Publications by authors named "Hannah Smith"

82 Publications

Trichuris muris infection drives cell-intrinsic IL4R alpha independent colonic RELMα+ macrophages.

PLoS Pathog 2021 Jul 30;17(7):e1009768. Epub 2021 Jul 30.

Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection.
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http://dx.doi.org/10.1371/journal.ppat.1009768DOI Listing
July 2021

Diabetes distress and glycaemic control in young adults with type 1 diabetes: associations by use of insulin pumps and continuous glucose monitors.

Diabet Med 2021 Jul 26:e14660. Epub 2021 Jul 26.

Columbia-Bassett Program, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Aims: We determined whether high diabetes distress (DD) in young adults with type 1 diabetes was associated with higher glycated haemoglobin (HbA ) levels and whether this association was similar among those who were and were not using diabetes devices (insulin pumps and/or continuous glucose monitors [CGMs]).

Methods: In 2017 an online survey was completed by 423 of 743 (57%) young adults (19-31 years) with type 1 diabetes receiving care at a specialty clinic in New York City. HbA level was the primary outcome measure, and high DD (Diabetes Distress Scale score ≥3) was the primary exposure. Associations were adjusted for sociodemographic covariates.

Results: Of the 419 respondents with complete DD data, 59% were female and 69% were non-Hispanic white. Both devices (pump and CGM) were used by 35%, either device by 42%, and neither device by 24%. The mean (SD) HbA was 64 (19) mmol/mol [8.0 (1.7) %], and 24% had high DD. The adjusted mean (95% confidence interval) HbA was 10 (6, 14) mmol/mol [0.9 (0.5, 1.2) %] greater in those with high DD than in those without it. This HbA difference associated with high DD was similar regardless of device use: 9 (3, 15) mmol/mol [0.8 (0.3, 1.4) %] greater among those using both devices; and 9 (-0.9, 18) mmol/mol [0.8 (-0.1, 1.7) %] greater among those using neither device.

Conclusions: High DD in young adults requires more attention because it is associated with higher HbA levels, even among those using insulin pumps and CGMs.
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http://dx.doi.org/10.1111/dme.14660DOI Listing
July 2021

B-lines beyond the thoracic cavity - ultrasound identification of intercostal pulmonary hernia.

J Clin Ultrasound 2021 Jul 12. Epub 2021 Jul 12.

International University of the Health Sciences, Basseterre, Saint Kitts and Nevis.

Intercostal pulmonary hernia is a rare condition that may present to the emergency department spontaneously, following blunt trauma or as a complication of thoracic surgery. With the evolution of minimally invasive thoracic surgery pulmonary hernia may become more common. In this case of postoperative chest pain, incisional swelling, and shortness of breath, we present the ultrasound characteristics of a postoperative intercostal pulmonary hernia and its resemblance to subcutaneous emphysema.
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http://dx.doi.org/10.1002/jcu.23035DOI Listing
July 2021

Screening by single-molecule molecular inversion probes targeted sequencing panel of candidate genes of infertility in azoospermic infertile Jordanian males.

Hum Fertil (Camb) 2021 Jun 30:1-8. Epub 2021 Jun 30.

Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Infertility is a common health problem that affects around 1 in 6 couples in the United States, where half of these cases are attributed to male factors. Genetics play an important role in infertility and it is estimated that up to 50% of cases are due to genetic factors. Despite this, many male infertility cases are still idiopathic. This study aimed to identify the presence of possibly pathogenic rare variants in a set of candidate genes related to azoospermia in 69 Jordanian men using a next-generation sequencing-based panel covering more than a hundred male infertility related genes. A total of 9 variants were found and validated. Among them, two variants included reported pathogenic variants in and one novel pathogenic variant in the gene. We also report the detection of 6 other variants with uncertain significance in other genes. Interestingly, male cases with variants did not show the expected cystic fibrosis phenotypes except for infertility. This work helps to uncover the contribution of additional genetic factors to the aetiology of male infertility and highlights the importance to obtain more reliable information about the presence of genetic variation in the Jordanian population.
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http://dx.doi.org/10.1080/14647273.2021.1946173DOI Listing
June 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Jun 14. Epub 2021 Jun 14.

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
June 2021

Genome-Wide Screening of Oxidizing Agent Resistance Genes in .

Antioxidants (Basel) 2021 May 27;10(6). Epub 2021 May 27.

Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR 72701, USA.

