The Origins of Diverse Domains of Mathematics: Generalist Genes but Specialist Environments.
The authors assessed 2,502 ten-year-old children, members of 1,251 pairs of twins, on a Web-based battery of problems from 5 diverse aspects of mathematics assessed as part of the U.K. national curriculum. This 1st genetic study into the etiology of variation in different domains of mathematics showed that the heritability estimates were moderate and highly similar across domains and that these genetic influences were mostly general. Environmental factors unique to each twin in a family (rather than shared by the 2 twins) explained most of the remaining variance, and these factors were mostly specific to each domain.


Occupational Therapy Interventions Supporting Social Participation and Leisure Engagement for Community-Dwelling Older Adults: A Systematic Review.
This systematic review examines the evidence for the effectiveness of interventions within the scope of occupational therapy that address leisure engagement and social participation among community-dwelling older adults. Eleven Level I, 1 Level II, 1 Level III, and 1 Level IV studies met inclusion criteria. Included articles addressed two themes: interventions supporting social participation and interventions supporting leisure engagement. Strong evidence supports leisure education interventions to enhance leisure engagement, and moderate evidence supports chronic disease self-management programs to support leisure engagement. Mixed evidence exists for community-based group interventions and electronic gaming to support social participation. Routine use of leisure education and chronic disease self-management programs to enhance leisure engagement and selective use of community-based groups and electronic gaming to support social participation are recommended.


The emergence of translational epidemiology: from scientific discovery to population health impact.
Recent emphasis on translational research (TR) is highlighting the role of epidemiology in translating scientific discoveries into population health impact. The authors present applications of epidemiology in TR through 4 phases designated T1-T4, illustrated by examples from human genomics. In T1, epidemiology explores the role of a basic scientific discovery (e.g., a disease risk factor or biomarker) in developing a "candidate application" for use in practice (e.g., a test used to guide interventions). In T2, epidemiology can help to evaluate the efficacy of a candidate application by using observational studies and randomized controlled trials. In T3, epidemiology can help to assess facilitators and barriers for uptake and implementation of candidate applications in practice. In T4, epidemiology can help to assess the impact of using candidate applications on population health outcomes. Epidemiology also has a leading role in knowledge synthesis, especially using quantitative methods (e.g., meta-analysis). To explore the emergence of TR in epidemiology, the authors compared articles published in selected issues of the Journal in 1999 and 2009. The proportion of articles identified as translational doubled from 16% (11/69) in 1999 to 33% (22/66) in 2009 (P = 0.02). Epidemiology is increasingly recognized as an important component of TR. By quantifying and integrating knowledge across disciplines, epidemiology provides crucial methods and tools for TR.


Enhancement of the viability of T cells electroporated with DNA via osmotic dampening of the DNA-sensing cGAS-STING pathway.
Viral delivery of DNA for the targeted reprogramming of human T cells can lead to random genomic integration, and electroporation is inefficient and can be toxic. Here we show that electroporation-induced toxicity in primary human T cells is mediated by the cytosolic pathway cGAS-STING (cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase-stimulator of interferon genes). We also show that an isotonic buffer, identified by screening electroporation conditions, that reduces cGAS-STING surveillance allowed for the production of chimaeric antigen receptor (CAR) T cells with up to 20-fold higher CAR T cell numbers than standard electroporation and with higher antitumour activity in vivo than lentivirally generated CAR T cells. The osmotic pressure of the electroporation buffer dampened cGAS-DNA interactions, affecting the production of the STING activator 2'3'-cGAMP. The buffer also led to superior efficiencies in the transfection of therapeutically relevant primary T cells and human haematopoietic stem cells. Our findings may facilitate the optimization of electroporation-mediated DNA delivery for the production of genome-engineered T cells.


A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes.
Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.


Substantial air quality and climate co-benefits achievable now with sectoral mitigation strategies in China.
China is the world's top carbon emitter and suffers from severe air pollution. We examine near-term air quality and CO2 co-benefits of various current sector-based policies in China. Using a 2015 base case, we evaluate the potential benefits of four sectoral mitigation strategies. All scenarios include a 20% increase in conventional air pollution controls as well as the following sector-specific fuel switching or technology upgrade strategies. Power sector (POW): 80% replacement of small coal power plants with larger more efficient ones; Industry sector (IND): 10% improvement in energy efficiency; Transport sector (TRA): replacement of high emitters with average vehicle fleet emissions; and Residential sector (RES): replacement of 20% of coal-based stoves with stoves using liquefied petroleum gas (LPG). Conducting an integrated assessment using the regional air pollution model WRF-Chem, we find that the IND scenario reduces national air-pollution-related deaths the most of the four scenarios examined (27,000, 24,000, 13,000 and 23,000 deaths reduced annually in IND, POW, TRA and RES, respectively). In addition, the IND scenario reduces CO2 emissions more than 8times as much as any other scenario (440, 53, 0 and 52Mt CO2 reduced in IND, POW, TRA and RES, respectively). We also examine the benefits of an industrial efficiency improvement of just 5%. We find the resulting air quality and health benefits are still among the largest of the sectoral scenarios, while the carbon mitigation benefits remain more than 3 times larger than any other scenario. Our analysis hence highlights the importance of even modest industrial energy efficiency improvements and air pollution control technology upgrades for air quality, health and climate benefits in China.


EGL-5/ABD-B plays an instructive role in male cell fate determination in the C. elegans somatic gonad.
Hox genes of the Abdominal-B (Abd-B) class regulate gonadal development in diverse metazoans. Here we have investigated the role of the Abd-B homolog egl-5 in C. elegans gonadal development. Previous work showed that egl-5 is required male-specifically in the gonad and that mutant gonads are highly dysgenic and possibly feminized. We have used sex-specific gonadal reporter genes to confirm that the gonads of egl-5 males are extensively feminized. Sex-specific expression of egl-5 requires the global sex determination gene tra-1 and the gonadal masculinizing gene fkh-6, but mutagenesis of a short male gonadal enhancer element in egl-5 suggested that this regulation is indirect. Ectopic expression of EGL-5 in hermaphrodites is sufficient to induce male gonadal gene expression, indicating that EGL-5 plays an instructive role in male gonadal fate determination. EGL-5 acts in parallel with a Wnt/beta-catenin pathway to regulate male gonadal fates and can physically interact with the Wnt pathway transcription factor POP-1 and modulate activity of a POP-1 dependent reporter gene. We propose that EGL-5 imparts sex-specific function on POP-1 by recruiting it to male-specific gonadal target genes.


Hyaluronic acid production by Streptococcus zooepidemicus in marine by-products media from mussel processing wastewaters and tuna peptone viscera.
Hyaluronic acid is one of the biopolymers most commonly used by the pharmaceutical industry. Thus, there is an increasing number of recent works that deal with the production of microbial hyaluronic acid. Different properties and characteristics of the fermentation process have been extensively optimised; however, new carbon and protein sources obtained from by-products or cheap substrates have not yet been studied. Mussel processing wastewater (MPW) was used as a sugar source and tuna peptone (TP) from viscera residue as a protein substrate for the production of hyaluronic acid (HA), biomass and lactic acid (LA) by Streptococcus zooepidemicus in batch fermentation. Commercial medium formulated with glucose and tryptone was used as the control. The parametric estimations obtained from logistic equations and maintenance energy model utilized for modelling experimental data were compared in commercial and low-cost media. Complete residual media achieved high production (3.67, 2.46 and 30.83 g l(-1) of biomass, HA and LA respectively) and a high molecular weight of HA (approximately 2500 kDa). A simple economic analysis highlighted the potential viability of this marine media for reducing the production costs by more than 50%. The experimental data and mathematical descriptions reported in this article demonstrate the potential of media formulated with MPW and TP to be used as substrates for HA production by S. zooepidemicus. Furthermore, the proposed equations accurately simulated the experimental profiles and generated a set of interesting parameters that can be used to compare the different bacterial cultures. To the best of our knowledge, this is the first work in which a culture media formed by marine by-products has been successfully used for microbial HA production.


Changing use of surgical antibiotic prophylaxis in Thika Hospital, Kenya: a quality improvement intervention with an interrupted time series design.
In low-income countries, Surgical Site Infection (SSI) is a common form of hospital-acquired infection. Antibiotic prophylaxis is an effective method of preventing these infections, if given immediately before the start of surgery. Although several studies in Africa have compared pre-operative versus post-operative prophylaxis, there are no studies describing the implementation of policies to improve prescribing of surgical antibiotic prophylaxis in African hospitals. We conducted SSI surveillance at a typical Government hospital in Kenya over a 16 month period between August 2010 and December 2011, using standard definitions of SSI and the extent of contamination of surgical wounds. As an intervention, we developed a hospital policy that advised pre-operative antibiotic prophylaxis and discouraged extended post-operative antibiotics use. We measured process, outcome and balancing effects of this intervention in using an interrupted time series design. From a starting point of near-exclusive post-operative antibiotic use, after policy introduction in February 2011 there was rapid adoption of the use of pre-operative antibiotic prophylaxis (60% of operations at 1 week; 98% at 6 weeks) and a substantial decrease in the use of post-operative antibiotics (40% of operations at 1 week; 10% at 6 weeks) in Clean and Clean-Contaminated surgery. There was no immediate step-change in risk of SSI, but overall, there appeared to be a moderate reduction in the risk of superficial SSI across all levels of wound contamination. There were marked reductions in the costs associated with antibiotic use, the number of intravenous injections performed and nursing time spent administering these. Implementation of a locally developed policy regarding surgical antibiotic prophylaxis is an achievable quality improvement target for hospitals in low-income countries, and can lead to substantial benefits for individual patients and the institution.


