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Task-related studies have consistently reported that listening to speech sounds activate the temporal and prefrontal regions of the brain. However, it is not well understood how functional organization of auditory and language networks differ when processing speech sounds from its resting state form. The knowledge of language network organization in typically developing infants could serve as an important biomarker to understand network-level disruptions expected in infants with hearing impairment. We hypothesized that topological differences of language networks can be characterized using functional connectivity measures in two experimental conditions (1) complete silence (resting) and (2) in response to repetitive continuous speech sounds (steady). Thirty normal-hearing infants (14 males and 16 females, age: 7.8 ± 4.8 months) were recruited in this study. Brain activity was recorded from bilateral temporal and prefrontal regions associated with speech and language processing for two experimental conditions: resting and steady states. Topological differences of functional language networks were characterized using graph theoretical analysis. The normalized global efficiency and clustering coefficient were used as measures of functional integration and segregation, respectively. We found that overall, language networks of infants demonstrate the economic small-world organization in both resting and steady states. Moreover, language networks exhibited significantly higher functional integration and significantly lower functional segregation in resting state compared to steady state. A secondary analysis that investigated developmental effects of infants aged 6-months or below and above 6-months revealed that such topological differences in functional integration and segregation across resting and steady states can be reliably detected after the first 6-months of life. The higher functional integration observed in resting state suggests that language networks of infants facilitate more efficient parallel information processing across distributed language regions in the absence of speech stimuli. Moreover, higher functional segregation in steady state indicates that the speech information processing occurs within densely interconnected specialized regions in the language network.

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Accurate definition of the borders of cortical visual areas is essential for the study of neuronal processes leading to perception. However, data used for definition of areal boundaries have suffered from issues related to resolution, uniform coverage, or suitability for objective analysis, leading to ambiguity. Here, we present a novel approach that combines widefield optical imaging, presentation of naturalistic movies, and encoding model analysis, to objectively define borders in the primate extrastriate cortex. We applied this method to test conflicting hypotheses about the third-tier visual cortex, where areal boundaries have remained controversial. We demonstrate pronounced tuning preferences in the third-tier areas, and an organizational structure in which the dorsomedial area (DM) contains representations of both the upper and lower contralateral quadrants, and is located immediate anterior to V2. High-density electrophysiological recordings with a Neuropixels probe confirm these findings. Our encoding-model approach offers a powerful, objective way to disambiguate areal boundaries.

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OBJECTIVE: There is limited evidence on which immunosuppressive agents produce the best outcomes for adult patients with steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS). This review compares the remission rate and adverse effects of various immunosuppressants used. METHODS: Studies of adult patients with biopsy-proven SDNS/FRNS, administered any immunosuppressive agents and reported complete remission results as one of the clinical outcomes were included. Articles were independently screened by two researchers. ROBINS-I was used for risk of bias assessment. Random-effects model was used for statistical analysis and corresponding 95% confidence intervals (CIs) were calculated. RESULTS: 574 patients across 28 studies were included in the analysis. Patients receiving rituximab have a complete remission rate of 89% (95% CI = 83% to 94%; τ2 = 0.0070; I2 = 62%; overall p < 0.01, low certainty) and adverse event rate of 0.26, cyclosporine (CR 40%; 95% CI = 21% to 59%; τ2 = 0.0205; I2 = 55%; overall p = 0.08, low certainty), tacrolimus (CR 84%; 95% CI = 70% to 98%; τ2 = 0.0060; I2 = 33%; overall p = 0.21, moderate certainty), mycophenolate mofetil (CR 82%; 95% CI = 74% to 90%; τ2 < 0.0001; I2 = 15%; overall p = 0.32, moderate certainty) and cyclophosphamide (CR 79%; 95% CI = 69% to 89%; τ2 = 0; I2 = 0%; overall p = 0.52, moderate certainty). CONCLUSION: Among the commonly used immunosuppressive agents, only rituximab has a statistically significant effect in achieving complete remission among patients with SDNS/FRNS and has a relatively good safety profile, but this is limited by low quality of evidence with high degree of heterogeneity causing a lack of statistical power.

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As a result of recombination, adjacent nucleotides can have different paths of genetic inheritance and therefore the genealogical trees for a sample of DNA sequences vary along the genome. The structure capturing the details of these intricately interwoven paths of inheritance is referred to as an ancestral recombination graph (ARG). Classical formalisms have focused on mapping coalescence and recombination events to the nodes in an ARG. However, this approach is out of step with some modern developments, which do not represent genetic inheritance in terms of these events or explicitly infer them. We present a simple formalism that defines an ARG in terms of specific genomes and their intervals of genetic inheritance, and show how it generalizes these classical treatments and encompasses the outputs of recent methods. We discuss nuances arising from this more general structure, and argue that it forms an appropriate basis for a software standard in this rapidly growing field.

