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Conservation and education outreach programs often highlight charismatic species or species of economic or ecological importance. However, without appreciable connections to nature, the foundation necessary to empathize with these programs is insufficient. While many students are familiar with charismatic organisms, such as large mammals or sea turtles, there are countless other species of conservation concern that many students are entirely unaware of. As species loss is expedited, it is imperative to counter biodiversity naivety, particularly as public education and awareness are central to successful conservation efforts. The most impactful educational experiences foster direct engagement with biodiversity by students. We highlight the use of project-based learning to nurture student exposure and understanding of biodiversity in undergraduate- and graduate-level courses through the use of iNaturalist. In these courses, students were required to document observations from class field experiences as well as personal explorations. These projects transformed the learning of biodiversity from passive in nature to a meaningful and active process allowing students to connect with species observed while concurrently participating in citizen science initiatives. We share recommendations for successful implementation of iNaturalist projects by educators as well as challenges and issues based on our experiences.

Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD. Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported. Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Fourteen subjects completed the study. Median age was 42 years (range 22 - 52 years); median body weight was 73.6 kg (range 63.7 - 89.3 kg). Through the pre-specified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. During the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were headache, myalgia, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean C max following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated predose PLA formation was 33 - 39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained through at least 12 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects. Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed through at least 12 weeks, consistent with prior observations. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs. Funding: This study was supported by Global Blood Therapeutics. Disclosures Mayer: Global Blood Therapeutics: Consultancy. Redfern: Linear Clinical Research: Current Employment; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board; Eisai: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Geng: Global Blood Therapeutics: Current Employment. Shi: Global Blood Therapeutics: Current Employment. van Zutphen-van Geffen: Global Blood Therapeutics: Consultancy. Kuan: Global Blood Therapeutics: Consultancy. Koeck: Global Blood Therapeutics: Consultancy. Kastrissios: Global Blood Therapeutics: Consultancy. Patel: Global Blood Therapeutics: Consultancy. Davis: Global Blood Therapeutics: Current Employment. Yue: Global Blood Therapeutics: Current Employment.

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibres with striking nemaline rods and hypertrophy of slow fibres that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G>A, NM_006757.3:c.681+1G>A). TNNT3 encodes skeletal troponin-T(fast) and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy, a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T(fast) protein with secondary loss of troponin-I(fast). We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital nemaline myopathy with distal arthrogryposis (NM-DA), characterised by specific involvement of Type-2 fibres and deficiency of troponin-T(fast).

peer-reviewed Poorly water-soluble drugs are a significant and ongoing issue for the pharmaceutical industry. An overview of recent developments for the preparation of spray-dried delivery systems is presented. Examples include amorphous solid dispersions, spray dried dispersions, microparticles, nanoparticles, surfactant systems and self-emulsifying drug delivery systems. Several aspects of formulation are considered, such as pre-screening, choosing excipient(s), the effect of polymer structure on performance, formulation optimisation, ternary dispersions, fixed-dose combinations, solvent selection and component miscibility. Process optimisation techniques including nozzle selection are discussed. Comparisons are drawn with other preparation techniques such as hot melt extrusion, freeze drying, milling, electro spinning and film casting. Novel analytical and dissolution techniques for the characterization of amorphous solid dispersions are included. Progress in understanding of amorphous supersaturation or recrystallisation from solution gathered from mechanistic studies is discussed. Aspects of powder flow and compression are considered in a section on downstream processing. Overall, spray drying has a bright future due to its versatility, efficiency and the driving force of poorly soluble drugs

The decline of savanna habitat in the upper Midwest has resulted in a decline of savanna and grassland birds. Many savanna restoration efforts involve the re- introduction of fire, a method which kills fire-sensitive trees, often leaving them standing as snags. The purpose of this study was to assess how the number of snags (standing dead trees) is associated with the breeding bird community and to document how the number of snags at a site varied over a 23 y period of restoration by fire. The effect of snags on bird communities was studied by establishing bird census plots along a wide range of snag abundances. To determine for what purposes birds utilized snags, observers documented all visits during an hour-long period for pairs of a dead and live tree. Change in the abundance of snags over time was documented over 23 y in a 16 ha grid. We found both bird species richness and abundance were positively associated with the number of snags and that birds used dead trees for mating and reproductiv...

