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Columbia Neuroscientist Rafael Yuste Awarded Eliasson Global Leadership Prize

Date: 
Wednesday, October 17, 2018

Rafael Yuste, a professor of Biological Sciences at Columbia University, has been awarded the Eliasson Global Leadership Prize by the Tällberg Foundation for his seminal contributions in inspiring the US and International BRAIN initiatives and for his efforts toward building ethical guidelines...

Image: 
Rafael Yuste

Long-term Exposure to Ambient Air Pollution and Trajectories of Cognitive Decline in Northern Manhattan

Age-related cognitive decline is a growing public health issue as increases in life expectancy are expected to substantially raise the prevalence of cognitive impairment and dementia. An estimated 46.8 million individuals are currently living with dementia, with the global prevalence expected to double every 20 years. Emerging evidence suggests that ambient air pollution from traffic and other sources may be an important risk factor for cognitive decline in addition to its association with other cardiovascular and neurological outcomes.
The aim of this dissertation was to first investigate the association between long-term exposure to ambient air pollution and cognitive decline among older adults in an urban population within Northern Manhattan. I then set out to assess specific mechanisms involved in the association between long-term exposure to ambient air pollution and cognitive decline, specifically investigating the ApoE4 allele, age, and current smoking behavior as effect modifiers of the association between long-term exposure to ambient air pollution and cognitive decline.
I found evidence of an adverse effect of ambient air pollution on the cognitive functioning of older adults. Overall, exposure to higher levels of ambient air pollution was highly predictive of lower cognitive scores, but at baseline only. Contrary to the current hypothesis, limited evidence was found for an association between estimates of air pollution and trajectories of cognitive decline. The patterns of effect were similar across pollutant types and cognitive domains in this aging, urban population. I found strong evidence of effect modification by smoking status, where contrary to the hypothesis; the overall effects of ambient air pollution on cognition and cognitive decline were stronger among individuals who never smoked. The impact of effect modification by age category was most prominent in the memory and language cognitive domains. Among individuals less than 75 years old at baseline, there was a stronger association between a one IQR increase in air pollutants and cognitive domain scores at baseline as compared to individuals 75 years and older. I did not observe conclusive evidence of an association between air pollution and cognition in models stratified by APOE-4 status.
To my knowledge, this is the largest study to analyze the association of ambient air pollution on cognition and cognitive decline over time in a racially and ethnically diverse sample. These results further support the current evidence on the role of air pollution on accelerated cognitive aging and brain health.

Author: 
Erin Ryan Kulick
Subjects: 
Epidemiology
Neurosciences
Environmental health
Air--Pollution--Health aspects
Cognition--Research
Public health
Title string: 
Long-term Exposure to Ambient Air Pollution and Trajectories of Cognitive Decline in Northern Manhattan
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:hhmgqnk9c1

Dissolved organic matter uptake by Trichodesmium in the Southwest Pacific

The globally distributed diazotroph Trichodesmium contributes importantly to nitrogen inputs in the oligotrophic oceans. Sites of dissolved organic matter (DOM) accumulation could promote the mixotrophic nutrition of Trichodesmium when inorganic nutrients are scarce. Nano-scale secondary ion mass spectrometry (nanoSIMS) analyses of individual trichomes sampled in the South Pacific Ocean, showed significant 13C-enrichments after incubation with either 13C-labeled carbohydrates or amino acids. These results suggest that DOM could be directly taken up by Trichodesmium or primarily consumed by heterotrophic epibiont bacteria that ultimately transfer reduced DOM compounds to their host trichomes. Although the addition of carbohydrates or amino acids did not significantly affect bulk N2 fixation rates, N2 fixation was enhanced by amino acids in individual colonies of Trichodesmium. We discuss the ecological advantages of DOM use by Trichodesmium as an alternative to autotrophic nutrition in oligotrophic open ocean waters.

Publication type: 
Author: 
Mar Benavides
Hugo Berthelot
Solange Duhamel
Patrick Raimbault
Sophie Bonnet
Subjects: 
Microbiology
Microorganisms
Trichodesmium
Seawater--Organic compound content
Title string: 
Dissolved organic matter uptake by Trichodesmium in the Southwest Pacific
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:cz8w9ghx5f

Large- to submesoscale surface circulation and its implications on biogeochemical/biological horizontal distributions during the OUTPACE cruise (southwest Pacific)

