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Background Intervertebral disc (IVD) degeneration contributes significantly to chronic low back pain and represents a major clinical challenge. Quantitative MRI (qMRI) techniques offer the potential to assess biochemical and structural disc changes noninvasively, but its use has been slow to be incorporated into studies utilizing spontaneous large animal models. This study characterizes qMRI‐derived biomarkers of IVD degeneration across the lifespan in a clinically relevant ovine model. Methods Ex vivo thoracolumbar spine segments from 10 sheep (13–130 months old) were assessed using 3T MRI, including T2, T2*, T1ρ, adiabatic T1ρ, adiabatic T2ρ, and ADC mapping. Relaxation times were compared with Pfirrmann grade, disc height index, biomechanical testing, GAG/water content, and histological scores. Results T2 and T2* values in the nucleus pulposus (NP) were negatively correlated with age, Pfirrmann grade, and histological degeneration, and positively correlated with GAG and water content. T2 relaxation times in the annulus fibrosus (AF) were inversely related to biomechanical stiffness, whereas T2* relaxation times in the NP were positively associated. Strong inter‐metric correlations were observed between most qMRI measures, but aT1ρ and ADC showed more distinct profiles. Conclusion These findings support the sensitivity of qMRI in detecting regional and age‐related IVD changes and reinforce its utility for noninvasive disc assessment in translational models of degeneration. Quantitative MRI reveals age‐related degeneration of lumbar intervertebral discs. Axial T2 and T2* relaxation time maps from representative young (15‐month) and old (130‐month) sheep demonstrate substantially higher relaxation times in young discs, particularly within the nucleus pulposus, indicating a well‐hydrated and proteoglycan‐rich matrix. In contrast, older discs exhibit markedly reduced relaxation times consistent with dehydration and matrix degeneration. These imaging biomarkers highlight the sensitivity of T2 and T2* mapping for detecting age‐related changes in disc composition.

Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non–small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. PubMed was searched to identify relevant clinical studies of PD-1/PD-L1–targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Resting-state functional magnetic resonance imaging (fMRI) has provided converging descriptions of group-level functional brain organization. Recent work has revealed that functional networks identified in individuals contain local features that differ from the group-level description. We define these features as network variants. Building on these studies, we ask whether distributions of network variants reflect stable, trait-like differences in brain organization. Across several datasets of highly-sampled individuals we show that 1) variants are highly stable within individuals, 2) variants are found in characteristic locations and associate with characteristic functional networks across large groups, 3) task-evoked signals in variants demonstrate a link to functional variation, and 4) individuals cluster into subgroups on the basis of variant characteristics that are related to differences in behavior. These results suggest that distributions of network variants may reflect stable, trait-like, functionally relevant individual differences in functional brain organization.

The ability to envision specific future episodes is a ubiquitous mental phenomenon that has seldom been discussed in the neuroscience literature. In this study, subjects underwent functional MRI while using event cues (e.g., Birthday) as a guide to vividly envision a personal future event, remember a personal memory, or imagine an event involving a familiar individual. Two basic patterns of data emerged. One set of regions (e.g., within left lateral premotor cortex; left precuneus; right posterior cerebellum) was more active while envisioning the future than while recollecting the past (and more active in both of these conditions than in the task involving imagining another person). These regions appear similar to those emerging from the literature on imagined (simulated) bodily movements. A second set of regions (e.g., bilateral posterior cingulate; bilateral parahippocampal gyrus; left occipital cortex) demonstrated indistinguishable activity during the future and past tasks (but greater activity in both tasks than the imagery control task); similar regions have been shown to be important for remembering previously encountered visual-spatial contexts. Hence, differences between the future and past tasks are attributed to differences in the demands placed on regions that underlie motor imagery of bodily movements, and similarities in activity for these two tasks are attributed to the reactivation of previously experienced visual-spatial contexts. That is, subjects appear to place their future scenarios in well known visual-spatial contexts. Our results offer insight into the fundamental and little-studied capacity of vivid mental projection of oneself in the future.

Plausible personal events envisioned as occurring in the near future tend to be reported as more vivid than those set in the far future. Why is this? The present set of three experiments identified one’s familiarity with the location in which the event is placed as critical in this regard. Specifically, Experiment 1 demonstrated that amongst a wide range of phenomenological characteristics, clarity of location appears to drive the overall difference in vividness between events imagined to take place in the near and the far future. Experiments 2 and 3 were designed to further elucidate this finding. Experiment 2 demonstrated that near future events are more likely than far future events to be imagined in familiar locations. Experiment 3 showed that future events set in familiar locations tend to be imagined with greater clarity than those set in unfamiliar locations. The results of all three experiments converge on the conclusion that the difference in vividness of events imagined as occurring in the near and far future is mediated by one’s familiarity with the location in which the event is imagined to occur.

A total of 33 participants who received both doses of the Moderna mRNA-1273 vaccine against SARS-CoV-2 had blood drawn over a period of 6 months after vaccination. SARS-CoV-2 neutralizing activity was maintained in all the patients through the entire period of follow-up. A half-life of 202 days was determined for the live-virus neutralization activity.

Thirty-four adults received two 100-μg injections of Moderna’s mRNA SARS-CoV-2 vaccine, and serum anti–spike protein and neutralizing antibody titers were measured at day 119 — 90 days after the second injection. By three different assays, binding and neutralizing antibody titers declined slightly but remained elevated and higher than titers in convalescent plasma.

People differ in how quickly they learn information and how long they remember it, yet individual differences in learning abilities within healthy adults have been relatively neglected. In two studies, we examined the relation between learning rate and subsequent retention using a new foreign-language paired-associates task (the learning-efficiency task), which was designed to eliminate ceiling effects that often accompany standardized tests of learning and memory in healthy adults. A key finding was that quicker learners were also more durable learners (i.e., exhibited better retention across a delay), despite studying the material for less time. Additionally, measures of learning and memory from this task were reliable in Study 1 (N = 281) across 30 hr and Study 2 (N = 92; follow-up n = 46) across 3 years. We conclude that people vary in how efficiently they learn, and we describe a reliable and valid method for assessing learning efficiency within healthy adults.

Testing, or retrieval practice, has become a central topic in memory research. One potentially important effect of retrieval practice has received little attention, however: It may enhance, or potentiate, subsequent learning. We introduce a paradigm that can measure the indirect, potentiating effect of free recall tests on subsequent learning, and then test a hypothesis for why tests may have this potentiating effect. In two experiments, the benefit of a restudy trial was enhanced when prior free recall tests had been taken. The results from a third, correlational study suggested that this effect might be mediated by the effect of testing on organization. Not only do encoding conditions affect later retrievability, but also retrieval attempts affect subsequent encoding effectiveness.

Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization. A wealth of gene expression data is publicly available, yet is little use without additional human curation. Ma’ayan and colleagues report a crowdsourcing project involving over 70 participants to annotate and analyse thousands of human disease-related gene expression datasets.