Showing papers by "Kettering University published in 2019"
TL;DR: It is shown that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion.
Abstract: Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1-3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4-9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.
332 citations
TL;DR: It is determined that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy, which has significant implications for both the cellular mechanisms of action and biomarkers of response to monotherapies and combination therapy.
Abstract: Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.
203 citations
TL;DR: This work presents a system to trigger a Sonic Hedgehog protein gradient in developing forebrain organoids that enables ordered self-organization along dorso-ventral and antero-posterior positional axes and identifies inductive signaling as an effective organizing strategy to recapitulate in vivo-like topography in human brain organoids.
Abstract: Human brain organoids generated with current technologies recapitulate histological features of the human brain, but they lack a reproducible topographic organization. During development, spatial topography is determined by gradients of signaling molecules released from discrete signaling centers. We hypothesized that introduction of a signaling center into forebrain organoids would specify the positional identity of neural tissue in a distance-dependent manner. Here, we present a system to trigger a Sonic Hedgehog (SHH) protein gradient in developing forebrain organoids that enables ordered self-organization along dorso-ventral and antero-posterior positional axes. SHH-patterned forebrain organoids establish major forebrain subdivisions that are positioned with in vivo-like topography. Consistent with its behavior in vivo, SHH exhibits long-range signaling activity in organoids. Finally, we use SHH-patterned cerebral organoids as a tool to study the role of cholesterol metabolism in SHH signaling. Together, this work identifies inductive signaling as an effective organizing strategy to recapitulate in vivo-like topography in human brain organoids.
201 citations
TL;DR: It is demonstrated that CAR T cells against GPRC5D are effective in mouse models, even those with tumors that are resistant to the earlier CARs, and they are safe in mice and primates.
Abstract: Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell–derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.
194 citations
TL;DR: In this article, the authors introduce the concept of LICs, criteria for materials selection and recent trends in the anode and cathode materials development and discuss the achievements and prospects associated with LICs.
147 citations
TL;DR: This study defines key mechanisms of the gliogenic switch and enables the rapid production of human astrocytes for disease modeling and regenerative medicine.
Abstract: The mechanistic basis of gliogenesis, which occurs late in human development, is poorly understood. Here we identify nuclear factor IA (NFIA) as a molecular switch inducing human glial competency. Transient expression of NFIA is sufficient to trigger glial competency of human pluripotent stem cell-derived neural stem cells within 5 days and to convert these cells into astrocytes in the presence of glial-promoting factors, as compared to 3–6 months using current protocols. NFIA-induced astrocytes promote synaptogenesis, exhibit neuroprotective properties, display calcium transients in response to appropriate stimuli and engraft in the adult mouse brain. Differentiation involves rapid but reversible chromatin remodeling, glial fibrillary acidic protein (GFAP) promoter demethylation and a striking lengthening of the G1 cell cycle phase. Genetic or pharmacological manipulation of G1 length partially mimics NFIA function. We used the approach to generate astrocytes with region-specific or reactive features. Our study defines key mechanisms of the gliogenic switch and enables the rapid production of human astrocytes for disease modeling and regenerative medicine. A new method generates astrocytes from human pluripotent stem cells in 5 days.
127 citations
TL;DR: Two distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis are defined, one of which is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF), indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction.
Abstract: Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, medication redirected them into a state that is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions.
122 citations
TL;DR: This study provides an integrative view of the complex activities of a lineage-specifying transcription factor and offers novel insights into the nature of the molecular events that follow transcription factor binding.
Abstract: Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors, as is exemplified by reprogramming somatic cells to pluripotent stem cells through the expression of OCT4, KLF4, SOX2 and cMYC. How transcription factors orchestrate the complex molecular changes around their target gene loci remains incompletely understood. Here, using KLF4 as a paradigm, we provide a transcription-factor-centric view of chromatin reorganization and its association with three-dimensional enhancer rewiring and transcriptional changes during the reprogramming of mouse embryonic fibroblasts to pluripotent stem cells. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in enhancer connectivity, whereas disruption of individual KLF4 binding sites within pluripotent-stem-cell-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce the expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying transcription factor and offers novel insights into the nature of the molecular events that follow transcription factor binding.
