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As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

Glioblastoma is the most lethal form of human brain cancer. The genomic alterations and gene expression profiles characterizing this tumor type have been widely studied. Puchalski et al. created the Ivy Glioblastoma Atlas, a freely available online resource for the research community. The atlas, a collaborative effort between bioinformaticians and pathologists, maps molecular features of glioblastomas, such as transcriptional signatures, to histologically defined anatomical regions of the tumors. The relationships identified in this atlas, in conjunction with associated databases of clinical and genomic information, could provide new insights into the pathogenesis, diagnosis, and treatment of glioblastoma. Science , this issue p. 660 An online resource maps the molecular genetic features of glioblastoma, a lethal brain cancer, to its anatomic features. Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor’s molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey ( Macaca mulatta ) brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical division of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons. Cortical layers and areas acquire adult-like molecular profiles surprisingly late in postnatal development. Disparate cell populations exhibit distinct developmental timing of gene expression, but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, although approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny compared to monkey. A high-resolution gene expression atlas of prenatal and postnatal brain development of rhesus monkey charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex. Gene expression in the primate brain Following the publication of the mouse and human brain gene expression atlases in recent years, Ed Lein and colleagues now present a high-resolution transcriptional atlas of pre- and post-natal brain development for the rhesus monkey — the dominant non-human primate model for human brain development and disease. The data charts global transcriptional dynamics in relation to brain maturation, while comparative analysis reveals human-specific gene trajectories; candidate risk genes associated with human neurodevelopmental disorders tend to be co-expressed in disease-specific patterns in the developing monkey neocortex.

The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development. A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders. New whole-brain mapping resources With President Barack Obama's BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative now entering year two, this issue of Nature presents two landmark papers that mobilize 'big science' resources to the cause. Hongkui Zeng and colleagues present the first brain-wide, mesoscale connectome for a mammalian species — the laboratory mouse — based on cell-type-specific tracing of axonal projections. The wiring diagram of a complete nervous system has long been available for a small roundworm, but neuronal connectivity data for larger animals has been patchy until now. The new three-dimensional Allen Mouse Brain Connectivity Atlas is a whole-brain connectivity matrix that will provide insights into how brain regions communicate. Much of the data generated in this project will be of relevance to investigations of neural networks in humans and should help to further our understanding of human brain connectivity and its involvement in brain disorders. In a separate report Ed Lein and colleagues present a transcriptional atlas of the mid-gestational human brain at high spatial resolution, based on laser microdissection and DNA microarray technology. The structure and function of the human brain is largely determined by prenatal transcriptional processes that initiate gene expression, but our understanding of the developing brain has been limited. The new data set reveals transcriptional signatures for developmental processes associated with the massive expansion of neocortex during human evolution, and suggests new cortical germinal zones or postmitotic neurons as sites of dynamic expression for many genes associated with neurological or psychiatric disorders.

The complexity of the value chain in the thermoplastic elastomer industry creates a relatively high cost-to-serve business environment for the resin supplier. Programs of value chain analysis will aid supplier companies in understanding value migration and identifying the best cost-competitive practices. Overall, traditional market segments are experiencing better-than-average growth rates for elastomer materials. However, new growth opportunities will be driven by niche market applications demanding specialized products. These new and emerging opportunities will require suppliers to invest in product innovations and new technologies on an application basis.