Elemental diet for refractory atopic eczema.
A total of 37 children with refractory wide-spread atopic eczema were treated with an antigen avoidance regimen comprising hospitalisation, exclusive feeding with an elemental formula for a median duration of 30 days, and measures to reduce exposure to pet and dust mite antigens at home. After the initial period of food exclusion, food challenges were performed at intervals of seven days, and the patients followed up for at least 12 months. Ten of the children (27%) either failed to respond to the regimen or relapsed within 12 months. Improvement in the eczema was seen in 27/37 (73%) patients, by discharge from hospital their disease severity score had fallen to a median of 27% of the pretreatment figure, and only 3/27 required topical corticosteroids. There were no clinical or laboratory findings which could be used to predict the outcome. Drawbacks to the regimen were prolonged hospitalisation (median 70 days), a fall in body weight and serum albumin concentration, and a risk of anaphylactic shock (4/37 cases). A strict antigen avoidance regimen may be associated with improvement of atopic eczema where conventional treatments have failed.


Interrater reliability of the Observer Rating of Medication Taking scale in an inpatient mental health facility.
Non-adherence to medication remains a major barrier to recovery from mental illnesses. Identification of those patients likely to experience adherence difficulties is best undertaken during inpatient treatment, prior to discharge into the community. More objective assessments of adherence behaviours might assist staff to more effectively target support to those patients most in need. This study investigated the interrater reliability of an inpatient behavioural observation scale of patient engagement with medication: the Observer Rating of Medication Taking (ORMT) scale. Eight mental health nurses working in a psychiatric hospital inpatient setting were trained in the use of the ORMT using video-based vignettes. Working in pairs, staff then independently rated adherence behaviours of 13 inpatients in a rehabilitation unit (total of 160 ratings) over a 1-week period. Concurrently, two expert raters also undertook independent ratings of patient medication-taking behaviour using the ORMT. Interrater reliability was assessed across both staff and expert raters. The results indicated that the ORMT has satisfactory interrater reliability, and can be appropriately used in an inpatient setting. The observational location of raters on the ward influenced the range of medication-taking behaviours observed, and thus the extent of concordance between raters. Further research to determine if the ORMT predicts adherence in the community is warranted.


Carbohydrate supplementation and prolonged intermittent high-intensity exercise in adolescents: research findings, ethical issues and suggestions for the future.
In the last decade, research has begun to investigate the efficacy of carbohydrate supplementation for improving aspects of physical capacity and skill performance during sport-specific exercise in adolescent team games players. This research remains in its infancy, and further study would be beneficial considering the large youth population actively involved in team games. Literature on the influence of carbohydrate supplementation on skill performance is scarce, limited to shooting accuracy in adolescent basketball players and conflicting in its findings. Between-study differences in the exercise protocol, volume of fluid and carbohydrate consumed, use of prior fatiguing exercise and timing of skill tests may contribute to the different findings. Conversely, initial data supports carbohydrate supplementation in solution and gel form for improving intermittent endurance running capacity following soccer-specific shuttle running. These studies produced reliable data, but were subject to limitations including lack of quantification of the metabolic response of participants, limited generalization of data due to narrow participant age and maturation ranges, use of males and females within the same sample and non-standardized pre-exercise nutritional status between participants. There is a lack of consensus regarding the influence of frequently consuming carbohydrate-containing products on tooth enamel erosion and the development of obesity or being overweight in adolescent athletes and non-athletes. These discrepancies mean that the initiation or exacerbation of health issues due to frequent consumption of carbohydrate-containing products by adolescents cannot be conclusively refuted. Coupled with the knowledge that consuming a natural, high-carbohydrate diet -3-8 hours before exercise can significantly alter substrate use and improve exercise performance in adults, a moral and ethical concern is raised regarding the direction of future research in order to further knowledge while safeguarding the health and well-being of young participants. It could be deemed unethical to continue study into carbohydrate supplementation while ignoring the potential health concerns and the possibility of generating similar performance enhancements using natural dietary interventions. Therefore, future work should investigate the influence of pre-exercise dietary intake on the prolonged intermittent, high-intensity exercise performance of adolescents. This would enable quantification of whether pre-exercise nutrition can modulate exercise performance and, if so, the optimum dietary composition to achieve this. Research could then combine this knowledge with ingestion of carbohydrate-containing products during exercise to facilitate ethical and healthy nutritional guidelines for enhancing the exercise performance of adolescents. This article addresses the available evidence regarding carbohydrate supplementation and prolonged intermittent, high-intensity exercise in adolescent team games players. It discusses the potential health concerns associated with the frequent use of carbohydrate-containing products by adolescents and how this affects the research ethics of the field, and considers directions for future work.


Three-Dimensional Growth of Li2S in Lithium-Sulfur Batteries Promoted by a Redox Mediator.
During the discharge of a lithium-sulfur (Li-S) battery, an electronically insulating 2D layer of Li2S is electrodeposited onto the current collector. Once the current collector is enveloped, the overpotential of the cell increases, and its discharge is arrested, often before reaching the full capacity of the active material. Guided by a new computational platform known as the Electrolyte Genome, we advance and apply benzo[ghi]peryleneimide (BPI) as a redox mediator for the reduction of dissolved polysulfides to Li2S. With BPI present, we show that it is now possible to electrodeposit Li2S as porous, 3D deposits onto carbon current collectors during cell discharge. As a result, sulfur utilization improved 220% due to a 6-fold increase in Li2S formation. To understand the growth mechanism, electrodeposition of Li2S was carried out under both galvanostatic and potentiostatic control. The observed kinetics under potentiostatic control were modeled using modified Avrami phase transformation kinetics, which showed that BPI slows the impingement of insulating Li2S islands on carbon. Conceptually, the pairing of conductive carbons with BPI can be viewed as a vascular approach to the design of current collectors for energy storage devices: here, conductive carbon "arteries" dominate long-range electron transport, while BPI "capillaries" mediate short-range transport and electron transfer between the storage materials and the carbon electrode.


Effect of roscovitine on nuclear maturation, MPF and MAP kinase activity and embryo development of prepubertal goat oocytes.
The low number of embryos obtained from IVM-IVF-IVC of prepubertal goat oocytes could be due to an incomplete cytoplasmic maturation. Roscovitine (ROS) inhibits MPF and MAP kinase activity and maintains the oocyte at Germinal Vesicle (GV) stage. The aim of this study was to determine if meiotic activity is arrested in prepubertal goat oocytes cultured with 0, 12.5, 25, 50 and 100 microM of ROS for 24 h. A group of oocytes from adult goats was cultured with 25 microM of ROS to compare the effect of ROS on prepubertal and adult goat oocytes. A sample of oocytes was stained to evaluate the nuclear stage at oocyte collection time and after ROS incubation. IVM-oocytes not exposed to ROS formed the control group. Prepubertal goat IVM-oocytes were inseminated and cultured for 8 days. The percentage of oocytes at GV stage, after exposition to ROS was significantly higher in adult goat oocytes (64.5%) than in prepubertal goat oocytes. No differences were found among 25, 50 and 100 microM ROS concentrations (29, 23 and 26%, oocytes at GV stage, respectively). After 8 days of culture, no differences in total embryos were observed between control oocytes and oocytes treated with 12.5 and 25 microM (45.2, 36.1 and 39.4%, respectively), however the percentage of blastocysts was higher in the control group. Western blot for the MAPK and p34(cdc2) showed that both enzymes were active in prepubertal goat oocytes after 24h of ROS exposition. In conclusion, a low percentage of prepubertal goat oocytes reached GV stage after ROS incubation; possibly because most of them had reinitiated the meiosis inside the follicle. ROS did not affect fertilization or total embryos but ROS showed a negative effect on blastocyst development.


Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie.
Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid beta-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man(5)GlcNAc(2) structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.


Time-restricted feeding improves markers of cardiometabolic health in physically active college-age men: a 4-week randomized pre-post pilot study.
Time-restricted feeding (TRF) has been shown to improve body composition, blood lipids, and reduce markers of inflammation and oxidative stress. However, most of these studies come from rodent models and small human samples, and it is not clear if the benefits are dependent upon a caloric deficit, or the time restriction nature of TRF. Based off of previous research, we hypothesized that humans following an ad libitum TRF protocol would reduce caloric intake and this caloric deficit would be associated with greater improvements in cardiometabolic health including blood pressure, body composition, blood lipids, and markers of inflammation and antioxidant status compared to an isocaloric TRF protocol. The purpose of this study was to: (1) examine the impact of TRF on markers of cardio-metabolic health and antioxidant status and (2) determine if the adaptations from TRF would differ under ad libitum compared to isocaloric conditions. Twenty-three healthy men were randomized to either an ad libitum or isocaloric 16:8 (fasting: feeding) TRF protocol. A total of 22 men completed the 28-day TRF protocol (mean ± SD; age: 22 ± 2.5 yrs.; height: 178.4 ± 6.9 cm; weight: 90.3 ± 24 kg; BMI: 28.5 ± 8.3 kg/m2). Fasting blood samples were analyzed for glucose, lipids, as well as adiponectin, human growth hormone, insulin, cortisol, C-reactive protein, superoxide dismutase, total nitrate/nitrite, and glutathione. Time-restricted feeding in both groups was associated with significant (P < .05) reductions in body fat, blood pressure, and significant increases in adiponectin and HDL-c. No changes in caloric intake were detected. In summary, the results from this pilot study in metabolically healthy, active young men, suggest that TRF can improve markers of cardiometabolic health.


Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome.
Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ∼200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes.


RIG-I-like receptor activation drives type I IFN and antiviral signaling to limit Hantaan orthohantavirus replication.
Pathogenic hantaviruses, genus Orthohantaviridae, are maintained in rodent reservoirs with zoonotic transmission to humans occurring through inhalation of rodent excreta. Hantavirus disease in humans is characterized by localized vascular leakage and elevated levels of circulating proinflammatory cytokines. Despite the constant potential for deadly zoonotic transmission to humans, specific virus-host interactions of hantaviruses that lead to innate immune activation, and how these processes impart disease, remain unclear. In this study, we examined the mechanisms of viral recognition and innate immune activation of Hantaan orthohantavirus (HTNV) infection. We identified the RIG-I-like receptor (RLR) pathway as essential for innate immune activation, interferon (IFN) production, and interferon stimulated gene (ISG) expression in response to HTNV infection in human endothelial cells, and in murine cells representative of a non-reservoir host. Our results demonstrate that innate immune activation and signaling through the RLR pathway depends on viral replication wherein the host response can significantly restrict replication in target cells in a manner dependent on the type 1 interferon receptor (IFNAR). Importantly, following HTNV infection of a non-reservoir host murine model, IFNAR-deficient mice had higher viral loads, increased persistence, and greater viral dissemination to lung, spleen, and kidney compared to wild-type animals. Surprisingly, this response was MAVS independent in vivo. Innate immune profiling in these tissues demonstrates that HTNV infection triggers expression of IFN-regulated cytokines early during infection. We conclude that the RLR pathway is essential for recognition of HTNV infection to direct innate immune activation and control of viral replication in vitro, and that additional virus sensing and innate immune response pathways of IFN and cytokine regulation contribute to control of HTNV in vivo. These results reveal a critical role for innate immune regulation in driving divergent outcomes of HTNV infection, and serve to inform studies to identify therapeutic targets to alleviate human hantavirus disease.


Challenges to neonatal care in Cambodia amid the COVID-19 pandemic.
Since mid-February, 2020, coronavirus disease-2019 (COVID-19) has been spreading in Cambodia and, as of April 9, 2020, the Ministry of Health has identified 119 polymerase chain reaction (PCR)-positive cases. However, the PCR test is available in only two specialized institutes in the capital city Phnom Penh; therefore, exact and adequate identification of the cases remains still limited. Many vulnerable newborn infants have been admitted to the neonatal care unit (NCU) at the National Maternal and Child Health Center in Phnom Penh. Although the staff have implemented strict infection prevention and control measures, formidable gaps in neonatal care between Cambodia and Japan exist. Due to the shortages in professional workforce, one family member of sick newborn(s) should stay for 24 hours in the NCU to care for the baby. This situation, however, may lead to several errors, including hospital-acquired infection. It is crucial not only to make all efforts to prevent infections but also to strengthen the professional healthcare workforce instead of relying on task sharing with family members.


The therapeutic promise of the cancer stem cell concept.
Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for those malignancies that are currently refractory to conventional anticancer agents directed predominantly at tumor bulk populations.


Disordered langasites La3Ga5MO14 : Eu3+ (M = Si, Ge, Ti) as red-emitting LED phosphors.
Polycrystalline powders of La3Ga5SiO14 (LGSi), La3Ga5GeO14 (LGGe), and La3Ga5TiO14 (LGTi) doped with Eu3+ were studied with respect to their use as luminescent materials in solid state lighting based on light-emitting diodes. The langasites were synthesized with up to 35% of trivalent europium to achieve the highest possible doping amount. According to diffuse reflection measurements the undoped compounds have band gap energies of 4.51 eV (LGSi), 4.54 eV (LGGe) and 4.07 eV (LGTi). The luminescence behavior between 77 K and 500 K was investigated, including excitation, emission and lifetime measurements to analyze the impact of the structural differences between the three langasites on the spectroscopic properties of the materials. Depending on the excitation wavelengths, 300 nm (charge transfer) and 394 nm (4f levels, i.e.7F0 → 5L6), different quenching temperatures were achieved for LGSi : Eu3+ 20% (TQ,300 = 438 K, TQ,394 = 422 K), LGGe : Eu3+ 20% (TQ,300 = 325 K, TQ,394 = 441 K) and LGTi : Eu3+ 20% (TQ,300 = 500 K, TQ,394 = 467 K). The quenching observed can be explained by three semi-quantitative configurational coordinate diagrams. Independent from the excitation wavelength and the temperature (77-300 K) decay times of 1.1 ms were measured. At room temperature and with an excitation wavelength of 394 nm maximum quantum efficiencies of 40% for LGSi : Eu, of 80% for LGGe : Eu, and of 81% for LGTi : Eu were reached. Finally, to prove the applicability as red LED phosphors, the langasites were built into LEDs with (In,Ga)N chips emitting at 394 nm.


Application of Taxonomic Modeling to Microbiota Data Mining for Detection of Helminth Infection in Global Populations.
Human microbiome data from genomic sequencing technologies is fast accumulating, giving us insights into bacterial taxa that contribute to health and disease. The predictive modeling of such microbiota count data for the classification of human infection from parasitic worms, such as helminths, can help in the detection and management across global populations. Real-world datasets of microbiome experiments are typically sparse, containing hundreds of measurements for bacterial species, of which only a few are detected in the bio-specimens that are analyzed. This feature of microbiome data produces the challenge of needing more observations for accurate predictive modeling and has been dealt with previously, using different methods of feature reduction. To our knowledge, integrative methods, such as transfer learning, have not yet been explored in the microbiome domain as a way to deal with data sparsity by incorporating knowledge of different but related datasets. One way of incorporating this knowledge is by using a meaningful mapping among features of these datasets. In this paper, we claim that this mapping would exist among members of each individual cluster, grouped based on phylogenetic dependency among taxa and their association to the phenotype. We validate our claim by showing that models incorporating associations in such a grouped feature space result in no performance deterioration for the given classification task. In this paper, we test our hypothesis by using classification models that detect helminth infection in microbiota of human fecal samples obtained from Indonesia and Liberia countries. In our experiments, we first learn binary classifiers for helminth infection detection by using Naive Bayes, Support Vector Machines, Multilayer Perceptrons, and Random Forest methods. In the next step, we add taxonomic modeling by using the SMART-scan module to group the data, and learn classifiers using the same four methods, to test the validity of the achieved groupings. We observed a 6% to 23% and 7% to 26% performance improvement based on the Area Under the receiver operating characteristic (ROC) Curve (AUC) and Balanced Accuracy (Bacc) measures, respectively, over 10 runs of 10-fold cross-validation. These results show that using phylogenetic dependency for grouping our microbiota data actually results in a noticeable improvement in classification performance for helminth infection detection. These promising results from this feasibility study demonstrate that methods such as SMART-scan can be utilized in the future for knowledge transfer from different but related microbiome datasets by phylogenetically-related functional mapping, to enable novel integrative biomarker discovery.


Dextran sulfate-coated superparamagnetic iron oxide nanoparticles as a contrast agent for atherosclerosis imaging.
The hallmark of atherosclerosis in its early pathogenic process is the overexpression of class A scavenger receptors (SR-A) by activated macrophages. In this study, dextran sulfate-coated superparamagnetic iron oxide nanoparticles (DS-SPIONs), as a magnetic resonance (MR) imaging contrast agent of atherosclerosis, was prepared via the facile co-precipitation method using a versatile double-hydrophilic block copolymer comprising of a DS segment (ligand for SR-A) and a poly(glyclerol methacrylate) segment (SPIONs surface-anchoring unit). The physicochemical properties of the DS-SPIONs were investigated using various instruments. DS-SPIONs exhibited high aqueous stability compared to dextran-coated SPIONs (Dex-SPIONs), which were used as controls. The cellular uptake behaviors of DS-SPIONs and Dex-SPIONs were evaluated using Prussian blue assay. Interestingly, the DS-SPIONs were effectively taken up by activated macrophages compared to Dex-SPIONs. However, the cellular uptake of DS-SPIONs by activated macrophages was remarkably reduced in the presence of free DS. These results suggest that activated macrophages internalize DS-SPIONs via receptor (SR-A)-mediated endocytosis. T2-weighted MR imaging of the cells demonstrated that activated macrophages treated with DS-SPIONs showed a significantly lower signal intensity compared to those treated with Dex-SPIONs. Overall, these results suggest that DS-SPIONs may be utilized as a potential contrast agent for atherosclerosis MR imaging.