114 citations
Imperial College London1, University of Oxford2, Southern Health NHS Foundation Trust3, Aston University4, Brighton and Sussex University Hospitals NHS Trust5, South London and Maudsley NHS Foundation Trust6, South Essex Partnership University Foundation NHS Trust7, North Bristol NHS Trust8, Kettering University9, Nottinghamshire Healthcare NHS Foundation Trust10, Queen's University Belfast11, Surrey and Borders Partnership NHS Foundation Trust12, NHS Ayrshire and Arran13, NHS Lanarkshire14, Derbyshire Healthcare NHS Foundation Trust15, Vanderbilt University Medical Center16, King's College London17, Newcastle University18, Cardiff University19
TL;DR: If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer’s treatment.
Abstract: Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. Methods/design: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study - Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. Trial registration: ClinicalTrials.gov, NCT01843075. Registration 30 April 2013.
110 citations
TL;DR: To enable data scientists to build more accurate predictive models of pipe failure, this paper summarises typical factors influencing failure for 5 common groups of materials for water pipes.
80 citations
TL;DR: Direct pharmacological inhibition of JNK significantly improves the efficiencies of generating DE and DE-derived pancreatic and lung progenitor cells, highlighting the potential of harnessing the knowledge from developmental studies for regenerative medicine.
Abstract: Human embryonic stem cells (ESCs) and human induced pluripotent stem cells hold great promise for cell-based therapies and drug discovery. However, homogeneous differentiation remains a major challenge, highlighting the need for understanding developmental mechanisms. We performed genome-scale CRISPR screens to uncover regulators of definitive endoderm (DE) differentiation, which unexpectedly uncovered five Jun N-terminal kinase (JNK)–JUN family genes as key barriers of DE differentiation. The JNK–JUN pathway does not act through directly inhibiting the DE enhancers. Instead, JUN co-occupies ESC enhancers with OCT4, NANOG, SMAD2 and SMAD3, and specifically inhibits the exit from the pluripotent state by impeding the decommissioning of ESC enhancers and inhibiting the reconfiguration of SMAD2 and SMAD3 chromatin binding from ESC to DE enhancers. Therefore, the JNK–JUN pathway safeguards pluripotency from precocious DE differentiation. Direct pharmacological inhibition of JNK significantly improves the efficiencies of generating DE and DE-derived pancreatic and lung progenitor cells, highlighting the potential of harnessing the knowledge from developmental studies for regenerative medicine. CRISPR screens identify JNK–JUN family genes as repressors of definitive endoderm differentiation in human pluripotent stem cells. JUN co-occupies stem cell enhancers with OCT4, NANOG, SMAD2 and SMAD3 and inhibits the exit from pluripotency.
TL;DR: This review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules.
Rockefeller University1, Kettering University2, Paris Descartes University3, Icahn School of Medicine at Mount Sinai4, Northwestern University5, Biogen Idec6, Aarhus University7, Aarhus University Hospital8, Ludwig Maximilian University of Munich9, National Institutes of Health10, Yale University11, University of Sharjah12, King Saud University13, University of Southern California14, University of Paris15, Pasteur Institute16, Stanford University17
TL;DR: It is shown that CRISPR/Cas9-introduced biallelic and monoallelic SNORA31 deletions render human pluripotent stem cells (hPSCs)-derived cortical neurons susceptible to HSV-1, and human SNOR a31 controls CNS neuron-intrinsic immunity to HSv-1 by a distinctive mechanism.
Abstract: Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
TL;DR: These findings implicate negative co‐stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of Tcell phenotypes.
TL;DR: The results of this study reveal the advantage of performing advanced oxidation processes (AOPs) at a basic pH, which enables performance of further degradation of organic contaminants at an acidic pH, ensuring high efficiency of treatment based on the Fenton reaction without the risk of release of hydrogen sulfide to the atmosphere.
