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Brain stimulation is a powerful treatment for an increasing number of psychiatric and neurological diseases, but it is unclear why certain stimulation sites work or where in the brain is the best place to stimulate to treat a given patient or disease. We found that although different types of brain stimulation are applied in different locations, targets used to treat the same disease most often are nodes in the same brain network. These results suggest that brain networks might be used to understand why brain stimulation works and to improve therapy by identifying the best places to stimulate the brain. Brain stimulation, a therapy increasingly used for neurological and psychiatric disease, traditionally is divided into invasive approaches, such as deep brain stimulation (DBS), and noninvasive approaches, such as transcranial magnetic stimulation. The relationship between these approaches is unknown, therapeutic mechanisms remain unclear, and the ideal stimulation site for a given technique is often ambiguous, limiting optimization of the stimulation and its application in further disorders. In this article, we identify diseases treated with both types of stimulation, list the stimulation sites thought to be most effective in each disease, and test the hypothesis that these sites are different nodes within the same brain network as defined by resting-state functional-connectivity MRI. Sites where DBS was effective were functionally connected to sites where noninvasive brain stimulation was effective across diseases including depression, Parkinson's disease, obsessive-compulsive disorder, essential tremor, addiction, pain, minimally conscious states, and Alzheimer’s disease. A lack of functional connectivity identified sites where stimulation was ineffective, and the sign of the correlation related to whether excitatory or inhibitory noninvasive stimulation was found clinically effective. These results suggest that resting-state functional connectivity may be useful for translating therapy between stimulation modalities, optimizing treatment, and identifying new stimulation targets. More broadly, this work supports a network perspective toward understanding and treating neuropsychiatric disease, highlighting the therapeutic potential of targeted brain network modulation.

“Climate dice,” describing the chance of unusually warm or cool seasons, have become more and more “loaded” in the past 30 y, coincident with rapid global warming. The distribution of seasonal mean temperature anomalies has shifted toward higher temperatures and the range of anomalies has increased. An important change is the emergence of a category of summertime extremely hot outliers, more than three standard deviations (3σ) warmer than the climatology of the 1951–1980 base period. This hot extreme, which covered much less than 1% of Earth’s surface during the base period, now typically covers about 10% of the land area. It follows that we can state, with a high degree of confidence, that extreme anomalies such as those in Texas and Oklahoma in 2011 and Moscow in 2010 were a consequence of global warming because their likelihood in the absence of global warming was exceedingly small. We discuss practical implications of this substantial, growing, climate change.

SignificanceAlcohol-dependent subjects frequently develop emotional symptoms that contribute to the persistence of alcohol drinking. These subjects are also characterized by gastrointestinal disturbances. In this study, we showed that alcohol-dependent subjects with altered intestinal permeability had also altered gut-microbiota composition and activity and remained with high scores of depression, anxiety, and alcohol craving after a short-term detoxification program. These results are consistent with the existence of a gut–brain axis in alcohol dependence, in which the gut microbiota could alter the gut-barrier function and influence behavior in alcohol dependence. Therefore, this study opens a previously unidentified field of research for the treatment and the management of alcohol dependence, targeting the gut microbiota. Alcohol dependence has traditionally been considered a brain disorder. Alteration in the composition of the gut microbiota has recently been shown to be present in psychiatric disorders, which suggests the possibility of gut-to-brain interactions in the development of alcohol dependence. The aim of the present study was to explore whether changes in gut permeability are linked to gut-microbiota composition and activity in alcohol-dependent subjects. We also investigated whether gut dysfunction is associated with the psychological symptoms of alcohol dependence. Finally, we tested the reversibility of the biological and behavioral parameters after a short-term detoxification program. We found that some, but not all, alcohol-dependent subjects developed gut leakiness, which was associated with higher scores of depression, anxiety, and alcohol craving after 3 wk of abstinence, which may be important psychological factors of relapse. Moreover, subjects with increased gut permeability also had altered composition and activity of the gut microbiota. These results suggest the existence of a gut–brain axis in alcohol dependence, which implicates the gut microbiota as an actor in the gut barrier and in behavioral disorders. Thus, the gut microbiota seems to be a previously unidentified target in the management of alcohol dependence.

