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Blumeria graminis f. sp. tritici (Bgt) is a globally important fungal pathogen of wheat that can rapidly evolve to defeat wheat powdery mildew (Pm) resistance genes. Despite periodic regional deployment of the Pm1a resistance gene in U.S. wheat production, Bgt strains that overcome Pm1a have been notably non-persistent in the U.S., while on other continents they are more widely established. A genome-wide association study (GWAS) was conducted to map sequence variants associated with Pm1a virulence in 216 Bgt isolates from six countries, including the U.S. A virulence variant apparently unique to Bgt isolates from the U.S. was detected in the previously mapped gene AvrPm1a (BgtE-5612) on Bgt chromosome 6; an in-vitro growth assay suggested no fitness reduction associated with this variant. A gene on Bgt chromosome 8, Bgt-51526, was shown to function as a second determinant of Pm1a virulence and despite 85% of their secondary structure. A co-expression study in Nicotiana benthamiana showed that BGTE-5612 and BGT-51526 each produce a PM1A-dependent hypersensitive response. More than one member of a B. graminis effector family can be recognized by a single wheat immune receptor, and a two-gene model is necessary to explain virulence to Pm1a.

Standard practice for acetabular component placement in total hip arthroplasty (THA) is to medialise the acetabular component. Bone preservation techniques during primary THA are beneficial for possible future revisions. The goal of this study is to examine the effect of downsizing and minimising medialisation of the acetabular component on bone resection volume. The volume of bone resected during acetabular preparation for different sizes of components was calculated and the volume of bone preserved by downsizing the cup was determined. Minimising medialisation of the acetabular component by 1–3 mm from the true floor was calculated. Absolute values and percentage of bone volume preserved when acetabular components are downsized or less medialised is presented. Downsizing the acetabular component by one size (2 mm) preserves between 2.6 cm3 (size 40 vs 42) and 8.4 cm3 (size 72 vs 74) of bone volume and consistently reduces resected bone volume by at least 35% (range 35.2%–37.5%). Similarly, reducing medialisation of a 56 mm acetabular cup (as an example of a commonly implanted component) by 3 mm reduces bone loss by 5.9 cm3– 44% less bone volume resection. Downsizing and minimising medialisation of the cup in THA substantially preserves bone which may benefit future revision surgeries. Surgeons could consider implanting the smallest acceptable acetabular shell to preserve bone without compromising on head size.

Purpose: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. Patients and Methods: Anti–PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). Results: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. Conclusions: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167

Using latent profile analysis, we derived psychological profiles of undergraduates during the pandemic and investigated profiles’ differential associations with COVID-19 impact and social adjustment. Participants ( N = 517) completed measures of depression, loneliness, and anxiety, and two indices of social adjustment: friendship support and social connectedness. We identified Severe, Moderate, and Mild symptom profiles. Higher COVID-19 impact was associated with increased odds of belonging to the Severe versus Moderate and Mild profiles, and the Moderate versus Mild profile. On social adjustment, the Mild profile outscored the Moderate profile, which outscored the Severe profile. Overall, findings imply that individuals who perceive high levels of COVID-19 impact are especially likely to belong to a profile characterized by severe psychological symptoms and that membership in this profile is associated with social maladjustment.

Peptide epitope tags offer a valuable means for detection and manipulation of protein targets for which high quality detection reagents are not available. Most commonly used epitope tags are bound by conventional, full-size antibodies (Abs). The complex architecture of Abs complicates their application in protein engineering and intracellular applications. To address these shortcomings, single domain antibodies (nanobodies, Nbs) that recognize short peptide epitopes have become increasingly prized. Here we characterize the interaction between a Nb (Nb6E) and a 14-mer peptide epitope. We identify residues in the peptide epitope essential for high affinity binding. Using this information in combination with computational modeling we propose a mode of interaction between Nb6E and this epitope. We apply this nanobody-epitope pair to augment the potency of a ligand at an engineered adenosine A2A receptor. This characterization of the nanobody-epitope pair opens the door to diverse applications including mechanistic studies of G protein-coupled receptor function.