The patterns of the large-scale, meso- and submesoscale surface circulation on biogeochemical and biological distributions are examined in the western tropical South Pacific (WTSP) in the context of the OUTPACE cruise (February–April 2015). Multi-disciplinary original in situ observations were achieved along a zonal transect through the WTSP and their analysis was coupled with satellite data. The use of Lagrangian diagnostics allows for the identification of water mass pathways, mesoscale structures, and submesoscale features such as fronts. In particular, we confirmed the existence of a global wind-driven southward circulation of surface waters in the entire WTSP, using a new high-resolution altimetry-derived product, validated by in situ drifters, that includes cyclogeostrophy and Ekman components with geostrophy. The mesoscale activity is shown to be responsible for counter-intuitive water mass trajectories in two subregions: (i) the Coral Sea, with surface exchanges between the North Vanuatu Jet and the North Caledonian Jet, and (ii) around 170° W, with an eastward pathway, whereas a westward general direction dominates. Fronts and small-scale features, detected with finite-size Lyapunov exponents (FSLEs), are correlated with 25 % of surface tracer gradients, which reveals the significance of such structures in the generation of submesoscale surface gradients. Additionally, two high-frequency sampling transects of biogeochemical parameters and microorganism abundances demonstrate the influence of fronts in controlling the spatial distribution of bacteria and phytoplankton, and as a consequence the microbial community structure. All circulation scales play an important role that has to be taken into account not only when analysing the data from OUTPACE but also, more generally, for understanding the global distribution of biogeochemical components.

Publication type: 
Author: 
Louise Rousselet
de Alain Verneil
Andrea M. Doglioli
Anne A. Petrenko
Solange Duhamel
Christophe Maes
Bruno Blanke
Subjects: 
Biogeochemistry
Ocean circulation
Microorganisms
Phytoplankton--Geographical distribution
Title string: 
Large- to submesoscale surface circulation and its implications on biogeochemical/biological horizontal distributions during the OUTPACE cruise (southwest Pacific)
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:stqjq2bvtg

Systematically Mapping the Epigenetic Context Dependence of Transcription Factor Binding

At the core of gene regulatory networks are transcription factors (TFs) that recognize specific DNA sequences and target distinct gene sets. Characterizing the DNA binding specificity of all TFs is a prerequisite for understanding global gene regulatory logic, which in recent years has resulted in the development of high-throughput methods that probe TF specificity in vitro and are now routinely used to inform or interpret in vivo studies. Despite the broad success of such methods, several challenges remain, two of which are addressed in this thesis.
Genomic DNA can harbor different epigenetic marks that have the potential to alter TF binding, the most prominent being CpG methylation. Given the vast number of modified CpGs in the human genome and an increasing body of literature suggesting a link between epigenetic changes and genome instability, or the onset of disease such as cancer, methods that can characterize the sensitivity of TFs to DNA methylation are needed to mechanistically interpret its impact on gene expression. We developed a high-throughput in vitro method (EpiSELEX-seq) that probes TF binding to unmodified and modified DNA sequences in competition, resulting in high-resolution maps of TF binding preferences. We found that methylation sensitivity can vary between TFs of the the same structural family and is dependent on the position of the 5mCpG within the TF binding site. The importance of our in vitro profiling of methylation sensitivity is demonstrated by the preference of human p53 tetramers for 5mCpGs within its binding site core. This previously unknown, stabilizing effect is also detectable in p53 ChIP-seq data when comparing methylated and unmethylated sites genome-wide.
A second impediment to predicting TF binding is our limited understanding of i) how cooperative participation of a TF in different complexes can alter their binding preference, and ii) how the detailed shape of DNA aids in creating a substrate for adaptive multi-TF binding. To address these questions in detail, we studied the in vitro binding preferences of three D. melanogaster homeodomain TFs: Homothorax (Hth), Extradenticle(Exd) and one of the eight Hox proteins. In vivo, Hth occurs in two splice forms: with (HthFL) and without (HthHM) the DNA binding domain (DBD). HthHM-Exd itself is a Hox cofactor that has been shown to induce latent sequence specificity upon complex formation with Hox proteins. There are three possible complexes that can be formed, all potentially having specific target genes: HthHM-Exd-Hox, HthFL-Exd-Hox, and HthFL-Exd. We characterized the in vitro binding preferences of each of these by developing new computational approaches to analyze high-throughput SELEX-seq data. We found distinct orientation and spacing preference for HthFL-Exd-Hox, alternative recognition modes that depend on the affinity class a sequence falls into, and a strong preference for a narrow DNA minor grove near Exd's N-terminal DBD. Strikingly, this shape readout is crucial to stabilize the HthHM-Exd-Hox complex in the absence of a Hth DBD and can thus be used to distinguish HthHM from HthFL isoform binding. Mutating the amino acids responsible for the shape readout by Exd and reinserting the engineered protein into the fly genome allowed us to classify in vivo binding sites based on ChIP-seq signal comparison between “shape-mutant” and wild-type Exd.
In summary, the research presented here has investigated TF binding preferences beyond sequence context by combining novel high-throughput experimental and computational methods. This interdisciplinary approach has enabled us to study binding preferences of TF complexes with respect to the epigenetic landscape of their cognate binding sites. Our novel mechanistic insights into DNA shape readout have provided a new avenue of exploiting guided protein engineering to probe how specific TFs interact with their co-factors in a cellular context, and how flanking genomic sequence helps determine which multi-TF complexes will form and which binding mode a complex adopts.

