A Low Cost Magnetic Resonance Relaxometry Sensor

Magnetic resonance relaxometry, conducted by measuring relaxation parameters at different field strengths, has become an increasingly popular technique in recent years. This technique, known as field cycling, often uses expensive and large electromagnets. In this work we present a small, portable field cycling sensor. Fast field cycling is a technique that uses a varying magnetic field applied to a sample, polarising it at a high field, allowing it time to develop at a lower field and then collecting the data at the same initial high field. This causes changes in T1 and can reveal interesting proper ties of the samples not seen by traditional methods. A prototype portable magnetic resonance sensor that undertakes relaxometry measurements using fast field cycling has been developed using a combination of permanent magnets which has been used to conduct preliminary studies on a water sample. We demonstrate the effectiveness of this sensor by conducting measurements of T1 at different field strengths

UBE2QL1 is Disrupted by a Constitutional Translocation Associated with Renal Tumor Predisposition and is a Novel Candidate Renal Tumor Suppressor Gene

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gen

Non-invasive measurements of the dry solids content of whole potatoes using unilateral magnetic resonance: towards automation

Crisps or chips are considered a popular snack food around the world and at their most fundamental are potatoes which are sliced and then fried. It has been known for some time that during their production industrially, controlling the final oil content requires prior knowledge of the dry solids of the potatoes to modify the temperature and frying time to give the best product. The dry weight of a batch of potatoes is most commonly performed using a buoyancy measurement. In preliminary experiments, we have found evidence that such a measurement, whilst representative of the average dry solids, does not offer the most appropriate measurement since the variation within the batch is significant. We present an investigation into the properties of intact potatoes using magnetic resonance relaxation measurements and relate these to the dry solids content. This preliminary study will lay the groundwork for the development of an online process monitoring device based around a unilateral sensor to allow batch sorting of incoming potatoes

Domestic ventilation rates, indoor humidity and dust mite allergens : are our homes causing the asthma pandemic?

This paper is concerned with historical changes in domestic ventilation rates, relative humidity and the associated risk of house dust mite colonization. A controlled trial evaluated allergen and water vapour control measures on the level of house dust mite (HDM) Der p1 allergen and indoor humidity, concurrently with changes in lung function in 54 subjects who completed the protocol. Mechanical heat recovery ventilation units significantly reduced moisture content in the active group, while HDM allergen reservoirs in carpets and beds were reduced by circa 96%. Self reported health status confirmed a significant clinical improvement in the active group. The study can form the basis for assessing minimum winter ventilation rates that can suppress RH below the critical ambient equilibrium humidity of 60% and thus inhibit dust mite colonization and activity in temperate and maritime in' uenced climatic regions

The formation and function of the neutrophil phagosome.

Neutrophils are the most abundant circulating leukocyte and are crucial to the initial innate immune response to infection. One of their key pathogen-eliminating mechanisms is phagocytosis, the process of particle engulfment into a vacuole-like structure called the phagosome. The antimicrobial activity of the phagocytic process results from a collaboration of multiple systems and mechanisms within this organelle, where a complex interplay of ion fluxes, pH, reactive oxygen species, and antimicrobial proteins creates a dynamic antimicrobial environment. This complexity, combined with the difficulties of studying neutrophils ex vivo, has led to gaps in our knowledge of how the neutrophil phagosome optimizes pathogen killing. In particular, controversy has arisen regarding the relative contribution and integration of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived antimicrobial agents and granule-delivered antimicrobial proteins. Clinical syndromes arising from dysfunction in these systems in humans allow useful insight into these mechanisms, but their redundancy and synergy add to the complexity. In this article, we review the current knowledge regarding the formation and function of the neutrophil phagosome, examine new insights into the phagosomal environment that have been permitted by technological advances in recent years, and discuss aspects of the phagocytic process that are still under debate

Academic achievement at ages 11 and 16 in children born with congenital anomalies in England: A multi‐registry linked cohort study

