Engineering of NEMO as calcium indicators with large dynamics and high sensitivity.

Genetically encoded calcium indicators (GECIs) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of suboptimal peak signal-to-baseline ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+ transients with peak SBRs around 20-fold larger than the top-of-the-range GCaMP6 series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared with GCaMP6s, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times larger in vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+ signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.

Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment.

Differing from other subtypes of inhibitory interneuron, chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment (AIS) of targeted pyramidal cells (PCs). However, the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved. Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs, we quantitatively demonstrate that the onset-timing of AIS-GABAergic input, relative to dendritic excitatory glutamatergic inputs, determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC. More specifically, AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+ channels on summed synaptic excitation when they precede glutamatergic inputs by >15 ms, while for nearly concurrent excitatory inputs, they primarily produce a shunting inhibition at the AIS. Thus, our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.

Chemical Reaction Networks' Programming for Solving Equations.

The computational ability of the chemical reaction networks (CRNs) using DNA as the substrate has been verified previously. To solve more complex computational problems and perform the computational steps as expected, the practical design of the basic modules of calculation and the steps in the reactions have become the basic requirements for biomolecular computing. This paper presents a method for solving nonlinear equations in the CRNs with DNA as the substrate. We used the basic calculation module of the CRNs with a gateless structure to design discrete and analog algorithms and realized the nonlinear equations that could not be solved in the previous work, such as exponential, logarithmic, and simple triangle equations. The solution of the equation uses the transformation method, Taylor expansion, and Newton iteration method, and the simulation verified this through examples. We used and improved the basic calculation module of the CRN++ programming language, optimized the error in the basic module, and analyzed the error's variation over time.

Schizophrenia risk-gene Crmp2 deficiency causes precocious critical period plasticity and deteriorated binocular vision.

Brain-specific loss of a microtubule-binding protein collapsin response mediator protein-2 (CRMP2) in the mouse recapitulates many schizophrenia-like behaviors of human patients, possibly resulting from associated developmental deficits in neuronal differentiation, path-finding, and synapse formation. However, it is still unclear how the Crmp2 loss affects neuronal circuit function and plasticity. By conducting in vivo and ex vivo electrophysiological recording in the mouse primary visual cortex (V1), we reveal that CRMP2 exerts a key regulation on the timing of postnatal critical period (CP) for experience-dependent circuit plasticity of sensory cortex. In the developing V1, the Crmp2 deficiency induces not only a delayed maturation of visual tuning functions but also a precocious CP for visual input-induced ocular dominance plasticity and its induction activity - coincident binocular inputs right after eye-opening. Mechanistically, the Crmp2 deficiency accelerates the maturation process of cortical inhibitory transmission and subsequently promotes an early emergence of balanced excitatory-inhibitory cortical circuits during the postnatal development. Moreover, the precocious CP plasticity results in deteriorated binocular depth perception in adulthood. Thus, these findings suggest that the Crmp2 deficiency dysregulates the timing of CP for experience-dependent refinement of circuit connections and further leads to impaired sensory perception in later life.

Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors in Mice and Children.

Zika virus (ZIKV) has evolved into a global health threat because of its causal link to congenital Zika syndrome. ZIKV infection of pregnant women may cause a spectrum of abnormalities in children. In the studies in Brazil, a large cohort of children with perinatal exposure to ZIKV is followed, and a spectrum of neurodevelopmental abnormalities is identified. In parallel, it is demonstrated that infection of the mouse neonatal brain by a contemporary ZIKV strain instead of an Asian ancestral strain can cause microcephaly and various abnormal neurological functions. These include defects in social interaction and depression, impaired learning and memory, in addition to severe motor defects, which are present in adult mice as well as in the prospective cohort of children. Importantly, although mouse brains infected later after birth do not have apparent abnormal brain structure, those mice still show significant impairments of visual cortical functions, circuit organization, and experience-dependent plasticity. Thus, the study suggests that special attention should be paid to all children born to ZIKV infected mothers for screening of abnormal behaviors and sensory function during childhood.

Characteristics of air pollution in different zones of Sichuan Basin, China.

Sichuan Basin, located in southwest China, has been ranked as the fourth of heavily air polluted regions in China partly due to its deep mountain-basin topography. However, spatial-temporal distribution of air pollution over the basin is still unclear due to the lack of monitoring data and poor knowledge. Since January 2015, six criteria air pollutants began to be monitored in 20 cities across the basin. The measured data enable us to analyze the basin-wide spatial-temporal distribution characteristics of these air pollutants. Results revealed heavy air pollution in the bottom zone, medium in the slope zone, and light pollution in the edge zone of the Basin in terms of the altitudes of air quality monitoring stations across the Basin. The average concentrations of PM2.5 and PM10 were 55.87µg/m3 and 86.49µg/m3 in the bottom, 33.76µg/m3 and 63.33µg/m3 in the slope, and 19.71µg/m3 and 35.06µg/m3 in the edge, respectively. In the bottom and slope of the basin, high PM2.5 concentration events occurred most frequently in winter. While in summer, ozone became primary pollutant. Among the six air pollutants, concentrations of PM2.5 and PM10 decrease dramatically with increasing altitude which was fitted by a nonlinear relationship between particulate matter (PM) concentrations and altitude. This relationship was validated by extinction coefficient profiles from CALIPSO observations and EV-lidar data, and hence used to reflect vertical distribution of air PM concentrations. It has been found that the thickness of higher PM concentrations is less than 500m in the basin. In the bottom of the basin, PM concentrations exhibited stronger horizontal homogeneities as compared with those in the North China Plain and Yangtze River Delta. However, gaseous pollutants seemed not to show clear relationships between their concentrations and altitudes in the basin. Their horizontal homogeneities were less significant compared to PM.