Background The development of fast-growing hardwood trees as a source of lignocellulosic biomass for biofuel and biomaterial production requires a thorough understanding of the plant cell wall structure and function that underlie the inherent recalcitrance properties of woody biomass. Downregulation of GAUT12.1 in Populus deltoides was recently reported to result in improved biomass saccharification, plant growth, and biomass yield. To further understand GAUT12.1 function in biomass recalcitrance and plant growth, here we report the effects of P. trichocarpa GAUT12.1 overexpression in P. deltoides. Results Increasing GAUT12.1 transcript expression by 7–49% in P. deltoides PtGAUT12.1-overexpression (OE) lines resulted in a nearly complete opposite biomass saccharification and plant growth phenotype to that observed previously in PdGAUT12.1-knockdown (KD) lines. This included significantly reduced glucose, xylose, and total sugar release (12–13%), plant height (6–54%), stem diameter (8–40%), and overall total aerial biomass yield (48–61%) in 3-month-old, greenhouse-grown PtGAUT12.1-OE lines compared to controls. Total lignin content was unaffected by the gene overexpression. Importantly, selected PtGAUT12.1-OE lines retained the recalcitrance and growth phenotypes upon growth for 9 months in the greenhouse and 2.8 years in the field. PtGAUT12.1-OE plants had significantly smaller leaves with lower relative water content, and significantly reduced stem wood xylem cell numbers and size. At the cell wall level, xylose and galacturonic acid contents increased markedly in total cell walls as well as in soluble and insoluble cell wall extracts, consistent with increased amounts of xylan and homogalacturonan in the PtGAUT12.1-OE lines. This led to increased cell wall recalcitrance, as manifested by the 9–15% reduced amounts of recovered extractable wall materials and 8–15% greater amounts of final insoluble pellet in the PtGAUT12.1-OE lines compared to controls. Conclusions The combined phenotype and chemotype data from P. deltoides PtGAUT12.1-OE and PdGAUT12.1-KD transgenics clearly establish GAUT12.1 as a recalcitrance- and growth-associated gene in poplar. Overall, the data support the hypothesis that GAUT12.1 synthesizes either an HG-containing primer for xylan synthesis or an HG glycan required for proper xylan deposition, anchoring, and/or architecture in the wall, and the possibility of HG and xylan glycans being connected to each other by a base-sensitive covalent linkage.

Background\ud\udA core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed‐upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e‐Delphi surveys. In this manuscript, we describe two in‐person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items.\ud\ud\udObjectives\ud\udTo consider which items from a long list of candidate items to exclude and which to cluster into outcome domains.\ud\ud\udMethods\ud\udThe study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey.\ud\ud\udResults\ud\udForty‐one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS‐specific quality of life, satisfaction, symptoms, pain and global assessments.\ud\ud\udConclusions\ud\udThe HISTORIC consensus meetings I and II will be followed by further e‐Delphi rounds to finalize the core domain set, building on the work of the in‐person consensus meetings.

Researchers have extensively explored the early and middle stages of romantic and sexual relationships for those high on the Dark Triad traits (i.e., psychopathy, Machiavellianism, and narcissism) but they have generally missed the termination stage of relationships. In this study we examined (N = 341) the role these traits play in one termination strategy, ghosting. Ghosting is when a person discontinues a relationship through silence; it is considered an indirect form of relationship termination. We found that (1) those who reported ghosting someone in the past (vs. those who did not) found ghosting to be acceptable and were more Machiavellian and psychopathic, (2) ghosting was most acceptable in the short-term (vs. long-term) context especially for those who had previously ghosted someone, and (3) those high in the Dark Triad traits rated ghosting more acceptable to terminate short-term relationships, but not long-term ones. We also found that the correlations between acceptability and ghosting short-term partners and the Dark Triad traits was localized to narcissistic men with a similar-yet-weak effect for psychopathy. Results are discussed in relation to how ghosting may be primarily committed by people who are interested in casual sex where investment is low and may be part of the fast life history strategies linked to the Dark Triad traits.

Purpose This paper aims to compare style and behavior-focused individual difference measures in their ability to uniquely predict naturally occurring conflict acts. Design/methodology/approach Primary participants (and a friend of their choosing) completed a style measure and a behavior-focused measure about the primary participants and reported on the occurrence of a variety of conflict actions over a 60-day period. Findings For self-ratings and friend ratings, both the style measure and the behavior-focused measure were significantly related to the occurrence of conflict acts. However, the unique effect of the behavior-focused measure was stronger than that of the style measure. Research limitations/implications The data were collected from college students, thus limiting the generalizability of the findings. The measure of conflict acts was based on recall, which may also be subject to error and bias. In terms of implications, the findings strongly suggest that behavior-focused instruments are superior to style measures in predicting everyday conflict acts. Practical implications Because the behavior-focused individual difference measure was a better predictor of actual behavior than the style measure, investigators interested in such prediction may want to seriously consider using such measures. Originality/value Little research exists regarding the relative predictive abilities of style measures and behavior-focused measures; this paper provides some of the first such evidence.

Background Genital or vulval lichen planus (VLP) may have a disabling effect on a patient's quality of life. Evidence-based management guidelines are lacking for VLP. Objective We sought to review clinical presentation and treatment of patients who received a diagnosis of VLP. Methods The 100 consecutive patients who received a diagnosis of VLP at Mayo Clinic between January 1, 1997, and December 31, 2015, were reviewed retrospectively. Descriptive statistics were used for data analysis. Fisher's exact test and the Wilcoxon rank sum test were used for analysis of categorical and continuous variables, respectively. All statistical tests were 2 sided, with the α level set at .05 for statistical significance. Results The time to diagnosis for 49% of patients was more than 1 year. Three patients (3%) had vulval dysplasia, including invasive squamous cell carcinoma. Sixty-eight patients (68%) had multisite lichen planus disease. Eleven patients (11%) had disease remission. Dermatology was the lead specialty for 9 of these cases of remission. Limitations This was a retrospective, small-cohort study. Conclusion A low frequency of disease remission was seen in patients with VLP. Patients with lichen planus benefit considerably from dermatology consultation. Further research is warranted to establish high-quality, evidence-based guidelines for multidisciplinary management of this challenging disease.