Pupillary light reaction in preclinical Alzheimer's disease subjects compared with normal ageing controls.
We wished to determine whether the pupillary light reaction can differentiate preclinical Alzheimer's disease (AD) subjects from normal ageing controls. We performed a prospective study evaluating the pupillary light reaction in a cohort of well-characterised subjects with preclinical AD versus normal ageing controls. We recruited 57 subjects from our institution's Memory and Aging Project, part of our Alzheimer's Disease Research Center. All subjects completed PET-PiB imaging, cerebrospinal fluid analysis and at least 1 neuropsychiatric assessment after their baseline assessment. All participants were assigned a clinical dementia rating and underwent a complete neuro-ophthalmic examination. Participants were divided into a dementia biomarker+ (preclinical AD) and biomarker- (normal ageing) group based on preclinical risk for Alzheimer's dementia. Pupillometry measurements were performed by using the NeurOptics PLR-200 Pupillometer. A total of 57 subjects were recruited with 24 dementia biomarker+ and 33 dementia biomarker- individuals. A variety of pupil flash response (PLR) parameters were assessed. Comparisons between groups were analysed using generalised estimating equations. None of the pupillary parameters showed a significant difference between groups. We found no significant differences in PLR between preclinical AD subjects and normal ageing controls. This suggests that the disease effect on the PLR may be small and difficult to detect at the earliest stages of the disease. Future studies could include larger sample size and chromatic pupillometry.


Comparative analyses of Pasteurella multocida strains associated with the ovine respiratory and vaginal tracts.
Thirty-five isolates of Pasteurella multocida from the vagina and respiratory tract of sheep were compared by analysing their capsular polysaccharide types and outer membrane protein profiles. The phylogenetic relationships of selected isolates with respect to reference strains of P. multocida were also determined by comparative 16S rRNA sequence analysis. Three capsular types, A, D and F, and three major outer membrane protein types were identified, and there were four different combinations of these characteristics which probably marked four individual clones of P. multocida. Strains representing three of these clones were recovered from cases of ovine pneumonia, whereas isolates of the fourth clone were associated exclusively with the vagina of healthy ewes and the liver of a dead septicaemic lamb on the same farm. Analysis of the 16S rRNA sequences showed that there was 100 per cent identity between representative pneumonic isolates and reference strains of P. multocida subspecies galliseptica and P. multocida subspecies multocida. The 16S rRNA genes of representative vaginal and liver isolates from the same farm were identical but differed from the other strains at one nucleotide position, providing strong evidence that the vaginal and liver isolates represent a distinct subpopulation of P. multocida.


Migratory culture, population structure and stock identity in North Pacific beluga whales (Delphinapterus leucas).
The annual return of beluga whales, Delphinapterus leucas, to traditional seasonal locations across the Arctic may involve migratory culture, while the convergence of discrete summering aggregations on common wintering grounds may facilitate outbreeding. Natal philopatry and cultural inheritance, however, has been difficult to assess as earlier studies were of too short a duration, while genetic analyses of breeding patterns, especially across the beluga's Pacific range, have been hampered by inadequate sampling and sparse information on wintering areas. Using a much expanded sample and genetic marker set comprising 1,647 whales, spanning more than two decades and encompassing all major coastal summering aggregations in the Pacific Ocean, we found evolutionary-level divergence among three geographic regions: the Gulf of Alaska, the Bering-Chukchi-Beaufort Seas, and the Sea of Okhotsk (Φst = 0.11-0.32, Rst = 0.09-0.13), and likely demographic independence of (Fst-mtDNA = 0.02-0.66), and in many cases limited gene flow (Fst-nDNA = 0.0-0.02; K = 5-6) among, summering groups within regions. Assignment tests identified few immigrants within summering aggregations, linked migrating groups to specific summering areas, and found that some migratory corridors comprise whales from multiple subpopulations (PBAYES = 0.31:0.69). Further, dispersal is male-biased and substantial numbers of closely related whales congregate together at coastal summering areas. Stable patterns of heterogeneity between areas and consistently high proportions (~20%) of close kin (including parent-offspring) sampled up to 20 years apart within areas (G = 0.2-2.9, p>0.5) is the first direct evidence of natal philopatry to migration destinations in belugas. Using recent satellite telemetry findings on belugas we found that the spatial proximity of winter ranges has a greater influence on the degree of both individual and genetic exchange than summer ranges (rwinter-Fst-mtDNA = 0.9, rsummer-Fst-nDNA = 0.1). These findings indicate widespread natal philopatry to summering aggregation and entire migratory circuits, and provide compelling evidence that migratory culture and kinship helps maintain demographically discrete beluga stocks that can overlap in time and space.


The influence of electromyographic biofeedback therapy on knee extension following anterior cruciate ligament reconstruction: a randomized controlled trial.
Loss of knee extension and a deficit in quadriceps strength are frequently found following anterior cruciate ligament (ACL) reconstruction. The aim of this study was to investigate whether the addition of Eletromyographic Biofeedback (EMG BFB) therapy for the vastus medialis muscle to the in the early phase of the standard rehabilitation programme could improve the range of knee extension and strength after ACL reconstruction more than a standard rehabilitation programme. The correlation between EMG measurement and passive knee extension was also investigated. Sixteen patients, all of whom underwent endoscopic ACL reconstruction using patellar tendon autograft, were randomly assigned to two groups:• Control group (8 patients): standard rehabilitation protocol; with full weight-bearing postoperative, knee brace (0° extension, 90° flexion), electrical stimulation, aquatics and proprioceptive training.• The EMG BFB group (8 patients): EMG BFB was added to the standard rehabilitation protocol within the first postoperative week and during each session for the next 6 weeks.Each patent attended a total of 16 outpatient physiotherapy sessions following surgery. High-Heel-Distance (HHD) Test, range of motion (ROM) and integrated EMG (iEMG) for vastus medialis were measured preoperatively, and at the 1, 2, 4 and 6-week follow ups. Additionally, knee function, swelling and pain were evaluated using standardized scoring scales. At 6 weeks, passive knee extension (p < 0.002) and the HHD Test were significantly (p < 0.01) better in the EMG BFB group compared to controls. Integrated EMG (vastus medialis) of the EMG BFB group also showed a significant increase after 2 (p < 0.01) and 6 (p < 0.01) weeks. At the 6-week follow up, no significant (p > 0.01) differences were found between the two groups for the assessment of knee function, swelling and pain. The results indicate that EMG BFB therapy, in the early phase of rehabilitation after ACL reconstruction, is useful in enhancing knee extension. Improved innervation of the vastus medialis can play a key role in the development of postoperative knee extension. EMG BFB therapy is a simple, inexpensive and valuable adjunct to conventional therapeutic modalities.


Effects of geometric parameters on swimming of micro organisms with single helical flagellum in circular channels.
We present a computational fluid dynamics (CFD) model for the swimming of micro organisms with a single helical flagellum in circular channels. The CFD model is developed to obtain numerical solutions of Stokes equations in three dimensions, validated with experiments reported in literature, and used to analyze the effects of geometric parameters, such as the helical radius, wavelength, radii of the channel and the tail and the tail length on forward and lateral swimming velocities, rotation rates, and the efficiency of the swimmer. Optimal shapes for the speed and the power efficiency are reported. Effects of Brownian motion and electrostatic interactions are excluded to emphasize the role of hydrodynamic forces on lateral velocities and rotations on the trajectory of swimmers. For thin flagella, as the channel radius decreases, forward velocity and the power efficiency of the swimmer decreases as well; however, for thick flagella, there is an optimal radius of the channel that maximizes the velocity and the efficiency depending on other geometric parameters. Lateral motion of the swimmer is suppressed as the channel is constricted below a critical radius, for which the magnitude of the lateral velocity reaches a maximum. Results contribute significantly to the understanding of the swimming of bacteria in micro channels and capillary tubes.


Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers.
Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers. We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3). A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type. Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.


A landmark contribution to poultry science--Immunological function of the bursa of Fabricius.
The article "The bursa of Fabricius and antibody production" by Bruce Glick, Timothy S. Chang, and R. George Jaap first demonstrated the role of the bursa in immune development. Birds, including chickens, possess a peculiar organ, the bursa of Fabricius. The organ was recognized for more than 300 yr before its function was described in 1956. Discovery of the bursa as an essential component of the immune response began by accident. Removal of the bursa, bursectomy, during the rapid growth period diminished the antibody response to Salmonella. A paper describing this exceptional finding was initially rejected by Science and ultimately published in Poultry Science. This revelation triggered sequential events leading to the understanding of the dichotomy of the immune response. Additional work in multiple laboratories over many years revealed fundamental immune mechanisms attributable to the bursa. Understanding those mechanisms advanced agricultural and biomedical science.