Author: 
Judith Franziska Kribelbauer
Subjects: 
Biochemistry
Bioinformatics
Biophysics
Transcription factors
Gene regulatory networks
Epigenetics
Title string: 
Systematically Mapping the Epigenetic Context Dependence of Transcription Factor Binding
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:v6wwpzgmw7

Aphotic N2 fixation along an oligotrophic to ultraoligotrophic transect in the Western Tropical South Pacific Ocean

The western tropical South Pacific (WTSP) Ocean has been recognized as a global hot spot of dinitrogen (N2) fixation. Here, as in other marine environments across the oceans, N2 fixation studies have focused on the sunlit layer. However, studies have confirmed the importance of aphotic N2 fixation activity, although until now only one had been performed in the WTSP. In order to increase our knowledge of aphotic N2 fixation in the WTSP, we measured N2 fixation rates and identified diazotrophic phylotypes in the mesopelagic layer along a transect spanning from New Caledonia to French Polynesia. Because non-cyanobacterial diazotrophs presumably need external dissolved organic matter (DOM) sources for their nutrition, we also identified DOM compounds using Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS) with the aim of searching for relationships between the composition of DOM and non-cyanobacterial N2 fixation in the aphotic ocean. N2 fixation rates were low (average 0.63 ± 0.07 nmol N L−1 d−1) but consistently detected across all depths and stations, representing ∼ 6–88 % of photic N2 fixation. N2 fixation rates were not significantly correlated with DOM compounds. The analysis of nifH gene amplicons revealed a wide diversity of non-cyanobacterial diazotrophs, mostly matching clusters 1 and 3. Interestingly, a distinct phylotype from the major nifH subcluster 1G dominated at 650 dbar, coinciding with the oxygenated Subantarctic Mode Water (SAMW). This consistent pattern suggests that the distribution of aphotic diazotroph communities is to some extent controlled by water mass structure. While the data available are still too scarce to elucidate the distribution and controls of mesopelagic non-cyanobacterial diazotrophs in the WTSP, their prevalence in the mesopelagic layer and the consistent detection of active N2 fixation activity at all depths sampled during our study suggest that aphotic N2 fixation may contribute significantly to fixed nitrogen inputs in this area and/or areas downstream of water mass circulation.

Publication type: 
Author: 
Mar Benavides
Katyanne M. Shoemaker
Pia H. Moisander
Jutta Niggemann
Thorsten Dittmar
Solange Duhamel
Olivier Grosso
Mireille Pujo-Pay
HéSandra lias-Nunige
Alain Fumenia
Sophie Bonnet
Subjects: 
Nitrogen--Fixation
Biogeochemistry
Oceanography
Title string: 
Aphotic N2 fixation along an oligotrophic to ultraoligotrophic transect in the Western Tropical South Pacific Ocean
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:q573n5tb5f

Microbial community structure in the western tropical South Pacific

Oligotrophic regions play a central role in global biogeochemical cycles, with microbial communities in these areas representing an important term in global carbon budgets. While the general structure of microbial communities has been well documented in the global ocean, some remote regions such as the western tropical South Pacific (WTSP) remain fundamentally unexplored. Moreover, the biotic and abiotic factors constraining microbial abundances and distribution remain not well resolved. In this study, we quantified the spatial (vertical and horizontal) distribution of major microbial plankton groups along a transect through the WTSP during the austral summer of 2015, capturing important autotrophic and heterotrophic assemblages including cytometrically determined abundances of non-pigmented protists (also called flagellates). Using environmental parameters (e.g., nutrients and light availability) as well as statistical analyses, we estimated the role of bottom–up and top–down controls in constraining the structure of the WTSP microbial communities in biogeochemically distinct regions. At the most general level, we found a “typical tropical structure”, characterized by a shallow mixed layer, a clear deep chlorophyll maximum at all sampling sites, and a deep nitracline. Prochlorococcus was especially abundant along the transect, accounting for 68 ± 10.6 % of depth-integrated phytoplankton biomass. Despite their relatively low abundances, picophytoeukaryotes (PPE) accounted for up to 26 ± 11.6 % of depth-integrated phytoplankton biomass, while Synechococcus accounted for only 6 ± 6.9 %. Our results show that the microbial community structure of the WTSP is typical of highly stratified regions, and underline the significant contribution to total biomass by PPE populations. Strong relationships between N2 fixation rates and plankton abundances demonstrate the central role of N2 fixation in regulating ecosystem processes in the WTSP, while comparative analyses of abundance data suggest microbial community structure to be increasingly regulated by bottom–up processes under nutrient limitation, possibly in response to shifts in abundances of high nucleic acid bacteria (HNA).