Decision bias is traditionally conceptualized as an internal reference against which sensory evidence is compared. Instead, we show that individuals implement decision bias by shifting the rate of sensory evidence accumulation toward a decision bound. Participants performed a target detection task while we recorded EEG. We experimentally manipulated participants’ decision criterion for reporting targets using different stimulus-response reward contingencies, inducing either a liberal or a conservative bias. Drift diffusion modeling revealed that a liberal strategy biased sensory evidence accumulation toward target-present choices. Moreover, a liberal bias resulted in stronger midfrontal pre-stimulus 2—6 Hz (theta) power and suppression of pre-stimulus 8—12 Hz (alpha) power in posterior cortex. Alpha suppression in turn was linked to the output activity in visual cortex, as expressed through 59—100 Hz (gamma) power. These findings show that observers can intentionally control cortical excitability to strategically bias evidence accumulation toward the decision bound that maximizes reward. How do you decide whether to buy a new car? One factor to consider is how well the economy is doing. During an economic boom, you might happily commit to buying a new vehicle that goes on sale, but prefer to sit on your savings during a financial crisis, despite how good the offer may be. Adjusting how you make decisions in situations like this can help you optimize choices in an ever-changing world. It’s currently thought that when deciding, we accumulate evidence for each of the available options. When evidence for one of the options passes a threshold, we choose that option. External factors – such as a booming economy when considering buying a car – could bias this process in two different ways. The standard view is that they move the starting point of evidence accumulation towards one of the two choices, so that the threshold for choosing that option is more easily reached. Alternatively, they could bias the accumulation process itself, so that evidence builds up more quickly towards one of the choices. To distinguish between these possibilities, Kloosterman et al. asked volunteers to press a button whenever they detected a target hidden among a stream of visual patterns. To bias their decisions, volunteers were penalized differently in two experimental conditions: either when they failed to report a target (a ‘miss’), or when they ‘detected’ a target when in fact nothing was there (a ‘false alarm’). As expected, punishing participants for missing a target made them more liberal towards reporting targets, whereas penalizing false alarms made them more conservative. Computational modeling of behavior revealed that when participants used a liberal strategy, they did not move closer to the threshold for deciding target presence. Instead, they accumulated evidence for target presence at a faster rate, even when in fact no target was shown. Brain activity recorded during this task reveals how this bias in evidence accumulation might come about. When a volunteer adopted a liberal response strategy, visual brain areas showed a reduction in low-frequency ‘alpha’ waves, suggesting increased attention. This in turn triggered an increase in high-frequency ‘gamma’ waves, reflecting biased evidence accumulation for target presence (irrespective of whether a target actually appeared or not). Overall, the findings reported by Kloosterman et al. suggest that we can strategically bias perceptual decision-making by varying how quickly we accumulate evidence in favor of different response options. This might explain how we are able to adapt our decisions to environments that differ in payoffs and punishments. The next challenge is to understand whether such biases also affect high-level decisions, for example, when purchasing a new car.

Background The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer’s disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown. Methods Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age. Results In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells ( Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-β accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib −/− mice. Conclusion Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

Background Obesity is associated with derangement of cardiac metabolism and the development of subclinical cardiovascular disease. This prospective study examined the impact of bariatric surgery on cardiac function and metabolism. Methods Subjects with obesity underwent cardiac magnetic resonance imaging (CMR) at Massachusetts General Hospital before and after bariatric surgery between 2019 and 2021. The imaging protocol included Cine for global cardiac function assessment and creatine chemical exchange saturation transfer (CEST) CMR for myocardial creatine mapping. Results Thirteen subjects were enrolled, and 6 subjects [mean BMI 40.5 ± 2.6] had completed the second CMR (i.e. post-surgery), with a median follow-up of 10 months. The median age was 46.5 years, 67% were female, and 16.67% had diabetes. Bariatric surgery led to significant weight loss, with achieved mean BMI of 31.0 ± 2.0. Additionally, bariatric surgery resulted in significant reduction in left ventricular (LV) mass, LV mass index, and epicardial adipose tissue (EAT) volume. This was accompanied by slight improvement in LV ejection fraction compared to baseline. Following bariatric surgery, there was a significant increase in creatine CEST contrast. Subjects with obesity had significantly lower CEST contrast compared to subjects with normal BMI ( n = 10), but this contrast was normalized after the surgery, and statistically similar to non-obese cohort, indicating an improvement in myocardial energetics. Conclusions CEST-CMR has the ability to identify and characterize myocardial metabolism in vivo non-invasively. These results demonstrate that in addition to reducing BMI, bariatric surgery may favorably affect cardiac function and metabolism. Graphical Abstract

A Boy with Abdominal Pain, Hematochezia, and Anemia A 15-year-old boy had intermittent abdominal pain and diarrhea for 8 months. The abdomen was mildly tender. There was iron deficiency and occult blood in the stool. A diagnostic test was performed. Presentation of Case A 15-year-old boy was admitted to this hospital because of recurrent abdominal pain and diarrhea. The patient had been well until approximately 8 months earlier, when episodes of midline low back pain developed, which were worse in the morning and improved with activity and flexion. During the next few months, intermittent, stabbing periumbilical and left upper abdominal pain occurred, associated with nausea and diarrhea. The pain occurred once or twice a week, developed suddenly, and lasted from a few hours to a week, but typically 1 to 2 days. The pain had no relationship to eating, was . . .

A 15-year-old boy had intermittent abdominal pain and diarrhea for 8 months. The abdomen was mildly tender. There was iron deficiency and occult blood in the stool. A diagnostic test was performed.