The use of oxidizing agents is one of the most favorable approaches to kill bacteria in daily life. However, bacteria have been evolving to survive in the presence of different oxidizing agents. In this study, we aimed to obtain a comprehensive list of genes whose expression can make cells resistant to different oxidizing agents. For this purpose, we utilized the ASKA library and performed a genome-wide screening of ~4200 genes. Hydrogen peroxide (HO) and hypochlorite (HOCl) were tested as representative oxidizing agents in this study. To further validate our screening results, we used different strains as host cells to express or inactivate selected resistance genes individually. More than 100 genes obtained in this screening were not known to associate with oxidative stress responses before. Thus, this study is expected to facilitate both basic studies on oxidative stress and the development of antibacterial agents.
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http://dx.doi.org/10.3390/antiox10060861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228696PMC
May 2021

YML018C protein localizes to the vacuolar membrane independently of Atg27p.

MicroPubl Biol 2021 May 12;2021. Epub 2021 May 12.

Department of Biology, High Point University, High Point, NC, USA 27268.

The function of the budding yeast YML018C protein remains to be determined. High-throughput studies have reported that the YML018C protein localizes to the vacuolar membrane and physically interacts with the autophagy-related protein Atg27p. While this evidence suggests a potential role for this uncharacterized protein in the process of autophagy, the function of this putative interaction remains uncharacterized. In this micropublication, we report our finding that the localization of the YML018C protein to the vacuolar membrane does not require Atg27p.
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http://dx.doi.org/10.17912/micropub.biology.000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116935PMC
May 2021

Automated in vivo drug screen in zebrafish identifies synapse-stabilising drugs with relevance to spinal muscular atrophy.

Dis Model Mech 2021 Apr 26;14(4). Epub 2021 Apr 26.

Centre for Discovery Brain Sciences, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB.

Synapses are particularly vulnerable in many neurodegenerative diseases and often the first to degenerate, for example in the motor neuron disease spinal muscular atrophy (SMA). Compounds that can counteract synaptic destabilisation are rare. Here, we describe an automated screening paradigm in zebrafish for small-molecule compounds that stabilize the neuromuscular synapse in vivo. We make use of a mutant for the axonal C-type lectin chondrolectin (chodl), one of the main genes dysregulated in SMA. In chodl-/- mutants, neuromuscular synapses that are formed at the first synaptic site by growing axons are not fully mature, causing axons to stall, thereby impeding further axon growth beyond that synaptic site. This makes axon length a convenient read-out for synapse stability. We screened 982 small-molecule compounds in chodl chodl-/- mutants and found four that strongly rescued motor axon length. Aberrant presynaptic neuromuscular synapse morphology was also corrected. The most-effective compound, the adenosine uptake inhibitor drug dipyridamole, also rescued axon growth defects in the UBA1-dependent zebrafish model of SMA. Hence, we describe an automated screening pipeline that can detect compounds with relevance to SMA. This versatile platform can be used for drug and genetic screens, with wider relevance to synapse formation and stabilisation.
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http://dx.doi.org/10.1242/dmm.047761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106959PMC
April 2021

The emerging norms of e-cigarette use among adolescents: A meta-ethnography of qualitative evidence.

Int J Drug Policy 2021 Mar 26;94:103227. Epub 2021 Mar 26.

School of Social and Political Science, University of Edinburgh, UK.

While qualitative research has indicated that adolescents' motivation for e-cigarette use is different than adults', this body of literature has not yet been brought together and synthesised. We reviewed qualitative evidence on perceptions and uses of e-cigarettes in order to explore the emerging norms of vaping among adolescents. We searched five databases for qualitative research in October 2019 with no restrictions on date of publication or data collection. We identified fifteen papers from thirteen studies. Using a meta-ethnographic approach, we identified a spectrum of descriptive and injunctive norms of vaping across the themes of addiction; perceptions of comparative harm; parental perceptions and peer perceptions. We found addiction and perceptions of comparative harm to reflect descriptive norms, while we found clearer evidence explaining the use and non-use of e-cigarettes through parental and peer approval of vaping. However, these norms were fluid, diverse and sometimes contradictory. This review provides a resource for researchers, policymakers and practitioners to better understand the ways that emerging norms could be influenced through policy and practice.
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http://dx.doi.org/10.1016/j.drugpo.2021.103227DOI Listing
March 2021

The utilisation of glutamine and glucose by a 3-D tumour model trapped in quiescence.