Kettering University1, Stanford University2, Harvard University3, Institut Gustave Roussy4, Oregon Health & Science University5, Nemours Foundation6, Kaiser Permanente7, Boston Children's Hospital8, Great Ormond Street Hospital9, University of Texas Southwestern Medical Center10, University of Texas MD Anderson Cancer Center11
TL;DR: LPXO-195 had preliminary efficacy in pts with resistance to prior TRKi mediated by TRK kinase mutations, and Cmax at doses ≥50 mg exceeded the predicted IC50 for TRK Kinase mutations.
Abstract: Background: Larotrectinib, a selective TRKi, is now FDA approved for pediatric and adult TRK-fusion solid tumors, regardless of tumor origin. Emergent TRK kinase mutations are a common mechanism of resistance to TRKis. LOXO-195, a selective TRKi, was developed to maintain potency against multiple TRK kinase domain mutations. Methods: Patients (pts) received LOXO-195 via a Phase I study (NCT03215511, n=20) or FDA expanded access single patient protocol (SPP, n=11). Eligible pts were ≥4-weeks old with a locally identified TRK fusion and had progressed or were intolerant to at least 1 priorTRKi. Parallel 3+3 dose escalations were pursued in adults and children, with intra-patient dose escalation permitted based on tolerance and pharmacokinetics. Pts aged Results: As of 03-DEC-2018, a total of 31 TRK-fusion pts (7 children, 24 adults) with 11 cancer types had been treated. Median duration on last prior TRKi was 9.5 months (range, 2-30). In the Phase 1, doses of 32 mg QD to 150mg BID were explored, and TEAEs (all grades/cause, in >3 pts) were dizziness/ataxia (65%), nausea/vomiting (50%), anemia (30%), myalgia, abdominal pain, fatigue, & lymphopenia (all 20%). Five Phase I pts (all adults) had DLTs: ataxia/dizziness (4), and ataxia/vomiting (1). For the SPPs: 1 pt dose-reduced and none discontinued for a TEAE. Cmax at doses ≥50 mg exceeded the predicted IC50 for TRK kinase mutations. Pretreatment tissue and/or plasma, as available, defined TRK kinase mutation status. Preliminary efficacy overall, and by TRK kinase mutation status, is shown in the Table. Discussion: LOXO-195 had preliminary efficacy in pts with resistance to prior TRKi mediated by TRK kinase mutations. The subset of pts who develop TRK-independent resistance are unlikely to benefit from LOXO-195. Dose selection is ongoing in both children and adults. Citation Format: David Hyman, Shivaani Kummar, Anna Farago, Birgit Geoerger, Morten Mau-Sorensen, Matthew Taylor, Elena Garralda, Ramamoorthy Nagasubramanian, Michael Natheson, Lucy Song, Michael Capra, Mette Jorgensen, Alan Ho, Neerav Shukla, Steve Smith, Xin Huang, Brian Tuch, Nora Ku, Theodore W. Laetsch, Alexander Drilon, David Hong. Phase I and expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT127.
TL;DR: The paper is a review of the procedures for the determination of volatile and semivolatile oxygenated organic compounds (O-VOCs) in effluent samples by gas chromatography, pointing out the lack of legal regulations and the availability of just a few procedures allowing a comprehensive evaluation of the O-V OC content in effluents.
19 Mar 2019
TL;DR: A prototype for a virtual learning environment designed and built by the author and known as LeProf is discussed along with its application in the design of an educational site for learning electrical circuits.
Abstract: The theory of experiential learning is briefly reviewed and a model of the learning process is presented. The paper then discusses and characterizes a virtual learning environment and its relationship to experiential learning and learning styles. An approach for designing virtual learning environments is presented taking into account the technology for learning. A prototype for a virtual learning environment designed and built by the author and known as LeProf is then discussed along with its application in the design of an educational site for learning electrical circuits.
TL;DR: F fluorouracil-labeled RNA sequencing (Flura-seq) was developed for in situ analysis with high sensitivity and utility, confirming lung metastasis-specific increase in oxidative stress and upregulation of antioxidants in clinical samples, thus validating Flura- sequencing’s utility in identifying clinically actionable microenvironmental adaptations in early metastasis.