Connectivity of the brain at rest can reflect individual differences and impact behavioral outcomes, including memory. The present study investigated how culture influences functional connectivity with regions of the medial temporal lobe. In this study, 46 Americans and 59 East Asians completed a resting state scan after encoding pictures of objects. To investigate cross-cultural differences in resting state functional connectivity, left parahippocampal gyrus (anterior and posterior regions) and left hippocampus were selected as seed regions. These regions were selected, because they were previously implicated in a study of cultural differences during the successful encoding of detailed memories. Results revealed that left posterior parahippocampal gyrus had stronger connectivity with temporo-occipital regions for East Asians compared with Americans and stronger connectivity with parieto-occipital regions for Americans compared with East Asians. Left anterior parahippocampal gyrus had stronger connectivity with temporal regions for East Asians than Americans and stronger connectivity with frontal regions for Americans than East Asians. Although connectivity did not relate to memory performance, patterns did relate to cultural values. The degree of independent self-construal and subjective value of tradition were associated with functional connectivity involving left anterior parahippocampal gyrus. Findings are discussed in terms of potential cultural differences in memory consolidation or more general trait or state-based processes, such as holistic versus analytic processing.

The pancreaticoduodenal groove (PDG) is a small space between the pancreatic head and duodenum where vital interactions between multiple organs and physiologic processes take place. Muscles, nerves, and hormones perform a coordinated dance, allowing bile and pancreatic enzymes to aid in digestion and absorption of critical nutrition. Given the multitude of organs and cells working together, a variety of benign and malignant entities can arise in or adjacent to this space. Management of lesions in this region is also complex and can involve observation, endoscopic resection, or challenging surgeries such as the Whipple procedure. The radiologist plays an important role in evaluation of abnormalities involving the PDG. While CT is usually the first-line examination for evaluation of this complex region, MRI offers complementary information. Although features of abnormalities involving the PDG can often overlap, understanding the characteristic imaging and pathologic features generally allows categorization of disease entities based on the suspected organ of origin and the presence of ancillary features. The goal of the authors is to provide radiologists with a conceptual approach to entities implicating the PDG to increase the accuracy of diagnosis and assist in appropriate management or presurgical planning. They briefly discuss the anatomy of the PDG, followed by a more in-depth presentation of the features of disease categories. A table summarizing the entities that occur in this region by underlying cause and anatomic location is provided.

Slides for the keynote presentation "Thinking about Vector Symbolic Architectures" given on 2023-06-15 at the Midnight Sun Workshop on Vector Symbolic Architectures in Luleå, Sweden. Abstract Vector Symbolic Architectures are defined in terms of a very small set of operators acting on a vector space. The task of the VSA researcher is to discover the implications that follow from the definition in terms of the systems that can be implemented with VSAs. The VSA definitions are the researcher’s raw materials, but they also need tools to transform those raw materials into useful hypotheses and system designs. One important tool for a researcher is a conceptual framework, which specifies how the researcher thinks about VSAs and relates them to the other things they know. It is the researcher’s mental model of how VSAs work. The primary requirement for a conceptual framework is that it is productive; it should make it easy for the researcher to generate interesting hypotheses and designs. These hypotheses and designs don’t have to be correct, just plausible. Beating them into shape is a different part of the research process. Most VSA research papers contain a statement of the VSA definition. Very few mention the researcher’s conceptual framework. In this talk I will sketch out my conceptual framework - how I think about Vector Symbolic Architectures - in the hope that it might be interesting and useful to other researchers., As presented and live-streamed 2023-06-15 (except for addition of final slide with DOIs)

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) (‘converters’; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years’ follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