Background: Camptothecin (CPT) derivatives such as irinotecan have activity in 2nd-line therapy in advanced GEC with reported response rates of 0-15%. CRLX101 is an investigational nanoparticle-drug conjugate (NDC) with a CPT payload. Preclinical evidence indicates preferential uptake in tumors, and animal GEC xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in patients with chemotherapy-refractory GEC. Data demonstrating preferential tumor uptake of CRLX101 has been presented separately and here we report on the clinical outcomes of patients enrolled. Methods: All pts initiated CRLX101 dosed intravenously at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle until disease progression or intolerant toxicity. While detection of preferential CRLX101 tumor uptake was the primary endpoint, with 10 pts enrolled a secondary analysis could be performed with the study having 90% power to detect ≥ 1 responder if the true response rate is ≥ 21%. Responses were assessed using RECIST 1.1. Results: Between Dec. 2012 and Dec. 2014, 10 patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) GEC and adenocarcinoma histology were enrolled and evaluable for response and toxicity. The median time-to-progression was 1.9 mo (range 0.6-8.7 mo). Best response was seen in 1 pt with stable disease (SD) for 8 cycles. Only ≥ grade 3 toxicities related to CRLX101 occurred in a single patient with grade 3 anemia and chest pain who was able to resume therapy without any further toxicity after CRLX101 was reduced to 12 mg/m2. Conclusions: CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in advanced GEC should focus on combination strategies. Its favorable toxicity profile and evidence of preferential tumor uptake support further clinical research of combining CRLX101 with other targeted therapies such as anti-angiogenesis (ramucirumab) and/or immune checkpoint inhibitors. Clinical trial information: NCT01612546 Clinical trial information: NCT01612546.

Background Lignin dehydrogenation polymers (DHPs) are polymers generated from phenolic precursors for the purpose of studying lignin structure and polymerization processes Methods Here, DHPs were synthesized using a Zutropfverfahren method with horseradish peroxidase and three lignin monomers, sinapyl (S), coumaryl (H), and coniferyl (G) alcohols, in the presence of hydrogen peroxide. The H monomer was reacted with G and a 1:1 molar mixture of S:G monomers at H molar compositions of 0, 5, 10, and 20 mol% to study how the presence of the H monomer affected the structure and composition of the recovered polymers. Results At low H concentrations, solid-state NMR spectra suggest that the H and G monomers interact to form G:H polymers that have a lower average molecular weight than the solely G-based polymer or the G:H polymer produced at higher H concentrations. Solid-state NMR and pyrolysis–MBMS analyses suggest that at higher H concentrations, the H monomer primarily self-polymerizes to produce clusters of H-based polymer that are segregated from clusters of G- or S:G-based polymers. Thioacidolysis generally showed higher recoveries of thioethylated products from S:G or S:G:H polymers made with higher H content, indicating an increase in the linear ether linkages. Conclusions Overall, the experimental results support theoretical predictions for the reactivity and structural influences of the H monomer on the formation of lignin-like polymers. Electronic supplementary material The online version of this article (10.1186/s13068-017-0962-2) contains supplementary material, which is available to authorized users.

Background Classic Sezary syndrome (SS) is defined by erythroderma, generalized lymphadenopathy, and leukemic blood involvement. Clinical observations suggest that SS begins as a nonerythrodermic disease. Objective To describe the early clinical characteristics of patients with SS. Methods A retrospective, multicenter chart review was performed for 263 confirmed cases of SS diagnosed during 1976-2015. Results Erythroderma was the earliest recorded skin sign of SS in only 25.5% of cases, although most patients (86.3%) eventually developed erythroderma. In patients without erythroderma during their initial visit, the first cutaneous signs of SS were nonspecific dermatitis (49%), atopic dermatitis-like eruption (4.9%), or patches and plaques of mycosis fungoides (10.6%). The mean diagnostic delay was 4.2 years overall, 2.2 years for cases involving erythroderma at the initial presentation, and 5.0 years for cases not involving erythroderma at the initial presentation. Limitations This study is retrospective. Conclusion Erythroderma is uncommon as an initial sign of SS. Early SS should be considered in cases of nonerythrodermic dermatitis that is refractory to conventional treatments. In these cases, examination of the blood by PCR for monoclonal T-cell receptor rearrangement and by flow cytometry to identify an expanded or aberrant T-cell population should be considered.

See Ginevrino and Valente (doi:10.1093/brain/awx260) for a scientific commentary on this article. Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.