Int J Biochem Cell Biol 2021 Apr 30;133:105935. Epub 2021 Jan 30.

Nuffield Department of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Research School of Biology, and the Medical School, Australian National University Canberra, ACT 2601, Australia. Electronic address:

Solid tumours modify their metabolic strategy to ensure sufficient biomass and energy to maintain a high rate of proliferation. However, solid tumours are characterised by a high proportion of quiescent cells and little is known about their metabolic profile. A tumour spheroid model with DLD1 cells was used to investigate the influence of a quiescent state on the cellular utilisation of glucose and glutamine. Quiescent DLD1 spheroids displayed increased depletion of both nutrients from the bathing medium compared to their proliferative counterparts and displayed highly active overall metabolism. A combination of biochemical and metabolomics approaches demonstrated that glucose utilisation resulted in an increased production of the 3-carbon intermediates lactate and alanine in quiescent spheroids. In addition, glutamine metabolism was directed to anabolic pathways; including the "reverse TCA cycle" to produce citrate for fatty-acid synthesis. These adaptations in DLD1 spheroids may propose a metabolic altruism of quiescent regions in solid tumours to provide biosynthetic intermediates required to sustain tumour growth, angiogenesis and metastasis.
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http://dx.doi.org/10.1016/j.biocel.2021.105935DOI Listing
April 2021

Domain binding and isotype dictate the activity of anti-human OX40 antibodies.

J Immunother Cancer 2020 12;8(2)

Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK

Background: Previous data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. Human trials with anti-OX40 antibodies have shown that these entities are well tolerated but to date have delivered disappointing clinical responses, indicating that the rules for the optimal use of anti-human OX40 (hOX40) antibodies is not yet fully understood. Changes to timing and dosages may lead to improved outcomes; however, here we focus on addressing the role of agonism versus depleting activity in determining therapeutic outcomes. We investigated a novel panel of anti-hOX40 mAb to understand how these reagents and mechanisms may be optimized for therapeutic benefit.

Methods: This study examines the binding activity and in vitro activity of a panel of anti-hOX40 antibodies. They were further evaluated in several in vivo models to address how isotype and epitope determine mechanism of action and efficacy of anti-hOX40 mAb.

Results: Binding analysis revealed the antibodies to be high affinity, with epitopes spanning all four cysteine-rich domains of the OX40 extracellular domain. In vivo analysis showed that their activities relate directly to two key properties: (1) isotype-with mIgG1 mAb evoking receptor agonism and CD8+ T-cell expansion and mIgG2a mAb evoking deletion of Treg and (2) epitope-with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumor models by engaging these different mechanisms.

Conclusion: These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T-cell expansion or Treg depletion might be preferred according to the composition of different tumors. As many of the current clinical trials using OX40 antibodies are now using combination therapies, this understanding of how to manipulate therapeutic activity will be vital in directing new combinations that are more likely to improve efficacy and clinical outcomes.
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http://dx.doi.org/10.1136/jitc-2020-001557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754644PMC
December 2020

Draft Genome Sequences of Four Isolates Recovered from Wild Australian Shorebirds.

Microbiol Resour Announc 2021 Jan 7;10(1). Epub 2021 Jan 7.

School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia

is a ubiquitous bacterial genus whose members inhabit a variety of niches. Some species are clinically important for both antimicrobial resistance (AMR) carriage and as the cause of nosocomial infections. Surveillance of species in the environment can provide indicators of the spread of AMR genes outside clinical spaces. In this study, we present draft genome sequences of four isolates obtained from three species of wild Australian shorebirds.
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http://dx.doi.org/10.1128/MRA.01113-20DOI Listing
January 2021

Improving trainee engagement in science: Lessons from a virtual seminar series.

Authors:
Hannah J Smith

Transl Med Aging 2020 27;4:76-77. Epub 2020 Jun 27.

Harvard T.H. Chan School of Public Health, Department of Molecular Metabolism, United States.

To be a successful researcher, you are expected to have important skills beyond the bench such as being able to ask questions, talk about science with your peers, and organize scientific events. However, there is frequently little to no training or emphasis on these skills at the student and postdoc level. The virtual Aging Science Talks seminar series and Slack group have benefitted the scientific community in many ways amidst the chaos of coronavirus quarantines and lab shutdowns, but as a 2 year PhD student, I was particularly excited about how this format was able to engage trainees. We should end the era of trainees sitting at the back of the room while PIs dominate discussions and Q&A sessions with speakers. Reflecting on the advantages of Aging Science Talks can show us how to make future scientific events more engaging and inclusive for everyone.
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http://dx.doi.org/10.1016/j.tma.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695127PMC
June 2020

Improving trainee engagement in science: Lessons from a virtual seminar series.

