient by Doppler in bileaflet and stented biologic valves. Our data indicate that important PR is also present in stented biologic valves.


An investigation into teaching games for understanding: effects on skill, knowledge, and game play.
The purpose of this study was to test the validity of the games for understanding model by comparing it to a technique approach to instruction and a control group. The technique method focused primarily on skill instruction where the skill taught initially was incorporated into a game at the end of each lesson. The games for understanding approach emphasized developing tactical awareness and decision making in small game situations. Two physical education specialists taught field hockey using these approaches for 15 lessons (45 min each). The control group did not receive any field hockey instruction. Data were collected from 71 middle school children. Pretests and posttests were administered for hockey knowledge, skill, and game performance. Separate analyses of variance or analyses of covariance were conducted to examine group differences for cognitive and skill outcomes. The games for understanding group scored significantly higher on passing decision making than the technique and control groups during posttest game play and significantly higher than the control group for declarative and procedural knowledge. The games for understanding group scored significantly higher on control and passing execution than the other groups during posttest game play. For hockey skill, there were no significant differences among the treatment groups for accuracy, but the technique group recorded faster times than the control group on the posttest.


Increased blood viscosity and red blood cell aggregation in patients with COVID-19.
The aim of this study was to (1) analyze blood viscosity, red blood cell (RBC) deformability, and aggregation in hospitalized patients with Coronavirus disease 19 (COVID-19); (2) test the associations between impaired blood rheology and blood coagulation; and (3) test the associations between impaired blood rheology and several indicators of clinical severity. A total of 172 patients with COVID-19, hospitalized in COVID-unit of the Internal Medicine Department (Lyon, France) participated in this study between January and May 2021. Clinical parameters were collected for each patient. Routine hematological/biochemical parameters, blood viscosity, RBC deformability and aggregation, and RBC senescence markers were measured on the first day of hospitalization. A control group of 38 healthy individuals was constituted to compare the blood rheological and RBC profile. Rotational thromboelastography was performed in 76 patients to study clot formation dynamics. Our study demonstrated that patients with COVID-19 had increased blood viscosity despite lower hematocrit than healthy individuals, as well as increased RBC aggregation. In-vitro experiments demonstrated a strong contribution of plasma fibrinogen in this RBC hyper-aggregation. RBC aggregation correlated positively with clot firmness, negatively with clot formation time, and positively with the length of hospitalization. Patients with oxygen supplementation had higher RBC aggregation and blood viscosity than those without, and patients with pulmonary lesions had higher RBC aggregation and enhanced coagulation than those without. This study is the first to demonstrate blood hyper-viscosity and RBC hyper-aggregation in a large cohort of patients with COVID-19 and describe associations with enhanced coagulation and clinical outcomes.


Voltages and resistances of the anterior Malpighian tubule of Drosophila melanogaster.
The small size of Malpighian tubules in the fruit fly Drosophila melanogaster has discouraged measurements of the transepithelial electrical resistance. The present study introduces two methods for measuring the transepithelial resistance in isolated D. melanogaster Malpighian tubules using conventional microelectrodes and PClamp hardware and software. The first method uses three microelectrodes to measure the specific transepithelial resistance normalized to tubule length or luminal surface area for comparison with resistances of other epithelia. The second method uses only two microelectrodes to measure the relative resistance for comparing before and after effects in a single Malpighian tubule. Knowledge of the specific transepithelial resistance allows the first electrical model of electrolyte secretion by the main segment of the anterior Malpighian tubule of D. melanogaster The electrical model is remarkably similar to that of the distal Malpighian tubule of Aedes aegypti when tubules of Drosophila and Aedes are studied in vitro under the same experimental conditions. Thus, despite 189 millions of years of evolution separating these two genera, the electrophysiological properties of their Malpighian tubules remains remarkably conserved.


Immunohistochemical expression of kallikrein 7 in oral squamous cell carcinoma.
The kallikrein (KLK) family of genes consists of 15 members, many of which are highly expressed in number of cancers compared to their normal parent tissues. KLK7 was initially characterized as an enzyme implicated in the degradation of intercellular cohesive structures in the stratum corneum of stratified squamous epithelia, preceding desquamation in the skin. It catalyzes the degradation of desmosomes in the outermost layer of skin and permits cell shedding to take place at the skin surface. Overexpression of KLK7 in tumor cells has been reported to significantly enhance the invasive potential in intracranial malignancies and ovarian cancer cells. Thus, KLK7 could contribute to the degradation of extracellular matrices in oral squamous cell carcinoma (OSCC) tissues, promoting invasion of neoplastic cells locally and facilitating metastasis to regional lymph nodes. The objectives of the present study were to compare the expression of KLK 7 in normal subjects and patients with OSCC, to correlate the expression of KLK 7 with respect to the clinical staging of OSCC and to evaluate the expression of KLK 7with respect to different histopathological grades of OSCC. Thirty cases of OSCC were staged clinically and graded histopathologically. The immunohistochemical method was used to detect the expression of KLK 7 in OSCC. The scores obtained were documented and compared statistically. KLK 7 immunoreactivity was noticed in all cases of OSCC. A statistically significant difference was observed in immunoreactivity of KLK 7 between the normal and OSCC (P = 0.0001*) and in different histopathological grades (P = 0.0001*) and in different clinical stages (P = 0.0127*) of OSCC using Kruskal-Wallis analysis of variance test. The KLK 7 immunoexpression histopathologically increased from low grade to high grade and clinically from Stage 1 to Stage 4 in OSCC. Hence, increased expression of KLK 7 may be related to poor prognosis in patients with OSCC.


Modeling of Tool-Tissue Interactions for Computer-Based Surgical Simulation: A Literature Review.
Surgical simulators present a safe and potentially effective method for surgical training, and can also be used in robot-assisted surgery for pre- and intra-operative planning. Accurate modeling of the interaction between surgical instruments and organs has been recognized as a key requirement in the development of high-fidelity surgical simulators. Researchers have attempted to model tool-tissue interactions in a wide variety of ways, which can be broadly classified as (1) linear elasticity-based, (2) nonlinear (hyperelastic) elasticity-based finite element (FE) methods, and (3) other techniques that not based on FE methods or continuum mechanics. Realistic modeling of organ deformation requires populating the model with real tissue data (which are difficult to acquire in vivo) and simulating organ response in real time (which is computationally expensive). Further, it is challenging to account for connective tissue supporting the organ, friction, and topological changes resulting from tool-tissue interactions during invasive surgical procedures. Overcoming such obstacles will not only help us to model tool-tissue interactions in real time, but also enable realistic force feedback to the user during surgical simulation. This review paper classifies the existing research on tool-tissue interactions for surgical simulators specifically based on the modeling techniques employed and the kind of surgical operation being simulated, in order to inform and motivate future research on improved tool-tissue interaction models.