A synthetic, fault-free gmelinite (GME) zeolite is prepared using a specific organic structure-directing agent (OSDA), cis-3,5-dimethylpiperidinium. The cis-isomers align in the main 12-membered ring (MR) channel of GME. Trans-isomer OSDA leads to the small-pore zeolite SSZ-39 with the OSDA in its cages. Data from N_2-physisorption and rotation electron diffraction provide evidence for the openness of the 12 MR channel in the GME 12×8×8 pore architecture and the absence of stacking faults, respectively. CIT-9 is hydrothermally stable when K^+-exchanged, while in the absence of exchange, the material transforms into an aluminous AFI-zeolite. The process of this phase-change was followed by in situ variable temperature powder X-ray diffraction. CIT-9 has the highest Si/Al ratio reported for GME, and along with its good porosity, opens the possibility of using GME in a variety of applications including catalysis.

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca2+channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La3+; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca2+channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway.

Multiple myeloma is characterized by the clonal expansion of malignant plasma cells in the bone marrow. But the phenotypic diversity and the contribution of less predominant B-lineage clones to the biology of this disease have been controversial. Here, we asked whether cells bearing the dominant multiple myeloma immunoglobulin rearrangement occupy phenotypic compartments other than that of plasma cells. To accomplish this, we combined 13-parameter FACS index sorting and t-Stochastic Neighbor Embedding (t-SNE) visualization with high-throughput single-cell immunoglobulin sequencing to track selected B-lineage clones across different stages of human B-cell development. As expected, the predominant clones preferentially mapped to aberrant plasma cell compartments, albeit phenotypically altered from wild type. Interestingly, up to 1.2% of cells of the predominant clones colocalized with B-lineage cells of a normal phenotype. In addition, minor clones with distinct immunoglobulin sequences were detected in up to 9% of sequenced cells, but only 2 out of 12 of these clones showed aberrant immune phenotypes. The majority of these minor clones showed intraclonal silent nucleotide differences within the CDR3s and varying frequencies of somatic mutations in the immunoglobulin genes. Therefore, the phenotypic range of multiple myeloma cells in the bone marrow is not confined to aberrant-phenotype plasma cells but extends to low frequencies of normal-phenotype B cells, in line with the recently reported success of B cell–targeting cellular therapies in some patients. The majority of minor clones result from parallel nonmalignant expansion. Cancer Immunol Res; 5(9); 744–54. ©2017 AACR.

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1β (Mip1β), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors' blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.

Autosomal dominant mutations of DYNC1H1 cause a range of neurogenetic diseases, including mental retardation with cortical malformations, hereditary spastic paraplegia and spinal muscular atrophy. Using SNP array, linkage analysis and next generation sequencing, we identified two families and one isolated proband sharing a known spinal muscular atrophy, lower extremity predominant (SMALED) causing mutation DYNC1H1 c.1792C>T, p.Arg598Cys, and another family harbouring a c.2327C>T, p.Pro776Leu mutation. Here, we present a detailed clinical and pathological examination of these patients, and show that patients with DYNC1H1 mutations may present with a phenotype mimicking a congenital myopathy. We also highlight features that increase the phenotypic overlap with BICD2, which causes SMALED2. Serial muscle biopsies were available for several patients, spanning from infancy and early childhood to middle age. These provide a unique insight into the developmental and pathological origins of SMALED, suggesting in utero denervation with reinnervation by surrounding intact motor neurons and segmental anterior horn cell deficits. We characterise biopsy features that may make diagnosis of this condition easier in the future.

Deoxynivalenol (DON) levels in harvested grain samples are used to evaluate the Fusarium head blight (FHB) resistance of wheat cultivars and breeding lines. Fourier transform near-infrared (FT-NIR) calibrations were developed to estimate the DON level and moisture content (MC) of bulk wheat grain samples harvested from FHB screening trials. Grains in a rotating glass petri dish were scanned in the 10,000–4,000 cm−1 (1,000–2,500 nm) spectral range using a Perkin Elmer Spectrum 400 FT-IR/FT-NIR spectrometer. The DON calibration predicted the DON levels in test samples with R2 = 0.62 and root mean square error of prediction (RMSEP) = 8.01 ppm. When 5–25 ppm of DON was used as the cut-off to classify samples into low- and high-DON groups, 60.8–82.3% of the low-DON samples were correctly classified, whereas the classification accuracy of the high-DON group was 82.3–94.0%. The MC calibration predicted the MC in grain samples with R2 = 0.98 and RMSEP = 0.19%. Therefore, these FT-NIR calibrations can be used to r...

Systems-biology approaches in immunology take various forms, but here we review strategies for measuring a broad swath of immunological functions as a means of discovering previously unknown relationships and phenomena and as a powerful way of understanding the immune system as a whole. This approach has rejuvenated the field of vaccine development and has fostered hope that new ways will be found to combat infectious diseases that have proven refractory to classical approaches. Systems immunology also presents an important new strategy for understanding human immunity directly, taking advantage of the many ways the immune system of humans can be manipulated.

