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Fast and robust quantum control protocols are often based on an idealized approximate description of the relevant quantum system. While this may provide a performance that is close to optimal, improvements can be made by incorporating elements of the full system representation. We propose a technique for such scenarios, called enhanced shortcuts to adiabaticity (eSTA). The eSTA method works for previously intractable Hamiltonians by providing an analytical correction to existing STA protocols. This correction can be easily calculated, and the resulting protocols are outside the class of STA schemes. We demonstrate the effectiveness of the method for three distinct cases: manipulation of an internal atomic state beyond the rotating-wave approximation, transport of a neutral atom in an optical Gaussian trap, and transport of two trapped ions in an anharmonic trap.

Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite (β-hydroxybutyrate [βHB]) rescued EAE, whereas transgenic mice unable to produce βHB in the intestine developed more severe disease. Transplantation of the βHB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 cell activation in vitro. Finally, we isolated an L. murinus strain that protected from EAE, which was phenocopied by a Lactobacillus metabolite enriched by βHB supplementation, indole lactate. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions., Competing Interests: Declaration of interests P.J.T. is on the scientific advisory boards for Pendulum, Seed, and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. P.A.C. has served as an external consultant for Pfizer, Inc., Abbott Laboratories, Janssen Research & Development, and Selah Therapeutics. J.C.N. is scientific co-founder and stockholder for BHB Therapeutics (which provided the ketone ester) and Selah Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system 1-7 , although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (T H 2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent T H 17 inflammation. We also observed divergent responses to biologic therapies targeting T H 2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in T H 2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo T H response towards a T H 2-predominant state and prevent aberrant non-T H 2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of T H 17 pathology and unlocked therapeutic responsiveness to targeted anti-T H 2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Attempts to utilise growth factors (GF) such as bone morphogenic proteins (BMPs) to treat osteoarthritis (OA) in the clinic have not secured widespread adoption. However, the novel crystalline GF formulation called PODS offers new perspectives. This study investigated the hypothesis that Polyhedrin Delivery System (PODS) BMP-2 and PODS BMP-7, compared with conventional BMP-2 and BMP-7 increase capacity for cartilage repair., Design: Sustained release from PODS BMP-2 and PODS BMP-7 and their effects on OA patient-derived cells as well as a chondrocyte cell line were first assessed in vitro. Here, extra cellular matrix (ECM) protein gene expression and actual ECM deposition were measured and compared to the effect achieved with conventional, soluble BMPs. Subsequently, in an established murine model of cartilage regeneration of the knee joint, changes were traced over 8 weeks and scored with two metrics, modified Pineda and Mankin., Results: Both crystalline PODS BMP formulations strongly induced proliferation in primary as well as immortal cell line chondrocytes, outperforming conventional soluble BMP-2 and BMP-7. Furthermore, ECM-producing genes were upregulated and the production of ECM could be demonstrated. In the murine cartilage regeneration model, both PODS BMP-2 and PODS-BMP-7 improved cartilage repair assessed with both histological scoring methods., Conclusions: This study showed that the sustained release of GF from PODS BMPs is effective in promoting chondrogenesis in vitro . The small animal data suggests that this novel approach of delivering therapeutic proteins sustainably and locally to the knee has promise for developing future disease-modifying therapies of OA., Competing Interests: CW, CM, CP and MJ work for the company Cell Guidance Systems (CellGS) developing PODS® proteins. FH is a scientific advisor to CellGS and AM has no affiliation with CellGS or other commercial interests related to this study. The work reported in this study is the subject of a patent application., (© 2022 The Authors.)

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.

The spatial and temporal availability of cytokines, and the microenvironments this creates, is critical to tissue development and homeostasis. Creating concentration gradients in vitro using soluble proteins is challenging as they do not provide a self-sustainable source. To mimic the sustained cytokine secretion seen in vivo from the extracellular matrix (ECM), we encapsulated a cargo protein into insect virus-derived proteins to form nanoparticle co-crystals and studied the release of this cargo protein mediated by matrix metalloproteinase-2 (MMP-2) and MMP-8. Specifically, when nerve growth factor (NGF), a neurotrophin, was encapsulated into nanoparticles, its release was promoted by MMPs secreted by a PC12 neuronal cell line. When these NGF nanoparticles were spotted onto a cover slip to create a uniform circular field, movement and alignment of PC12 cells via their extended axons along the periphery of the NGF nanoparticle field was observed. Neural cell differentiation was confirmed by the expression of specific markers of tau, neurofilament, and GAP-43. Connections between the extended axons and the growth cones were also observed, and expression of connexin 43 was consistent with the formation of gap junctions. Extensions and connection of very fine filopodia occurred between growth cones. Our studies indicate that crystalline protein nanoparticles can be utilized to generate a highly stable cytokine gradient microenvironment that regulates the alignment and differentiation of nerve cells. This technique greatly simplifies the creation of protein concentration gradients and may lead to therapies for neuronal injuries and disease.

