Publications by authors named "Benjamin Weiner"

12 Publications

  • Page 1 of 1

Decoding the physical principles of two-component biomolecular phase separation.

Elife 2021 Mar 11;10. Epub 2021 Mar 11.

Department of Molecular Biology, Princeton University, Princeton, United States.

Cells possess a multiplicity of non-membrane-bound compartments, which form via liquid-liquid phase separation. These condensates assemble and dissolve as needed to enable central cellular functions. One important class of condensates is those composed of two associating polymer species that form one-to-one specific bonds. What are the physical principles that underlie phase separation in such systems? To address this question, we employed coarse-grained molecular dynamics simulations to examine how the phase boundaries depend on polymer valence, stoichiometry, and binding strength. We discovered a striking phenomenon - for sufficiently strong binding, phase separation is suppressed at rational polymer stoichiometries, which we termed the magic-ratio effect. We further developed an analytical dimer-gel theory that confirmed the magic-ratio effect and disentangled the individual roles of polymer properties in shaping the phase diagram. Our work provides new insights into the factors controlling the phase diagrams of biomolecular condensates, with implications for natural and synthetic systems.
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http://dx.doi.org/10.7554/eLife.62403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952089PMC
March 2021

Nutrient levels and trade-offs control diversity in a serial dilution ecosystem.

Elife 2020 09 11;9. Epub 2020 Sep 11.

Department of Molecular Biology, Princeton University, Princeton, United States.

Microbial communities feature an immense diversity of species and this diversity is linked to outcomes ranging from ecosystem stability to medical prognoses. Yet the mechanisms underlying microbial diversity are under debate. While simple resource-competition models don't allow for coexistence of a large number of species, it was recently shown that metabolic trade-offs can allow unlimited diversity. Does this diversity persist with more realistic, intermittent nutrient supply? Here, we demonstrate theoretically that in serial dilution culture, metabolic trade-offs allow for high diversity. When a small amount of nutrient is supplied to each batch, the serial dilution dynamics mimic a chemostat-like steady state. If more nutrient is supplied, community diversity shifts due to an 'early-bird' effect. The interplay of this effect with different environmental factors and diversity-supporting mechanisms leads to a variety of relationships between nutrient supply and diversity, suggesting that real ecosystems may not obey a universal nutrient-diversity relationship.
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http://dx.doi.org/10.7554/eLife.57790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486120PMC
September 2020

Temporal structure of mouse courtship vocalizations facilitates syllable labeling.

Commun Biol 2020 Jun 26;3(1):333. Epub 2020 Jun 26.

The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Mice emit sequences of ultrasonic vocalizations (USVs) but little is known about the rules governing their temporal order and no consensus exists on the classification of USVs into syllables. To address these questions, we recorded USVs during male-female courtship and found a significant temporal structure. We labeled USVs using three popular algorithms and found that there was no one-to-one relationships between their labels. As label assignment affects the high order temporal structure, we developed the Syntax Information Score (based on information theory) to rank labeling algorithms based on how well they predict the next syllable in a sequence. Finally, we derived a novel algorithm (Syntax Information Maximization) that utilizes sequence statistics to improve the clustering of individual USVs with respect to the underlying sequence structure. Improvement in USV classification is crucial for understanding neural control of vocalization. We demonstrate that USV syntax holds valuable information towards achieving this goal.
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http://dx.doi.org/10.1038/s42003-020-1053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320152PMC
June 2020

Rigidity enhances a magic-number effect in polymer phase separation.

Nat Commun 2020 03 25;11(1):1561. Epub 2020 Mar 25.

Department of Molecular Biology, Princeton University, Princeton, NJ, 08540, USA.

Cells possess non-membrane-bound bodies, many of which are now understood as phase-separated condensates. One class of such condensates is composed of two polymer species, where each consists of repeated binding sites that interact in a one-to-one fashion with the binding sites of the other polymer. Biologically-motivated modeling revealed that phase separation is suppressed by a "magic-number effect" which occurs if the two polymers can form fully-bonded small oligomers by virtue of the number of binding sites in one polymer being an integer multiple of the number of binding sites of the other. Here we use lattice-model simulations and analytical calculations to show that this magic-number effect can be greatly enhanced if one of the polymer species has a rigid shape that allows for multiple distinct bonding conformations. Moreover, if one species is rigid, the effect is robust over a much greater range of relative concentrations of the two species.
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http://dx.doi.org/10.1038/s41467-020-15395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096466PMC
March 2020

Spatial ecology of territorial populations.