How well are parent held records kept and completed?
During 1986 and 1987 parents in part of the Oxfordshire district health authority were given their child's health and development records while in the other part of the health district the records remained with the clinic. Between August 1988 and February 1989 an audit was made of a sample of parents attending child health clinics in the two areas: the study examined 284 parents who had parent held records and 168 who did not; how many records were available and if not, why not; how well and by whom records were completed and parents' views on who they felt should keep the record. Interviews revealed that parents with a parent held record liked the scheme and were confident about remembering to take the record to the clinic. Those without experience were less confident and more concerned about losing the record. At the time of the audit 7% of parent held records had been lost or forgotten, but 5% of clinic held records were not available for inspection. Overall, parent held records were more likely to have comments contributed by parents and to be more thoroughly completed by professionals. The results suggest that parent held records are not only workable but desirable.


Preoperative Optimism Related to Low Anxiety in Patients 1 Month After Open Heart Surgery.
Anxiety can contribute to poor prognosis in cardiac patients. Few studies have examined the role of optimism in anxiety after open heart surgery (OHS). This study investigated the influence of preoperative optimism on post-OHS anxiety, adjusting cardiac indices used by cardiac surgeons. Data were collected before and 1 month after OHS in 481 patients (58% men; age, 62.4 ± 11.94 years). Optimism was measured using the Life Orientation Test. Anxiety was measured using the Trait Anxiety Inventory. Medical and cardiac indices were retrieved from the Society of Thoracic Surgeon's national database. Multiple regression analyses showed that greater pre-OHS optimism was associated with lower levels of post-OHS anxiety (F[6, N = 306] = 50.18, p < 0.001, R = 0.502). No other factors showed similar protection. Pre-OHS anxiety, younger age, and minority status were associated with anxiety in the critical recovery month. The findings demonstrate the potential benefit of optimism against post-OHS anxiety, which may have clinical implications for improving disease management.


Application Effect of Acupoint Massage on Zusanli on Premature Infants with Feeding Intolerance and Their Clinical Symptoms.
FI is mainly caused by functional disturbance in premature infants, which greatly poses a threat to their growth and development, so a large number of studies on the clinical features of FI should be conducted to provide theoretical support for treatment. The purpose of the study was to investigate the therapeutic effect of acupoint massage on Zusanli on premature infants with feeding intolerance (FI) and their clinical symptoms. A total of 60 premature infants with FI admitted to our hospital over the past two years were selected as the FI group, and another 60 premature infants without FI were selected as the control group. The birthweight and gestational age of the premature infants in the FI group were significantly lower than those in the control group (P < 0.001), whereas there were no significant differences in general information of the premature infants between the two groups (P > 0.05). Vomiting, abdominal distension, and gastric retention are the main clinical symptoms of premature infants with FI, and acupoint massage on Zusanli combined with routine treatment can effectively improve digestive function, relieve clinical symptoms, and shorten treatment time of premature infants with FI, which is worthy of application and promotion in clinical practice.


Construction of a dense SNP map of a highly heterozygous diploid potato population and QTL analysis of tuber shape and eye depth.
Generation of a dense SNP-based linkage map of a diploid potato population and identification of major QTLs for tuber shape and eye depth on chromosomes 2 and 10. This paper reports the construction of a genetic map of a highly heterozygous full-sib diploid potato population (06H1) based on the use of a set of 8,303 single nucleotide polymorphism (SNP) markers. The map contains 1,355 distinct loci and 2,157 SNPs, 802 of which co-segregate with other markers. We find high levels of collinearity between the 12 chromosomal maps with a recently improved version of the potato genome assembly, with the expected genetic clustering in centromeric regions. The linkage maps are used in combination with highly detailed phenotypic assessments conducted over two growing seasons to perform quantitative trait loci analysis of two important potato traits, tuber shape and eye depth. The major loci segregating for tuber shape in 06H1 map to loci on chromosomes 2 and 10, with smaller effects mapping to three other chromosomes. A major locus for tuber eye depth co-locates with the tuber shape locus on chromosome 10. To assess when tuber shape is established in the developing tuber, we have performed staged observations of tuber formation. Our observations suggest that tuber shape is determined very early in tuber development.


[Epidemiologic studies of the occurrence of bovine virus diarrhea/mucosal disease in 2892 cattle in 95 dairy farms].
Blood samples were collected from 2892 cows and heifers of various ages from 95 dairy farms in the Kanton of St. Gallen and were tested for antibodies against bovine virus diarrhea. The percentages of seropositive, seronegative and inconclusive cases were 83.7%, 13.0% and 3.3%, respectively. In all herds, at least one case was seropositive, and in 29% of the herds, all the animals tested were seropositive. On a herd basis, the seroprevalence ranged from 16.2% to 100% with a mean (+/- SD) of 85.8 +/- 17.6%. The seroprevalence in one to two-year-old heifers was not significantly different from that of the entire sample.


When the future becomes the past: Differences in brain activation patterns for episodic memory and episodic future thinking.
Episodic memory and episodic future thinking activate a network of overlapping brain regions, but little is known about the mechanism with which the brain separates the two processes. It was recently suggested that differential activity for memory and future thinking may be linked to differences in the phenomenal properties (e.g., richness of detail). Using functional magnetic resonance imaging in healthy subjects and a novel experimental design, we investigated the networks involved in the imagery of future and the recall of past events for the same target occasion, i.e. the Christmas and New Year's holidays, thereby keeping temporal distance and content similar across conditions. Although ratings of phenomenal characteristics were comparable for future thoughts and memories, differential activation patterns emerged. The right posterior hippocampus exhibited stronger memory-related activity during early event recall, and stronger future thought-related activity during late event imagination. Other regions, e.g., the precuneus and lateral prefrontal cortex, showed the reverse activation pattern with early future-associated and late past-associated activation. Memories compared to future thoughts were further related to stronger activation in several visual processing regions, which accords with a reactivation of the original perceptual experience. In conclusion, the results showed for the first time unique neural signatures for both memory and future thinking even in the absence of differences in phenomenal properties and suggested different time courses of brain activation for episodic memory and future thinking.


Trends in Labor Force Participation: How Much is Due to Changes in Pensions?
In the United States, beginning in the late 1980s there was a substantial increase in the labor force participation of men and women in their 60s. Over the same time period the type of pension plans offered by employers shifted strongly from defined benefit plans to defined contribution plans. Defined benefit plans typically have optimal retirement ages embedded in their structure which induce early retirement, whereas defined contribution plans do not favor any particular retirement age. Based on panel data, this paper quantifies the increase in participation due to the change in pension structure. The main result is that the pension changes account for a considerable part of the increase, but other factors also made a contribution.


Plasma production of nanomaterials for energy storage: continuous gas-phase synthesis of metal oxide CNT materials via a microwave plasma.
In this work we show for the first time that a continuous plasma process can synthesize materials from bulk industrial powders to produce hierarchical structures for energy storage applications. The plasma production process's unique advantages are that it is fast, inexpensive, and scalable due to its high energy density that enables low-cost precursors. The synthesized hierarchical material is comprised of iron oxide and aluminum oxide aggregate particles and carbon nanotubes grown in situ from the iron particles. New aerosol-based methods were used for the first time on a battery material to characterize aggregate and primary particle morphologies, while showing good agreement with observations from TEM measurements. As an anode for lithium ion batteries, a reversible capacity of 870 mA h g-1 based on metal oxide mass was observed and the material showed good recovery from high rate cycling. The high rate of material synthesis (∼10 s residence time) enables this plasma hierarchical material synthesis platform to be optimized as a means for energetic material production for the global energy storage material supply chain.