Abstract: Metastasis-initiating cells dynamically adapt to the distinct microenvironments of different organs, but these early adaptations are poorly understood due to the limited sensitivity of in situ transcriptomics. We developed fluorouracil-labeled RNA sequencing (Flura-seq) for in situ analysis with high sensitivity. Flura-seq utilizes cytosine deaminase (CD) to convert fluorocytosine to fluorouracil, metabolically labeling nascent RNA in rare cell populations in situ for purification and sequencing. Flura-seq revealed hundreds of unique, dynamic organ-specific gene signatures depending on the microenvironment in mouse xenograft breast cancer micrometastases. Specifically, the mitochondrial electron transport Complex I, oxidative stress and counteracting antioxidant programs were induced in pulmonary micrometastases, compared to mammary tumors or brain micrometastases. We confirmed lung metastasis-specific increase in oxidative stress and upregulation of antioxidants in clinical samples, thus validating Flura-seq's utility in identifying clinically actionable microenvironmental adaptations in early metastasis. The sensitivity, robustness and economy of Flura-seq are broadly applicable beyond cancer research.
TL;DR: This work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/B-catenin signaling, but that APC genotype is a crucial determinant of this response.
Abstract: The majority of colorectal cancers (CRCs) show hyperactivated WNT signaling due to inactivating mutations in the APC tumor suppressor. Genetically restoring Apc suppresses WNT and induces rapid and sustained tumor regression, implying that re-engaging this endogenous tumor suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that Tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the Mutation Cluster Region (MCR) region physically engage the destruction complex and suppress the WNT transcriptional program, while early APC truncations (i.e. ApcMin) show limited interaction with AXIN1 and B-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/B-catenin signaling, but that APC genotype is a crucial determinant of this response.
TL;DR: The ways in which cell death can propagate between cells in normal physiology and disease, as well as the potential exploitation of cell death propagation for cancer therapy are discussed.
Abstract: Cell death can occur through numerous regulated mechanisms that are categorized by their molecular machineries and differing effects on physiology. Apoptosis and necrosis, for example, have opposite effects on tissue inflammation due to their different modes of execution. Another feature that can distinguish different forms of cell death is that they have distinct intrinsic effects on the cell populations in which they occur. For example, a regulated mechanism of necrosis called ferroptosis has the unusual ability to spread between cells in a wave-like manner, thereby eliminating entire cell populations. Here we discuss the ways in which cell death can propagate between cells in normal physiology and disease, as well as the potential exploitation of cell death propagation for cancer therapy.
TL;DR: No reliably effective technical solutions to reduce small cetacean bycatch in trawl nets are available, although loud pingers have shown potential, and there are currently no technical options that effectively reduce marine mammal interactions in longline fisheries, although development of catch and hook protection devices is promising.
Abstract: Fisheries bycatch is one of the biggest threats to marine mammal populations. A literature review was undertaken to provide a comprehensive assessment and synopsis of gear modifications and technical devices to reduce marine mammal bycatch in commercial trawl, purse seine, longline, gillnet and pot/trap fisheries. Successfully implemented mitigation measures include acoustic deterrent devices (pingers) which reduced the bycatch of some small cetacean species in gillnets, appropriately designed exclusion devices which reduced pinniped bycatch in some trawl fisheries, and various pot/trap guard designs that reduced marine mammal entrapment. However, substantial development and research of mitigation options is required to address the bycatch of a range of species in many fisheries. No reliably effective technical solutions to reduce small cetacean bycatch in trawl nets are available, although loud pingers have shown potential. There are currently no technical options that effectively reduce marine mammal interactions in longline fisheries, although development of catch and hook protection devices is promising. Solutions are also needed for species, particularly pinnipeds and small cetaceans, that are not deterred by pingers and continue to be caught in static gillnets. Large whale entanglements in static gear, particularly buoy lines for pots/traps, needs urgent attention although there is encouraging research on rope-less pot/trap systems and identification of rope colours that are more detectable to whale species. Future mitigation development and deployment requires rigorous scientific testing to determine if significant bycatch reduction has been achieved, as well as consideration of potentially conflicting mitigation outcomes if multiple species are impacted by a fishery.