The PiGeOn project: protocol for a longitudinal study examining psychosocial, behavioural and ethical issues and outcomes in cancer tumour genomic profiling.
Genomic sequencing in cancer (both tumour and germline), and development of therapies targeted to tumour genetic status, hold great promise for improvement of patient outcomes. However, the imminent introduction of genomics into clinical practice calls for better understanding of how patients value, experience, and cope with this novel technology and its often complex results. Here we describe a protocol for a novel mixed-methods, prospective study (PiGeOn) that aims to examine patients' psychosocial, cognitive, affective and behavioural responses to tumour genomic profiling and to integrate a parallel critical ethical analysis of returning results. This is a cohort sub-study of a parent tumour genomic profiling programme enrolling patients with advanced cancer. One thousand patients will be recruited for the parent study in Sydney, Australia from 2016 to 2019. They will be asked to complete surveys at baseline, three, and five months. Primary outcomes are: knowledge, preferences, attitudes and values. A purposively sampled subset of patients will be asked to participate in three semi-structured interviews (at each time point) to provide deeper data interpretation. Relevant ethical themes will be critically analysed to iteratively develop or refine normative ethical concepts or frameworks currently used in the return of genetic information. This will be the first Australian study to collect longitudinal data on cancer patients' experience of tumour genomic profiling. Findings will be used to inform ongoing ethical debates on issues such as how to effectively obtain informed consent for genomic profiling return results, distinguish between research and clinical practice and manage patient expectations. The combination of quantitative and qualitative methods will provide comprehensive and critical data on how patients cope with 'actionable' and 'non-actionable' results. This information is needed to ensure that when tumour genomic profiling becomes part of routine clinical care, ethical considerations are embedded, and patients are adequately prepared and supported during and after receiving results. Not required for this sub-study, parent trial registration ACTRN12616000908437 .


Abundant expression of nucleosome assembly protein 1 (NAP1) gene in goldfish scale with lateral line.
To explore the possible utilization of goldfish scale in monitoring environmental toxicants as well as that for calcified tissue research, characteristics of cells in the scale were examined by identifying genes differentially expressed in those cells. Subtraction cloning was subjected to RNAs between scale-gill (SG), gill-scale (GS) and scale with lateral line-scale without lateral line (LS). Total numbers of 4, 6, and 9 clones were isolated respectively from SG, GS and LS pools. Blast search of their sequence showed only low homology to other fish sequences so that 5' rapid amplification of cDNA (5'RACE) was applied to the obtained 5' terminal side of each sequence. Among 19 clones, LS3 alone showed the high homology to zebrafish nucleosome assembly protein 1 (NAP1) and the rest of 18 was not yet identified. In situ hybridization confirmed that faint expression of NAP1 mRNA was observed in cells along the ridge of the scale without lateral line. On the other hand, in small cells not along the ridge of the scale with lateral line, very intense hybridization was found as expected. They were abundant at the surrounding area of the lateral line tube. NAP1 plays an enhancing role on gene expression by promoting nucleosome assembly. Thus, cell viability in the scale with lateral line seemed to be higher than that in the scale without lateral line. The scale can be a good model to monitor the effects of environmental pollutants because simultaneous observation against cells with different cell viability is available through comparison between cells in the scale with or without lateral line.


Comparative effectiveness and safety of antipsychotic drugs in schizophrenia treatment: a real-world observational study.
The objective was to compare, in a real-world setting, the risk of mental and physical health events associated with different antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine and first-generation antipsychotics) in patients with SZ. This is a retrospective cohort study using administrative data. Outcome measures included any mental health event (suicide, hospitalization or emergency visit for mental disorders) and physical health event (death other than suicide, hospitalization or emergency visit for physical disorders). Cox proportional hazard models were used to estimate the hazard ratios of the events associated with the use of the different antipsychotic drugs. The cohort included 18 869 adult patients living in the province of Quebec (Canada) with SZ and starting antipsychotic drugs between January 1998 and December 2005. Results show that quetiapine and not using any antipsychotics were associated with an increased risk of mental and physical health events as compared to other drugs. The second finding is the confirmation of better performance of clozapine. The results were robust across sensitivity analyses. Both findings call for an international public health and drug agencies surveillance of 'real-world' antipsychotic medication to ensure the optimal choices in treatment guidelines for SZ.


Regulation of acetyl-CoA synthetase transcription by the CrbS/R two-component system is conserved in genetically diverse environmental pathogens.
The CrbS/R two-component signal transduction system is a conserved regulatory mechanism through which specific Gram-negative bacteria control acetate flux into primary metabolic pathways. CrbS/R governs expression of acetyl-CoA synthase (acsA), an enzyme that converts acetate to acetyl-CoA, a metabolite at the nexus of the cell's most important energy-harvesting and biosynthetic reactions. During infection, bacteria can utilize this system to hijack host acetate metabolism and alter the course of colonization and pathogenesis. In toxigenic strains of Vibrio cholerae, CrbS/R-dependent expression of acsA is required for virulence in an arthropod model. Here, we investigate the function of the CrbS/R system in Pseudomonas aeruginosa, Pseudomonas entomophila, and non-toxigenic V. cholerae strains. We demonstrate that its role in acetate metabolism is conserved; this system regulates expression of the acsA gene and is required for growth on acetate as a sole carbon source. As a first step towards describing the mechanism of signaling through this pathway, we identify residues and domains that may be critical for phosphotransfer. We further demonstrate that although CrbS, the putative hybrid sensor kinase, carries both a histidine kinase domain and a receiver domain, the latter is not required for acsA transcription. In order to determine whether our findings are relevant to pathogenesis, we tested our strains in a Drosophila model of oral infection previously employed for the study of acetate-dependent virulence by V. cholerae. We show that non-toxigenic V. cholerae strains lacking CrbS or CrbR are significantly less virulent than are wild-type strains, while P. aeruginosa and P. entomophila lacking CrbS or CrbR are fully pathogenic. Together, the data suggest that the CrbS/R system plays a central role in acetate metabolism in V. cholerae, P. aeruginosa, and P. entomophila. However, each microbe's unique environmental adaptations and pathogenesis strategies may dictate conditions under which CrbS/R-mediated acs expression is most critical.


Pancreatoprotective effects of Geniotrigona thoracica stingless bee honey in streptozotocin-nicotinamide-induced male diabetic rats.
Stingless bee honey (SLBH) has been claimed to possess multiple health benefits. Its anti-diabetic properties are however unknown. In this study, ability of SLBH from Geniotrigona thoracica stingless bee species in ameliorating pancreatic damage and in maintaining metabolic profiles were investigated in diabetic condition. SLBH at 1 and 2g/kg/b.w. was given orally to streptozotocin (STZ)-nicotinamide-induced male diabetic rats for 28days. Metabolic parameters (fasting blood glucose-FBG and lipid profiles-LP and serum insulin) were measured by biochemical assays. Distribution and expression level of insulin, oxidative stress marker i.e. catalase, inflammatory markers i.e. IKK-β, TNF-α, IL-1β and apoptosis marker i.e. caspase-9 in the pancreatic islets were identified and quantified respectively by immunohistochemistry. Levels of NF-κβ in pancreas were determined by enzyme-linked immunoassay (ELISA). SLBH administration to diabetic male rats prevented increase in FBG, total cholesterols (TC), triglyceride (TG) and low density lipoprotein (LDL) levels. However, high density lipoprotein (HDL) and serum insulin levels in diabetic rats receiving SLBH increased. Additionally, histopathological changes and expression level of oxidative stress, inflammation and apoptosis markers in pancreatic islets of diabetic rats decreased with increased expression level of insulin in the islets. LC-MS analysis revealed the presence of several compounds in SLBH that might be responsible for these effects. SLBH has great potential to be used as agent to protect the pancreas against damage and dysfunction where these could account for its anti-diabetic properties.


Type III intermediate filament peripherin inhibits neuritogenesis in type II spiral ganglion neurons in vitro.
Peripherin, a type III intermediate filament protein, forms part of the cytoskeleton in a subset of neurons, most of which have peripheral fibre projections. Studies suggest a role for peripherin in axon outgrowth and regeneration, but evidence for this in sensory and brain tissues is limited. The exclusive expression of peripherin in a sub-population of primary auditory neurons, the type II spiral ganglion neurons (SGN) prompted our investigation of the effect of peripherin gene deletion (pphKO) on these neurons. We used confocal immunofluorescence to examine the establishment of the innervation of the cochlear outer hair cells by the type II SGN neurites in vivo and in vitro, in wildtype (WT) and pphKO mice, in the first postnatal week. The distribution of the type II SGN nerve fibres was normal in pphKO cochleae. However, using P1 spiral ganglion explants under culture conditions where the majority of neurites were derived from type II SGN, pphKO resulted in increased numbers of neurites/explant compared to WT controls. Type II SGN neurites from pphKO explants extended approximately double the distance of WT neurites, and had reduced complexity based on greater distance between turning points. Addition of brain-derived neurotrophic factor (BDNF) to the culture media increased neurite number in WT and KO explants approximately 30-fold, but did not affect neurite length or distance between turning. These results indicate that peripherin may interact with other cytoskeletal elements to regulate outgrowth of the peripheral neurites of type II SGN, distinguishing these neurons from the type I SGN innervating the inner hair cells.


Computed Binding of Peptides to Proteins with MELD-Accelerated Molecular Dynamics.
It has been a challenge to compute the poses and affinities for binding of peptides to proteins by molecular dynamics (MD) simulations. Such computations would be valuable for capturing the physics and the conformational freedom of the molecules, but they are currently too computationally expensive. Here we describe using MELD (Modeling Employing Limited Data)-accelerated MD for finding the binding poses and approximate relative binding free energies for flexible-peptide/protein interactions. MELD uses only weak information about the binding motif and not the detailed binding mode that is typically required by other free-energy-based methods. We apply this technique to study binding of P53-derived peptides to MDM2 and MDMX. We find that MELD finds correct poses, that the binding induces the peptide into the correct helical conformation, and that it is capable of roughly estimating relative binding affinities. This method may be useful in peptide drug discovery.


Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin.
The gamma-secretase complex is an unusual multimeric protease responsible for the intramembrane cleavage of a variety of type 1 transmembrane proteins, including the beta-amyloid precursor protein and Notch. Genetic and biochemical data have revealed that this protease consists of the presenilin heterodimer, a highly glycosylated form of nicastrin, and the recently identified gene products, Aph-1 and Pen-2. Whereas current evidence supports the notion that presenilin comprises the active site of the protease and that the other three components are members of the active complex required for proteolytic activity, the individual roles of the three co-factors remain unclear. Here, we demonstrate that endogenous Aph-1 interacts with an immature species of nicastrin, forming a stable intermediate early in the assembly of the gamma-secretase complex, prior to the addition of presenilin and Pen-2. Our data suggest 1) that Aph-1 is involved in the early stages of gamma-secretase assembly through the stabilization and perhaps glycosylation of nicastrin and by scaffolding nicastrin to the immature gamma-secretase complex, and 2) that presenilin, and later Pen-2, bind to this intermediate during the formation of the mature protease.


Characterization of biofilm-like structures formed by Pseudomonas aeruginosa in a synthetic mucus medium.
The accumulation of thick stagnant mucus provides a suitable environment for the growth of Pseudomonas aeruginosa and Staphylococcus aureus within the lung alveoli of cystic fibrosis (CF) patients. These infections cause significant lung damage, leading to respiratory failure and death. In an artificial mucin containing medium ASM+, P. aeruginosa forms structures that resemble typical biofilms but are not attached to any surface. We refer to these structures as biofilm like structures (BLS). Using ASM+ in a static microtiter plate culture system, we examined the roles of mucin, extracellular DNA, environmental oxygen (EO2), and quorum sensing (QS) in the development of biofilm-like structures (BLS) by P. aeruginosa; and the effect of EO2 and P. aeruginosa on S. aureus BLS. Under 20% EO2, P. aeruginosa strain PAO1 produced BLS that resemble typical biofilms but are confined to the ASM+ and not attached to the surface. Levels of mucin and extracellular DNA within the ASM+ were optimized to produce robust well developed BLS. At 10% EO2, PAO1 produced thicker, more developed BLS, while under 0% EO2, BLS production was diminished. In contrast, the S. aureus strain AH133 produced well-developed BLS only under 20% EO2. In PAO1, loss of the QS system genes rhlI and rhlR affected the formation of BLS in ASM+ in terms of both structure and architecture. Whether co-inoculated into ASM+ with AH133, or added to established AH133 BLS, PAO1 eliminated AH133 within 48-56 h. The thick, viscous ASM+, which contains mucin and extracellular DNA levels similar to those found in the CF lung, supports the formation of biofilm-like structures similar to the aggregates described within CF airways. Alterations in environmental conditions or in the QS genes of P. aeruginosa, as occurs naturally during the progression of CF lung infection, affect the architecture and quantitative structural features of these BLS. Thus, ASM+ provides an in vitro medium in which the effect of changing levels of substances produced by the host and the bacteria can be analyzed to determine the effect on such structures and on the susceptibility of the bacteria within the BLS to various treatments.


Increased eosinophilic cationic protein in nasal fluid in hospitalized wheezy infants with RSV infection.
Respiratory syncytial virus (RSV) is a major respiratory pathogen which causes bronchiolitis with dyspnea and wheezing in children less than 2 years old. RSV bronchiolitis in infancy severe enough to cause hospitalization might be a risk factor for allergic sensitization and bronchial asthma in future. However, the pathophysiology behind this development has not been clearly characterized. To evaluate the existence of airway inflammation and characteristic of RSV bronchiolitis, we analyzed and compared the concentrations of eosinophilic cationic protein (ECP) in nasal fluid and plasma. From 69 infants (aged <2 years) hospitalized for possible lower respiratory tract infections including RSV infection, we collected nasal fluid and plasma and determined the ECP concentrations. ECP concentrations in nasal fluid were significantly higher in patients with wheezing and/or bronchial rales than in patients without them (1733 ± 660 ng/mL vs 680 ± 450 ng/mL, p = 0.018), and those of the respiratory syncitial virus-infected group were significantly higher than those of the uninfected group (p = 0.04). Meanwhile, there was no significant difference in plasma ECP levels between patients with wheezing and patients without wheezing, and no significant difference between RSV-infected and other pathogen-infected patients. There were significant correlations between nasal fluid ECP concentrations and both neutrophil and eosinophil counts in the peripheral blood. Nasal fluid ECP concentrations are increased in infants with lower respiratory infections including RSV infection accompanied with wheezing. ECP probably originates from neutrophils as well as eosinophils migrated into airways. The monitoring of ECP concentration in nasal fluid may be useful for evaluating leukocyte (including eosinophils and neutrophils)-mediated airway inflammation during infancy and its severity.


Lateral pharyngeal wall motion analysis using ultrasonography in stroke patients with dysphagia.
We aimed to analyze lateral pharyngeal wall (LPW) motion using ultrasonography. The subjects were stroke patients with dysphagia (n = 26) and normal controls (n = 15). The stroke patients were divided into two groups based on a videofluoroscopic swallowing study (VFSS). Group A (n = 12) had a penetration or aspiration in VFSS findings, while group B (n = 14) had no evidence of a penetration or aspiration. We assessed LPW motion using B/M-mode ultrasonography. We performed the comparative analysis among each group and the relationship between LPW motion parameters and the VFSS parameters of the pharyngeal phase. The mean LPW displacement of group A, B was significantly decreased than that of normal controls. The mean LPW duration of group A, B was increased than that of normal controls, but not statistically significant. The mean LPW displacement of group A was significantly correlated with the residue in valleculae, pharyngeal delay time and laryngeal elevation, but that of group B was not significantly correlated. The mean LPW duration of group A, B was not significantly correlated with the VFSS parameters of the pharyngeal phase. We suggest that LPW motion analysis could be a useful alternative method for the evaluation of the pharyngeal phase in stroke patients with a penetration or aspiration in VFSS findings.


Automated synthesis of [68Ga]oxine, improved preparation of 68Ga-labeled erythrocytes for blood-pool imaging, and preclinical evaluation in rodents.
Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities. With the coming of age of modern 68Ge/68Ga generator systems, gallium-68 is now widely accessible. In this paper we describe an updated method for the preparation of 68Ga-labeled erythrocytes and their preliminary use in rodent blood pool imaging. A novel automated synthesis of [68Ga]oxine using a 68Ga/68Ge generator and automated synthesis module is reported. [68Ga]Oxine was synthesized in 50 ± 5% (n = 3) non-decay corrected radiochemical yield and >99% radiochemical purity. Rat and human erythrocytes were successfully labeled with the complex in 42% RCY, and the 68Ga-labeled erythrocytes have been shown to clearly image the blood pool in a healthy rat. Human erythrocytes labelled with [68Ga]oxine were shown to be viable up to 2 hours post-labelling, and washout of the radiolabel was minimal up to 1 hour post-labelling. Further optimization of the labeling method to translate for use in human cardiac and oncologic blood pool PET imaging studies, is underway.


Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons.
The reactive species of oxygen and chlorine damage cellular components, potentially leading to cell death. In proteins, the sulfur-containing amino acid methionine is converted to methionine sulfoxide, which can cause a loss of biological activity. To rescue proteins with methionine sulfoxide residues, living cells express methionine sulfoxide reductases (Msrs) in most subcellular compartments, including the cytosol, mitochondria and chloroplasts. Here we report the identification of an enzymatic system, MsrPQ, repairing proteins containing methionine sulfoxide in the bacterial cell envelope, a compartment particularly exposed to the reactive species of oxygen and chlorine generated by the host defence mechanisms. MsrP, a molybdo-enzyme, and MsrQ, a haem-binding membrane protein, are widely conserved throughout Gram-negative bacteria, including major human pathogens. MsrPQ synthesis is induced by hypochlorous acid, a powerful antimicrobial released by neutrophils. Consistently, MsrPQ is essential for the maintenance of envelope integrity under bleach stress, rescuing a wide series of structurally unrelated periplasmic proteins from methionine oxidation, including the primary periplasmic chaperone SurA. For this activity, MsrPQ uses electrons from the respiratory chain, which represents a novel mechanism to import reducing equivalents into the bacterial cell envelope. A remarkable feature of MsrPQ is its capacity to reduce both rectus (R-) and sinister (S-) diastereoisomers of methionine sulfoxide, making this oxidoreductase complex functionally different from previously identified Msrs. The discovery that a large class of bacteria contain a single, non-stereospecific enzymatic complex fully protecting methionine residues from oxidation should prompt a search for similar systems in eukaryotic subcellular oxidizing compartments, including the endoplasmic reticulum.


Validation of a screening survey to assess local public health performance.
The study seeks to validate an abbreviated protocol for measuring local public health performance. Primary data were collected during 1993 on a series of indicators keyed to defined public health core functions and their associated practices. The data were obtained from responses provided by local health department directors and were reviewed for accuracy by respective state health department personnel. All local public health jurisdictions (370) in six states were surveyed with a screening protocol. A sample of 36 of these jurisdictions was then resurveyed by means of a full-length protocol using 84 different indicators of public health performance. Correlations between scores obtained from the screening survey and those from the reference survey were high for overall public health performance, for each of the three functions, and for some of the ten practices. A group of only four queries was shown to predict reliably the overall scores. Findings support the conclusion that public health practice can be defined, measured, and monitored. A proposed surveillance system is feasible.