Authors:
Hannah J Smith

Transl Med Aging 2020 27;4:76-77. Epub 2020 Jun 27.

Harvard T.H. Chan School of Public Health, Department of Molecular Metabolism, United States.

To be a successful researcher, you are expected to have important skills beyond the bench such as being able to ask questions, talk about science with your peers, and organize scientific events. However, there is frequently little to no training or emphasis on these skills at the student and postdoc level. The virtual Aging Science Talks seminar series and Slack group have benefitted the scientific community in many ways amidst the chaos of coronavirus quarantines and lab shutdowns, but as a 2 year PhD student, I was particularly excited about how this format was able to engage trainees. We should end the era of trainees sitting at the back of the room while PIs dominate discussions and Q&A sessions with speakers. Reflecting on the advantages of Aging Science Talks can show us how to make future scientific events more engaging and inclusive for everyone.
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http://dx.doi.org/10.1016/j.tma.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695127PMC
June 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

The Role of Pre-Clinical 3-Dimensional Models of Osteosarcoma.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Bone and Joint Group, Institute for Developmental Sciences, University of Southampton, Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.

Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.
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http://dx.doi.org/10.3390/ijms21155499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432883PMC
July 2020

Salmonella enterica Serovar Hvittingfoss in Bar-Tailed Godwits (Limosa lapponica) from Roebuck Bay, Northwestern Australia.

Appl Environ Microbiol 2020 09 17;86(19). Epub 2020 Sep 17.

School of Health and Life Sciences, Federation University, Churchill, Victoria, Australia

serovar Hvittingfoss is an important foodborne serotype of , being detected in many countries where surveillance is conducted. Outbreaks can occur, and there was a recent multistate foodborne outbreak in Australia. Hvittingfoss can be found in animal populations, though a definitive animal host has not been established. Six species of birds were sampled at Roebuck Bay, a designated Ramsar site in northwestern Australia, resulting in 326 cloacal swabs for bacterial culture. Among a single flock of 63 bar-tailed godwits () caught at Wader Spit, Roebuck Bay, in 2018, 17 (27%) were culture positive for All other birds were negative for The isolates were identified as serovar Hvittingfoss. Phylogenetic analysis revealed a close relationship between isolates collected from godwits and the Hvittingfoss strain responsible for a 2016 multistate foodborne outbreak originating from tainted cantaloupes (rock melons) in Australia. While it is not possible to determine how this strain of Hvittingfoss was introduced into the bar-tailed godwits, these findings show that wild Australian birds are capable of carrying strains of public health importance. is a zoonotic pathogen that causes gastroenteritis and other disease presentations in both humans and animals. Serovars of commonly cause foodborne disease in Australia and globally. In 2016-2017, Hvittingfoss was responsible for an outbreak that resulted in 110 clinically confirmed human cases throughout Australia. The origin of the contamination that led to the outbreak was never definitively established. Here, we identify a migratory shorebird, the bar-tailed godwit, as an animal reservoir of Hvittingfoss. These birds were sampled in northwestern Australia during their nonbreeding period. The presence of a genetically similar Hvittingfoss strain circulating in a wild bird population, 2 years after the 2016-2017 outbreak and ∼1,500 km from the suspected source of the outbreak, demonstrates a potentially unidentified environmental reservoir of Hvittingfoss. While the birds cannot be implicated in the outbreak that occurred 2 years prior, this study does demonstrate the potential role for wild birds in the transmission of this important foodborne pathogen.
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http://dx.doi.org/10.1128/AEM.01312-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499044PMC
September 2020

Improving the Timeliness and Safety of Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy.

Pediatr Qual Saf 2020 May-Jun;5(3):e283. Epub 2020 May 12.

Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Md.

Introduction: Therapeutic hypothermia (TH) is a time-sensitive, efficacious treatment for newborns who experience perinatal hypoxic-ischemic encephalopathy. Optimal management of patient temperatures during TH may improve newborn outcomes and reduce side effects. We noted that patients undergoing TH were often outside of the target temperature range during treatment. This project sought to improve the timely initiation of effective treatment and temperature stability during TH through system-based changes in practice.