Right ventricular thrombus: a rare complication of ovarian hyperstimulation syndrome.
A 22 years old lady was admitted because of progressive dyspnea, severe abdominal protrusion and lower extremity edema. She had undergone ovarian hyperstimulation for primary infertility by Clomiphen and Human chorionic gonadotropin for 3 months. Abdominopelvic ultrasonography revealed bilateral enlarged multi cystic ovaries and massive ascites. Transesophageal echocardiography revealed a large thrombus in right ventrice apex. Spiral chest CT scan showed normal pulmonary vasculature with no evidence of pulmonary thromboembolism. Heparin was started and repeat echocardiographic study showed gradual disappearance of right ventricular thrombus. Human chorionic gonadotropin is the most important substance which leads to capillary leakage and fluid accumulation in third space. Fluid shift and hypovolemia may cause hypotension, hemoconcentration and formation of vascular thrombus.


Chitosan-hyaluronic acid/VEGF loaded fibrin nanoparticles composite sponges for enhancing angiogenesis in wounds.
Reduced levels of endogenous growth factors and diminished angiogenesis are contributory factors for impaired wound healing in diabetic patients. Vascular endothelial growth factor (VEGF) is the most potent angiogenic growth factor which stimulates multiple phases of wound healing angiogenesis and thereby accelerates healing. The aim of this work was to develop chitosan-hyaluronic acid composite sponge incorporated with fibrin nanoparticles loaded with VEGF as a wound dressing for diabetic wounds. VEGF loaded fibrin nanoparticles (150-180 nm) were prepared and characterized which were then incorporated to the composite sponge. The prepared sponges were characterized by SEM and FT-IR. Porosity, swelling, biodegradation, mechanical properties and haemostatic potential of the sponges were also studied. Release of VEGF from the composite sponges was evaluated using ELISA kit. More than 60% of the loaded VEGF was released in three days. Cell viability and attachment studies of the composite sponges were evaluated using human dermal fibroblast (HDF) cells and human umbilical vein endothelial cells (HUVECs). HUVECs seeded on VEGF containing sponges showed capillary like tube formation which was absent in control sponges. The results suggest that the prepared chitosan-hyaluronic acid/VEGF loaded nanofibrin composite sponges (CHVFS) have potential to induce angiogenesis in wound healing.


The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus.
Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and BDNF produces antidepressant-like effects in behavioral models of depression. In our previous work, we identified genes induced by BDNF and defined their specific roles in hippocampal neuronal development and plasticity. To identify genes downstream of BDNF that may play roles in psychiatric disorders, we examined a subset of BDNF-induced genes also regulated by 5-HT (serotonin), which includes the neuropeptide VGF (nonacronymic). To explore the function of VGF in depression, we first investigated the expression of the neuropeptide in animal models of depression. VGF was downregulated in the hippocampus after both the learned helplessness and forced swim test (FST) paradigms. Conversely, VGF infusion in the hippocampus of mice subjected to FST reduced the time spent immobile for up to 6 d, thus demonstrating a novel role for VGF as an antidepressant-like agent. Recent evidence indicates that chronic treatment of rodents with antidepressants increases neurogenesis in the adult dentate gyrus and that neurogenesis is required for the behavioral effects of antidepressants. Our studies using [(3)H]thymidine and bromodeoxyuridine as markers of DNA synthesis indicate that chronic VGF treatment enhances proliferation of hippocampal progenitor cells both in vitro and in vivo with survival up to 21 d. By double immunocytochemical analysis of hippocampal neurons, we demonstrate that VGF increases the number of dividing cells that express neuronal markers in vitro. Thus, VGF may act downstream of BDNF and exert its effects as an antidepressant-like agent by enhancing neurogenesis in the hippocampus.


Phylogenetic characterization of H5N1 highly pathogenic avian influenza viruses isolated in Switzerland in 2006.
In the winter 2005/2006 H5N1 highly pathogenic avian influenza virus (HPAIV) reached Western Europe and caused numerous deaths primarily in migratory water birds. Between February and April 2006 34 cases of H5N1 HPAIV-infected dead water fowl were identified in Switzerland, almost exclusively occurring in the Lake Constance area, a large overwintering area for migratory birds in the eastern part of the country. In total, 13 of these virus isolates were genetically characterized in the present study by full-length nucleotide sequence analysis of the hemagglutinin and neuraminidase-coding region. All viruses could be confirmed as HPAIV based on the amino acid sequence of their hemagglutinin cleavage site. Phylogenetic analysis revealed that all the virus isolates were highly similar to each other and to other H5N1 strains found in neighboring countries. All analyzed Swiss virus isolates belonged to the influenza virus subclade 2.2.1.


Radioimmunoassay of serum parathyrin: comparison of five commercial kits.
We compared serum parathyrin radioimmunoassay data obtained with five commercially available kits for normal subjects, patients on dialysis, and patients with hyperparathyroidism. The Cambridge Nuclear kit gave low results, did not distinguish the dialysis-group sera from the normal sera, and had the greatest CV (56%) both inter- and intra-assay. The Immuno Nuclear PTH-II kit gave more satisfactory clinical data than their PTH-C-terminal kit; however, as with most procedures involving a substantial and variable nonspecific binding correction for each serum, parallelism between samples and the standard curve was poor, turnaround time slow, and inter-assay CV high (39%). Unlike the other kits, the Nichols and the Iso-Tex products depend on a direct methodology; they displayed good parallelism and distinguished among our three populations. A Scatchard plot of results with the Nichols kit was closest to the ideal linear model; the Iso-Tex kit had the shortest turnaround time.


Balancing the risks and benefits of parenteral nutrition for preterm infants: can we define the optimal composition?
Nutrient intakes in preterm infants are frequently inadequate and are associated with worse neuro-developmental outcome. Preterm infants take time to establish enteral intakes, and parenteral nutrition (PN) is now an integral component of care. Despite this, the evidence base for PN intakes is extremely limited. There remains uncertainty over safe initial and maximum amounts of macronutrients, and the optimal amino acid and lipid composition. Studies have tended to focus on short-term growth measures and there are few studies with long-term follow-up. There may be a tradeoff between improving cognitive outcomes while minimising metabolic harm that means determining the optimal regimen will require long-term follow-up. Given the importance of appropriate nutrition for long-term metabolic and cognitive health, and the associated healthcare costs, optimising the composition of PN deserves to be seen as a research priority in neonatal medicine.