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Cortical visual prostheses are designed to treat blindness by restoring visual perceptions through artificial electrical stimulation of the primary visual cortex (V1). Intracortical microelectrodes produce the smallest visual percepts and thus higher resolution vision - like a higher density of pixels on a monitor. However, intracortical microelectrodes must maintain a minimum spacing to preserve tissue integrity. One solution to increase the density of percepts is to implant and stimulate multiple visual areas, such as V1 and V2, although the properties of microstimulation in V2 remain largely unexplored. We provide a direct comparison of V1 and V2 microstimulation in two common marmoset monkeys. We find similarities in response trends between V1 and V2 but differences in threshold, neural activity duration, and spread of activity at the threshold current. This has implications for using multi-area stimulation to increase the resolution of cortical visual prostheses.

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It has been shown that we can restore sensations of light by stimulating the visual cortex. Cortical prosthetic vision consists of light perception in the visual field named phosphenes. Phosphenes are like pixels on a monitor which we can control to form the desired perception. However, the locations of phosphenes evoked vary between individuals. One of the biggest challenges is how to utilize phosphenes to present recognizable patterns that represent real-world scenes. Because of the difficulties of recruiting participants, and the risks of neurosurgery, researchers have used computer simulations to investigate the outcome of cortical visual prostheses. Previous simulations used regular phosphene maps, which may overestimate the visual ability cortical visual prosthesis can provide. This study aims to develop a more realistic simulation for cortical visual prostheses. We derived realistic phosphene maps using an existing cortical retinotopy dataset and decided implant placement by considering neurosurgery restrictions. We rendered some visual stimuli to evaluate the usability of those phosphene maps. The results indicate that presenting information on phosphenes maps may be more challenging than previously estimated.

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Resting-state functional connectivity is a promising tool for understanding and characterizing brain network architecture. However, obtaining uninterrupted long recording of resting-state data is challenging in many clinically relevant populations. Moreover, the interpretation of connectivity results may heavily depend on the data length and functional connectivity measure used. We compared the performance of three frequency-domain connectivity measures: magnitude-squared, wavelet and multitaper coherence; and the effect of data length ranging from 3 to 9 minutes. Performance was characterized by distinguishing two groups of channel pairs with known different connectivity strengths. While all methods considered improved the ability to distinguish the two groups with increasing data lengths, wavelet coherence performed best for the shortest time window of 3 minutes. Knowledge of which measure is more reliably used when shorter fNIRS recordings are available could make the utility of functional connectivity biomarkers more feasible in clinical populations of interest.

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As a result of recombination, adjacent nucleotides can have different paths of genetic inheritance and therefore the genealogical trees for a sample of DNA sequences vary along the genome. The structure capturing the details of these intricately interwoven paths of inheritance is referred to as an ancestral recombination graph (ARG). New developments have made it possible to infer ARGs at scale, enabling many new applications in population and statistical genetics. This rapid progress, however, has led to a substantial gap opening between theory and practice. Standard mathematical formalisms, based on exhaustively detailing the "events" that occur in the history of a sample, are insufficient to describe the outputs of current methods. Moreover, we argue that the underlying assumption that all events can be known and precisely estimated is fundamentally unsuited to the realities of modern, population-scale datasets. We propose an alternative mathematical formulation that encompasses the outputs of recent methods and can capture the full richness of modern large-scale datasets. By defining this ARG encoding in terms of specific genomes and their intervals of genetic inheritance, we avoid the need to exhaustively list (and estimate) all events. The effects of multiple events can be aggregated in different ways, providing a natural way to express many forms of approximate and partial knowledge about the recombinant ancestry of a sample.