The Ex Vivo Eye Irritation Test as an alternative test method for serious eye damage/eye irritation.
Ocular irritation testing is a common requirement for the classification, labelling and packaging of chemicals (substances and mixtures). The in vivo Draize rabbit eye test (OECD Test Guideline 405) is considered to be the regulatory reference method for the classification of chemicals according to their potential to induce eye injury. In the Draize test, chemicals are applied to rabbit eyes in vivo, and changes are monitored over time. If no damage is observed, the chemical is not categorised. Otherwise, the classification depends on the severity and reversibility of the damage. Alternative test methods have to be designed to match the classifications from the in vivo reference method. However, observation of damage reversibility is usually not possible in vitro. Within the present study, a new organotypic method based on rabbit corneas obtained from food production is demonstrated to close this gap. The Ex Vivo Eye Irritation Test (EVEIT) retains the full biochemical activity of the corneal epithelium, epithelial stem cells and endothelium. This permits the in-depth analysis of ocular chemical trauma beyond that achievable by using established in vitro methods. In particular, the EVEIT is the first test to permit the direct monitoring of recovery of all corneal layers after damage. To develop a prediction model for the EVEIT that is comparable to the GHS system, 37 reference chemicals were analysed. The experimental data were used to derive a three-level potency ranking of eye irritation and corrosion that best fits the GHS categorisation. In vivo data available in the literature were used for comparison. When compared with GHS classification predictions, the overall accuracy of the three-level potency ranking was 78%. The classification of chemicals as irritating versus non-irritating resulted in 96% sensitivity, 91% specificity and 95% accuracy.


Pain management in the paediatric population: the regulatory situation in Europe.
This study compared the availability and the licensing status of analgesic drugs marketed in three European countries (Italy, France and the UK) and evaluated the evidence on safety and efficacy in the paediatric population of the drugs reported in the European Medicines Evaluation (EMA) document "Assessment of Pediatric Needs: Pain" (2005). Ten of 17 drugs reported in the EMA document were marketed with a paediatric licence in all three countries but with wide differences concerning age groups. In all, 594 randomised controlled trials (RCTs) concerning the 17 drugs in the EMA list were found through biomedical literature databases. Bupivacaine was the drug with the most trials retrieved (171 RCTs, 29%); 32 (5%) RCTs concerned clonidine not licensed for pain control, and 51 (9%) concerned ketamine licensed for paediatric use only in the UK. Access to, and the rational use, of drugs to prevent or control pain and its functional consequences pose a considerable challenge. There is a pressing need for further research and clinical development in the assessment and management of pain in children.


Dose response association of objective physical activity with mental health in a representative national sample of adults: A cross-sectional study.
Although higher physical activity (PA) levels are associated with better mental health, previous findings about the shape of the dose-response relationship between PA and mental health are inconsistent. Furthermore, this association may differ according to sedentary levels. We investigated the cross-sectional dose-response associations between objectively measured PA and mental health in a representative national sample of adults. We also examined whether sedentary time modified the PA-mental health associations. Based on 2007-2013 Canadian Health Measures Survey data, PA and sedentary time were measured using accelerometry among 8150 participants, aged 20 to 79 years. Generalized additive models with a smooth function were fitted to examine associations between minutes per day of moderate and vigorous PA (MVPA), light PA (LPA), daily steps (combined or not with sedentary time) and self-rated mental health. A significant curvilinear relationship between average daily minutes of MVPA and mental health was observed, with increasing benefits up to 50 minutes/day. For LPA, a more complex shape (monotonic and curvilinear) was found. For daily steps, inverted U-shaped curve suggested increasing benefits until a plateau between 5 000 and 16 000 steps. The MVPA-LPA combination was significantly associated with mental health but with a complex pattern (p < 0.0005E-06). The tested PA-sedentary time combinations showed that increasing sedentary time decreased the positive PA-mental health associations. Non-linear dose-response patterns between the PA modalities and self-reported mental health were observed. Optimal doses of daily minutes of MVPA, LPA, MVPA combined with LPA and daily steps are independently associated with better mental health in adults. The results also suggest that PA-mental health associations could be hampered by daily sedentary time.


Seroprevalence and Trend of HBV, HCV, and HIV Infections among Blood Donors of Fars Province, Iran (2006-2018).
Blood transfusion is a life-saving procedure; millions of lives are saved each year. However, blood transfusions are associated with certain risks that can lead to adverse consequences. This study aimed to survey the prevalence and trend of hepatitis B virus (HBV), hepatitis C virus (HCV), and Human immunodeficiency virus (HIV) among blood donors of Fars province, Iran (2006-2018). This retrospective cross-sectional study was conducted by reviewing the records of the blood transfusion organization of Fars province. A total of 1952478 blood units were screened for transfusion-transmitted infections (TTIs). Then, data were entered into SPSS software (Negare. version 25). Chi-square test was used to compare the sof TTIs among blood donors. Chisquare test for trend was used to analyze the variations in trends of TTIs during this period. Finally, p-values less than 0.05 were considered statistically significant. GraphPad Prism software was used for the depiction of the graphs. Among the 1952478 blood donations within the 13-years, 4479(0.229 %) of donors were HBsAg, HCV Ab, and HIV Ag-Ab positive. The seroprevalence of HBV, HCV, and HIV was 2684(0.137%), 1703(0.087 %), and 92(0.0047%), respectively. The current study showed that the overall prevalence of TTIs among blood donors was low and had a descending trend over the years of study.


Dynamic covalent single chain nanoparticles based on hetero Diels-Alder chemistry.
We introduce the fully reversible folding of single chain nanoparticles (SCNPs) based on covalent hetero Diels-Alder (HDA) chemistry. A cyclopentadiene (Cp)-protected cyanodithioester (CDTE) monomer is designed and copolymerized with methyl methacrylate (MMA) via RAFT polymerization. The polymer chains are folded and subsequently unfolded by exploiting the reversible nature of the HDA reaction.


First Report of Pythium irregulare on Lentils in the United States.
In late June and early July 2002, stunted, chlorotic, and partially defoliated lentils (Lens culinaris Medik.) were observed throughout the lentil-growing areas of eastern Washington. These symptoms were investigated in two fields near Garfield, WA and one field near Genesee, ID. Cv. Mason was more affected than cv. Brewer. Roots were dry and brittle with black discoloration in some cases. Isolates of Fusarium oxysporum and F. solani were obtained from washed roots plated on water agar, but they were nonpathogenic in greenhouse testing in pasteurized field soil and peat-based growing mixes. On 21 April 2003, volunteer lentils growing in the same fields showed symptoms of root rot, and Pythium oospores were observed in the roots. Pythium spp. were isolated by using a selective medium (2). Oospores were aplerotic, intercalary, 12.6 to 21 μm long × 11.2 to 18.2 μm wide, mostly smooth, and often formed in chains. Isolates resembled P. paroecandrum Drechs. and P. irregulare Buisman on the basis of morphological characters (3), but DNA sequences of the internal transcribed spacer region were closer to P. irregulare on the basis of a comparison with a worldwide database of Pythium sequences (C. A. Lévesque, personal communication). Isolates were deposited with the USDA-ARS Western Regional Plant Introduction Station, Pullman, WA. Four hyphal-tip isolates were tested in the greenhouse with inoculum grown in autoclaved sandy loam amended with 1% ground rolled oats. Experiments were performed twice in Thatuna silt loam, first in pasteurized and then in nonpasteurized soil. Inoculum was added to the soil at 500 CFU/g, and seeds were planted on the same day. Each isolate was tested on cvs. Brewer and Mason, with five replicates per treatment. Plants were grown in 4- × 20.5-cm plastic tubes (two plants per tube) for 1 month at 16 to 22°C and supplemented with 14 h of light per day. P. irregulare was reisolated from infected roots in both experiments. Damping-off, stunting, chlorosis, and root rot were observed in the Pythium-inoculated treatments, which corresponded to symptoms observed in the field in 2002. In pasteurized soil, only one isolate reduced the whole, dry, plant weight of Brewer, but the other three isolates reduced the dry weight of Mason. All isolates reduced the root dry weight of Mason in natural soil, but only two isolates reduced the root dry weight of Brewer. To our knowledge, Pythium spp., but not P. irregulare, have been reported previously from lentils (1). P. irregulare also causes root rot on winter wheat, which is rotated with lentils, and this pathogen likely causes yield reduction in both crops. References: (1) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN, 1989. (2) S. M. Mircetich and J. M. Kraft. Mycopathol. Mycol. Appl. 50:151, 1973. (3) A. J. van der Plaats-Niterink. Stud. Mycol. 21:1, 1981.


