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1.
Sci Immunol ; 6(58)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811061

RESUMO

Charting the gene-expression landscape of glioma-infiltrating T cells demonstrates that these T cells can express NK cell receptors, which inhibit the killing of glioma cells.

2.
J Neurophysiol ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33788616

RESUMO

Selective attention is necessary to sift through, form a coherent percept of, and make behavioral decisions on the vast amount of information present in most sensory environments. How and where selective attention is employed in cortex and how this perceptual information then informs the relevant behavioral decisions is still not well understood. Studies probing selective attention and decision making in visual cortex have been enlightening as to how sensory attention might work in that modality; whether or not similar mechanisms are employed in auditory attention is not yet clear. Therefore, we trained rhesus macaques on a feature selective attention task, where they switched between reporting changes in temporal (amplitude modulation, AM) and spectral (carrier bandwidth) features of a broadband noise stimulus. We investigated how the encoding of these features by single neurons in primary (A1) and secondary (middle lateral belt, ML) auditory cortex were affected by the different attention conditions. We found that neurons in A1 and ML showed mixed-selectivity to the sound and task features. We found no difference in AM encoding between the attention conditions. We found that choice-related activity in both A1 and ML neurons shifts between attentional conditions. This finding suggests that choice-related activity in auditory cortex does not simply reflect motor preparation or action, and supports the relationship between reported choice-related activity and the decision and perceptual process.

3.
Am J Transplant ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33616250

RESUMO

In this issue, Doby et al describe a performance improvement initiative in a single OPO using the CALC method to identify opportunities for improvement and report an increase in organ donors of 44% and organs transplanted of 29% for the 12 month period ending 9/30/2020, as a result of targeted practice changes (1). The CALC analysis for the study OPO identified an opportunity for increasing the number of donors aged 50-64 and 65-75 years.

4.
Microb Biotechnol ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33404203

RESUMO

The throwaway culture related to the single-use materials such as polyethylene terephthalate (PET) has created a major environmental concern. Recycling of PET waste into biodegradable plastic polyhydroxyalkanoate (PHA) creates an opportunity to improve resource efficiency and contribute to a circular economy. We sequenced the genome of Pseudomonas umsongensis GO16 previously shown to convert PET-derived terephthalic acid (TA) into PHA and performed an in-depth genome analysis. GO16 can degrade a range of aromatic substrates in addition to TA, due to the presence of a catabolic plasmid pENK22. The genetic complement required for the degradation of TA via protocatechuate was identified and its functionality was confirmed by transferring the tph operon into Pseudomonas putida KT2440, which is unable to utilize TA naturally. We also identified the genes involved in ethylene glycol (EG) metabolism, the second PET monomer, and validated the capacity of GO16 to use EG as a sole source of carbon and energy. Moreover, GO16 possesses genes for the synthesis of both medium and short chain length PHA and we have demonstrated the capacity of the strain to convert mixed TA and EG into PHA. The metabolic versatility of GO16 highlights the potential of this organism for biotransformations using PET waste as a feedstock.

5.
Blood ; 137(4): 500-512, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33507291

RESUMO

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.

6.
Microbiology (Reading) ; 167(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33493102

RESUMO

Our knowledge and understanding of micro-organisms have led to the development of safe food, clean water, novel foods, antibiotics, vaccines, healthier plants, animals and soils, and more, which feeds into the United Nations Sustainable Development Goals (UN SDGs). The circular economy can contribute to the UN SDGs and micro-organisms are central to circular nutrient cycles. The circular economy as described by the Ellen MacArthur foundation has two halves, i.e. technical and biological. On the technical side, non-biological resources enter manufacturing paths where resource efficiency, renewable energy and design extend the life of materials so that they are more easily reused and recycled. Biological resources exist on the other half of the circular economy. These are used to manufacture products such as bioplastics and paper. The conservation of nature's stocks, resource efficiency and recycling of materials are key facets of the biological half of the circular economy. Microbes play a critical role in both the biological and technical parts of the circular economy. Microbes are key to a functioning circular economy, where natural resources, including biological wastes, are converted by microbes into products of value and use for society, e.g. biogas, bioethanol, bioplastics, building block chemicals and compost for healthy soils. In more recent times, microbes have also been seen as part of the tool kit in the technical side of the circular economy, where microbial enzymes can degrade plastics and microbes can convert those monomers to value-added products.