Background: Children born with major congenital anomalies (CAs) have lower academic achievement compared with their peers, but the existing evidence is restricted to a number of specific CAs. Objectives: To investigate academic outcomes at ages 11 and 16 years in children with major isolated structural CAs and children with Down or Turner syndromes.Methods: This population-based cohort study linked data on approximately 11,000 school-aged children born with major CAs in 1994-2004 registered by four regional CA registries in England with education data from the National Pupil Database (NPD). The comparison group was a random sample of children without major CAs from the background population recorded in the NPD that were frequency matched (5:1) to children with CAs by birth year, sex and geographical area.Results: Overall, 71.9%, 73.0% and 80.9% of children with isolated structural CAs achieved the expected attainment level at age 11 compared to 78.3%, 80.6% and 86.7% of the comparison group in English language, mathematics and science respectively. Children with nervous system CAs as a whole had the lowest proportion who achieved the expected attainment at age 11. At age 16, 46.9% of children with CAs achieved the expected level compared to 52.5% of their peers. Major CAs were associated with being up to 9% (95% CI 8%, 11%) and 12% (95% CI 9%, 14%) less likely to achieve expected levels at ages 11 and 16 respectively, after adjustment for socioeconomic deprivation.Conclusions: Although many children with isolated CAs achieved the expected academic level at age 11 and 16 years, they were at higher risk of underachievement compared to their peers. These stark yet cautiously encouraging results are important for counselling parents of children with specific CAs and also highlight the possible need for special education support to reduce potential academic difficulties.<br/

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE Study): prospective cohort study and systematic review

OBJECTIVES: To determine the yield of antenatal exome sequencing (ES) over chromosome microarray (CMA) / conventional karyotyping in; (i) any prenatally diagnosed congenital heart disease (CHD); (ii) isolated CHD; (iii) multi‐system CHD and; (iv) CHD by phenotypic subgroup. / METHODS: A prospective cohort study of 197 trios undergoing ES following CMA/karyotype because CHD was identified prenatally and a systematic review of the literature was performed. MEDLINE, EMBASE and CINAHL (2000–Oct 2019) databases were searched electronically. Selected studies included those with; (i) >3 cases; (ii) initiation of testing based upon a prenatal phenotype only and; (iii) where CMA/karyotyping was negative. PROSPERO No. CRD42019140309. / RESULTS: In our cohort ES gave an additional diagnostic yield in; (i) all CHD; (ii) isolated CHD and; (iii) multi‐system CHD of 12.7% (n=25/197), 11.5% (n=14/122) and 14.7% (n=11/75) (p=0.81). The pooled incremental yields for the aforementioned categories from 18‐studies (n=636) were 21% (95% CI, 15‐27%), 11% (95% CI, 7‐15%) and 37% (95% CI, 18%‐56%) respectively. This did not differ significantly when sub‐analyses were limited to studies including >20 cases. In instances of multi‐system CHD in the primary analysis, the commonest extra‐cardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system 44.2% (n=23/52). Cardiac shunt lesions had the greatest incremental yield, 41% (95% CI, 19‐63%), followed by right‐sided lesions 26% (95% CI, 9‐43%). In the majority of instances pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes (68/96; 70.8%). The commonest monogenic syndrome identified was Kabuki syndrome (n=19/96; 19.8%). / CONCLUSIONS: Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Whilst the greatest yield is with multi‐system anomalies, consideration may also be given to performing ES in the presence of isolated cardiac abnormalities

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

OBJECTIVE: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd

A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity

African sleeping sickness is a disease found in sub-Saharan Africa that is caused by the single-celled parasite Trypanosoma brucei. The drugs used widely now to treat infections are 50 years old and notable for their toxicity, emphasizing the need for development of new therapeutics. In the search for potential drug targets, researchers typically focus on enzymes or proteins that are essential to the survival of the infectious agent while being distinct enough from the host to avoid accidental targeting of the host enzyme. This work describes our research on one such trypanosome enzyme, hexokinase, which is a protein that the parasite requires to make energy. Here we describe the results of our search for inhibitors of the parasite enzyme. By screening 220,223 compounds for anti-hexokinase activity, we have identified new inhibitors of the parasite enzyme. Some of these are toxic to trypanosomes while having no effect on mammalian cells, suggesting that they may hold promise for the development of new anti-parasitic compounds