Photoactive retinal pigments in haloalkaliphilic bacteria.
Light-induced fast transient absorbance changes were detected by time-resolved spectroscopy in 38 of 51 haloalkaliphilic isolates from alkaline salt lakes in Kenya and the Wadi Natrun in Egypt. They indicate the presence of two retinal pigments, Pf and Ps, which undergo cyclic photoreactions with half-times of 2 ms and 500 ms respectively. Pf absorbs maximally near 580 nm and Ps near 500 nm. The pigments differ in their sensitivity to hydroxylamine and detergent bleaching and the photoreactions of Pf are strongly dependent on chloride concentration. Of the 38 pigment-containing strains, 29 possess both Pf and Ps, 9 possess only Ps. Inhibition of retinal synthesis with nicotine blocks pigment formation and addition of retinal restores it. Hydroxylamine-bleached pigments can be reconstituted with retinal or retinal analogues. Their similarity to the retinal pigments of Halobacterium halobium strongly suggests that they are also rhodopsin-like retinyledene proteins. Pf in all properties tested is almost identical to halorhodopsin, the light-driven chloride pump of H. halobium, and may serve the same function in the haloalkaliphiles. Ps has photocycle kinetics similar to sensory rhodopsin and a far-blue-shifted long-lived photocycle intermediate, but its ground state absorption maximum is near 500 nm instead of 587 nm. We have not found a bacteriorhodopsin-like pigment in the haloalkaliphiles.


Serum amino acid profiles and their alterations in colorectal cancer.
Mass spectrometry-based serum metabolic profiling is a promising tool to analyse complex cancer associated metabolic alterations, which may broaden our pathophysiological understanding of the disease and may function as a source of new cancer-associated biomarkers. Highly standardized serum samples of patients suffering from colon cancer (n = 59) and controls (n = 58) were collected at the University Hospital Leipzig. We based our investigations on amino acid screening profiles using electrospray tandem-mass spectrometry. Metabolic profiles were evaluated using the Analyst 1.4.2 software. General, comparative and equivalence statistics were performed by R 2.12.2. 11 out of 26 serum amino acid concentrations were significantly different between colorectal cancer patients and healthy controls. We found a model including CEA, glycine, and tyrosine as best discriminating and superior to CEA alone with an AUROC of 0.878 (95% CI 0.815-0.941). Our serum metabolic profiling in colon cancer revealed multiple significant disease-associated alterations in the amino acid profile with promising diagnostic power. Further large-scale studies are necessary to elucidate the potential of our model also to discriminate between cancer and potential differential diagnoses. In conclusion, serum glycine and tyrosine in combination with CEA are superior to CEA for the discrimination between colorectal cancer patients and controls.


Impact of the in situ rise in hydrogen partial pressure on graphene shape evolution during CVD growth of graphene.
Exposing graphene to a hydrogen post-etching process yields dendritic graphene shapes. Here, we demonstrate that similar dendritic structures can be achieved at long growth times without adding hydrogen externally. These shapes are not a result of a surface diffusion controlled growth but of the competing backward reaction (etching), which dominates the growth dynamics at long times due to an in situ rise in the hydrogen partial pressure. We have performed a systematic study on the growth of graphene as a function of time to identify the onset and gradual evolution of graphene shapes caused by etching and then demonstrated that the etching can be stopped by reducing the flow of hydrogen from the feed. In addition, we have found that the etching rate due to the in situ rise in hydrogen is strongly dependent on the confinement (geometrical confinement) of copper foil. Highly etched graphene with dendritic shapes was observed in unconfined copper foil regions while no etching was found in graphene grown in a confined reaction region. This highlights the effect of the dynamic reactant distribution in activating the in situ etching process during growth, which needs to be counteracted or controlled for large scale growth.


Evaluation of the caries-preventive effect of toothpaste containing surface prereacted glass-ionomer filler.
Although fluoride interventions have the most consistent benefit in preventing caries, caries still develop in high-risk individuals. Authors have evaluated the effectiveness of toothpastes containing surface prereacted glass-ionomer (S-PRG) filler in preventing tooth demineralization. Human tooth enamel blocks were randomly assigned to six groups (30 blocks/group): no treatment (a), and toothpaste containing either 1500 ppm fluoride as sodium monofluorophosphate (NaMFP) (b), 0 wt% S-PRG (b), 1 wt% S-PRG (d), 5 wt% S-PRG (e), or 20 wt% S-PRG (f). Early caries developed on each block by 7-days demineralization using a microbial caries model. Mineral loss (Δz) and lesion depth (LD) were determined using transverse microradiography. Relative to the control, all toothpastes, except 0% S-PRG, significantly (analysis of variance, Tukey's, P<.0001) reduced Δz and LD at varying percentages. With regard to Δz, all comparisons were significant (P<.0001), except 0% S-PRG vs the control. Otherwise, S-PRG 1%, 5%, and 20% had 0.50, 0.37, and 0.27 times Δz compared to the control, respectively, while NaMFP had 0.61 times Δz compared to the control. LD followed an almost similar trend as Δz. The findings of the present study demonstrate the effectiveness of toothpaste containing S-PRG filler in inhibiting tooth demineralization in the presence of bacterial plaque, thus highlighting its potential as an effective caries-control tool for individuals at high risk of developing caries.


Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study.
Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine. In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556. Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively. TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials. Teva Pharmaceuticals.


Sequential fractionation of phosphorus in lake sediments of Northern Greece.
The amounts and forms of potentially mobile P in surface sediments from two lakes, Volvi and Koronia, located in Northern Greece were evaluated using a sequential chemical extraction. Five sedimentary P reservoirs were separately quantified: loosely sorbed P (NH4Cl-P); iron associated P (BD-P); calcium bound P (HCl-P); metal oxide bound P (NaOH-P) and residual P (organic and refractory P). Samples were taken in two seasons and the average concentration of the fractions of phosphorus were calculated. The results indicated that the TP content and chemically extractable phosphorus in the sediments of Koronia Lake were higher than those of Volvi Lake. Sediment TP was also strongly and positively correlated with sediment Fe. Fine-sized sediments exhibited significantly higher concentrations for both lakes than the sand fraction. The P in the surface sediment mainly consisted of HCl-P and Res-P, while NH4Cl-P and BD-P only constituted a minor part. The rank order of the different P extracts was the same for the two lakes and was Residual-P > HCl-P > NaOH-P > BD-P > NH4Cl-P.


Mesoscale Dzyaloshinskii-Moriya interaction: geometrical tailoring of the magnetochirality.
Crystals with broken inversion symmetry can host fundamentally appealing and technologically relevant periodical or localized chiral magnetic textures. The type of the texture as well as its magnetochiral properties are determined by the intrinsic Dzyaloshinskii-Moriya interaction (DMI), which is a material property and can hardly be changed. Here we put forth a method to create new artificial chiral nanoscale objects with tunable magnetochiral properties from standard magnetic materials by using geometrical manipulations. We introduce a mesoscale Dzyaloshinskii-Moriya interaction that combines the intrinsic spin-orbit and extrinsic curvature-driven DMI terms and depends both on the material and geometrical parameters. The vector of the mesoscale DMI determines magnetochiral properties of any curved magnetic system with broken inversion symmetry. The strength and orientation of this vector can be changed by properly choosing the geometry. For a specific example of nanosized magnetic helix, the same material system with different geometrical parameters can acquire one of three zero-temperature magnetic phases, namely, phase with a quasitangential magnetization state, phase with a periodical state and one intermediate phase with a periodical domain wall state. Our approach paves the way towards the realization of a new class of nanoscale spintronic and spinorbitronic devices with the geometrically tunable magnetochirality.


Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression.
Residual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays. Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8 T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (<400 copies/mL) at their 6-month visit. Adherence was measured through medication event monitoring system and calculated as the ratio of observed/prescribed device openings per participant. We fit adjusted linear regression models to estimate the association between ART adherence and the log-transformed plasma concentrations of inflammatory biomarkers. We evaluated 282 participants (median age, 35 years; 70% women). The median (interquartile range) adherence was 93% (84-98). In the adjusted analyses, for every 10% increase in average ART adherence, we found a 15% [P < 0.0001; 95% confidence interval (CI), -21.0 to -7.9], 11% (P = 0.017; 95% CI, -18.3 to -2.0), and 3% (P = 0.028; 95% CI, -5.0 to -0.3) decrease in IL-6, D-dimer, and sCD14, respectively. Higher ART adherence was associated with lower levels of biomarkers of inflammation, immune activation, and coagulopathy among Ugandans living with HIV who achieved viral suppression shortly after ART initiation. This suggests that ART adherence could have biological consequences beyond viral suppression. Whether ART adherence optimization in virologically suppressed individuals could reduce residual inflammation remains unknown.


Atg11 tethers Atg9 vesicles to initiate selective autophagy.
Autophagy recycles cytoplasmic components by sequestering them in double membrane-surrounded autophagosomes. The two proteins Atg11 and Atg17 are scaffolding components of the Atg1 kinase complex. Atg17 recruits and tethers Atg9-donor vesicles, and the corresponding Atg1 kinase complex induces the formation of nonselective autophagosomes. Atg11 initiates selective autophagy and coordinates the switch to nonselective autophagy by recruiting Atg17. The molecular function of Atg11 remained, however, less well understood. Here, we demonstrate that Atg11 is activated by cargo through a direct interaction with autophagy receptors. Activated Atg11 dimerizes and tethers Atg9 vesicles, which leads to the nucleation of phagophores in direct vicinity of cargo. Starvation reciprocally regulates the activity of both tethering factors by initiating the degradation of Atg11 while Atg17 is activated. This allows Atg17 to sequester and tether Atg9 vesicles independent of cargo to nucleate nonselective phagophores. Our data reveal insights into the molecular mechanisms governing cargo selection and specificity in autophagy.