Proc Natl Acad Sci U S A 2019 09 21;116(36):17874-17879. Epub 2019 Aug 21.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544

Many ecosystems, from vegetation to biofilms, are composed of territorial populations that compete for both nutrients and physical space. What are the implications of such spatial organization for biodiversity? To address this question, we developed and analyzed a model of territorial resource competition. In the model, all species obey trade-offs inspired by biophysical constraints on metabolism; the species occupy nonoverlapping territories, while nutrients diffuse in space. We find that the nutrient diffusion time is an important control parameter for both biodiversity and the timescale of population dynamics. Interestingly, fast nutrient diffusion allows the populations of some species to fluctuate to zero, leading to extinctions. Moreover, territorial competition spontaneously gives rise to both multistability and the Allee effect (in which a minimum population is required for survival), so that small perturbations can have major ecological effects. While the assumption of trade-offs allows for the coexistence of more species than the number of nutrients-thus violating the principle of competitive exclusion-overall biodiversity is curbed by the domination of "oligotroph" species. Importantly, in contrast to well-mixed models, spatial structure renders diversity robust to inequalities in metabolic trade-offs. Our results suggest that territorial ecosystems can display high biodiversity and rich dynamics simply due to competition for resources in a spatial community.
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http://dx.doi.org/10.1073/pnas.1911570116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731762PMC
September 2019

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease.

Neurotherapeutics 2018 10;15(4):872-884

Department of Neurology, The Ohio State University, 395 West 12th Avenue, Columbus, OH, 43210, USA.

Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.
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http://dx.doi.org/10.1007/s13311-018-00679-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277298PMC
October 2018

Adrenergic Modulation Regulates the Dendritic Excitability of Layer 5 Pyramidal Neurons In Vivo.

Cell Rep 2018 04;23(4):1034-1044

Edmond and Lily Safra Center for Brain Sciences and Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address:

The excitability of the apical tuft of layer 5 pyramidal neurons is thought to play a crucial role in behavioral performance and synaptic plasticity. We show that the excitability of the apical tuft is sensitive to adrenergic neuromodulation. Using two-photon dendritic Ca imaging and in vivo whole-cell and extracellular recordings in awake mice, we show that application of the α2A-adrenoceptor agonist guanfacine increases the probability of dendritic Ca events in the tuft and lowers the threshold for dendritic Ca spikes. We further show that these effects are likely to be mediated by the dendritic current I. Modulation of I in a realistic compartmental model controlled both the generation and magnitude of dendritic calcium spikes in the apical tuft. These findings suggest that adrenergic neuromodulation may affect cognitive processes such as sensory integration, attention, and working memory by regulating the sensitivity of layer 5 pyramidal neurons to top-down inputs.
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http://dx.doi.org/10.1016/j.celrep.2018.03.103DOI Listing
April 2018

Social Ultrasonic Vocalization in Awake Head-Restrained Mouse.

Front Behav Neurosci 2016 19;10:236. Epub 2016 Dec 19.

Edmond and Lily Safra Center for Brain Sciences and Life Science Institute, The Hebrew University of Jerusalem Jerusalem, Israel.