Summary Sustainable utilization of lignocellulosic perennial grass feedstocks will be enabled by high biomass production and optimized cell wall chemistry for efficient conversion into biofuels. MicroRNAs are regulatory elements that modulate the expression of genes involved in various biological functions in plants, including growth and development. In greenhouse studies, overexpressing a microRNA (miR156) gene in switchgrass had dramatic effects on plant architecture and flowering, which appeared to be driven by transgene expression levels. High expressing lines were extremely dwarfed, whereas low and moderate expressing lines had higher biomass yields, improved sugar release, and delayed flowering. Four lines with moderate or low miR156 overexpression from the prior greenhouse study were selected for a field experiment to assess the relationship between miR156 expression and biomass production over three years. We also analyzed important bioenergy feedstock traits such as flowering, disease resistance, cell wall chemistry, and biofuel production. Phenotypes of the transgenic lines were inconsistent between the greenhouse and the field as well as among different field growing seasons. One low expressing transgenic line consistently produced more biomass (25-56%) than the control across all three seasons, which translated to the production of 30% more biofuel per plant during the final season. The other three transgenic lines produced less biomass than the control by the final season, and the two lines with moderate expression levels also exhibited altered disease susceptibilities. Results of this study emphasize the importance of performing multi-year field studies for plants with altered regulatory transgenes that target plant growth and development. This article is protected by copyright. All rights reserved.

Effective conservation and management of biodiversity is limited by a lack of critical knowledge on species’ distributions and abundances. This problem is particularly exacerbated for species living in habitats that are exceptionally difficult to access or survey, such as groundwater habitats. Environmental DNA (eDNA) represents a rapid, noninvasive, and potentially cost-effective new tool for detection and monitoring of biodiversity that occur in such habitats. In this study, we investigated the utility of eDNA in detecting the federally endangered Hay’s Spring Amphipod Stygobromus hayi and a co-occurring common congener S. tenuis potomacus from unique groundwater-associated habitats—hypotelminorheic seepage springs—in the Washington, DC metro area. We developed taxon-specific primers and probes for each species to amplify Stygobromus DNA using qPCR. In silico and in vitro validation demonstrated specificity of each designed assay. Assays were then used to screen water samples collected from ten seepage springs. Stygobromus hayi was detected at four seepage springs, including one potential new locality, while S. t. potomacus was detected at four springs, two of which were new localities. This study is the first to our knowledge to successfully employ an eDNA approach to detect rare or threatened invertebrates from subterranean ecosystems. Our study highlights challenges of employing an eDNA approach for the detection and monitoring of invertebrates in groundwater habitats that are difficult to study, including accounting for PCR inhibition and the potential for cryptic genetic diversity.

Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca2+entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high-glucose-increased Smad1 protein content. Treatment of human MCs with ANG II at 1 µM for 15 min, high glucose for 3 days, or TGF-β1 at 5 ng/ml for 30 min increased the level of phosphorylated Smad1. However, the phosphorylation of Smad1 by those stimuli was significantly attenuated by activation of SOCE. Knocking down Smad1 reduced, but expressing Smad1 increased, the amount of Col IV protein. Furthermore, activation of SOCE significantly attenuated high-glucose-induced Col IV protein production, and blockade of SOCE substantially increased the abundance of Col IV. To further verify those in vitro findings, we downregulated SOCE specifically in MCs in mice using small-interfering RNA (siRNA) against Orai1 (the channel protein mediating SOCE) delivered by the targeted nanoparticle delivery system. Immunohistochemical examinations showed that expression of both Smad1 and Col IV proteins was significantly greater in the glomeruli with positively transfected Orai1 siRNA compared with the glomeruli from the mice without Orai1 siRNA treatment. Taken together, our results indicate that SOCE negatively regulates the Smad1 signaling pathway and inhibits Col IV protein production in MCs.

Some accounts of social projection view it as an essentially cognitive phenomenon, prompted by the need for a relatively low-effort way to arrive at inferences about others. Other accounts argue that projection is motivated by self-enhancement and self-protection concerns. This investigation evaluates these accounts by having participants make inferences about liked and disliked real-world targets. In Studies 1 and 2, participants projected more to liked than disliked targets, supporting a motivational account; however, when perceived similarity was accounted for, this difference disappeared, supporting the cognitive account. In Study 3 participants made inferences about targets who varied along both the valence and similarity dimensions; there was greater projection to all similar targets, but target valence only influenced projection if the targets were also seen as similar. The implications of these findings are discussed.

Early-onset muscle disease includes three major entities that present generally at or before birth: congenital myopathies, congenital muscular dystrophies and congenital myasthenic syndromes. Almost exclusively there is weakness and hypotonia, although cases manifesting hypertonia are increasingly being recognised. These diseases display a wide phenotypic and genetic heterogeneity, with the uptake of next generation sequencing resulting in an unparalleled extension of the phenotype-genotype correlations and "diagnosis by sequencing" due to unbiased sequencing. Perhaps now more than ever, detailed clinical evaluations are necessary to guide the genetic diagnosis; with arrival at a molecular diagnosis frequently occurring following dialogue between the molecular geneticist, the referring clinician and the pathologist. There is an ever-increasing blurring of the boundaries between the congenital myopathies, dystrophies and myasthenic syndromes. In addition, many novel disease genes have been described and new insights have been gained into skeletal muscle development and function. Despite the advances made, a significant percentage of patients remain without a molecular diagnosis, suggesting that there are many more human disease genes and mechanisms to identify. It is now technically- and clinically-feasible to perform next generation sequencing for severe diseases on a population-wide scale, such that preconception-carrier screening can occur. Newborn screening for selected early-onset muscle diseases is also technically and ethically-achievable, with benefits to the patient and family from early management of these diseases and should also be implemented. The need for world-wide Reference Centres to meticulously curate polymorphisms and mutations within a particular gene is becoming increasingly apparent, particularly for interpretation of variants in the large genes which cause early-onset myopathies: NEB, RYR1 and TTN. Functional validation of candidate disease variants is crucial for accurate interpretation of next generation sequencing and appropriate genetic counseling. Many published "pathogenic" variants are too frequent in control populations and are thus likely rare polymorphisms. Mechanisms need to be put in place to systematically update the classification of variants such that accurate interpretation of variants occurs. In this review, we highlight the recent advances made and the challenges ahead for the molecular diagnosis of early-onset muscle diseases.

