Incremental Mutual Information: A New Method for Characterizing the Strength and Dynamics of Connections in Neuronal Circuits

Understanding the computations performed by neuronal circuits requires characterizing the strength and dynamics of the connections between individual neurons. This characterization is typically achieved by measuring the correlation in the activity of two neurons. We have developed a new measure for studying connectivity in neuronal circuits based on information theory, the incremental mutual information (IMI). By conditioning out the temporal dependencies in the responses of individual neurons before measuring the dependency between them, IMI improves on standard correlation-based measures in several important ways: 1) it has the potential to disambiguate statistical dependencies that reflect the connection between neurons from those caused by other sources (e. g. shared inputs or intrinsic cellular or network mechanisms) provided that the dependencies have appropriate timescales, 2) for the study of early sensory systems, it does not require responses to repeated trials of identical stimulation, and 3) it does not assume that the connection between neurons is linear. We describe the theory and implementation of IMI in detail and demonstrate its utility on experimental recordings from the primate visual system

An 11 Earth-mass, Long-period Sub-Neptune Orbiting a Sun-like Star

Although several thousands of exoplanets have now been detected and characterized, observational biases have led to a paucity of long-period, low-mass exoplanets with measured masses and a corresponding lag in our understanding of such planets. In this paper we report the mass estimation and characterization of the long-period exoplanet Kepler-538b. This planet orbits a Sun-like star (V = 11.27) with M_* = 0.892 +/- (0.051, 0.035) M_sun and R_* = 0.8717 +/- (0.0064, 0.0061) R_sun. Kepler-538b is a 2.215 +/- (0.040, 0.034) R_earth sub-Neptune with a period of P = 81.73778 +/- 0.00013 d. It is the only known planet in the system. We collected radial velocity (RV) observations with HIRES on Keck I and HARPS-N on the TNG. We characterized stellar activity by a Gaussian process with a quasi-periodic kernel applied to our RV and cross correlation function full width at half maximum (FWHM) observations. By simultaneously modeling Kepler photometry, RV, and FWHM observations, we found a semi-amplitude of K = 1.68 +/- (0.39, 0.38) m s^-1 and a planet mass of M_p = 10.6 +/- (2.5, 2.4) M_earth. Kepler-538b is the smallest planet beyond P = 50 d with an RV mass measurement. The planet likely consists of a significant fraction of ices (dominated by water ice), in addition to rocks/metals, and a small amount of gas. Sophisticated modeling techniques such as those used in this paper, combined with future spectrographs with ultra high-precision and stability will be vital for yielding more mass measurements in this poorly understood exoplanet regime. This in turn will improve our understanding of the relationship between planet composition and insolation flux and how the rocky to gaseous transition depends on planetary equilibrium temperature

Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo

Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living culture

Spike-Timing Theory of Working Memory

Working memory (WM) is the part of the brain's memory system that provides temporary storage and manipulation of information necessary for cognition. Although WM has limited capacity at any given time, it has vast memory content in the sense that it acts on the brain's nearly infinite repertoire of lifetime long-term memories. Using simulations, we show that large memory content and WM functionality emerge spontaneously if we take the spike-timing nature of neuronal processing into account. Here, memories are represented by extensively overlapping groups of neurons that exhibit stereotypical time-locked spatiotemporal spike-timing patterns, called polychronous patterns; and synapses forming such polychronous neuronal groups (PNGs) are subject to associative synaptic plasticity in the form of both long-term and short-term spike-timing dependent plasticity. While long-term potentiation is essential in PNG formation, we show how short-term plasticity can temporarily strengthen the synapses of selected PNGs and lead to an increase in the spontaneous reactivation rate of these PNGs. This increased reactivation rate, consistent with in vivo recordings during WM tasks, results in high interspike interval variability and irregular, yet systematically changing, elevated firing rate profiles within the neurons of the selected PNGs. Additionally, our theory explains the relationship between such slowly changing firing rates and precisely timed spikes, and it reveals a novel relationship between WM and the perception of time on the order of seconds