Site-specific quantitation of protein nitration using liquid chromatography/tandem mass spectrometry.
The native reference peptide (NRP) method has been adapted to the measure of the degree of protein nitration at a specific tyrosine residue. In these experiments, human serum albumin was modified in a myeloperoxidase-mediated reaction in the presence of nitrite, with nitration detected predominantly at one site, Y162. The time-dependent increase in nitration at this site was measured based on the increasing abundance of the peptide 162YnLYEIAR168 and the corresponding decrease in the 162YLYEIAR168 peptide in in-gel trypsin digests. The peptide 66LVNEVTEFAK75, also formed in the tryptic digest, was used as the native reference peptide. Quantitation was achieved by determining the chromatographic peak area of the two analyte peptides relative to the native reference peptide by LC/tandem mass spectrometric analyses with selected reaction monitoring. The NRP results were validated by correlation to the time-dependent increase in total protein-nitrotyrosine content determined by Western blot analysis. The precision and limit of detection of the assay were also evaluated and were found to be approximately 10% (relative standard deviation) and 5 fmol on-column, respectively. These results demonstrate the utility of the NRP method for quantitative analyses of posttranslation modifications, in terms of broad applicability, ease of experimental design, sensitivity, and precision.


NOTCH4 is a potential therapeutic target for triple-negative breast cancer.
The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC. In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples. NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells. NOTCH4 is a new potential therapeutic target for triple-negative breast cancer.


New species of Aberrapex Jensen, 2001 (Cestoda: Lecanicephalidea) from eagle rays of the genus Myliobatis Cuvier (Myliobatiformes: Myliobatidae) from off Argentina.
Three new species of Aberrapex Jensen, 2001 (Cestoda: Lecanicephalidea) have been collected from species of Myliobatis Cuvier along the coast of Argentina. Aberrapex ludmilae sp. n. parasitises M. goodei Garman in the San Matías Gulf. This species is unique in a combination of features including the shape and extent of the uterus, scolex size, testis distribution, and by lacking an external seminal vesicle and postovarian vitelline follicles. Aberrapex sanmartini sp. n. from M. goodei in San Blas Bay and A. vitalemuttiorum sp. n. from M. ridens Ruocco, Lucifora, Díaz de Astarloa, Mabragaña et Delpiani in coastal waters off Buenos Aires Province, are distinguished from all other congeners by the microthrix pattern on the scolex surface, uterus shape and extension, position of the connection of the uterine duct to the uterus, presence and extension of an external seminal vesicle, and its overall size and number of proglottids. The specimens of M. goodei and M. ridens show locally distinct cestode faunas, which are correlated with well-defined biogeographic regions. Some of these areas correspond with mating and nursery zones for species of Myliobatis.


In vitro studies of lactoferrin and murine granulopoiesis.
Human lactoferrin (LF) has been reported to inhibit in vitro granulopoiesis by means of decreasing colony-stimulating activity production by monocytes. We performed a series of experiments to determine if the reported experimental results could be replicated using highly purified murine LF and murine target cells. Three different types of experiments were performed. (1) Medium was conditioned by lung, femoral shaft, and adherent peritoneal cells in the presence and absence of LF, and the granulopoietic stimulating activity in the conditioned media was assayed by means of a 7-day agar colony assay and a 3-day liquid slide chamber assay, which quantitates 3H-TdR incorporation into DNA. (2) In cultures stimulated by an underlayer of adherent peritoneal cells, marrow cell colony formation in agar was determined after 7 days of culture in the presence or absence of LF. (3) LF was added to 3-day liquid marrow cell cultures that had been stimulated by lung or femoral shaft conditioned media. In all experimental situations, highly purified, iron-saturated LF in concentrations up to 10(-7) M had no effect on in vitro granulopoiesis. These results do not support LF's reputed regulatory role in granulopoiesis.


Taxonomy of the order Mononegavirales: update 2017.
In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).


Human papillomavirus (HPV) genotypes and HPV16 variants in human immunodeficiency virus-positive Italian women.
Human immunodeficiency virus (HIV)-positive women have high rates of cervical squamous intraepithelial lesions (SIL) and concurrent human papillomavirus (HPV) infections with a variety of genotypes whose oncogenic risk is poorly documented. The prevalence and persistence of HPV genotypes and HPV16 variants were analysed in 112 HIV-positive and 115 HIV-negative Italian women. HIV-positive women were more likely than HIV-negative women to be infected by HPV at the initial examination (39.3 vs 13.9 %, P<0.001) and to have a higher period prevalence of HPV infection over a 3-year follow-up (43.8 % vs 17.4 %, P<0.001), regardless of CD4+ cell counts and anti-retroviral therapy. 'High-risk' and 'probable high-risk' HPVs (types 16, 18, 31, 33, 35, 45, 52, 58 and 66), among the 20 different viral genotypes identified, were predominant in HIV-positive (33.9 %) compared with HIV-negative (13.9 %) women. Among HIV-infected women, with normal cytology as well as with SIL of any grade, the most common genotypes were HPV16 followed by HPV81, -58, -72, -33 and -62. HPV16 isolates from 18 HIV-positive and eight HIV-negative women were classified into variant lineages based on sequencing analysis of E6 and E7 genes and the long control region. Whilst the HPV16 G350 European variant was prevalent in both HIV-positive (10.7 %) and -negative women (3.5 %), HPV16 African 2 variant was only detected in HIV-positive women (3.6 %), suggesting different sexual mixing behaviours. The increased prevalence of uncommon viral genotypes and HPV16 variants in HIV-positive Italian women underscores the need to target a wide range of HPV types in cervical screening of high-risk women.


Assistive devices: usage in patients with rheumatoid arthritis.
We describe the usage of various assistive devices and identify factors associated with usage in patients with rheumatoid arthritis (RA). A cross-sectional, multicentre study was performed in three outpatient rheumatology clinics in the Netherlands. Two hundred forty patients with RA participated in the study. The main measures were questionnaires and a semi-structured interview regarding the possession and usage of 21 common assistive devices in the ISO9999 categories orthopaedic footwear, personal care, mobility, household and adaptations for housing. Potential factors associated with usage included sociodemographic variables, health status, quality of life, coping strategies, self-efficacy, outcome expectations and satisfaction. Out of 240 patients, 213 (89%) had one or more assistive devices in possession (median number of devices 3.0, interquartile range 3.0). The proportions of patients never using a device in possession varied between 8% for orthopaedic insoles and 23% for grab bars. The main factors related to usage varied among categories, but common determinants were a specific impairment or disability, satisfaction with the device or related services, self-efficacy and the number of devices in possession. In conclusion, in patients with RA, possession rates are high, with 23% or less of the devices in possession being abandoned. Overall, satisfaction rates were high. Factors associated with usage varied among categories and comprised, apart from the number of devices in possession and variables related to health status, also aspects of satisfaction with the device or related services or self-efficacy. The latter findings underline the need for a systematic evaluation of the outcomes of assistive devices by prescribing health professionals or suppliers in every individual case.