In this investigation, intimate partner support, relationship satisfaction, and separation proneness were assessed for four types of people: men in a relationship with a woman (MRW), men in a relationship with a man (MRM), women in a relationship with a man (WRM), and women in a relationship with a woman (WRW). Men and women in same-sex relationships received more support, were more satisfied, and reported fewer thoughts of separating than their counterparts in opposite-sex relationships. The effect of relationship type on satisfaction was not significant once the amount of received support was controlled. The implications of these findings for understanding the support process in same-sex relationships are discussed.

Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20–30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

Materials designed and engineered for technical applications must invariably meet or exceed multiple key specifications. Even if commercial realization is not intended, scientific interest is piqued if a challenging combination of properties is achieved, particularly if they are mutually exclusive for certain classes of materials. For example, the combination of mechanical toughness, chemical durability, and high thermal-shock resistance, with pore-free, smooth, aesthetically beautiful surfaces simultaneously realized in certain glasses that are crystallized in a controlled manner—glass-ceramics—have enabled two distinct, decades-long applications, cookware and flat cooktop panels. Other special glass-ceramic materials have been developed for electronic, photonic, dental, and biomedical applications. No other class of material could combine these properties in such an advantageous and economically feasible manner. This issue highlights six very different innovative applications of glass-ceramics, all of which owe their importance and continuing interest to “hard-to-combine” properties.

Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+ T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

Softwood is an abundant resource; however, currently its utilization for bioconversion to obtain platform sugars is limited. Pinus taeda trees which were genetically modified to either produce S lignin or to decrease lignin content were characterized with a suite of analytic techniques. Syringyl lignin was visualized in the secondary xylem of one genetic line with Maule staining. Solid-state nuclear magnetic resonance identified the S lignin units were coupled into the lignin through β-O-4 linkages, and thioacidolysis measured approximately 13% S lignin content in the same sample. Reductions of the lignin of as much as 33% were observed in the transgenics. To better understand how these modifications affect bioconversion, their amenability to hot water and dilute acid pretreatments and enzymatic hydrolysis was evaluated. Lignin reductions resulted in 1.9–3.2-fold increases in glucose release compared to the control. However, no apparent benefit was observed by S lignin incorporation at the concentrations reported in this study. These results highlight the potential for softwood cell wall properties to be improved for bioenergy/biochemical applications.

Review of Luis de Góngora and Lope de Vega: Masters of Parody by LINDSAY G. KERR.

Background & Aim NY-ESO-1 is a cancer testis antigen with ectopic expression on multiple myeloma (MM), melanoma and sarcoma but restricted expression on normal tissues, rendering it a good candidate target for cancer immunotherapy. We recently reported a phase 1 pilot trial of multiplex CRISPR/Cas9 genome-edited NY-ESO-1 TCR cells (NYCE T cells; NCT03399448) for patients (pts) with advanced MM, synovial sarcoma and myxoid/round cell liposarcoma (MRCL) demonstrated safety and feasibility as well as persistence of T cells. Here, we characterize the phenotype and function of the ex vivo manufactured NYCE T cells from the 3 pts that were infused in the trial. Methods, Results & Conclusion The 3 infusion products (2 MM – pt #35 and Pt #7, and 1 MRCL – pt #39) were used to compare expanded T cells with either CRISPR/Cas9 editing without TCR transduction or with Mock-editing and TCR transduction from the same pt. We examined the phenotypic markers of T cell differentiation and checkpoint inhibitors by multicolor flow cytometry and assessed in vitro anti-tumor efficacy via a luciferase-based killing assay. We found heterogeneity in the composition of T cell subsets from all 3 infusion products with various CD4 and CD8 ratios, ranging from 0.12-1.1. Transduction efficiencies (determined by Vbeta8.1+ staining) varied between 1-11% and different levels of knockout efficiency in TRAC, TRBC and PDCD1 genes were observed by digital PCR. Three NYCE T cell infusion products displayed a terminally differentiated T cell phenotype similar to CRISPR/Cas9 edited counterpart. In contrast to Mock-edited T cells from the same pt, NYCE T cells exhibited lower levels of differing combinations of exhaustion-associated markers (PD1, TIM3, LAG3, EOMES and CTLA4) in both CD4+ and CD8+ T cell compartments. All 3 infusion products elicited antigen-specific killing of NY-ESO-1 expressing target cells. We demonstrate that NYCE T cells are heterogeneous in composition. Furthermore, we showed that CRISPR/Cas9 editing does not affect T cell differentiation and anti-tumor efficacy, but does reduce levels of exhaustion-associated markers expressed by the final products. This work provides an in-depth characterization of the heterogeneous product composition and function of the first multiplex CRISPR/Cas9-edited T cells tested in humans.