Sclerostin is a clinically important protein with key functions in the musculoskeletal system playing a key role in bone formation and remodelling. Whilst a wide range of mechanisms have been identified which regulate sclerostin expression, little is known about the degradation of the protein. The aim of this study was to identify enzymes capable of degrading sclerostin in peridontal ligament (PDL) fibroblasts cells in vitro and to investigate the functionality of these enzymes. We have demonstrated that cathepsin K cleaves sclerostin in vitro in PDL. We have shown that cathepsin K and sclerostin are co-localised in PDL cells and, using cathepsin K knockdown experiments, we have shown that cathepsin K actively controls sclerostin levels in these cells, through a lysosomal mechanism that is affected by hypoxia. These results are the first description of the degradative control of sclerostin in musculoskeletally derived cells in vitro and suggest that degradation of the protein may well play an important role in the control of bone formation and remodelling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sclerostin is widely reported to be a monomeric osteocyte specific protein. In this study we have investigated whether sclerostin is produced in different forms and in which cell and tissue types they are produced. We have demonstrated that recombinant sclerostin is composed of monomers and dimers, and that these, and other forms, notably 46 and 70 kDa forms, are found widely throughout the musculo-skeletal system. We have shown that 'dimeric' sclerostin is highly resistant to reduction, implying the presence of highly stable, non-reducible covalent bonds. We have also demonstrated that the form of sclerostin is not associated with the mineralisation state of the tissue or cell. Sclerostin was secreted by bone explants as high molecular weight forms that were reducible to the dimeric form. This dimeric form was detected in sera and in non-skeletal soft tissues specifically kidney, live, heart and lung. We therefore hypothesise: (a) sclerostin exists in multiple forms not associated with the mineralised state of the cell/tissue and (b) circulating sclerostin is dimeric, as is the sclerostin found in non-musculoskeletal soft tissues. These observations may have significant implications for the therapeutic modulation of sclerostin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Foreword: The UK Department for International Development (DFID) is committed to investing in research to combat poverty, reduce high mortality and morbidity in resource poor contexts and support progress towards meeting the Millennium Development Goals. Research helps us to identify what works, what does not work and how to understand the local context when introducing new ways of working. There is no point doing research if the findings do not get into policy and practice. DFID strongly encourages all research programmes to consider research uptake activities as an integral part of the research.This special supplement draws on the work of the Sexual Health HIV Evidence into Practice (SHHEP) initiative. SHHEP is a collaboration across four DFID Research Programme Consortia (RPC) that undertake research and action on HIV and Sexual and Reproductive Health in resource poor contexts. Each consortium consists of 5 or more research, advocacy or service provider institutions from the south and the north working together over a five year period on critical areas of sexual and reproductive health. The essence of SHHEP is to share learning on research uptake and research engagement in Sexual and Reproductive Health, including HIV. The group has formulated a range of targeted mechanisms to communicate health research to different audiences and spearhead change, and were finalists for the British Medical Journal 2010 Getting Research into Practice (GRiP) prize.The papers in this special supplement focus on lesson learning on getting research into policy and practice. They highlight the range of methodologies and approaches researchers and communication specialists have used in different contexts to try to ensure research does not simply gather dust on library shelves but feeds into and is relevant to policy and practice in different contexts (for example South Africa, Swaziland, Tanzania, Uganda, Malawi, Ghana, Bangladesh) and on a diversity of topic areas (Gender based violence, sexualities, orphans and vulnerable children, HIV care and treatment including male circumcision, cotrimoxazole and links with nutrition).The work reported in this supplement provides examples of approaches that have been tried and from which other researchers can learn. They demonstrate that getting research into policy and practice is complex, dynamic and multi-faceted; and a wide range of context and issue specific conceptual and practical approaches have to be used. I hope that the innovative approaches and promising ways forward, presented in these papers, will inspire and motivate others.Professor Christopher WhittyDirector Research and Evidence DivisionDepartment for International DevelopmentDr Sue KinnHead of Health ResearchDepartment for International Development.