Methods: Measures include the time to target temperature, the percentage of core temperatures outside of the target range, and the absolute difference between core and peripheral temperatures over 41 months. System-based changes in the TH protocol included changing from passive to active hypothermia on transport and utilizing a delivery mode that uses more gradual temperature fluctuations during TH. We compared measures of health status and side effects as balancing measures.

Results: The TH protocol changes resulted in a significant reduction of time to goal temperature from 1.67 to 0.49 hours, in the percentage of temperature readings outside goal range from 12.6% to 6.3%, and the average absolute difference between core and peripheral temperatures from 1.78°C to 1.47°C. No adverse health outcomes were detected. We observed decreases in vasopressor use with each protocol change.

Conclusions: This study demonstrates that detailed attention to the method of delivery of TH has an impact on ensuring effective delivery of therapy and minimizing the risks of treatment. The protocol changes were not associated with an increase in adverse events and were associated with a reduction in vasopressor use.
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http://dx.doi.org/10.1097/pq9.0000000000000283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297405PMC
May 2020

Metabolic Communication and Healthy Aging: Where Should We Focus Our Energy?

Dev Cell 2020 07 2;54(2):196-211. Epub 2020 Jul 2.

Harvard T.H. Chan School of Public Health, Department of Molecular Metabolism, Boston, MA, USA. Electronic address:

Aging is associated with a loss of metabolic homeostasis and plasticity, which is causally linked to multiple age-onset pathologies. The majority of the interventions-genetic, dietary, and pharmacological-that have been found to slow aging and protect against age-related disease in various organisms do so by targeting central metabolic pathways. However, targeting metabolic pathways chronically and ubiquitously makes it difficult to define the downstream effects responsible for lifespan extension and often results in negative effects on growth and health, limiting therapeutic potential. Insight into how metabolic signals are relayed between tissues, cells, and organelles opens up new avenues to target metabolic regulators locally rather than globally for healthy aging. In this review, we discuss the pro-longevity effects of targeting metabolic pathways in specific tissues and how these interventions communicate with distal cells to modulate aging. These studies may be crucial in designing interventions that promote longevity without negative health consequences.
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http://dx.doi.org/10.1016/j.devcel.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168458PMC
July 2020

DNA damage checkpoint kinases in cancer.

Expert Rev Mol Med 2020 06 8;22:e2. Epub 2020 Jun 8.

Newcastle Centre for Cancer Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.
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http://dx.doi.org/10.1017/erm.2020.3DOI Listing
June 2020

Exploring the Synergy between PARP and CHK1 Inhibition in Matched Mutant and Corrected Cells.

Cancers (Basel) 2020 Apr 4;12(4). Epub 2020 Apr 4.

Newcastle Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

PARP inhibition results in the accumulation of DNA SSBs, causing replication stress (RS) and lesions that can only be resolved by homologous recombination repair (HRR). Defects in HRR, e.g., due to mutation, confer profound sensitivity to PARP inhibitor (PARPi) cytotoxicity. In response to RS, CHK1 is activated to signal to S and G2/M cell cycle checkpoints and also to HRR. To determine the relative contribution of these two functions of CHK1 to survival following PARPi exposure, we investigated the effects of rucaparib (a PARPi) and PF-477736 (a CHK1 inhibitor) alone and in combination in cells with mutated and corrected . The mutated V-C8 cells were 1000× more sensitive to rucaparib cytotoxicity than their matched corrected V-C8.B2 cells, but no more sensitive to PF-477736 despite having seven-fold higher levels of RS. PF-477736 caused a five-fold enhancement of rucaparib cytotoxicity in the V-C8.B2 cells, but no enhancement in the V-C8 cells. This differential sensitivity was not due to a difference in PARP1 or CHK1 expression or activity. PF-477736 increased rucaparib-induced RS (γH2AX foci) and completely inhibited RAD51 focus formation, indicating a profound suppression of HRR. Our data suggested that inhibition of HRR was the main mechanism of sensitisation to rucaparib, compounded with an inhibition of cell cycle checkpoints by PF-477736.
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http://dx.doi.org/10.3390/cancers12040878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226483PMC
April 2020

In silico design of a T-cell epitope vaccine candidate for parasitic helminth infection.

PLoS Pathog 2020 03 23;16(3):e1008243. Epub 2020 Mar 23.

Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Trichuris trichiura is a parasite that infects 500 million people worldwide, leading to colitis, growth retardation and Trichuris dysentery syndrome. There are no licensed vaccines available to prevent Trichuris infection and current treatments are of limited efficacy. Trichuris infections are linked to poverty, reducing children's educational performance and the economic productivity of adults. We employed a systematic, multi-stage process to identify a candidate vaccine against trichuriasis based on the incorporation of selected T-cell epitopes into virus-like particles. We conducted a systematic review to identify the most appropriate in silico prediction tools to predict histocompatibility complex class II (MHC-II) molecule T-cell epitopes. These tools were used to identify candidate MHC-II epitopes from predicted ORFs in the Trichuris genome, selected using inclusion and exclusion criteria. Selected epitopes were incorporated into Hepatitis B core antigen virus-like particles (VLPs). Bone marrow-derived dendritic cells and bone marrow-derived macrophages responded in vitro to VLPs irrespective of whether the VLP also included T-cell epitopes. The VLPs were internalized and co-localized in the antigen presenting cell lysosomes. Upon challenge infection, mice vaccinated with the VLPs+T-cell epitopes showed a significantly reduced worm burden, and mounted Trichuris-specific IgM and IgG2c antibody responses. The protection of mice by VLPs+T-cell epitopes was characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines and goblet cell hyperplasia. Collectively our data establishes that a combination of in silico genome-based CD4+ T-cell epitope prediction, combined with VLP delivery, offers a promising pipeline for the development of an effective, safe and affordable helminth vaccine.
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http://dx.doi.org/10.1371/journal.ppat.1008243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117776PMC
March 2020

Association of Childhood Family Connection With Flourishing in Young Adulthood Among Those With Type 1 Diabetes.

JAMA Netw Open 2020 03 2;3(3):e200427. Epub 2020 Mar 2.

Columbia-Bassett Program, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York.

Importance: Higher levels of childhood family connection have been associated with measures of adult flourishing or eudaimonic well-being, such as purpose, self-acceptance, positive relationships, and growth. However, this association has not been examined among those with childhood-onset chronic disease.

Objectives: To investigate whether higher levels of childhood family connection were associated with greater flourishing in young adulthood among those with type 1 diabetes and, secondarily, whether this association was present across levels of adverse childhood experiences and childhood social position.

Design, Setting, And Participants: In 2017, the cross-sectional Type 1 Flourish survey was administered to all 743 young adults, aged 18 to 29 years, with type 1 diabetes who had received outpatient care in 2016 at a diabetes specialty clinic in New York, New York. Eligible participants completed the survey online or during clinic visits. Data analyses were conducted in September and October 2019.

Exposures: The main exposure was childhood family connection (sample-defined tertiles), based on scores from a 7-item scale assessing parental attention, affection, and communication during childhood. Adverse childhood experiences, childhood social position, and other sociodemographic characteristics were also reported. Recent hemoglobin A1c levels were abstracted from medical records.

Main Outcomes And Measures: Flourishing score calculated from the 42-item Psychological Well-being Scale developed by Ryff.

Results: The survey was completed by 423 of 743 patients (56.9%), and the analysis included 415 participants (98.1%) with complete data on family connection and flourishing. The mean (SD) age of the sample was 25.0 (3.2) years, with 246 (59.3%) female respondents and 288 (69.6%) non-Hispanic white respondents. The mean (SD) flourishing score was 221.8 (37.7). After adjusting for age, sex, race/ethnicity, education, income, age at type 1 diabetes diagnosis, and hemoglobin A1c level, mean flourishing scores increased from the lowest (201.0; 95% CI, 195.0-207.0) to medium (225.2; 95% CI, 219.4-231.0) to highest (240.4; 95% CI, 234.4-246.4) tertiles of family connection; compared with those in the lowest tertile of family connection, the flourishing scores were 1.04 (95% CI, 0.81-1.27) SD units higher among those in the highest tertile and 0.64 (95% CI, 0.42-0.86) SD units higher among those in the middle tertile. This association was also present across levels of childhood adversity. In the subgroup of respondents with 2 or more adverse childhood experiences, those in the highest tertile of family connection had adjusted flourishing scores 0.76 (95% CI, 0.14-1.38) SD units higher than those in the lowest tertile. In the subgroup with low childhood social position, those in the highest tertile of family connection had flourishing scores 1.08 (95% CI, 0.63-1.52) SD units higher than those in the lowest tertile.