Publication type: 
Author: 
Nicholas Andrew Bock
Van France Wambeke
Mo Dionïra
Solange Duhamel
Subjects: 
Microbial ecology
Biogeochemistry
Statistics
Marine plankton
Oceanography
Title string: 
Microbial community structure in the western tropical South Pacific
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:wwpzgmsbgd

Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry

Cells adapt to familiar changes in their environment by activating predefined regulatory programs that establish adaptive gene expression states. These hard-wired pathways, however, may be inadequate for adaptation to environments never encountered before. Here, we reveal evidence for an alternative mode of gene regulation that enables adaptation to adverse conditions without relying on external sensory information or genetically predetermined cis-regulation. Instead, individual genes achieve optimal expression levels through a stochastic search for improved fitness. By focusing on improving the overall health of the cell, the proposed stochastic tuning mechanism discovers global gene expression states that are fundamentally new and yet optimized for novel environments. We provide experimental evidence for stochastic tuning in the adaptation of Saccharomyces cerevisiae to laboratory-engineered environments that are foreign to its native gene-regulatory network. Stochastic tuning operates locally at individual gene promoters, and its efficacy is modulated by perturbations to chromatin modification machinery.

Publication type: 
Author: 
Peter L. Freddolino
Jamie Siyu Yang
Amir Momen-Roknabadi
Saeed Tavazoie
Subjects: 
Gene regulatory networks
Systems biology
Gene expression
Stochastic processes
Epigenetics
Title string: 
Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:cc2fqz614g

An Object-Oriented, Python-Based Moving Mesh Hydrodynamics Code Inspired by Astrophysical Problems

The role of radiative cooling plays an important role in the formation of structures in collapsing gas. In this dissertation I examine the impact of cooling in two formation scenarios: first, the role of H2 cooling in collapsing gas in primordial dark matter halos in the possible formation of supermassive black holes; second, low metallicity cooling in collapsing clouds and its possible role in explaining low-metallicity globular clusters. Further, I introduce a new hydrodynamics code, with a design guided by current software principles. In chapter 2, I examined the proposed mechanism to explain the formation of super-massive black holes through direct collapse. The presence of quasars at redshifts z > 6 indicates the existence of supermassive black holes (SMBHs) as massive as a few times 10^9 mass of the sun, challenging models for SMBH formation. One pathway is through the direct collapse of gas in T_vir ≳ 10^4 K halos; however, this requires the suppression of H2 cooling to prevent fragmentation. In this dissertation, I examine a proposed mechanism for this suppression which relies on cold-mode accretion flows leading to shocks at high densities (n > 10^4 cm^−3 ) and temperatures (T > 10^4 K). In such gas, H2 is efficiently collisionally dissociated. I use high-resolution numerical simulations to test this idea, demonstrating that such halos typically have lower temperature progenitors, in which cooling is efficient. Those halos do show filamentary flows; however, the gas shocks at or near the virial radius (at low densities), thus preventing the proposed collisional mechanism from operating. I do find that, if we artificially suppress H2 formation with a high UV background, so as to allow gas in the halo center to enter the high-temperature, high-density “zone of no return”, it will remain there even if the UV flux is turned off, collapsing to high density at high temperature. Due to computational limitations, we simulated only three halos. However, we demonstrate, using Monte Carlo calculations of 10^6 halo merger histories, that a few rare halos could assemble rapidly enough to avoid efficient H2 cooling in all of their progenitor halos, provided that the UV background exceeds J_21 ∼ few at redshifts as high as z ∼ 20. In chapter 3, I explore the relative role of small-scale fragmentation and global collapse in low-metallicity clouds, pointing out that in such clouds the cooling time may be longer than the dynamical time, allowing the cloud to collapse globally before it can fragment. This, I suggest, may help to explain the formation of the low-metallicity globular cluster population, since such dense stellar systems need a large amount of gas to be collected in a small region (without significant feedback during the collapse). To explore this further, I carried out numerical simulations of low-metallicity Bonner-Ebert stable gas clouds, demonstrating that there exists a critical metallicity (between 0.001 and 0.01 metallicity of the sun ) below which the cloud collapses globally without fragmentation. I also run simulations including a background radiative heating source, showing that this can also produce clouds that do not fragment, and that the critical metallicity – which can exceed the no-radiation case – increases with the heating rate. Lastly in chapter 4, I describe the structure and implementation of the new open-source parallel moving-mesh hydrodynamic code, Python Hydro-Dynamics (phd). The code has been written from the ground up to be easy to use and facilitate future modifications. The code is written in a mixture of Python and Cython and makes extensive use of object-oriented programming. I outline the algorithms used and describe the design philosophy and the reasoning of my choices during the code development. I end by validating the code through a series of test problems.