Metabolic exchange between microbes is a crucial process driving the development of microbial ecosystems. The exchange of essential amino acids presents an opportunity to investigate the guiding principles underlying microbial trade in nature. In this study, we devised synthetic communities of Escherichia coli bacteria of increasing complexity to measure general properties enabling metabolic exchange of amino acids. We identified numerous syntrophic interactions that enable cooperative growth, which exhibited both positive and negative epistasis with increasing community complexity. Our results suggest that amino acid auxotrophy may be an evolutionarily optimizing strategy to reduce biosynthetic burden while promoting cooperative interactions between different bacteria in the microbiome. Metabolic crossfeeding is an important process that can broadly shape microbial communities. However, little is known about specific crossfeeding principles that drive the formation and maintenance of individuals within a mixed population. Here, we devised a series of synthetic syntrophic communities to probe the complex interactions underlying metabolic exchange of amino acids. We experimentally analyzed multimember, multidimensional communities of Escherichia coli of increasing sophistication to assess the outcomes of synergistic crossfeeding. We find that biosynthetically costly amino acids including methionine, lysine, isoleucine, arginine, and aromatics, tend to promote stronger cooperative interactions than amino acids that are cheaper to produce. Furthermore, cells that share common intermediates along branching pathways yielded more synergistic growth, but exhibited many instances of both positive and negative epistasis when these interactions scaled to higher dimensions. In more complex communities, we find certain members exhibiting keystone species-like behavior that drastically impact the community dynamics. Based on comparative genomic analysis of >6,000 sequenced bacteria from diverse environments, we present evidence suggesting that amino acid biosynthesis has been broadly optimized to reduce individual metabolic burden in favor of enhanced crossfeeding to support synergistic growth across the biosphere. These results improve our basic understanding of microbial syntrophy while also highlighting the utility and limitations of current modeling approaches to describe the dynamic complexities underlying microbial ecosystems. This work sets the foundation for future endeavors to resolve key questions in microbial ecology and evolution, and presents a platform to develop better and more robust engineered synthetic communities for industrial biotechnology.

SignificanceA number of studies reported that the pupil dilates (under constant illumination) during decision-making. Pupil dilation is also associated with the brain-wide release of modulatory neurotransmitters. It has remained unknown which specific elements of decision processes drive pupil dilation. Using a visual detection task, we here show that pupil dilation is primarily driven during, and not at the end of, a protracted decision. Further, pupil dilation differentiates between “yes” and “no” choices for conservative subjects deciding yes against their bias. Thus, pupil dilation reveals the content of the evolving decision and the decision maker’s attitude. These findings have important implications for interpreting decision-related brain activity. They also point to a possible role of neuromodulation in interacting with decision biases. A number of studies have shown that pupil size increases transiently during effortful decisions. These decision-related changes in pupil size are mediated by central neuromodulatory systems, which also influence the internal state of brain regions engaged in decision making. It has been proposed that pupil-linked neuromodulatory systems are activated by the termination of decision processes, and, consequently, that these systems primarily affect the postdecisional brain state. Here, we present pupil results that run contrary to this proposal, suggesting an important intradecisional role. We measured pupil size while subjects formed protracted decisions about the presence or absence (“yes” vs. “no”) of a visual contrast signal embedded in dynamic noise. Linear systems analysis revealed that the pupil was significantly driven by a sustained input throughout the course of the decision formation. This sustained component was larger than the transient component during the final choice (indicated by button press). The overall amplitude of pupil dilation during decision formation was bigger before yes than no choices, irrespective of the physical presence of the target signal. Remarkably, the magnitude of this pupil choice effect (yes > no) reflected the individual criterion: it was strongest in conservative subjects choosing yes against their bias. We conclude that the central neuromodulatory systems controlling pupil size are continuously engaged during decision formation in a way that reveals how the upcoming choice relates to the decision maker’s attitude. Changes in brain state seem to interact with biased decision making in the face of uncertainty.

Specialized microenvironments (or “niches”) are essential for metastasis, but how cancer cells and host cells contribute to their establishment remains poorly understood. Our study reveals that platelets and granulocytes are sequentially recruited to disseminated tumor cells to form “early metastatic niches” that promote metastatic progression. Importantly, the recruitment of granulocytes is not primarily due to tumor cell-derived signals but rather relies on platelet-derived CXCL5/7 chemokines. Prevention of granulocyte recruitment via inhibition of the CXCL5/7 receptor CXCR2, or depletion of either platelets or granulocytes inhibits metastasis, thereby uncovering a key role for platelet-to-granulocyte signaling in the establishment of metastases. Specific inhibition of platelet-to-granulocyte interactions may thus represent a valuable antimetastatic therapy in addition to cancer cell-centered treatments. During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments (“niches”) that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to tumor cells to form “early metastatic niches.” Granulocyte recruitment relies on the secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells. Blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, platelets recruit granulocytes and guide the formation of early metastatic niches, which are crucial for metastasis.

Microbial natural products are a major source of new drug leads, yet discovery efforts are constrained by the lack of information describing the diversity and distributions of the associated biosynthetic pathways among bacteria. Using the marine actinomycete genus Salinispora as a model, we analyzed genome sequence data from 75 closely related strains. The results provide evidence for high levels of pathway diversity, with most being acquired relatively recently in the evolution of the genus. The distributions and evolutionary histories of these pathways provide insight into the mechanisms that generate new chemical diversity and the strategies used by bacteria to maximize their population-level capacity to produce diverse secondary metabolites. Access to genome sequence data has challenged traditional natural product discovery paradigms by revealing that the products of most bacterial biosynthetic pathways have yet to be discovered. Despite the insight afforded by this technology, little is known about the diversity and distributions of natural product biosynthetic pathways among bacteria and how they evolve to generate structural diversity. Here we analyze genome sequence data derived from 75 strains of the marine actinomycete genus Salinispora for pathways associated with polyketide and nonribosomal peptide biosynthesis, the products of which account for some of today’s most important medicines. The results reveal high levels of diversity, with a total of 124 pathways identified and 229 predicted with continued sequencing. Recent horizontal gene transfer accounts for the majority of pathways, which occur in only one or two strains. Acquired pathways are incorporated into genomic islands and are commonly exchanged within and between species. Acquisition and transfer events largely involve complete pathways, which subsequently evolve by gene gain, loss, and duplication followed by divergence. The exchange of similar pathway types at the precise chromosomal locations in different strains suggests that the mechanisms of integration include pathway-level homologous recombination. Despite extensive horizontal gene transfer there is clear evidence of species-level vertical inheritance, supporting the concept that secondary metabolites represent functional traits that help define Salinispora species. The plasticity of the Salinispora secondary metabolome provides an effective mechanism to maximize population-level secondary metabolite diversity while limiting the number of pathways maintained within any individual genome.