Development of commercially relevant bioenergy switchgrass cultivars requires reducing recalcitrance for bioprocessing without compromising biomass yield. Low-lignin transgenic switchgrass has been produced via down-regulation of caffeic acid O-methyltransferase (COMT), a lignin biosynthetic enzyme, or by over-expression of the MYB4 transcription factor, a repressor of the lignin biosynthetic pathway. The aim of this study was to evaluate parents and selected hybrids obtained from COMT and MYB4 hybrid families under field conditions for agronomic performance and biomass quality. Plant height, width, number of tillers, dry weight, cell wall composition including lignin content, and sugar release were measured after the establishment year (2014) and the second growing season (2015). For COMT hybrids, biomass yield of the transgenic hybrids was similar to or greater than the wild-type parents selected for high biomass. Lignin content of COMT transgenic hybrids was reduced by 10%, S/G ratio decreased by 27%, and sugar release increased between 20% and 44% compared to their wild-type parents. These results indicate that hybridization of COMT with a high-yielding locally selected genotype resulted in both improved agronomic performance and enhanced biomass quality in the offspring. On the other hand, the MYB transgenic hybrid showed a 10% reduction in biomass yield compared with its wild-type parent in year 1, but not in year 2. The lignin S/G ratio was not reduced in MYB transgenic hybrids, nor was sugar release increased. These data indicate that the MYB transgene may not be suitable for an agronomic setting. More testing is needed of transgenic and wild-type, high-biomass selections for use as breeding parents. These results show that combining low-lignin transgenic switchgrass with a breeding and selection program for biomass yield will allow for the deployment of effective transgenes in high-yielding genetic backgrounds.

Peanut-specific CD8(+) T cells in nonallergic individuals are not deleted, but have an expansion block that can be released by impairing regulatory T cell associated signaling pathways.

In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic agents against brain metastases is limited by their inability to permeate the blood–brain and blood–tumor barriers (BBB and BTB) in therapeutic amounts. Here, we investigate the potential of mucic acid-based, targeted nanoparticles designed to transcytose the BBB/BTB to deliver a small molecule drug, camptothecin (CPT), and therapeutic antibody, Herceptin, to brain metastases in mice. Treatment with BBB-targeted combination CPT/Herceptin nanoparticles significantly inhibits tumor growth compared to free CPT/Herceptin and BBB-targeted nanoparticles carrying CPT alone. Though not as efficacious, BBB-targeted nanoparticles carrying only Herceptin also elicit considerable antitumor activity. These results demonstrate the potential of the targeted nanoparticle system for the delivery of an antibody alone or in combination with other drugs across the BBB/BTB to improve the therapeutic outcome.

The small-pore zeolite with the chabazite framework topology, SSZ-13, is found to be an active catalyst in the carbonylation of dimethyl ether to methyl acetate (MA). The production of MA over SSZ-13 after 24 h on stream at 165 °C and 1 bar approaches that obtained from mordenite and is significantly higher than from ferrierite at comparable Si/Al of ca. 10. To understand the origin of the activity, SSZ-13 materials are synthesized with variable Si/Al, characterized via several techniques including multinuclear magic-angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, and evaluated for their carbonylation activity. While MA production rates increase with decreasing Si/Al, the correlation is nonlinear due to the effect of Si/Al on the acid site distribution within different confining environments, and the associated impact of the latter on the rate-determining transition state barrier. Enhanced MA production rates trend with acid sites located at the eight-membered ring (8MR) that are increasingly populated as framework Al content increases. Density functional theory analyses of transition state energies as a function of active site location support the experimental findings, where the lowest apparent barriers are associated with the methoxy groups that orient within the plane of the 8MR window. This is due to an optimal charge stabilization of the cationic transition states with the negatively charged oxygens within the 8MR window. The effects of catalyst chemical composition, separate from framework topology, are also investigated using SAPO-34 (the silicoaluminophosphate analog of SSZ-13). Analyses of the ¹H MAS NMR signals and carbonylation activity suggest that the higher acid site strength of SSZ-13 compared to that of the SAPO material is required for effective Brønsted acid catalysis of Koch-type carbonylation pathways.

Background Few large studies have assessed spironolactone treatment of adult female acne. Objectives To explore the role of spironolactone in the treatment of adult female acne. Methods We performed a retrospective case series assessing the efficacy of spironolactone treatment of a cohort of women evaluated at Mayo Clinic in Rochester, Minnesota, from 2007 through 2017. Results In total, 395 patients (median age, 32 years) received a median spironolactone dose of 100 mg daily. Approximately two-thirds of patients (66.1%) had a complete response; 85.1% had a complete response or a partial response greater than 50%. Median times to initial response and maximum response were 3 and 5 months. Efficacy was observed across all severity subtypes of acne, including those with papulopustular and nodulocystic acne. Patients received long-term treatment with spironolactone (median duration, 13 months) and had few adverse effects. Conclusions Spironolactone is a safe and effective treatment of acne for women.