Clinical and histologic comparison of two different composite grafts for sinus augmentation: a pilot clinical trial.
Sinus augmentation is a procedure used for augmenting insufficient bone height that is often observed in the maxillary posterior areas. Many different techniques as well as bone graft regimens have been suggested for performing this procedure. It was the goal of this study to compare, clinically and histologically, two different composite grafting regimens used for sinus augmentation. Five patients, needing a bilateral sinus augmentation to allow implant placement, were recruited for this study. Right sinuses were grafted with cortical bone (collected from overlying the sinus membrane) and bovine hydroxyapatite (HA), while the left side sinuses were grafted with overlying autologous bone plus a bioglass (BG) material. Bone core biopsies were taken at 6 months after sinus graft or at the time of implant insertion. A waiting period of 6 additional months was granted to allow healing, before prosthetic restoration and functional loading. The level of peri-implant bone was evaluated 12 months after loading. A comparative histomorphometric analysis was conducted and a statistical analysis was performed. All implants in both groups were functional after a 12-month loading period. No bone loss was observed radiographically or clinically in both groups. Histologic analysis revealed that both composite grafts had a high biocompatibility. In the bovine HA-containing group, minimal xenogenic graft absorption was noted. In contrast, BG group samples presented a high absorption rate with some remaining particles imbedded in new normal bone. Sinus augmentation using a combination of autogenous bone plus either bovine HA or BG is a predictable technique.


Carotenoid composition of hydroponic leafy vegetables.
Because hydroponic production of vegetables is becoming more common, the carotenoid composition of hydroponic leafy vegetables commercialized in Campinas, Brazil, was determined. All samples were collected and analyzed in winter. Lactucaxanthin was quantified for the first time and was found to have concentrations similar to that of neoxanthin in the four types of lettuce analyzed. Lutein predominated in cress, chicory, and roquette (75.4 +/- 10.2, 57.0 +/- 10.3, and 52.2 +/- 12.6 microg/g, respectively). In the lactucaxanthin-containing lettuces, beta-carotene and lutein were the principal carotenoids (ranging from 9.9 +/- 1.5 to 24.6 +/- 3.1 microg/g and from 10.2 +/- 1.0 to 22.9 +/- 2.6 microg/g, respectively). Comparison of hydroponic and field-produced curly lettuce, taken from neighboring farms, showed that the hydroponic lettuce had significantly lower lutein, beta-carotene, violaxanthin, and neoxanthin contents than the conventionally produced lettuce. Because the hydroponic farm had a polyethylene covering, less exposure to sunlight and lower temperatures may have decreased carotenogenesis.


TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death.
Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling. Exposure of mice deficient in IRAK-M (IRAK-M(-/-)) to 95% oxygen resulted in reduced mortality compared with wild-type mice and occurred in association with decreased alveolar permeability and cell death. Using a bone marrow chimera model, we determined that IRAK-M's effects were mediated by structural cells rather than bone marrow-derived cells. We confirmed the expression of IRAK-M in alveolar epithelial cells (AECs) and showed that hyperoxia can induce the expression of this protein. In addition, IRAK-M(-/-) AECs exposed to hyperoxia experienced a decrease in cell death. IRAK-M may potentiate hyperoxic injury by suppression of key antioxidant pathways, because lungs and AECs isolated from IRAK-M(-/-) mice have increased expression/activity of heme oxygenase-1, a phase II antioxidant, and NF (erythroid-derived)-related factor-2, a transcription factor that initiates antioxidant generation. Treatment of IRAK-M(-/-) mice in vivo and IRAK-M(-/-) AECs in vitro with the heme oxygenase-1 inhibitor, tin protoporphyrin, substantially decreased survival and significantly reduced the number of live cells after hyperoxia exposure. Collectively, our data suggest that IRAK-M inhibits the induction of antioxidants essential for protecting the lungs against cell death, resulting in enhanced susceptibility to hyperoxic lung injury.


Feeding the low-birth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism.
Taurine and cholesterol are constituents of human milk that are present in smaller amounts in infant formulas. Infants fed such formulas have lower plasma and urine concentrations of taurine and of serum total cholesterol. In the present investigation, in infants of 31 to 36 weeks gestational age, the effects of supplementing a 1.5 g/100 mL whey-predominant formula with taurine alone or with taurine plus cholesterol were examined. Infants fed the supplemented formula were compared with infants fed the unsupplemented formula and with infants fed pooled, expressed human milk (185 mL/kg/d). Approximately 45% of the human milk provided to each infant was that of the infant's mother (35% pasteurized and 10% fresh). From the time of reaching a weight of 2,400 g to 4 months of age the last group of infants was fed ad libitum. No consistent statistically significant differences in growth, as measured by rate of gain in crown-rump length, crown-heel length, or head circumference, were observed. There was a tendency, however, for the formula-fed infants to gain weight more slowly before reaching 2,400 g and to gain weight more quickly after a weight of 2,400 g was attained to 4 months of age. No differences in concentrations of BUN, total serum proteins, or acid-base status were observed among the formula-fed groups. The concentration of BUN increased in the formula-fed groups compared with the group fed human milk during the last half of the study. The formula-fed infants tended to have higher total serum proteins and to be slightly more acidotic than the infants fed human milk prior to discharge at a weight of 2,400 g but not thereafter. Thus, infants fed 185 mL/kg/d gained weight at rates comparable to those for fetuses of the same gestational age. Supplementation of formulas with taurine or taurine plus cholesterol did not produce changes in growth or general metabolism discernible under the present experimental conditions.


Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma.
Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2-M arrest in vitroIn vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide (P = 0.005), 11 days placebo (P < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide (P = 0.93), 14 days with placebo, P < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp-/- versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, P < 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. Mol Cancer Ther; 16(12); 2735-46. ©2017 AACR.


Ototoxicity after use of neomycin eardrops is unrelated to A1555G point mutation in mitochondrial DNA.
Ear drops containing neomycin only rarely cause ototoxicity. The authors report on three patients with a tympanic membrane perforation who developed severe ototoxicity after use of eardrops containing 0.35 per cent neomycin. Mitochondrial DNA analysis revealed that there was no A1555G point mutation in these patients. This finding indicates that application of low concentration neomycin to the middle ear can cause severe inner ear damage even in humans who are not hyper-susceptible to aminoglycosides.


Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts.
Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.


Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily affecting motor neurons. Mutations in optineurin cause a small proportion of familial ALS cases, and wild-type (WT) optineurin is misfolded and forms inclusions in sporadic ALS patient motor neurons. However, it is unknown how optineurin mutation or misfolding leads to ALS. Optineurin acts an adaptor protein connecting the molecular motor myosin VI to secretory vesicles and autophagosomes. Here, we demonstrate that ALS-linked mutations p.Q398X and p.E478G disrupt the association of optineurin with myosin VI, leading to an abnormal diffuse cytoplasmic distribution, inhibition of secretory protein trafficking, endoplasmic reticulum (ER) stress and Golgi fragmentation in motor neuron-like NSC-34 cells. We also provide further insight into the role of optineurin as an autophagy receptor. WT optineurin associated with lysosomes and promoted autophagosome fusion to lysosomes in neuronal cells, implying that it mediates trafficking of lysosomes during autophagy in association with myosin VI. However, either expression of ALS mutant optineurin or small interfering RNA-mediated knockdown of endogenous optineurin blocked lysosome fusion to autophagosomes, resulting in autophagosome accumulation. Together these results indicate that ALS-linked mutations in optineurin disrupt myosin VI-mediated intracellular trafficking processes. In addition, in control human patient tissues, optineurin displayed its normal vesicular localization, but in sporadic ALS patient tissues, vesicles were present in a significantly decreased proportion of motor neurons. Optineurin binding to myosin VI was also decreased in tissue lysates from sporadic ALS spinal cords. This study therefore links several previously described pathological mechanisms in ALS, including defects in autophagy, fragmentation of the Golgi and induction of ER stress, to disruption of optineurin function. These findings also indicate that optineurin-myosin VI dysfunction is a common feature of both sporadic and familial ALS.


Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice.
The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of "cooperation response genes" to modulate the function of cancer "driver" genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell-targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis. IMPLICATIONS: Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.


Bordetella pertussis entry into respiratory epithelial cells and intracellular survival.
Bordetella pertussis is the causative agent of pertussis, aka whooping cough. Although generally considered an extracellular pathogen, this bacterium has been found inside respiratory epithelial cells, which might represent a survival strategy inside the host. Relatively little is known, however, about the mechanism of internalization and the fate of B. pertussis inside the epithelia. We show here that B. pertussis is able to enter those cells by a mechanism dependent on microtubule assembly, lipid raft integrity, and the activation of a tyrosine-kinase-mediated signaling. Once inside the cell, a significant proportion of the intracellular bacteria evade phagolysosomal fusion and remain viable in nonacidic lysosome-associated membrane-protein-1-negative compartments. In addition, intracellular B. pertussis was found able to repopulate the extracellular environment after complete elimination of the extracellular bacteria with polymyxin B. Taken together, these data suggest that B. pertussis is able to survive within respiratory epithelial cells and by this means potentially contribute to host immune system evasion.


The decoding of electrosensory systems.
Progress in the study of electrosensory systems has been facilitated by the systematic use of behavior as a tool to probe the nervous system. Indeed, a specific behavior that is found in a subset of weakly electric fishes, the jamming avoidance response, was used to identify and characterize an entire suite of brain circuits, from sensory receptors to motor units, that are involved in control of this behavior. Recent progress has focused on a re-analysis of this circuit in relation to newly described electrosensory behaviors, including prey capture, social signaling and the tracking of electrosensory objects. This re-analysis has led to a re-evaluation of the broader functional relevance of specific neural solutions to computational problems that are related to the control of the jamming avoidance response. Some of the recent insights that have emerged from this work include descriptions of mechanisms underlying dynamic receptive field properties, descriptions of the neural activity related to simultaneously occurring sensory stimuli, and a greater understanding of the role of short-term synaptic plasticity in temporal processing.


Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor.
Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-alpha) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-alpha and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.


Early diagnosis of scrub typhus with a rapid flow assay using recombinant major outer membrane protein antigen (r56) of Orientia tsutsugamushi.
The variable 56-kDa major outer membrane protein of Orientia tsutsugamushi is the immunodominant antigen in human scrub typhus infections. We developed a rapid immunochromatographic flow assay (RFA) for the detection of immunoglobulin M (IgM) and IgG antibodies to O. tsutsugamushi. The RFA employs a truncated recombinant 56-kDa protein from the Karp strain as the antigen. The performance of the RFA was evaluated with a panel of 321 sera (serial bleedings of 85 individuals suspected of scrub typhus) which were collected in the Pescadore Islands, Taiwan, from 1976 to 1977. Among these 85 individuals, IgM tests were negative for 7 cases by both RFA and indirect fluorescence assay (IFA) using Karp whole-cell antigen. In 29 cases specific responses were detected by the RFA earlier than by IFA, 44 cases had the same detection time, and 5 cases were detected earlier by IFA than by RFA. For IgG responses, 4 individuals were negative with both methods, 37 cases exhibited earlier detection by RFA than IFA, 42 cases were detected at the same time, and 2 cases were detected earlier by IFA than by RFA. The sensitivities of RFA detection of antibody in sera from confirmed cases were 74 and 86% for IgM and IgG, respectively. When IgM and IgG results were combined, the sensitivity was 89%. A panel of 78 individual sera collected from patients with no evidence of scrub typhus was used to evaluate the specificity of the RFA. The specificities of the RFA were 99% for IgM and 97% for IgG. The sensitivities of IFA were 53 and 73% for IgM and IgG, respectively, and were 78% when the results of IgM and IgG were combined. The RFA test was significantly better than the IFA test for the early detection of antibody to scrub typhus in primary infections, while both tests were equally sensitive with reinfected individuals.


Effects of open water on the performance of a constructed wetland for nonpoint source pollution control.
The seasonal performance of four differently configured constructed wetland systems was compared for the treatment efficiency of nonpoint source pollution. Dead plants in the constructed wetlands increased the nitrogen removal rate during winter by providing organic carbon, which is essential for the denitrification process. However, when the wetlands released phosphorus from the dead plants, the removal rate of phosphorus decreased. After seven growing seasons, plant coverage was nearly 100%, and the dissolved oxygen (DO) concentration was lowered to 1.3-5.4 mg/L. Open-water sections were then constructed inside the wetlands, which resulted in enhanced DO concentrations as well as improved treatment efficiency of nutrients and biochemical oxygen demand (BOD). Overall, performance of the constructed wetland was improved BOD, total nitrogen, and total phosphorus with the establishment of open water sections in the constructed wetland system.


Chemical imaging of drug delivery systems with structured surfaces-a combined analytical approach of confocal raman microscopy and optical profilometry.
Confocal Raman microscopy is an analytical technique with a steadily increasing impact in the field of pharmaceutics as the instrumental setup allows for nondestructive visualization of component distribution within drug delivery systems. Here, the attention is mainly focused on classic solid carrier systems like tablets, pellets, or extrudates. Due to the opacity of these systems, Raman analysis is restricted either to exterior surfaces or cross sections. As Raman spectra are only recorded from one focal plane at a time, the sample is usually altered to create a smooth and even surface. However, this manipulation can lead to misinterpretation of the analytical results. Here, we present a trendsetting approach to overcome these analytical pitfalls with a combination of confocal Raman microscopy and optical profilometry. By acquiring a topography profile of the sample area of interest prior to Raman spectroscopy, the profile height information allowed to level the focal plane to the sample surface for each spectrum acquisition. We first demonstrated the basic principle of this complementary approach in a case study using a tilted silica wafer. In a second step, we successfully adapted the two techniques to investigate an extrudate and a lyophilisate as two exemplary solid drug carrier systems. Component distribution analysis with the novel analytical approach was neither hampered by the curvature of the cylindrical extrudate nor the highly structured surface of the lyophilisate. Therefore, the combined analytical approach bears a great potential to be implemented in diversified fields of pharmaceutical sciences.


Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability.
Recombinant antibody fragments, most notably Fab and scFv, have become important tools in research, diagnostics and therapy. Since different recombinant antibody formats exist, it is crucial to understand the difference in their respective biophysical properties. We assessed the potential stability benefits of changing the scFv into the Fab format, the influence of the variable domains on the stability of the Fab fragment, and the influence of the interchain disulfide bond in the Fab fragment. To analyze domain interactions, the Fab fragment was broken down into its individual domains, several two-domain assemblies and one three-domain assembly. The equilibrium denaturation properties of these constructs were then compared to those of the Fab fragment. It was found that mutual stabilization occurred across the VH/VL and the CH1/CL interface, whereas the direct interaction between the V) and the CL domain had no influence on the stability of either domain. This observation can be explained by the different interfaces used for interaction. In contrast, the whole CH1CL and VHVL unit showed significant mutual stabilization, indicating a high degree of cooperation between the VH/VL and CH1/CL interface. The interchain disulfide bond in the Fab fragment plays an essential role in this stabilization. In addition to the effects of domain association on the thermodynamic (equilibrium) stability, Fab fragments differ from scFv fragments of similar equilibrium stability by having a very slow unfolding rate. This kinetic stabilization may increase significantly the resistance of Fab fragments against short time exposure to adverse conditions.


Supplement to the 2004 update of the AAPM Task Group No. 43 Report.
Since publication of the 2004 update to the American Association of Physicists in Medicine (AAPM) Task Group No. 43 Report (TG-43U1), several new low-energy photon-emitting brachytherapy sources have become available. Many of these sources have satisfied the AAPM prerequisites for routine clinical use as of January 10, 2005, and are posted on the Joint AAPM/RPC Brachytherapy Seed Registry. Consequently, the AAPM has prepared this supplement to the 2004 AAPM TG-43 update. This paper presents the AAPM-approved consensus datasets for these sources, and includes the following 125I sources: Amersham model 6733, Draximage model LS-1, Implant Sciences model 3500, IBt model 1251L, IsoAid model IAI-125A, Mentor model SL-125/ SH-125, and SourceTech Medical model STM1251. The Best Medical model 2335 103Pd source is also included. While the methodology used to determine these data sets is identical to that published in the AAPM TG-43U1 report, additional information and discussion are presented here on some questions that arose since the publication of the TG-43U1 report. Specifically, details of interpolation and extrapolation methods are described further, new methodologies are recommended, and example calculations are provided. Despite these changes, additions, and clarifications, the overall methodology, the procedures for developing consensus data sets, and the dose calculation formalism largely remain the same as in the TG-43U1 report. Thus, the AAPM recommends that the consensus data sets and resultant source-specific dose-rate distributions included in this supplement be adopted by all end users for clinical treatment planning of low-energy photon-emitting brachytherapy sources. Adoption of these recommendations may result in changes to patient dose calculations, and these changes should be carefully evaluated and reviewed with the radiation oncologist prior to implementation of the current protocol.


Correction for resolution nonuniformities caused by anode angulation in computed tomography.
Most X-ray tubes comprise a rotating anode that is bombarded with electrons to produce X-rays. A substantial amount of heat is generated, and to increase the area of the anode exposed to the electrons, without increasing the apparent size of the focal spot, the focal track of the anode is generally beveled with a very shallow angle (typically 5 degrees-7 degrees in a computed tomography (CT) tube). Due to the line focus principle, this allows a fairly large area of the focal track to be exposed to electrons while retaining a fairly small effective projected focal spot. One side effect of anode angulation is that the focal spot appears different from different positions in the detector array; the effective focal spot size at a constant distance from the tube will be larger for a peripheral detector channel than for a central one. These differences in the effective size of the focal spot across the field-of-view lead to worse resolution in the periphery than in the center of reconstructed images. In this work we describe a method for achieving more uniform resolution in fanbeam CT images by correcting for these focal spot angulation effects. We do so by modeling the effects as a series of local blurrings in the space of transmitted CT intensities and determining the effective coefficients of the corresponding discrete convolutions. The effect of these blurrings can then be compensated for in the sinogram domain through the use of a penalized-likelihood sinogram restoration model we have recently developed.


How the coronavirus disease 2019 pandemic changed medical education and deans' perspectives in Korean medical schools.
This study explored how the Korean Medical Colleges responded to the coronavirus disease 2019 (COVID-19) pandemic and the medical deans' perspectives on what and how these adaptions influence the present and the future of medical education. An email survey combining short and open-ended questions was distributed to all 40 Korean school deans in May 2020. Thirty-seven deans out of 40 medical schools in Korea (92.5%) participated. Most lectures moved online but students' assessments were delayed and later held onsite. Clinical rotations continued except for an average of 3-week suspension during the first COVID-19 wave. The deans' remarks on the positive influences far outweighed the negative impact of COVID-19 on medical education. Although technological adaptations caused initial hardship, the experience gained through the use of various online learning systems led to attitudinal changes on the importance of adopting new technology and a tailored and student centric curriculum in medical education. The deans' perspective changes has shown the possibility of the deans' generation aligning more closely with the current Generation Z medical students. They projected further innovations in teaching and learning methods, especially applying flipped learning and highlighted the need to invest in faculty development so medical educators can be equipped and competent in diverse ICT (information and communications technology) learning platforms. Also, the need for advance preparations in medical education for future similar public health crises were stressed. Unprecedented changes brought by COVID-19 positively impacted Korean medical education in parts and the Korean deans envisioned further innovations using the experiences gained during this crisis.


Iatrogenic secondary post-partum haemorrhage: apropos of two uncommon cases.
In this article we would like to highlight uterine pseudoaneurysm as a cause of secondary post-partum haemorrhage following Caesarean section. We would like to stress Doppler ultrasound scan as the initial screening modality for this condition. We also describe angioembolization as the prudent treatment option for this condition rather than resorting to surgery.


Evolution and modulation of Ag filament dynamics within memristive devices based on necklace-like Ag@TiO2nanowire networks.
Random nanowire networks (NWNs) are regarded as promising memristive materials for applications in information storage, selectors, and neuromorphic computing. The further insight to understand their resistive switching properties and conduction mechanisms is crucial to realize the full potential of random NWNs. Here, a novel planar memristive device based on necklace-like structure Ag@TiO2NWN is reported, in which a strategy only using water to tailor the TiO2shell on Ag core for necklace-like core-shell structure is developed to achieve uniform topology connectivity. With analyzing the influence of compliance current on resistive switching characteristics and further tracing evolution trends of resistance state during the repetitive switching cycles, two distinctive evolution trends of low resistance state failure and high resistance state failure are revealed, which bear resemblance to memory loss and consolidation in biological systems. The underlying conduction mechanisms are related to the modulation of the Ag accumulation dynamics inside the filaments at cross-point junctions within conductive paths of NWNs. An optimizing principle is then proposed to design reproducible and reliable threshold switching devices by tuning the NWN density and electrical stimulation. The optimized threshold switching devices have a high ON/OFF ratio of ∼107with threshold voltage as low as 0.35 V. This work will provide insights into engineering random NWNs for diverse functions by modulating external excitation and optimizing NWN parameters to satisfy specific applications, transforming from neuromorphic systems to threshold switching devices as selectors.