Objectives: To examine factors that may influence maternal and perinatal mortality associated with caesarean section in an African country., Design: A prospective observational study, conducted between January 1998 and June 2000, of 8070 caesarean sections., Setting: 25 district and 2 central hospitals in Malawi. Main outcome measures. Association between hospital type, ward or operative care, training of surgical and anaesthesia personnel, preoperative complications, method of anaesthesia, blood loss and anaesthetic technique on maternal and perinatal mortality., Results: Questionnaires were returned for 5236 caesarean sections in district and 2834 in central hospitals. 95% were emergencies, 65% for obstructed labour. Pre-operative haemorrhagic shock was present in 7.6% of women, anaemia in 6.2% and ruptured uterus in 4.1%. Previous caesarean section did not appear to predispose to ruptured uterus. There were 85 maternal deaths (1.05% mortality), 65 of which occurred postoperatively on the wards. Maternal mortality was increased with ruptured uterus (adjusted odds ratio 3.9, 95% CI 2.3-6.5), little anaesthetic training (2.3, 1.3 to 4.1) and blood loss requiring transfusion (19.3, 9-41). In mothers without preoperative haemorrhage spinal anaesthesia was associated with lower maternal mortality than general anaesthesia (0.23, 0.1-0.7). Perinatal mortality was 11.2% overall, and was significantly associated with ruptured uterus, halothane and ketamine anaesthesia., Conclusion: Maternal and perinatal mortality rates among women undergoing caesarean section in Malawi are high. Improving resuscitation in postoperative wards might reduce maternal mortality. Blood loss and pre-operative complications are both strongly associated with mortality. Spinal anaesthesia was associated with good outcome.

Microvascular sequestration was assessed in the brains of 50 Thai and Vietnamese patients who died from severe malaria (Plasmodium falciparum, 49; P. vivax, 1). Malaria parasites were sequestered in 46 cases; in 3 intravascular malaria pigment but no parasites were evident; and in the P. vivax case there was no sequestration. Cerebrovascular endothelial expression of the putative cytoadherence receptors ICAM-1, VCAM-1, E-selectin, and chondroitin sulfate and also HLA class II was increased. The median (range) ratio of cerebral to peripheral blood parasitemia was 40 (1.8 to 1500). Within the same brain different vessels had discrete but different populations of parasites, indicating that the adhesion characteristics of cerebrovascular endothelium change asynchronously during malaria and also that significant recirculation of parasitized erythrocytes following sequestration is unlikely. The median (range) ratio of schizonts to trophozoites (0.15:1; 0.0 to 11.7) was significantly lower than predicted from the parasite life cycle (P < 0.001). Antimalarial treatment arrests development at the trophozoite stages which remain sequestered in the brain. There were significantly more ring form parasites (age < 26 hours) in the cerebral microvasculature (median range: 19%; 0-90%) than expected from free mixing of these cells in the systemic circulation (median range ring parasitemia: 1.8%; 0-36.2%). All developmental stages of P. falciparum are sequestered in the brain in severe malaria.

The objective of this study is to compare data about the quantity of alcohol consumed by university undergraduates using a prospective diary with those data collected using a retrospective diary. Five hundred and ninety-eight subjects were randomly selected and divided into two groups matched for age, sex, year of study and subject group; one group received a prospective and one a retrospective questionnaire-301 students received prospective and 297 retrospective questionnaires. Sixty-eight per cent responded to the prospective and 75 per cent to the retrospective survey. There was no significant difference in the median alcohol consumption detected for men or women in this study (p = 0.13; p = 0.47). However, the prospective diary recorded a greater proportion of heavy drinkers, this difference being significant for men and women (p less than 0.05). The quantitative results of the retrospective diary are similar to those obtained by a similar method in a previous survey. The conclusion is that a prospective diary detects a greater proportion of heavy drinkers than a retrospective diary. The prospective survey may be the most appropriate method for assessing alcohol use in certain situations.