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Objective.We developed a realistic simulation paradigm for cortical prosthetic vision and investigated whether we can improve visual performance using a novel clustering algorithm.Approach.Cortical visual prostheses have been developed to restore sight by stimulating the visual cortex. To investigate the visual experience, previous studies have used uniform phosphene maps, which may not accurately capture generated phosphene map distributions of implant recipients. The current simulation paradigm was based on the Human Connectome Project retinotopy dataset and the placement of implants on the cortices from magnetic resonance imaging scans. Five unique retinotopic maps were derived using this method. To improve performance on these retinotopic maps, we enabled head scanning and a density-based clustering algorithm was then used to relocate centroids of visual stimuli. The impact of these improvements on visual detection performance was tested. Using spatially evenly distributed maps as a control, we recruited ten subjects and evaluated their performance across five sessions on the Berkeley Rudimentary Visual Acuity test and the object recognition task.Main results.Performance on control maps is significantly better than on retinotopic maps in both tasks. Both head scanning and the clustering algorithm showed the potential of improving visual ability across multiple sessions in the object recognition task.Significance.The current paradigm is the first that simulates the experience of cortical prosthetic vision based on brain scans and implant placement, which captures the spatial distribution of phosphenes more realistically. Utilisation of evenly distributed maps may overestimate the performance that visual prosthetics can restore. This simulation paradigm could be used in clinical practice when making plans for where best to implant cortical visual prostheses.

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Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic datasets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than threefold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed the best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

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Objective.Blindness affects approximately 40 million people worldwide and has inspired the development of cortical visual prostheses for restoring sight. Cortical visual prostheses electrically stimulate neurons of the visual cortex to artificially evoke visual percepts. Of the 6 layers of the visual cortex, layer 4 contains neurons that are likely to evoke a visual percept. Intracortical prostheses therefore aim to target layer 4; however, this can be difficult due to cortical curvature, inter-subject cortical variability, blindness-induced anatomical changes in cortex, and electrode placement variations. We investigated the feasibility of using current steering to stimulate specific cortical layers between electrodes in the laminar column.Approach.We explored whether the multiunit neural activity peak can be manipulated between two simultaneously stimulating electrodes in different layers of the cortical column. A 64-channel, 4-shank electrode array was implanted into the visual cortex of Sprague-Dawley rats (n= 7) orthogonal to the cortical surface. A remote return electrode was positioned over the frontal cortex in the same hemisphere. Charge was supplied to two stimulating electrodes along a single shank. Differing ratios of charge (100:0, 75:25, 50:50) and separation distances (300-500µm) were tested.Results.Current steering across the cortical layers did not result in a consistent shift of the neural activity peak. Both single-electrode and dual-electrode stimulation induced activity throughout the cortical column. This contrasts observations that current steering evoked a controllable peak of neural activity between electrodes implanted at similar cortical depths. However, dual-electrode stimulation across the layers did reduce the stimulation threshold at each site compared to single-electrode stimulation.Significance.Multi-electrode stimulation is not suitable for targeted activation of layers using current steering. However, it can be used to reduce activation thresholds at adjacent electrodes within a given cortical layer. This may be applied to reduce the stimulation side effects of neural prostheses, such as seizures.

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In the reach and saccade regions of the posterior parietal cortex (PPC), multiregional communication depends on the timing of neuronal activity with respect to beta-frequency (10-30 Hz) local field potential (LFP) activity, termed dual coherence. Neural coherence is believed to reflect neural excitability, whereby spiking tends to occur at a particular phase of LFP activity, but the mechanisms of multiregional dual coherence remain unknown. Here, we investigate dual coherence in the PPC of non-human primates performing eye-hand movements. We computationally model dual coherence in terms of multiregional neural excitability and show that one latent component, a multiregional mode, reflects shared excitability across distributed PPC populations. Analyzing the power in the multiregional mode with respect to different putative cell types reveals significant modulations with the spiking of putative pyramidal neurons and not inhibitory interneurons. These results suggest a specific role for pyramidal neurons in dual coherence supporting multiregional communication in PPC.

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Objective.Hearing is an important sensory function that plays a key role in how children learn to speak and develop language skills. Although previous neuroimaging studies have established that much of brain network maturation happens in early childhood, our understanding of the developmental trajectory of language areas is still very limited. We hypothesized that typical development trajectory of language areas in early childhood could be established by analyzing the changes of functional connectivity in normal hearing infants at different ages using functional near-infrared spectroscopy.Approach.Resting-state data were recorded from two bilateral temporal and prefrontal regions associated with language processing by measuring the relative changes of oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR) concentrations. Connectivity was calculated using magnitude-squared coherence of channel pairs located in (a) inter-hemispheric homologous and (b) intra-hemispheric brain regions to assess connectivity between homologous regions across hemispheres and two regions of interest in the same hemisphere, respectively.Main results.A linear regression model fitted to the age vs coherence of inter-hemispheric homologous test group revealed a significant coefficient of determination for both HbO (R2= 0.216,p= 0.0169) and HbR (R2= 0.206,p= 0.0198). A significant coefficient of determination was also found for intra-hemispheric test group for HbO (R2= 0.237,p= 0.0117) but not for HbR (R2= 0.111,p= 0.0956).Significance.The findings from HbO data suggest that both inter-hemispheric homologous and intra-hemispheric connectivity between primary language regions significantly strengthen with age in the first year of life. Mapping out the developmental trajectory of primary language areas of normal hearing infants as measured by functional connectivity could potentially allow us to better understand the altered connectivity and its effects on language delays in infants with hearing impairments.