Evaluation of high-throughput genomic assays for the Fc gamma receptor locus

Cancer immunotherapy has been revolutionised by the use of monoclonal antibodies (mAb) that function through their interaction with Fc gamma receptors (FcγRs). The low-affinity FcγR genes are highly homologous, map to a complex locus at 1p23 and harbour single nucleotide polymorphisms (SNPs) and copy number variation (CNV) that can impact on receptor function and response to therapeutic mAbs. This complexity can hinder accurate characterisation of the locus. We therefore evaluated and optimised a suite of assays for the genomic analysis of the FcγR locus amenable to peripheral blood mononuclear cells and formalin-fixed paraffin-embedded (FFPE) material that can be employed in a high-throughput manner. Assessment of TaqMan genotyping for FCGR2A-131H/R, FCGR3A-158F/V and FCGR2B-232I/T SNPs demonstrated the need for additional methods to discriminate genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs due to sequence homology and CNV in the region. A multiplex ligation-dependent probe amplification assay provided high quality SNP and CNV data in PBMC cases, but there was greater data variability in FFPE material in a manner that was predicted by the BIOMED-2 multiplex PCR protocol. In conclusion, we have evaluated a suite of assays for the genomic analysis of the FcγR locus that are scalable for application in large clinical trials of mAb therapy. These assays will ultimately help establish the importance of FcγR genetics in predicting response to antibody therapeutics

Balancing Feed-Forward Excitation and Inhibition via Hebbian Inhibitory Synaptic Plasticity

It has been suggested that excitatory and inhibitory inputs to cortical cells are balanced, and that this balance is important for the highly irregular firing observed in the cortex. There are two hypotheses as to the origin of this balance. One assumes that it results from a stable solution of the recurrent neuronal dynamics. This model can account for a balance of steady state excitation and inhibition without fine tuning of parameters, but not for transient inputs. The second hypothesis suggests that the feed forward excitatory and inhibitory inputs to a postsynaptic cell are already balanced. This latter hypothesis thus does account for the balance of transient inputs. However, it remains unclear what mechanism underlies the fine tuning required for balancing feed forward excitatory and inhibitory inputs. Here we investigated whether inhibitory synaptic plasticity is responsible for the balance of transient feed forward excitation and inhibition. We address this issue in the framework of a model characterizing the stochastic dynamics of temporally anti-symmetric Hebbian spike timing dependent plasticity of feed forward excitatory and inhibitory synaptic inputs to a single post-synaptic cell. Our analysis shows that inhibitory Hebbian plasticity generates ‘negative feedback’ that balances excitation and inhibition, which contrasts with the ‘positive feedback’ of excitatory Hebbian synaptic plasticity. As a result, this balance may increase the sensitivity of the learning dynamics to the correlation structure of the excitatory inputs

TOI-1634 b: An Ultra-short-period Keystone Planet Sitting inside the M-dwarf Radius Valley

Studies of close-in planets orbiting M dwarfs have suggested that the M dwarf radius valley may be well-explained by distinct formation timescales between enveloped terrestrials, and rocky planets that form at late times in a gas-depleted environment. This scenario is at odds with the picture that close-in rocky planets form with a primordial gaseous envelope that is subsequently stripped away by some thermally-driven mass loss process. These two physical scenarios make unique predictions of the rocky/enveloped transition's dependence on orbital separation such that studying the compositions of planets within the M dwarf radius valley may be able to establish the dominant physics. Here, we present the discovery of one such keystone planet: the ultra-short period planet TOI-1634 b ($P=0.989$ days, $F=121 F_{\oplus}$, $r_p = 1.790^{+0.080}_{-0.081} R_{\oplus}$) orbiting a nearby M2 dwarf ($K_s=8.7$, $R_s=0.45 R_{\odot}$, $M_s=0.50 M_{\odot}$) and whose size and orbital period sit within the M dwarf radius valley. We confirm the TESS-discovered planet candidate using extensive ground-based follow-up campaigns, including a set of 32 precise radial velocity measurements from HARPS-N. We measure a planetary mass of $4.91^{+0.68}_{-0.70} M_{\oplus}$, which makes TOI-1634 b inconsistent with an Earth-like composition at $5.9\sigma$ and thus requires either an extended gaseous envelope, a large volatile-rich layer, or a rocky portion that is not dominated by iron and silicates to explain its mass and radius. The discovery that the bulk composition of TOI-1634 b is inconsistent with that of the Earth favors the gas-depleted formation mechanism to explain the emergence of the radius valley around M dwarfs with $M_s\lesssim 0.5 M_{\odot}$