[Background] UBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia., [Methods and results] We describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM_024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1., [Conclusion] This report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy., MC-S was supported by ISCIII (JR15/00042) and Junta de Andalucia-Consejeria de Salud (B-0005-2017). This work was supported by the NHMRC, grants to NGL and GR (APP1002147, APP1035955, APP1080587). MK is supported by a Grant-in-Aid for Scientific Research on Innovative Areas (19H0506), a Grant-in-Aid for Scientific Research (B) (18H02611), the Japan Society for the Promotion of Science (an A3 foresight program) and the Takeda Science Foundation (to MK). RI is supported by a Grant-in-Aid for Young Scientists (B) (18K15061).

In hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV+ HCC), the mechanisms by virus-derived antigens shape the T cell immune response remains unclear. Here, we employed bulk and single-cell multi-omics sequencing technologies to study the T cell receptor (TCR) repertoire, antigen specificity and epigenomic profiles in HBV+ HCC patients. We found that HBV is a major driver of T cells, with HBV-specific recurrent and expanding TCR clonotypes from CD8+ T cells, mucosal-associated invariant T (MAIT) cells and regulatory T cells (Tregs). HBV virions can directly activate MAIT cells in a MR1-dependent manner, indicating that these cells are not only sensors of metabolic products, but could participate directly in pathogen defense. And increased numbers of intratumoral Tregs, many of which are HBV specific, correlated with both increased viral titers and tumor size, while more a robust expansion of virus specific CD8+ T cells had better clinical prognosis after surgery. Integrating TCR and ATAC sequences also allowed us to track the epigenomic changes of specific T cell clonal lineages, with HBV-specific conventional CD8+ T cells expressing an effector phenotype when adjacent to the tumor, but cells of the same lineage exhibiting an “exhausted” phenotype in the tumor itself.

Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile., It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 “don’t eat me” signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis. Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer

The lignin biosynthetic pathway is highly conserved in angiosperms, yet pathway manipulations give rise to a variety of taxon-specific outcomes. Knockout of lignin-associated 4-coumarate:CoA ligases (4CLs) in herbaceous species mainly reduces guaiacyl (G) lignin and enhances cell wall saccharification. Here we show that CRISPR-knockout of 4CL1 in Populus tremula × alba preferentially reduced syringyl (S) lignin, with negligible effects on biomass recalcitrance. Concordant with reduced S-lignin was downregulation of ferulate 5-hydroxylases (F5Hs). Lignification was largely sustained by 4CL5, a low-affinity paralog of 4CL1 typically with only minor xylem expression or activity. Levels of caffeate, the preferred substrate of 4CL5, increased in line with significant upregulation of caffeoyl shikimate esterase1. Upregulation of caffeoyl-CoA O-methyltransferase1 and downregulation of F5Hs are consistent with preferential funneling of 4CL5 products toward G-lignin biosynthesis at the expense of S-lignin. Thus, transcriptional and metabolic adaptations to 4CL1-knockout appear to have enabled 4CL5 catalysis at a level sufficient to sustain lignification. Finally, genes involved in sulfur assimilation, the glutathione-ascorbate cycle and various antioxidant systems were upregulated in the mutants, suggesting cascading responses to perturbed thioesterification in lignin biosynthesis.One sentence summaryKnockout of lignin-associated 4CL1 in Populus reveals a 4CL5-dependent, caffeate-modulated compensatory pathway for lignification with links to thiol redox balance and sulfur assimilation.

Despite its imperative, biodiversity conservation is chronically underfunded, a deficiency that often forces management agencies to prioritize. Single-species recovery thus becomes a focus (often with socio-political implications), whereas a more economical approach would be the transition to multi-targeted management (= MTM). This challenge is best represented in Midwestern North America where biodiversity has been impacted by 300+ years of chronic anthropogenic disturbance such that native tall-grass prairie is now supplanted by an agroecosystem. Here, we develop an MTM with a population genetic metric to collaboratively manage three Illinois upland gamebirds: common pheasant (Phasianus colchicus; pheasant), northern bobwhite quail (Colinus virginianus; quail), and threatened-endangered (T&E) greater prairie chicken (Tympanuchus cupido pinnatus; prairie chicken). We first genotyped our study pheasant at 19 microsatellite DNA loci and identified three captive breeding stocks (N = 143; IL Department of Natural Resources) as being significantly bottlenecked, with relatedness >1st-cousin (μR = 0.158). ‘Wild’ (non-stocked) pheasant [N = 543; 14 Pheasant-Habitat-Areas (PHAs)] were also bottlenecked, significantly interrelated (μR = 0.150) and differentiated (μFST = 0.047), yet distinct from propagation stock. PHAs that encompassed significantly with larger areas also reflected greater effective population sizes (μNE = 43; P

International audience; Purpose High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. Methods We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenicTTNvariants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). Results Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final threeTTNexons (362-364). Conclusion Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.