Numerous animal species emit vocalizations in response to various social stimuli. The neural basis of vocal communication has been investigated in monkeys, songbirds, rats, bats, and invertebrates resulting in deep insights into motor control, neural coding, and learning. Mice, which recently became very popular as a model system for mammalian neuroscience, also utilize ultrasonic vocalizations (USVs) during mating behavior. However, our knowledge is lacking of both the behavior and its underlying neural mechanism. We developed a novel method for head-restrained male mice (HRMM) to interact with non-restrained female mice (NRFM) and show that mice can emit USVs in this context. We first recorded USVs in a free arena with non-restrained male mice (NRMM) and NRFM. Of the NRMM, which vocalized in the free arena, the majority could be habituated to also vocalize while head-restrained but only when a female mouse was present in proximity. The USVs emitted by HRMM are similar to the USVs of NRMM in the presence of a female mouse in their spectral structure, inter-syllable interval distribution, and USV sequence length, and therefore are interpreted as social USVs. By analyzing the vocalizations of NRMM, we established criteria to predict which individuals are likely to vocalize while head fixed based on the USV rate and average syllable duration. To characterize the USVs emitted by HRMM, we analyzed the syllable composition of HRMM and NRMM and found that USVs emitted by HRMM have a higher proportion of USVs with complex spectral representation, supporting previous studies showing that mice social USVs are context dependent. Our results suggest a way to study the neural mechanisms of production and control of social vocalization in mice using advanced methods requiring head fixation.
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http://dx.doi.org/10.3389/fnbeh.2016.00236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165246PMC
December 2016

Direct Observation of Charge Inversion in Divalent Nanofluidic Devices.

Nano Lett 2015 Aug 30;15(8):5046-51. Epub 2015 Jun 30.

§Department of Electrical Engineering, Pennsylvania State University, State College, Pennsylvania 16801, United States.

Solid-state nanofluidic devices have proven to be ideal systems for studying the physics of ionic transport at the nanometer length scale. When the geometrical confining size of fluids approaches the ionic Debye screening length, new transport phenomena occur, such as surface mediated transport and permselectivity. Prior work has explored these effects extensively in monovalent systems (e.g., predominantly KCl and NaCl). In this report, we present a new characterization method for the study of divalent ionic transport and have unambiguously observed divalent charge inversion at solid/fluid interfaces. This observation has important implications in applications ranging from biology to energy conversion.
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http://dx.doi.org/10.1021/acs.nanolett.5b01115DOI Listing
August 2015

Astrophysics. Multiple images of a highly magnified supernova formed by an early-type cluster galaxy lens.

Science 2015 Mar;347(6226):1123-6

Department of Astronomy, University of California, Berkeley, CA 94720-3411, USA.

In 1964, Refsdal hypothesized that a supernova whose light traversed multiple paths around a strong gravitational lens could be used to measure the rate of cosmic expansion. We report the discovery of such a system. In Hubble Space Telescope imaging, we have found four images of a single supernova forming an Einstein cross configuration around a redshift z = 0.54 elliptical galaxy in the MACS J1149.6+2223 cluster. The cluster's gravitational potential also creates multiple images of the z = 1.49 spiral supernova host galaxy, and a future appearance of the supernova elsewhere in the cluster field is expected. The magnifications and staggered arrivals of the supernova images probe the cosmic expansion rate, as well as the distribution of matter in the galaxy and cluster lenses.
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http://dx.doi.org/10.1126/science.aaa3350DOI Listing
March 2015

Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-α-deficient mice.

Cereb Cortex 2014 Jul 28;24(7):1956-65. Epub 2013 Feb 28.

Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA.

Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.
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http://dx.doi.org/10.1093/cercor/bht053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110455PMC
July 2014

Homeostatic plasticity drives tinnitus perception in an animal model.

Proc Natl Acad Sci U S A 2011 Sep 6;108(36):14974-9. Epub 2011 Sep 6.

Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.

Hearing loss often results in tinnitus and auditory cortical map changes, leading to the prevailing view that the phantom perception is associated with cortical reorganization. However, we show here that tinnitus is mediated by a cortical area lacking map reorganization. High-frequency hearing loss results in two distinct cortical regions: a sensory-deprived region characterized by a decrease in inhibitory synaptic transmission and a normal hearing region showing increases in inhibitory and excitatory transmission and map reorganization. Hearing-lesioned animals displayed tinnitus with a pitch in the hearing loss range. Furthermore, drugs that enhance inhibition, but not those that reduce excitation, reversibly eliminated the tinnitus behavior. These results suggest that sensory deprivation-induced homeostatic down-regulation of inhibitory synapses may contribute to tinnitus perception. Enhancing sensory input through map reorganization may plausibly alleviate phantom sensation.
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http://dx.doi.org/10.1073/pnas.1107998108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169130PMC
September 2011