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Antigen depot is not required for alum adjuvanticity

Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EαGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6–12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12–24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen-specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity

Element-Specific Depth Profile of Magnetism and Stoichiometry at the La0.67Sr0.33MnO3/BiFeO3 Interface

Depth-sensitive magnetic, structural and chemical characterization is important in the understanding and optimization of novel physical phenomena emerging at interfaces of transition metal oxide heterostructures. In a simultaneous approach we have used polarized neutron and resonant X-ray reflectometry to determine the magnetic profile across atomically sharp interfaces of ferromagnetic La0.67Sr0.33MnO3 / multiferroic BiFeO3 bi-layers with sub-nanometer resolution. In particular, the X-ray resonant magnetic reflectivity measurements at the Fe and Mn resonance edges allowed us to determine the element specific depth profile of the ferromagnetic moments in both the La0.67Sr0.33MnO3 and BiFeO3 layers. Our measurements indicate a magnetically diluted interface layer within the La0.67Sr0.33MnO3 layer, in contrast to previous observations on inversely deposited layers. Additional resonant X-ray reflection measurements indicate a region of an altered Mn- and O-content at the interface, with a thickness matching that of the magnetic diluted layer, as origin of the reduction of the magnetic moment.Comment: 13 pages, 4 figures, supplemental material include

Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in the US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. AA acknowledges personal funding from the UK Medical Research Council and Chief Scientist Office of the Scottish Government Health Directorates

A large interspersed repeat found in mouse DNA contains a long open reading frame that evolves as if it encodes a protein.

DNA sequence analysis of a region contained within a large, interspersed repetitive family of mice reveals a long open reading frame. This sequence extends 978 base pairs between two stop codons, creating a reading frame that is open for 326 amino acids. The DNA sequence in this region is conserved between three distantly related Mus species, as well as between mouse and monkey, in a manner that is characteristic of regions undergoing selection for protein function

The L1Md long interspersed repeat family in the mouse: almost all examples are truncated at one end

Caractérisation d'un grand élément répétitif détecté en sept localisations différentes dans le locus globine β de la souris Balb/C. Cette répétition possède la même extrémité de l'élément conservé alors que l'autre extrémité se termine en un point différent chez chaque membre de cette famille de répétitions

Overcoming challenges on an international project to advance systems engineering

The Body of Knowledge and Curriculum to Advance Systems Engineering (BKCASE) project's dual product development cycle spanned a three‐year period from the September 2009 to December, 2012. During this timeframe, BKCASE authors met quarterly at various locations, primarily in various regions of the United States, but also in Stockholm, Sweden; Toulouse, France; London, England; and Rome, Italy (BKCASE, 2009–2019). The team successfully worked through challenges and differences to produce The Guide to the Systems Engineering Body of Knowledge (SEBoK) wiki and a Graduate Reference Curriculum for Systems Engineering (GRCSE) publication. This article is a collection of personal stories from the team members that focus on overcoming obstacles to successfully produce the final published products

Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

Extensive movement of LINES ONE sequences in beta-globin loci of Mus caroli and Mus domesticus.

LINES ONE (L1) is a family of movable DNA sequences found in mammals. To measure the rate of their movement, we have compared the positions of L1 elements within homologous genetic loci that are separated by known divergence times. Two models that predict different outcomes of this analysis have been proposed for the behavior of L1 sequences. (i) Previous theoretical studies of concerted evolution in L1 have indicated that the majority of the 100,000 extant L1 elements may have inserted as recently as within the last 3 million years. (ii) Gene conversion has been proposed as an alternative to a history of prolific recent insertions. To distinguish between these two models, we cloned and characterized two embryonic beta-globin haplotypes from Mus caroli and compared them with those of M. domesticus. In 9 of 10 instances, we observed an L1 element to be present in one chromosome and absent at the same site in a homologous chromosome. This frequency is quantitatively consistent with the known rate of concerted evolution. Therefore, we conclude that gene conversion is not required for concerted evolution of the L1 family in the mouse. Furthermore, we show that the extensive movement of L1 sequences contributes to restriction fragment length polymorphism. L1 insertions may be the predominant cause of restriction fragment length polymorphisms in closely related haplotypes

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)