AbstractDespite growing literature characterizing the fecal microbiome and its association with health and disease, few studies have analyzed the microbiome of the small intestine. Here, we examine ...what is known about the human small intestinal microbiota in terms of community structure and functional properties. We examine temporal dynamics of select bacterial populations in the small intestine, and the effects of dietary carbohydrates and fats on shaping these populations. We then evaluate dysbiosis in the small intestine in several human disease models, including small bacterial overgrowth overgrowth, short bowel syndrome, pouchitis, environmental enteric dysfunction, and irritable bowel syndrome. What is clear is that the bacterial biology, and mechanisms of bacteria-induced pathophysiology, are enormously broad and elegant in the small intestine. Studying the small intestinal microbiota is challenged by rapidly fluctuating environmental conditions in these intestinal segments, as well as the complexity of sample collection and bioinformatic analysis. Since the functionality of the digestive tract is determined primarily by small intestine, efforts must be made to better characterize this unique and important microbial ecosystem.
Black carbon (BC) absorbs solar radiation, leading to a strong but uncertain warming effect on climate. A key challenge in modeling and quantifying BC’s radiative effect on climate is predicting ...enhancements in light absorption that result from internal mixing between BC and other aerosol components. Modeling and laboratory studies show that BC, when mixed with other aerosol components, absorbs more strongly than pure, uncoated BC; however, some ambient observations suggest more variable and weaker absorption enhancement. We show that the lower-than-expected enhancements in ambient measurements result from a combination of two factors. First, the often used spherical, concentric core-shell approximation generally overestimates the absorption by BC. Second, and more importantly, inadequate consideration of heterogeneity in particle-to-particle composition engenders substantial overestimation in absorption by the total particle population, with greater heterogeneity associated with larger model–measurement differences. We show that accounting for these two effects—variability in per-particle composition and deviations from the core-shell approximation—reconciles absorption enhancement predictions with laboratory and field observations and resolves the apparent discrepancy. Furthermore, our consistent model framework provides a path forward for improving predictions of BC’s radiative effect on climate.
Summer 2019 observations show a rapid resurgence of the Blob-like warm sea surface temperature (SST) anomalies that produced devastating marine impacts in the Northeast Pacific during winter ...2013/2014. Unlike the original Blob, Blob 2.0 peaked in the summer, a season when little is known about the physical drivers of such events. We show that Blob 2.0 primarily results from a prolonged weakening of the North Pacific High-Pressure System. This reduces surface winds and decreases evaporative cooling and wind-driven upper ocean mixing. Warmer ocean conditions then reduce low-cloud fraction, reinforcing the marine heatwave through a positive low-cloud feedback. Using an atmospheric model forced with observed SSTs, we also find that remote SST forcing from the central equatorial and, surprisingly, the subtropical North Pacific Ocean contribute to the weakened North Pacific High. Our multi-faceted analysis sheds light on the physical drivers governing the intensity and longevity of summertime North Pacific marine heatwaves.
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease worldwide, and its clinical and economic burden will continue to grow with parallel increases in rates of obesity, ...diabetes, and the metabolic syndrome. Evolving understanding of the natural history of NAFLD suggests that these patients are at risk for disease progression to steatohepatitis, fibrosis, and cirrhosis. Recent studies also suggest that these patients are at elevated risk for cardiovascular-, malignancy-, and liver-related morbidity and mortality, although their risk for progression, decompensation, and hepatocellular carcinoma may be less than that of patients with alternative causes of chronic liver disease.
Principles of Clinical Pharmacology is a successful survey covering the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development. This essential ...reference continues to focus on the basics of clinical pharmacology for the development, evaluation, and clinical use of pharmaceutical products while also addressing the most recent advances in the field. Written by leading experts in academia, industry, clinical and regulatory settings, the third edition has been thoroughly updated to provide readers with an ideal reference covering the wide range of important topics impacting clinical pharmacology as the discipline plays an increasingly significant role in drug development and regulatory science. The Third Edition has been endorsed by the American Society for Clinical Pharmacology and Therapeutics Includes new chapters on imaging and the pharmacogenetic basis of adverse drug reactions Offers an expanded regulatory section that addresses US and international issues and guidelines Provides extended coverage of earlier chapters on transporters, pharmacogenetics and biomarkers and also illustrates the impact of gender on drug response Presents a broadened discussion of clinical trials from Phase 1 to incorporate Phases II and III.
Visualization has been a key technology in the progress of structural molecular biology for as long as the field has existed. This perspective describes the nature of the visualization process in ...structural studies, how it has evolved over the years, and its relationship to the changes in technology that have supported and driven it. It focuses on how technical advances have changed the way we look at and interact with molecular structure, and how structural biology has fostered and challenged that technology.
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•Structural molecular biology visualization has evolved from physical models of the earliest protein structures to immersive interaction of mesoscale models of cellular environments.•Visualization has been a major driver in advancing the science of structural molecular biology.•Structural molecular biology continues to challenge the capabilities of visualization technology.
Episodic memories are encoded by a sparse population of hippocampal neurons. In mice, optogenetic manipulation of this memory engram established that these neurons are indispensable and inducing for ...memory recall. However, little is known about their in vivo activity or precise role in memory. We found that during memory encoding, only a fraction of CA1 place cells function as engram neurons, distinguished by firing repetitive bursts paced at the theta frequency. During memory recall, these neurons remained highly context specific, yet demonstrated preferential remapping of their place fields. These data demonstrate a dissociation of precise spatial coding and contextual indexing by distinct hippocampal ensembles and suggest that the hippocampal engram serves as an index of memory content.
Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of ...KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.
Some of the information that physicians convey to their patients can inadvertently amplify patients symptoms and become a source of heightened somatic distress, an effect that must be understood by ...physicians to ensure optimal management of patient care. This effect illustrates the iatrogenic potential of information, as opposed to the iatrogenic potential of drugs and procedures. Several common clinical scenarios exemplify the iatrogenic potential of the physician's words--for example, instituting a new medication regimen, reviewing an informed consent document, presenting ambiguous laboratory test information, and preparing patients for painful procedures.
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