7.
J Exp Med ; 218(3)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33326020

RESUMO

CD4+ follicular regulatory T (Tfr) cells control B cell responses through the modulation of follicular helper T (Tfh) cells and germinal center development while suppressing autoreactivity; however, their role in the regulation of productive germinal center B cell responses and humoral memory is incompletely defined. We show that Tfr cells promote antigen-specific germinal center B cell responses upon influenza virus infection. Following viral challenge, we found that Tfr cells are necessary for robust generation of virus-specific, long-lived plasma cells, antibody production against both hemagglutinin (HA) and neuraminidase (NA), the two major influenza virus glycoproteins, and appropriate regulation of the BCR repertoire. To further investigate the functional relevance of Tfr cells during viral challenge, we used a sequential immunization model with repeated exposure of antigenically partially conserved strains of influenza viruses, revealing that Tfr cells promote recall antibody responses against the conserved HA stalk region. Thus, Tfr cells promote antigen-specific B cell responses and are essential for the development of long-term humoral memory.

9.
Proc Natl Acad Sci U S A ; 117(48): 30649-30660, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33199596

RESUMO

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

10.
Mov Disord Clin Pract ; 7(8): 904-909, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33163561

RESUMO

Background: To date, 10 patients with GTPase Regulator Associated with Focal Adhesion Kinase 1/Rho GTPase Activating Protein 26-Immunoglobulin (GRAF1/ARHGAP26-IgG) associated neurological disorders have been described, most with ataxia. Objective: To report the clinical, oncological, and radiological associations of GRAF1 autoantibodies. Methods: We identified 17 patients whose serum and/or cerebrospinal fluid IgG was confirmed to target GRAF1/ARHGAP26-IgG by both tissue-based immunofluorescence and transfected cell-based assay. Clinical information was available on 14 patients. Results: The median age at neurological symptom onset was 51 years, and 8 (47%) were men. The predominant clinical features were subacute progressive cerebellar ataxia (13) or peripheral neuropathy (2). Magnetic resonance imaging brain (7 available) showed cerebellar atrophy (4, 1 also cerebrum and brainstem atrophy). Of 7 cerebrospinal fluids available for testing, 5 showed pleocytosis with oligoclonal bands in 3. Squamous cell carcinoma was observed in 3 patients (head and neck [2], lung [1]). Conclusion: GTPase Regulator Associated with Focal Adhesion Kinase 1 autoimmunity manifests commonly with subacute ataxia and cerebellar degeneration with a potential association with squamous cell carcinoma. Peripheral neuropathy may also be encountered. Cases in this series responded poorly to immunotherapy.

11.
Sci Immunol ; 5(53)2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158977

RESUMO

Two human-derived recombinant mAbs specific for IBV bind the neuraminidase active site by emulating the enzymatic substrate, which results in broad protection.

12.
J Neurophysiol ; 124(6): 1706-1726, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026929

RESUMO

In macaques, the middle lateral auditory cortex (ML) is a belt region adjacent to the primary auditory cortex (A1) and believed to be at a hierarchically higher level. Although ML single-unit responses have been studied for several auditory stimuli, the ability of ML cells to encode amplitude modulation (AM)-an ability that has been widely studied in A1-has not yet been characterized. Here, we compared the responses of A1 and ML neurons to amplitude-modulated (AM) noise in awake macaques. Although several of the basic properties of A1 and ML responses to AM noise were similar, we found several key differences. ML neurons were less likely to phase lock, did not phase lock as strongly, and were more likely to respond in a nonsynchronized fashion than A1 cells, consistent with a temporal-to-rate transformation as information ascends the auditory hierarchy. ML neurons tended to have lower temporally (phase-locking) based best modulation frequencies than A1 neurons. Neurons that decreased their firing rate in response to AM noise relative to their firing rate in response to unmodulated noise became more common at the level of ML than they were in A1. In both A1 and ML, we found a prevalent class of neurons that usually have enhanced rate responses relative to responses to the unmodulated noise at lower modulation frequencies and suppressed rate responses relative to responses to the unmodulated noise at middle modulation frequencies.NEW & NOTEWORTHY ML neurons synchronized less than A1 neurons, consistent with a hierarchical temporal-to-rate transformation. Both A1 and ML had a class of modulation transfer functions previously unreported in the cortex with a low-modulation-frequency (MF) peak, a middle-MF trough, and responses similar to unmodulated noise responses at high MFs. The results support a hierarchical shift toward a two-pool opponent code, where subtraction of neural activity between two populations of oppositely tuned neurons encodes AM.