A gradual buildup of neuronal activity known as the “readiness potential” reliably precedes voluntary self-initiated movements, in the average time locked to movement onset. This buildup is presumed to reflect the final stages of planning and preparation for movement. Here we present a different interpretation of the premovement buildup. We used a leaky stochastic accumulator to model the neural decision of “when” to move in a task where there is no specific temporal cue, but only a general imperative to produce a movement after an unspecified delay on the order of several seconds. According to our model, when the imperative to produce a movement is weak, the precise moment at which the decision threshold is crossed leading to movement is largely determined by spontaneous subthreshold fluctuations in neuronal activity. Time locking to movement onset ensures that these fluctuations appear in the average as a gradual exponential-looking increase in neuronal activity. Our model accounts for the behavioral and electroencephalography data recorded from human subjects performing the task and also makes a specific prediction that we confirmed in a second electroencephalography experiment: Fast responses to temporally unpredictable interruptions should be preceded by a slow negative-going voltage deflection beginning well before the interruption itself, even when the subject was not preparing to move at that particular moment.

SignificanceThis study shows that neurodegenerative changes induced by α-synuclein in midbrain dopamine neurons in vivo can be blocked through activation of the autophagy-lysosome pathway. Using an adeno-associated virus model of Parkinson disease to overexpress α-synuclein in the substantia nigra, we show that genetic [transcription factor EB (TFEB) and Beclin-1 overexpression] or pharmacological (rapalog) manipulations that enhance autophagy protect nigral neurons from α-synuclein toxicity, but inhibiting autophagy exacerbates α-synuclein toxicity. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and identify TFEB as a target for therapies aimed at neuroprotection and disease modification in Parkinson disease. The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator of the autophagy-lysosome pathway. The changes in lysosomal function, observed in the rat model as well as in human PD midbrain, were reversed by overexpression of TFEB, which afforded robust neuroprotection via the clearance of α-synuclein oligomers, and were aggravated by microRNA-128–mediated repression of TFEB in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function, and highlight TFEB as a key player in the induction of α-synuclein–induced toxicity and PD pathogenesis, thus identifying TFEB as a promising target for therapies aimed at neuroprotection and disease modification in PD.

Deep convective clouds (DCCs) play a key role in atmospheric circulation and the hydrological and energy cycle. How aerosol particles affect DCCs is poorly understood, making it difficult to understand current and future weather and climate. Our work showed that in addition to the invigoration of convection, which has been unanimously cited for explaining the observed results, the microphysical effects induced by aerosols are a fundamental reason for the observed increases in cloud fraction, cloud top height, and cloud thickness in the polluted environment, even when invigoration is absent. The finding calls for an augmented focus on understanding the changes in stratiform/anvils associated with convective life cycle. Deep convective clouds (DCCs) play a crucial role in the general circulation, energy, and hydrological cycle of our climate system. Aerosol particles can influence DCCs by altering cloud properties, precipitation regimes, and radiation balance. Previous studies reported both invigoration and suppression of DCCs by aerosols, but few were concerned with the whole life cycle of DCC. By conducting multiple monthlong cloud-resolving simulations with spectral-bin cloud microphysics that capture the observed macrophysical and microphysical properties of summer convective clouds and precipitation in the tropics and midlatitudes, this study provides a comprehensive view of how aerosols affect cloud cover, cloud top height, and radiative forcing. We found that although the widely accepted theory of DCC invigoration due to aerosol’s thermodynamic effect (additional latent heat release from freezing of greater amount of cloud water) may work during the growing stage, it is microphysical effect influenced by aerosols that drives the dramatic increase in cloud cover, cloud top height, and cloud thickness at the mature and dissipation stages by inducing larger amounts of smaller but longer-lasting ice particles in the stratiform/anvils of DCCs, even when thermodynamic invigoration of convection is absent. The thermodynamic invigoration effect contributes up to ∼27% of total increase in cloud cover. The overall aerosol indirect effect is an atmospheric radiative warming (3–5 W⋅m −2 ) and a surface cooling (−5 to −8 W⋅m −2 ). The modeling findings are confirmed by the analyses of ample measurements made at three sites of distinctly different environments.