Conclusions And Relevance: In this cross-sectional study of young adults with type 1 diabetes, higher levels of childhood family connection were associated with greater flourishing in young adulthood across levels of childhood adversity. Beyond disease management, clinician support of family connection may help children with type 1 diabetes flourish in adulthood.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.0427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059021PMC
March 2020

The association between dispositional mindfulness and glycemic control in type 1 diabetes during early adulthood: Differences by age and adverse childhood experiences.

Pediatr Diabetes 2020 06 16;21(4):681-691. Epub 2020 Mar 16.

Columbia-Bassett Program, Cooperstown, New York, USA.

Background: The study objective was to determine whether higher levels of dispositional mindfulness were associated with lower HbA levels among young adults with type 1 diabetes (T1D) and whether this association differed by age or exposure to adverse childhood experiences (ACEs).

Methods: An online cross-sectional survey, called T1 Flourish, was completed in 2017 by 423 of 743 (56.9%) young adults (19-31 years) with T1D receiving outpatient care at a diabetes specialty clinic in New York City. HbA levels were abstracted from medical records. Respondents were categorized by age, high and low dispositional mindfulness (median split on Cognitive and Affective Mindfulness Scale-Revised), and exposure to any of 10 ACEs.

Results: Respondents had a mean (SD) HbA of 64 (18) mmol/mol [8.0 (1.7)%]; 59.3% were female and 69.4% were non-Hispanic white. The covariate-adjusted association between dispositional mindfulness and HbA differed by age group and ACEs. Among 27- to 31-year-olds, those with high mindfulness had HbA levels that were 8 mmol/mol [0.7%] lower (95% confidence interval, 2-13 mmol/mol [0.2-1.2%]) than those with low mindfulness, and this association tended to be stronger in those with ≥1 ACEs. Weaker, non-significant associations in the same direction occurred in 23- to 26-year-olds. Among 19- to 22-year-olds, those with high mindfulness and no ACEs tended to have higher HbA levels.

Conclusions: In young adults with T1D, higher mindfulness was significantly associated with lower HbA only among 27- to 31-year-olds. In early adulthood, the impact of mindfulness-based interventions on glycemic control may vary by age and childhood trauma history.
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http://dx.doi.org/10.1111/pedi.13000DOI Listing
June 2020

Correction to: The effects of regenerative injection therapy compared to corticosteroids for the treatment of lateral Epicondylitis: a systematic review and meta-analysis.

Arch Physiother 2020;10. Epub 2020 Jan 27.

Department of Physical Therapy, School of Health Professions, UT Health San Antonio, 7703 Floyd Curl Drive, MSC 6247, San Antonio, TX 78229 USA.

[This corrects the article DOI: 10.1186/s40945-019-0063-6.].
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http://dx.doi.org/10.1186/s40945-020-0076-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986154PMC
January 2020

A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.

Nat Neurosci 2020 03 3;23(3):375-385. Epub 2020 Feb 3.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Pten and Mecp2). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.
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http://dx.doi.org/10.1038/s41593-019-0578-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065955PMC
March 2020

The effects of regenerative injection therapy compared to corticosteroids for the treatment of lateral Epicondylitis: a systematic review and meta-analysis.

Arch Physiother 2019 13;9:12. Epub 2019 Nov 13.

Department of Physical Therapy, School of Health Professions, UT Health San Antonio, 7703 Floyd Curl Drive, MSC 6247, San Antonio, TX 78229 USA.

Background: The lateral epicondyle is a common site for chronic tendinosis (i.e. lateral epicondylitis), a condition characterized by overuse and degeneration of a tendon due to repeated microtrauma. This leads to pain and functional limitations. There is a growing interest in non-surgical forms of treatment for this condition including provision of corticosteroid injections and regenerative injection therapy (provision of autologous blood and platelet rich plasma injections).

Objective: We compared the effectiveness of corticosteroids with regenerative injection therapy for the treatment of lateral epicondylitis.

Methods: We systematically reviewed randomized controlled trials published in English language from 2008 to 2018. Databases used included PEDro, Scopus, PubMed, and CINAHL. Nine articles met our selection criteria. The PEDRo scale scores helped assess study quality. Cochrane risk of bias criteria helped assess bias. We analyzed results focusing on pain and function using meta-analyses.

Results: Six out of 9 studies had low risk of bias. There were no short-term (1 and 2 month) differences in pain scores between the corticosteroid and regenerative injection groups. Participants receiving regenerative injections demonstrated greater long-term improvements lasting for a period of  years.