13.
Eur J Appl Physiol ; 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33099664

RESUMO

PURPOSE: High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and training-related adaptations. We hypothesized a serotonin agonist, known to improve respiratory function in animal models, would improve adaptations to whole-body functional electrical stimulation (FES) exercise training in patients with acute high-level SCI. METHODS: We identified 10 patients (< 2 years of injury with SCI from C4 to T3) in our program who had performed 6 months of FES-row training while on Buspirone (29 ± 17 mg/day) between 2012 and 2018. We also identified well-matched individuals who trained for six months but not on Buspirone (n = 11). A peak incremental FES-rowing exercise test and resting pulmonary function test had been performed before and after training. RESULTS: Those on Buspirone demonstrated greater increases in peak oxygen consumption (VO2peak: + 0.24 ± 0.23 vs. + 0.10 ± 0.13 L/min, p = 0.08) and peak ventilation (VEpeak: + 6.5 ± 8.1 vs. - 0.7 ± 6.9 L/min, p < 0.05) compared to control. In addition, changes in VO2peak and VEpeak were correlated across all patients (r = 0.63, p < 0.01), but most strongly in those on Buspirone (r = 0.85, p < 0.01). Furthermore, changes in respiratory function correlated with increased peak tidal volume in the Buspirone group (r > 0.66, p < 0.05). CONCLUSION: These results suggest Buspirone improves cardiorespiratory adaptations to FES-exercise training in individuals with acute, high-level SCI. The strong association between increases in ventilatory and aerobic capacities suggests improved respiratory function is a mechanism; however, controlled studies are needed to determine if this preliminary finding is reproducible.

14.
Proc Natl Acad Sci U S A ; 117(44): 27339-27345, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087561

RESUMO

Folding and other protein self-assembly processes are driven by favorable interactions between O, N, and C unified atoms of the polypeptide backbone and side chains. These processes are perturbed by solutes that interact with these atoms differently than water does. Amide NH···O=C hydrogen bonding and various π-system interactions have been better characterized structurally or by simulations than experimentally in water, and unfavorable interactions are relatively uncharacterized. To address this situation, we previously quantified interactions of alkyl ureas with amide and aromatic compounds, relative to interactions with water. Analysis yielded strengths of interaction of each alkylurea with unit areas of different hybridization states of unified O, N, and C atoms of amide and aromatic compounds. Here, by osmometry, we quantify interactions of 10 pairs of amides selected to complete this dataset. An analysis yields intrinsic strengths of six favorable and four unfavorable atom-atom interactions, expressed per unit area of each atom and relative to interactions with water. The most favorable interactions are sp2O-sp2C (lone pair-π, presumably n-π*), sp2C-sp2C (π-π and/or hydrophobic), sp2O-sp2N (hydrogen bonding) and sp3C-sp2C (CH-π and/or hydrophobic). Interactions of sp3C with itself (hydrophobic) and with sp2N are modestly favorable, while sp2N interactions with sp2N and with amide/aromatic sp2C are modestly unfavorable. Amide sp2O-sp2O interactions and sp2O-sp3C interactions are more unfavorable, indicating the preference of amide sp2O to interact with water. These intrinsic interaction strengths are used to predict interactions of amides with proteins and chemical effects of amides (including urea, N-ethylpyrrolidone [NEP], and polyvinylpyrrolidone [PVP]) on protein stability.

15.
Pain Rep ; 5(4): e828, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32766465

RESUMO

Opioid consumption for those in comprehensive inpatient rehabilitation units is high because of the complexity of their injuries. Notably, pain in rehabilitation leads to worsened clinical outcomes because of maladaptive behaviors and poor engagement during therapies. It is critical to developing evidence-based pharmacobehavioral interventions. Based on principles of classical conditioning, conditioning open-label placebo (COLP) is a promising approach for reducing opioid use in comprehensive inpatient rehabilitation, and this technique takes advantage of the possibility of association learning and opioid pharmacology to promote evoked placebo-driven analgesia. Objectives: In this brief report, we evaluate the feasibility of COLP as a pharmacobehavioral intervention to decrease total opioid consumption in patients with pain hospitalized at Spaulding Rehabilitation Hospital. Methods: Inpatients with spinal cord injury and polytrauma (n = 20) with moderate to severe pain were randomized to receive COLP (n = 10) or treatment-as-usual for 6 consecutive days. Opioid utilization was measured by morphine equivalents using the morphine equivalent dose conversion; pain severity was assessed using the numerical visual analog scale. Results: Conditioning open-label placebo significantly reduced total opioid consumption by the end of the intervention period (P ≤ 0.001). Pain reduction was also significant for the COLP group (P = 0.005), whereas the treatment-as-usual group demonstrated a trend towards pain reduction (P = 0.05). Conclusions: This study presents the first data in the use of a pharmacobehavioral intervention that capitalize on the benefits of open-label placebo and classical drug conditioning for opioid dose reduction in a population with moderate to severe pain exposed to intensive inpatient rehabilitation.