TL;DR: A detailed protocol for the induction of a regionally specific NC intermediate that occurs over the course of a 15-d interval and is an effective source for the in vitro derivation of functional enteric neurons (ENs) from hPSCs is presented.
Abstract: The enteric nervous system (ENS) represents a vast network of neuronal and glial cell types that develops entirely from migratory neural crest (NC) progenitor cells. Considerable improvements in the understanding of the molecular mechanisms underlying NC induction and regional specification have recently led to the development of a robust method to re-create the process in vitro using human pluripotent stem cells (hPSCs). Directing the fate of hPSCs toward the enteric NC (ENC) results in an accessible and scalable in vitro model of ENS development. The application of hPSC-derived enteric neural lineages provides a powerful platform for ENS-related disease modeling and drug discovery. Here we present a detailed protocol for the induction of a regionally specific NC intermediate that occurs over the course of a 15-d interval and is an effective source for the in vitro derivation of functional enteric neurons (ENs) from hPSCs. Additionally, we introduce a new and improved protocol that we have developed to optimize the protocol for future applications in regenerative medicine, in which components of undefined activity have been replaced with fully defined culture conditions. This protocol provides access to a broad range of human ENS lineages within a 30-d period. Human pluripotent stem cells are differentiated first into enteric neural crest cells and then into functional enteric neurons using a defined culture system.
TL;DR: The association between intestinal microbiota composition and treatment outcome in MM is reported and a higher relative abundance of Eubacterium hallii in the 16 MRD- patients relative to the 18 MRD+ patients is observed.
TL;DR: Findings indicate that the HPDMIM(C1):CuO thin films are a candidate for energy-storage applications, and the highest specific capacitance was achieved for the electrode with a nanosheet-like structure produced by functionalization with the H PDMIM (C1) ionic liquid.
TL;DR: The lack of reported association of psychrotrophic B. cereus with emetic illness and correctly stored commercially-produced minimally processed chilled foods indicates that a toxic dose of the emetic toxin has not been formed.
Abstract: Background Spores of psychrotrophic Bacillus cereus may survive the mild heat treatments given to minimally processed chilled foods. Subsequent germination and cell multiplication during refrigerated storage may lead to bacterial concentrations that are hazardous to health. Scope and approach This review is concerned with the characterisation of factors that prevent psychrotrophic B. cereus reaching hazardous concentrations in minimally processed chilled foods and associated foodborne illness. A risk assessment framework is used to quantify the risk associated with B. cereus and minimally processed chilled foods. Key findings and conclusions Bacillus cereus is responsible for two types of food poisoning, diarrhoeal (an infection) and emetic (an intoxication); however, no reported outbreaks of food poisoning have been associated with B. cereus and correctly stored commercially-produced minimally processed chilled foods. In the UK alone, more than 1010 packs of these foods have been sold in recent years without reported illness, thus the risk presented is very low. Further quantification of the risk is merited, and this requires additional data. The lack of association between diarrhoeal food poisoning and correctly stored commercially-produced minimally processed chilled foods indicates that an infectious dose has not been reached. This may reflect low pathogenicity of psychrotrophic strains. The lack of reported association of psychrotrophic B. cereus with emetic illness and correctly stored commercially-produced minimally processed chilled foods indicates that a toxic dose of the emetic toxin has not been formed. Laboratory studies show that strains form very small quantities of emetic toxin at chilled temperatures.
02 Jul 2019
TL;DR: The technical (optics and photonics) aspects of the most common lidar technologies are discussed, with the educational focus of identifying opportunities for employing such discussions in introducing optics to broader engineering audiences, drawing in part on experiences and examples from Kettering University.