During the past two decades, our understanding of mechanochemical reactivity has advanced considerably. Nevertheless, an incomplete knowledge of structure–activity relationships and the principles that govern mechanochemical transformations limits molecular design. The experimental development of mechanophores has thus benefited from simple computational tools like CoGEF, from which quantitative metrics like rupture force can be extracted to estimate reactivity. Furan–maleimide (FM) and anthracene–maleimide (AM) Diels–Alder adducts are widely studied mechanophores that undergo retro-Diels–Alder reactions upon mechanical activation in polymers. Despite possessing significantly different thermal stability, similar rupture forces predicted by CoGEF calculations suggest that these compounds exhibit similar mechanochemical reactivity. Here, we directly probe the relative mechanochemical reactivity of FM and AM adducts through competitive activation experiments. Ultrasound-induced mechanochemical activation of bis-adduct mechanophores comprising covalently tethered FM and AM subunits reveals pronounced selectivity─as high as ∼13:1─for reaction of the FM adduct compared to the AM adduct. Computational models provide insight into the greater reactivity of the FM mechanophore, indicating a more efficient mechanochemical coupling for the FM adduct compared to the AM adduct. The methodology employed here to directly interrogate the relative reactivity of two different mechanophores using a tethered bis-adduct configuration may be useful for other systems where more common sonication-based approaches are limited by poor sensitivity.

Representativeness of study participants

Supplementary figure 1. (A) Changes in other circulating cytokines. Colored box denotes the time when the patients were being treated with ATRA. (B) example gating strategy for CD8+ T cell activation.

Purpose:A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma.Patients and Methods:Anti–PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS).Results:Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs.Conclusions:With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation.See related commentary by Olson and Luke, p. 1167

Characteristics of patients experiencing clinical benefit

Supplemental Figure 1

Supplemental Table 1

Supplementary figure 2. Changes in other clinical hematologic measures. Colored box denotes the time when the patients were being treated with ATRA. * Denotes p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

High-risk human papillomavirus-associated cancers express viral oncoproteins (e.g., E6 and E7) that induce and maintain the malignant phenotype. The viral origin of these proteins makes them attractive targets for development of a therapeutic vaccine. Camelid-derived single-domain antibody fragments (nanobodies or VHHs) that recognize cell surface proteins on antigen-presenting cells (APC) can serve as targeted delivery vehicles for antigens attached to them. Such VHHs were shown to induce CD4+ and CD8+ T-cell responses against model antigens conjugated to them via sortase, but antitumor responses had not yet been investigated. Here, we tested the ability of an anti-CD11b VHH (VHHCD11b) to target APCs and serve as the basis for a therapeutic vaccine to induce CD8+ T-cell responses against HPV+ tumors. Mice immunized with VHHCD11b conjugated to an H-2Db-restricted immunodominant E7 epitope (E749-57) had more E7-specific CD8+ T cells compared with those immunized with E749-57 peptide alone. These CD8+ T cells acted prophylactically and conferred protection against a subsequent challenge with HPV E7-expressing tumor cells. In a therapeutic setting, VHHCD11b-E749-57 vaccination resulted in greater numbers of CD8+ tumor–infiltrating lymphocytes compared with mice receiving E749-57 peptide alone in HPV+ tumor-bearing mice, as measured by in vivo noninvasive VHH-based immune-positron emission tomography (immunoPET), which correlated with tumor regression and survival outcome. Together, these results demonstrate that VHHs can serve as a therapeutic cancer vaccine platform for HPV-induced cancers. Cancer Immunol Res; 6(7); 870–80. ©2018 AACR.