16.
J Exp Med ; 217(12)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-32820331

RESUMO

Pathogenic muscle-specific tyrosine kinase (MuSK)-specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm-exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.

17.
Immunity ; 53(4): 759-774.e9, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-32795402

RESUMO

Development and function of conventional dendritic cell (cDC) subsets, cDC1 and cDC2, depend on transcription factors (TFs) IRF8 and IRF4, respectively. Since IRF8 and IRF4 can each interact with TF BATF3 at AP1-IRF composite elements (AICEs) and with TF PU.1 at Ets-IRF composite elements (EICEs), it is unclear how these factors exert divergent actions. Here, we determined the basis for distinct effects of IRF8 and IRF4 in cDC development. Genes expressed commonly by cDC1 and cDC2 used EICE-dependent enhancers that were redundantly activated by low amounts of either IRF4 or IRF8. By contrast, cDC1-specific genes relied on AICE-dependent enhancers, which required high IRF concentrations, but were activated by either IRF4 or IRF8. IRF8 was specifically required only by a minority of cDC1-specific genes, such as Xcr1, which could distinguish between IRF8 and IRF4 DNA-binding domains. Thus, these results explain how BATF3-dependent Irf8 autoactivation underlies emergence of the cDC1-specific transcriptional program.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32753407

RESUMO

OBJECTIVE: To identify candidate biomarkers associated with neuromyelitis optica spectrum disorder (NMOSD) using high-throughput technologies that broadly assay the concentrations of serum analytes and frequencies of immune cell subsets. METHODS: Sera, peripheral blood mononuclear cells (PBMCs), and matched clinical data from participants with NMOSD and healthy controls (HCs) were obtained from the Collaborative International Research in Clinical and Longitudinal Experience Study NMOSD biorepository. Flow cytometry panels were used to measure the frequencies of 39 T-cell, B-cell, regulatory T-cell, monocyte, natural killer (NK) cell, and dendritic cell subsets in unstimulated PBMCs. In parallel, multiplex proteomics assays were used to measure 46 serum cytokines and chemokines in 2 independent NMOSD and HC cohorts. Multivariable regression models were used to assess molecular and cellular profiles in NMOSD compared with HC. RESULTS: NMOSD samples had a lower frequency of CD16+CD56+ NK cells. Both serum cohorts and multivariable logistic regression revealed increased levels of B-cell activating factor associated with NMOSD. Interleukin 6, CCL22, and CCL3 were also elevated in 1 NMOSD cohort of the 2 analyzed. Multivariable linear regression of serum analyte levels revealed a correlation between CX3CL1 (fractalkine) levels and the number of days since most recent disease relapse. CONCLUSIONS: Integrative analyses of cytokines, chemokines, and immune cells in participants with NMOSD and HCs provide congruence with previously identified biomarkers of NMOSD and highlight CD16+CD56+ NK cells and CX3CL1 as potential novel biomarker candidates.

19.
Blood ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32756933

RESUMO

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia (ALL) where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, shRNA screen in murine T cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cAMP signaling and are under-expressed in GC resistant or relapsed ALL patients. Silencing of the cAMP activating guanine nucleotide binding protein, alpha stimulating Gnas gene, interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that Prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC re-sensitization in relapsed pediatric T-ALL.

20.
Blood Adv ; 4(13): 3154-3168, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32658986

RESUMO

Synthetic glucocorticoids (GCs), such as dexamethasone and prednisone, remain key components of therapy for patients with lymphoid malignancies. For pediatric patients with acute lymphoblastic leukemia (ALL), response to GCs remains the most reliable prognostic indicator; failure to respond to GC correlates with poor event-free survival. To uncover GC resistance mechanisms, we performed a genome-wide, survival-based short hairpin RNA screen and identified the orphan nuclear receptor estrogen-related receptor-ß (ESRRB) as a critical transcription factor that cooperates with the GC receptor (GR) to mediate the GC gene expression signature in mouse and human ALL cells. Esrrb knockdown interfered with the expression of genes that were induced and repressed by GR and resulted in GC resistance in vitro and in vivo. Dexamethasone treatment stimulated ESRRB binding to estrogen-related receptor elements (ERREs) in canonical GC-regulated genes, and H3K27Ac Hi-chromatin immunoprecipitation revealed increased interactions between GR- and ERRE-containing regulatory regions in dexamethasone-treated human T-ALL cells. Furthermore, ESRRB agonists enhanced GC target gene expression and synergized with dexamethasone to induce leukemic cell death, indicating that ESRRB agonists may overcome GC resistance in ALL, and potentially, in other lymphoid malignancies.

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