Determinants of effective vaccine coverage in low and middle-income countries: a systematic review and interpretive synthesis.
Many children in low and middle-income countries remain unvaccinated, and vaccines do not always produce immunity. Extensive research has sought to understand why, but most studies have been limited in breadth and depth. This study documents existing evidence on determinants of vaccination and immunization and presents a conceptual framework of determinants. We used systematic review, content analysis, thematic analysis and interpretive synthesis to document and analyze the existing evidence on determinants of childhood vaccination and immunization. We documented 1609 articles, including content analysis of 78 articles. Three major thematic models were described in the context of one another. Interpretive synthesis identified similarities and differences between studies, resulting in a conceptual framework with three principal vaccine utilization determinants: 1) Intent to Vaccinate, 2) Community Access and 3) Health Facility Readiness. This study presents the most comprehensive systematic review of vaccine determinants to date. The conceptual framework represents a synthesis of multiple existing frameworks, is applicable in low and middle-income countries, and is quantitatively testable. Future researchers can use these results to develop competing conceptual frameworks, or to analyze data in a theoretically-grounded way. This review enables better research in the future, further understanding of immunization determinants, and greater progress against vaccine preventable diseases around the world.


Remotely sensed reflectance and its dependence on vertical structure: a theoretical derivation.
An exact expression for the remotely sensed reflectance (RSR, upwelling radiance divided by downwelling scalar irradiance) just beneath the surface of the ocean is derived from the equation of radiative transfer. It is shown that the RSR at a given depth in the ocean depends only on the inherent optical properties, the attenuation coefficient for upwelling radiance, and two shape factors that depend on the radiance distribution and volume scattering function. The shape factors are shown to be close to unity. An exact expression for the RSR just beneath the surface as a function of the vertical structure of inherent and apparent optical properties is derived. This expression is solved for an N-layered system, which presents the possibility of inverting remotely sensed reflectance data to obtain the vertical structure of chlorophyll in the ocean.


Evidence for phosphorylation and ubiquitinylation of the turnip yellow mosaic virus RNA-dependent RNA polymerase domain expressed in a baculovirus-insect cell system.
All RNA viruses known to date encode an RNA-dependent RNA polymerase (RdRp) that is required for replication of the viral genome. We have expressed and purified the turnip yellow mosaic virus (TYMV) RdRp in insect cells using a recombinant baculovirus, either in its native form, or fused to an hexa-histidine tag. Phosphorylation of the protein was demonstrated by labelling experiments in vivo, as well as phosphatase treatment of the purified protein in vitro. Phospho amino acid analysis and immunoblotting experiments identified serine and threonine residues as being the subject of phosphorylation. Peptide mass mapping using MS analysis of a protein digest revealed that phosphorylation sites are localized within a putative PEST sequence [a sequence rich in proline (P), glutamic acid (E), serine (S) and threonine (T) residues] in the N-terminal region of the protein. Using monoclonal antibodies specific for ubiquitin conjugates, we were able to demonstrate that the TYMV RdRp is conjugated to ubiquitin molecules when expressed in insect cells. These observations suggest that the TYMV RdRp may be processed selectively by the ubiquitin/proteasome degradation system upon phosphorylation of the PEST sequence.


Campanula macrostachya: biological activity and identification of phenolics using a liquid chromatography electrospray ionization tandem mass spectrometry system.
It is known that some Campanula species are traditionally used because of their anti-allergic, spasmolytic, antiphlogistic, antioxidant, and antiviral properties. This study was designed to evaluate the phytochemical composition, antioxidant, α-amylase, and tyrosinase inhibitory activity of ethyl acetate, methanol, and water extracts of Campanula macrostachya Waldst. & Kit. ex Willd. Chemical compositions were analyzed by spectrophotometric and chromatographic methods. Antioxidant activities of the samples were tested by using five different test systems. Enzyme inhibitory activities of the extracts were also studied. As a result of the LC-ESI-MS/MS analyses, chlorogenic acid, hesperidin, and hyperoside were found to be the major compounds of the extracts, especially the MeOH extract (6559.59, 2499.22, and 2047.66 μg/g extract, respectively). Antioxidant activity tests have proven that MeOH extract showed higher activity than others (DPPH: 4.15 mg/mL, ABTS: 2.05 mg/mL, CUPRAC: 1.80 mg/mL, FRAP: 0.83 mg/mL, phosphomolybdenum: 1.69 mg/mL). Ferrous ion chelating activity of the water extract was 1.03 mg/mL. In α-amylase and tyrosinase inhibitory assays, EtOAc (IC50: 2.54 mg/mL) and MeOH (IC50: 1.51 mg/mL) extracts showed higher activity than the others did. In phosphomolybdenum, CUPRAC, FRAP, and tyrosinase inhibitory assays, the activity was strongly correlated with flavonoids, chlorogenic acid, hesperidin, and hyperoside. On the other hand, phenolic compounds have been found to contribute more to radical scavenging activity. Pearson correlation analysis showed that phenolics and flavonoids were not responsible for the α-amylase inhibitory activity of EtOAc extract.


Outcomes of transition from premixed and intensive insulin therapies to insulin aspart/degludec co-formulation in type 2 diabetes mellitus: a real-world experience.
To evaluate the efficacy and safety of transition from premixed and intensive insulin to twice-daily insulin degludec/aspart (IDegAsp) co-formulation in patients with type 2 diabetes mellitus. In this 12-week study, patients receiving twice-daily premixed insulin therapy in group 1 (n = 55) were switched to twice-daily IDegAsp. In group 2 (n = 60), patients on intensive insulin therapy were switched to IDegAsp injected twice a day. Inter- and intragroup comparisons were made. A total of 115 patients were included in the study. There was a significant improvement in glycaemic control, median daily total insulin dose, body mass, body mass index, and hypoglycaemic events in group 1 and group 2 with the switch to IDegAsp (p < 0.05). The decrease in median daily total insulin dose requirement in group 2 was higher than that of group 1 (p = 0.001). There was no difference between groups in terms of other parameters (p > 0.05). The current analysis indicates that IDegAsp treatment improves outcomes, with the most notable differences observed in daily total insulin requirement, body mass, and hypoglycaemia.


Somatic cell mutations in atomic bomb survivors.
Mutant frequencies in peripheral blood lymphocytes and erythrocytes have been measured for atomic bomb survivors having various DS86 doses. Among the four assay systems utilized so far, erythrocyte glycophorin A assay revealed a dose related increase of mutant frequency, similar to the results obtained with in vitro mutagenesis studies at HPRT locus using human diploid cells. Mutant T-lymphocyte frequency of the HPRT locus detected as resistant to 6-thioguanine significantly increased with DS86 dose however the slope was very shallow compared with that of in vitro study. Mutation at T-cell receptor genes and the HLA-A gene did not show a significant increase in frequency with dose in cells of survivors studied.