Conclusion: Regenerative injections provision results in greater long-term pain relief and improved function for people with lateral epicondylitis.
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http://dx.doi.org/10.1186/s40945-019-0063-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854772PMC
November 2019

Effect of laminin environments and tumor factors on the biology of myeloid dendritic cells.

Immunobiology 2020 01 10;225(1):151854. Epub 2019 Nov 10.

Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, United States; Molecular and Cellular Biology Program, Ohio University, United States; Biomedical Engineering Program, Russ College of Engineering and Technology, Ohio University, United States; The Diabetes Institute at Ohio University, United States. Electronic address:

Dendritic cells (DCs) are immune cells that surveil the organism for infections or malignancies and activate specific T lymphocytes initiating specific immune responses. Contrariwise, DCs have been show to participate in the development of diseases, among them some types of cancer by inducing angiogenesis or immunosuppression. The ultimate fate of DC functions regarding their role in disease or health is prompted by signals from the microenvironment. We have previously shown that the interaction of DCs with various extracellular matrix components modifies the immune properties and angiogenic potential of these cells. The objective of the current studies was to investigate the angiogenic and immune profile of murine myeloid DCs upon interaction with laminin environments, with a particular emphasis on ovarian cancer. Our results show that murine ovarian tumors produce several types of laminins, as determined by PCR analysis, and also that tumor-associated DCs, both from ascites or solid tumors express adhesion molecules capable of interacting with these molecules as determined by flow cytometry and PCR analysis. Further, we established that DCs cultured on laminin upregulate both AKT and MEK signaling pathways, and that long-term culture on laminin surfaces decreases the immunological capacities of these cells when compared to the same cells cultured on synthetic substrates. In addition, we observed that tumor conditioned media was able to modify the metabolic status of these cells, and also reprogram the development of DCs from bone marrow precursors towards the generation of myeloid-derived suppressor cells. Overall, these studies demonstrate that the interaction between soluble factors and extracellular matrix components of the ovarian cancer microenvironment shape the biology of DCs and thus help them become co-conspirators of tumor growth.
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http://dx.doi.org/10.1016/j.imbio.2019.10.003DOI Listing
January 2020

Effects of inspiratory muscle training in advanced multiple sclerosis.

Mult Scler Relat Disord 2020 Jan 1;37:101492. Epub 2019 Nov 1.

Doctor of Physical Therapy Program, Franklin Pierce University, 670 North Commercial Street, Center Tower, Third Floor, Manchester, NH 03101, USA.

Background: Respiratory training using Threshold Inspiratory Muscle Trainer (IMT) has not been examined adequately in multiple sclerosis (MS). The primary objective in this study of persons with advanced MS was to investigate the training effect of IMT. The secondary objective was to evaluate the retention of IMT benefits.

Methods: This study was a repeated measures within-subject design (before-after trial).. Participants were recruited from a long-term care facility specialized in progressive neurologic conditions. Thirty-six non-ambulatory persons with advanced MS volunteered. Inspiratory muscle exercise using the threshold IMT were performed daily for 10 weeks at 3 sets of 15 repetitions per day. Resistance was progressed weekly based on perceived rate of exertion and symptoms. Primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) that were measured at baseline, after 5 and 10 weeks of IMT exercises (training period), and at 4 and 8 weeks after the IMT training ended (retention). Linear mixed-effect regression models with time (i.e. weeks from baseline) as the fixed factor and participants as the random effect factor were applied separately to test each hypothesis. Effect size was calculated using partial eta square (η2p). Two-tailed significance level was p < 0.05.

Results: Participants were 60.5 ± 8.6 years old. Expanded Disability Status Scale was 8.5 ± 0.4. Baseline MIP were 25.9 ± 16.4 cmH2O (33.2% %± 19.8% of predicted values) and MEP were 23.5 ± 15.7 cmH2O (25.8% %± 14.4% of predicted values). Compared to the baseline, MIP increased significantly to 30.1 ± 17.9 cmH2O (38.9% %± 22.4% of predicted values) and 30.6 ± 17.6 cmH2O (39.6% %± 22.3% of predicted values) after 5 (p < 0.05) and 10 weeks (p < 0.05) of IMT exercises. MIP improvements were retained in an 8-week washout period. MEP did not differ significantly by time.

Conclusion: In persons with advanced MS, 10-week IMT training increased inspiratory muscle strength. This study is the first to demonstrate the retention of benefits following daily IMT exercises at 8 weeks after training ended.
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http://dx.doi.org/10.1016/j.msard.2019.101492DOI Listing
January 2020
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