All adverse events experienced by patients, including those unrelated to treatment

Trial inclusion/exclusion criteria

Establishing recommended phase II dose (RP2D) and dose limiting toxicities (DLTs)

Considering the fame of the poet and the beauty of the poetry, it is intriguing and somewhat baffling that there are no musical settings of Shakespeare’s sonnets from his lifetime, whether from lack of preservation or a disinclination on the part of composers to set them. This was first wondered at by Charles Burney in 1789, but is essentially explained away today as ‘sonnets are pure poetry’. This article explores possible reasons for the avoidance of sonnet settings in the early song repertory, including the language, versification, structure, and subject matter. The few surviving period sonnet settings are analysed, alongside a version of Sonnet 116 by Henry Lawes, the sole surviving Shakespeare sonnet setting from the seventeenth century. Using criteria from that study, a conjectural musical setting of a Shakespeare sonnet is proposed, based on an existing song by John Dowland.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10

Bone morphogenetic protein (BMP) cascades are upregulated during bone marrow-derived stromal cell (BMSC) chondrogenesis, contributing to hypertrophy and preventing effective BMSC-mediated cartilage repair. Previous work demonstrated that a proprietary BMP inhibitor prevented BMSC hypertrophy, yielding stable cartilage tissue. Because of the significant therapeutic potential of a molecule capable of hypertrophy blockade, we evaluated the capacity of a commercially available BMP type I receptor inhibitor with similar properties, LDN 193189, to prevent BMSC hypertrophy. Using 14-day microtissue chondrogenic induction cultures we found that LDN 193189 permitted BMSC chondrogenesis but did not prevent hypertrophy. LDN 193189 was sufficiently potent to counter mineralization and adipogenesis in response to exogenous BMP-2 in osteogenic induction cultures. LDN 193189 did not modify BMSC behavior in adipogenic induction cultures. Although LDN 193189 is effective in countering BMP signaling in a manner that influences BMSC fate, this blockade is insufficient to prevent hypertrophy.

Purpose Little is known regarding medical neglect in children with Life-Threatening Complex Chronic Conditions (LT-CCCs). We examined the impact of COVID-19 on concern for medical neglect in this population. Methods Qualitative interview study of multi-disciplinary health care providers (HCPs) from critical care, palliative care, and complex care services on the topic of medical neglect in children with LT-CCCs. We used inductive thematic analysis to generate themes. Findings presented herein are derived from a sub-analysis of the larger study that focused specifically on discussion of COVID-19 by HCPs. Results 9 of the 20 HCPs interviewed mentioned COVID-19 as influencing situations of potential medical neglect. These 9 represent all disciplines and teams. Interviewees reported COVID-19 increased burden on parents and likelihood of medical neglect due to: 1) Familial distancing from medical and social support and, 2) Changes to medical care delivery that impaired the medical community’s ability to engage and support families. Conclusions The COVID-19 pandemic has exposed the fragility of the medical and social systems that supports families of children with LT-CCCs. These findings are consistent with previous literature that suggest that the COVID-19 pandemic has increased the risk for child maltreatment. It additionally highlights the vulnerability of this patient population.

Global differences of temperature and buoyancy flux at the ocean surface are responsible for small-scale convection at high latitudes, global overturning, and the top-to-bottom density difference in the oceans. With planetary rotation the convection also contributes to the large-scale horizontal, geostrophic circulation, and it crucially involves a 3D linkage between the geostrophic circulation and vertical overturning. The governing dynamics of such a surface-forced convective flow are fundamentally different from Rayleigh–Bénard convection, and the role of buoyancy forcing in the oceans is poorly understood. Geostrophic balance adds to the constraints on transport in horizontal convection, as illustrated by experiments, theoretical scaling, and turbulence-resolving simulations for closed (mid-latitude) basins and an annulus or reentrant zonal (circumpolar) channel. In these geometries, buoyancy drives either horizontal mid-latitude gyre recirculations or a strong Antarctic Circumpolar Current, respectively, in addition to overturning. At large Rayleigh numbers the release of available potential energy by convection leads to turbulent mixing with a mixing efficiency approaching unity. Turbulence-resolving models are also revealing the relative roles of wind stress and buoyancy when there is mixed forcing, and in future work they need to include the effects of turbulent mixing due to energy input from tides.