Abstract: Since Stanley, the self-driven Stanford car equipped with five SICK LIDAR sensors won the 2005 DARPA Challenge, the race to developing and deploying fully autonomous, self-driving vehicles has come to a full swing. By now, it has engulfed all major automotive companies and suppliers, major trucking and taxi companies, not to mention companies like Google (Waymo), Apple and Tesla. With the notable exception of the Tesla self-driving cars, a LIDAR (Light, Detection and Ranging) unit is a key component of the suit of sensors that allow autonomous vehicles to see and navigate the world. The market space for lidar units is by now downright crowded, with a number of companies and their respective technologies jockeying for long-run leading positions in the field. Major lidar technologies for autonomous driving include mechanical scanning (spinning) lidar, MEMS micro-mirror lidar, optical-phased array lidar, flash lidar, frequencymodulated continuous-wave (FMCW) lidar and others. A major technical specification of any lidar is the operating wavelength. Many existing systems use 905 nm diode lasers, a wavelength compatible with CMOS-technology detectors. But other wavelengths (like 850 nm, 940 nm and 1550 nm) are also investigated and, in the long run, the telecom nearinfrared range (1550 nm) is expected to experience significant growth because it offers a larger detecting distance range (200-300 meters) within eye safety laser power limits while also offering potential better performance in bad weather conditions. This paper discusses the above-mentioned technical (optics and photonics) aspects of the most common lidar technologies, with the educational focus of identifying opportunities for employing such discussions in introducing optics to broader engineering audiences, drawing in part on experiences and examples from Kettering University.
TL;DR: Results demonstrated that lateral areas, including face-selective areas in the posterior and anterior superior temporal sulcus, the extrastriate body area (EBA) and the occipital place area (OPA) responded more to moving than static stimuli.
Abstract: The human brain contains areas that respond selectively to faces, bodies and scenes. Neuroimaging studies have shown that a subset of these areas preferentially respond more to moving than static stimuli, but the reasons for this functional dissociation remain unclear. In the present study, we simultaneously mapped the responses to motion in face-, body- and scene-selective areas in the right hemisphere using moving and static stimuli. Participants (N = 22) were scanned using functional magnetic resonance imaging (fMRI) while viewing videos containing bodies, faces, objects, scenes or scrambled objects, and static pictures from the beginning, middle and end of each video. Results demonstrated that lateral areas, including face-selective areas in the posterior and anterior superior temporal sulcus (STS), the extrastriate body area (EBA) and the occipital place area (OPA) responded more to moving than static stimuli. By contrast, there was no difference between the response to moving and static stimuli in ventral and medial category-selective areas, including the fusiform face area (FFA), occipital face area (OFA), amygdala, fusiform body area (FBA), retrosplenial complex (RSC) and parahippocampal place area (PPA). This functional dissociation between lateral and ventral/medial brain areas that respond selectively to different visual categories suggests that face-, body- and scene-selective networks may be functionally organized along a common dimension.
TL;DR: It was shown that the proposed methodology could effectively expand the strain data at limited locations to accurately predict the strain at locations where no sensors were placed and predicted the full field strain on the spoiler.
TL;DR: A mechanism by which antidepressants could alter the function of diverse membrane proteins by partitioning into cell membranes and thereby altering the bilayer contribution to the energetics of membrane protein conformational changes is suggested.
Abstract: The two major classes of antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), inhibit neurotransmitter reuptake at synapses. They also have off-target effects on proteins other than neurotransmitter transporters, which may contribute to both desired changes in brain function and the development of side effects. Many proteins modulated by antidepressants are bilayer spanning and coupled to the bilayer through hydrophobic interactions such that the conformational changes underlying their function will perturb the surrounding lipid bilayer, with an energetic cost (Δ G def ) that varies with changes in bilayer properties. Here, we test whether changes in Δ G def caused by amphiphilic antidepressants partitioning into the bilayer are sufficient to alter membrane protein function. Using gramicidin A (gA) channels to probe whether TCAs and SSRIs alter the bilayer contribution to the free energy difference for the gramicidin monomer⇔dimer equilibrium (representing a well-defined conformational transition), we find that antidepressants alter gA channel activity with varying potency and no stereospecificity but with different effects on bilayer elasticity and intrinsic curvature. Measuring the antidepressant partition coefficients using isothermal titration calorimetry (ITC) or cLogP shows that the bilayer-modifying potency is predicted quite well by the ITC-determined partition coefficients, and channel activity is doubled at an antidepressant/lipid mole ratio of 0.02–0.07. These results suggest a mechanism by which antidepressants could alter the function of diverse membrane proteins by partitioning into cell membranes and thereby altering the bilayer contribution to the energetics of membrane protein conformational changes.