Department: 
Astronomy
Author: 
Ricardo Fernandez
Subjects: 
Astronomy
Hydrodynamics--Computer simulation
Astrophysics
Cooling
Computer science
Title string: 
An Object-Oriented, Python-Based Moving Mesh Hydrodynamics Code Inspired by Astrophysical Problems
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:7m0cfxpnz0

Intramolecular Singlet Fission in Acenes

In 2017, 98 gigawatts of solar capacity were added globally, outpacing new contributions from coal, gas and nuclear plants combined, based on 161 billion dollars of investment. Solar is the leading contributor to the clean energy revolution and continues to grow in market share and drop in price every year as economy of scale advances the technology. Within this market, silicon and cadmium telluride solar cells dominate nearly all of market share, converting roughly 20% of incident solar power into electricity. It is worth noting that the gains from a 1% increase in power conversion efficiency of the typical 20% solar cell to 21% would be measured, annually, in billions of dollars. If the solar cells installed last year had 1% more power conversion efficiency and the power displaced coal power generation, this enhancement in efficiency would now save roughly 8,000,000 pounds of carbon dioxide emission per hour every hour for the ~220,000-hour (~25 year) lifetime of the solar cells.
Within this context, enhancing the power conversion efficiency of solar cells is crucial economically and environmentally. Because sunlight is incident on the earth as a broad spectrum of different colors, the energy of the photons spans a wide range. Unfortunately, the spectral range limits power conversion efficiency. For example, solar cells are transparent to photons with insufficient energy, while photons with excess energy relax to the band edge of the solar material, losing the excess energy as heat. This thesis focuses on improving the utilization of high energy photons currently lost to this thermalization process.
In Chapter 1, we introduce the photophysical process of singlet exciton fission and give an overview of the field, with a focus on its potential for incorporation into photovoltaic devices. In Chapter 2-8, we discuss our results realizing singlet exciton fission in molecular systems, specifically bipentacenes. This chapter includes the synthesis of these materials, theoretical calculations predicting and rationalizing their photophysical behavior, and the spectroscopic characterization used to demonstrate the singlet fission process. In Chapter 3, we detail a modular synthetic approach to oligomers and even the first polymer of pentacene. We also discuss some basic properties of these materials using techniques such as linear absorption, cyclic voltammetry, and grazing incidence wide angle X-ray scattering spectroscopy. In Chapter 4, we investigate the photophysics of these materials. Photoluminescence upconversion spectroscopy reveals the decay of the singlet exciton on ultrafast timescales, while transient absorption spectroscopy is used to assign the singlet fission timescale, as well as to characterize the triplet absorption spectra.
Chapter 5 discusses the synthesis and photophysics of homoconjugated and non-conjugated pentacene dimers, where singlet fission occurs through sigma bonds. Again, transient absorption spectroscopy is crucial to the assignment of the photophysics at play, but continuous wave time resolved electron spin resonance measurements yield additional insights into interaction between the resulting triplet pair excitons. Chapter 6 provides further detail into the formation of strongly exchange coupled triplet pair states. Continuous wave time resolved electron spin resonance spectroscopy is used to determine the quintet character of these states, and pulsed electron spin resonance measurements nutate the spin of these states to confirm this assignment. Chapter 7 provides the first demonstration that singlet exciton fission is also possible in heterodimer systems. Finally, Chapter 8 delves more deeply into the exciton correlations in these materials with a special focus on the pentacene-tetracene dimer system.

Department: 
Chemistry
Author: 
Samuel Nathan Sanders
Subjects: 
Chemistry
Solar cells--Materials
Physics
Photons
Title string: 
Intramolecular Singlet Fission in Acenes
GUID update: 
https://academiccommons.columbia.edu/catalog/ac:m905qftthq

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