Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery
. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of ...processed tissue is time, resource and labor intensive
. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce
. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)
, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)
. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.
Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of the mRNA-1273 ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti–S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273–induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine–induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.
Blueberry is an important perennial fruit crop with expanding consumption and production worldwide. Consumer demand for blueberries has grown due to the desirable flavor and numerous health benefits, ...and fresh market production in the U.S. has risen in turn. U.S. imports have also increased to satisfy year-round consumer demand for fresh blueberries. Pre- and post-harvest fruit diseases such as anthracnose (caused by Colletotrichum spp.) and botrytis fruit rot (caused by Botrytis spp.) have a significant impact on fruit quality and consumer acceptance. These are also among the most difficult diseases to control in the blueberry cropping system. These latent pathogens can cause significant losses both in the field, and especially during transport and marketplace storage. Although both diseases result in rotted fruit, the biology and infection strategies of the causal pathogens are very different, and the management strategies differ. Innovations for management, such as improved molecular detection assays for fungicide resistance, postharvest imaging, breeding resistant cultivars, and biopesticides have been developed for improved fruit quality. Development and integration of new strategies is critical for the long-term success of the blueberry industry.
N6-methyldeoxyadenine (6mA) is a noncanonical DNA base modification present at low levels in plant and animal genomes, but its prevalence and association with genome function in other eukaryotic ...lineages remains poorly understood. Here we report that abundant 6mA is associated with transcriptionally active genes in early-diverging fungal lineages. Using single-molecule long-read sequencing of 16 diverse fungal genomes, we observed that up to 2.8% of all adenines were methylated in early-diverging fungi, far exceeding levels observed in other eukaryotes and more derived fungi. 6mA occurred symmetrically at ApT dinucleotides and was concentrated in dense methylated adenine clusters surrounding the transcriptional start sites of expressed genes; its distribution was inversely correlated with that of 5-methylcytosine. Our results show a striking contrast in the genomic distributions of 6mA and 5-methylcytosine and reinforce a distinct role for 6mA as a gene-expression-associated epigenomic mark in eukaryotes.
Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating ...that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (r
= 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
Having opioid dependence and HIV infection are associated with poor HIV-related treatment outcomes.
HIV-infected, opioid-dependent subjects (N = 295) recruited from 10 clinical sites initiated ...buprenorphine/naloxone (BUP/NX) and were assessed at baseline and quarterly for 12 months. Primary outcomes included receiving antiretroviral therapy (ART), HIV-1 RNA suppression, and mean changes in CD4 lymphocyte count. Analyses were stratified for the 119 subjects not on ART at baseline. Generalized estimating equations were deployed to examine time-dependent correlates for each outcome.
At baseline, subjects on ART (N = 176) were more likely than those not on ART (N = 119) to be older, heterosexual, have lower alcohol addiction severity scores, and lower HIV-1 RNA levels; they were less likely to be homeless and report sexual risk behaviors. Subjects initiating BUP/NX (N = 295) were significantly more likely to initiate or remain on ART and improve CD4 counts over time compared with baseline; however, these improvements were not significantly improved by longer retention on BUP/NX. Retention on BUP/NX for three or more quarters was, however, significantly associated with increased likelihood of initiating ART (β = 1.34 1.18, 1.53) and achieve viral suppression (β = 1.25 1.10, 1.42) for the 64 of 119 (54%) subjects not on ART at baseline compared with the 55 subjects not retained on BUP/NX. In longitudinal analyses, being on ART was positively associated with increasing time of observation from baseline and higher mental health quality of life scores (β = 1.25 1.06, 1.46) and negatively associated with being homo- or bisexual (β = 0.55 0.35, 0.97), homeless (β = 0.58 0.34, 0.98), and increasing levels of alcohol addiction severity (β = 0.17 0.03, 0.88). The strongest correlate of achieving viral suppression was being on ART (β = 10.27 5.79, 18.23). Female gender (β = 1.91 1.07, 3.41), Hispanic ethnicity (β = 2.82 1.44, 5.49), and increased general health quality of life (β = 1.02 1.00,1.04) were also independently correlated with viral suppression. Improvements in CD4 lymphocyte count were significantly associated with being on ART and increased over time.
Initiating BUP/NX in HIV clinical care settings is feasible and correlated with initiation of ART and improved CD4 lymphocyte counts. Longer retention on BPN/NX was not associated with improved prescription of ART, viral suppression, or CD4 lymphocyte counts for the overall sample in which the majority was already prescribed ART at baseline. Among those retained on BUP/NX, HIV treatment outcomes did not worsen and were sustained. Increasing time on BUP/NX, however, was especially important for improving HIV treatment outcomes for those not on ART at baseline, the group at highest risk for clinical deterioration. Retaining subjects on BUP/NX is an important goal for sustaining HIV treatment outcomes for those on ART and improving them for those who are not. Comorbid substance use disorders (especially alcohol), mental health problems, and quality-of-life indicators independently contributed to HIV treatment outcomes among HIV-infected persons with opioid dependence, suggesting the need for multidisciplinary treatment strategies for this population.
The availability of iron is known to exert a controlling influence on biological productivity in surface waters over large areas of the ocean and may have been an important factor in the variation of ...the concentration of atmospheric carbon dioxide over glacial cycles. The effect of iron in the Southern Ocean is particularly important because of its large area and abundant nitrate, yet iron-enhanced growth of phytoplankton may be differentially expressed between waters with high silicic acid in the south and low silicic acid in the north, where diatom growth may be limited by both silicic acid and iron. Two mesoscale experiments, designed to investigate the effects of iron enrichment in regions with high and low concentrations of silicic acid, were performed in the Southern Ocean. These experiments demonstrate iron's pivotal role in controlling carbon uptake and regulating atmospheric partial pressure of carbon dioxide.
Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger ...RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.β, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of ...high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
Both the ecological and social dimensions of fisheries are being affected by climate change. As a result, policymakers, managers, scientists and fishing communities are seeking guidance on how to ...holistically build resilience to climate change. Numerous studies have highlighted key attributes of resilience in fisheries, yet concrete examples that explicitly link these attributes to social‐ecological outcomes are lacking. To better understand climate resilience, we assembled 18 case studies spanning ecological, socio‐economic, governance and geographic contexts. Using a novel framework for evaluating 38 resilience attributes, the case studies were systematically assessed to understand how attributes enable or inhibit resilience to a given climate stressor. We found population abundance, learning capacity, and responsive governance were the most important attributes for conferring resilience, with ecosystem connectivity, place attachment, and accountable governance scoring the strongest across the climate‐resilient fisheries. We used these responses to develop an attribute typology that describes robust sources of resilience, actionable priority attributes and attributes that are case specific or require research. We identified five fishery archetypes to guide stakeholders as they set long‐term goals and prioritize actions to improve resilience. Lastly, we found evidence for two pathways to resilience: (1) building ecological assets and strengthening communities, which we observed in rural and small‐scale fisheries, and (2) building economic assets and improving effective governance, which was demonstrated in urban and wealthy fisheries. Our synthesis presents a novel framework that can be directly applied to identify approaches, pathways and actionable levers for improving climate resilience in fishery systems.
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