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Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

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Organic radicals feature unpaired electrons, and these compounds may have applications in biomedical technology and as materials for solar energy conversion. However, unpaired electrons tend to pair up (to form chemical bonds), making radicals unstable and hampering their applications. Here we report an organic radical system that is stable even at 350 °C, surpassing the upper temperature limit (200 °C) observed for other organic radicals. The system reported herein features a sulfur-rich organic linker that facilitates the formation of the radical centers; on the solid-state level, the molecules are crystallized with Eu(III) ions to form a 3D framework featuring stacks of linker molecules. The stacking is, however, somewhat loose and allows the molecules to wiggle and transform into sulfur-stabilized radicals at higher temperatures. In addition, the resulting solid framework remains crystalline, and it is stable to water and air. Moreover, it is black and features strong broad absorption in the visible and near IR region, thereby enhancing both photothermal conversion and solar-driven water evaporation.

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High-resolution maps of embryonic development suggest that acquisition of cell identity is not limited to canonical germ layers but proceeds via alternative routes. Despite evidence that visceral organs are formed via embryonic and extra-embryonic trajectories, the production of organ-specific cell types in vitro focuses on the embryonic one. Here we resolve these differentiation routes using massively parallel single-cell RNA sequencing to generate datasets from FOXA2Venus reporter mouse embryos and embryonic stem cell differentiation towards endoderm. To relate cell types in these datasets, we develop a single-parameter computational approach and identify an intermediate en route from extra-embryonic identity to embryonic endoderm, which we localize spatially in embryos at embryonic day 7.5. While there is little evidence for this cell type in embryonic stem cell differentiation, by following the extra-embryonic trajectory starting with naïve extra-embryonic endoderm stem cells we can generate embryonic gut spheroids. Exploiting developmental plasticity therefore offers alternatives to pluripotent cells and opens alternative avenues for in vitro differentiation.

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Objective.Intracortical visual prostheses are being developed to restore sight in people who are blind. The resolution of artificial vision is dictated by the location, proximity and number of electrodes implanted in the brain. However, increasing electrode count and proximity is traded off against tissue damage. Hence, new stimulation methods are needed that can improve the resolution of artificial vision without increasing the number of electrodes. We investigated whether a technique known as current steering can improve the resolution of artificial vision provided by intracortical prostheses without increasing the number of physical electrodes in the brain.Approach.We explored how the locus of neuronal activation could be steered when low amplitude microstimulation was applied simultaneously to two intracortical electrodes. A 64-channel, four-shank electrode array was implanted into the visual cortex of rats (n= 7). The distribution of charge ranged from single-electrode stimulation (100%:0%) to an equal distribution between the two electrodes (50%:50%), thereby steering the current between the physical electrodes. The stimulating electrode separation varied between 300 and 500µm. The peak of the evoked activity was defined as the 'virtual electrode' location.Main results.Current steering systematically shifted the virtual electrode on average between the stimulating electrodes as the distribution of charge was moved from one stimulating electrode to another. This effect was unclear in single trials due to the limited sampling of neurons. A model that scales the cortical response to each physical electrode when stimulated in isolation predicts the evoked virtual electrode response. Virtual electrodes were found to elicit a neural response as effectively and predictably as physical electrodes within cortical tissue on average.Significance.Current steering could be used to increase the resolution of intracortical electrode arrays without altering the number of physical electrodes which will reduce neural tissue damage, power consumption and potential heat dispersion issues.

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Brain-Machine Interfaces (BMI) offer the potential to modulate dysfunctional neurological networks by electrically stimulating the cerebral cortex via chronically-implanted microelectrodes. Wireless transmitters worn by BMI recipients must operate within electromagnetic emission and tissue heating limits, such as those prescribed by the IEEE and International Commission on Non-Ionizing Radiation Protection (ICNIRP), to ensure that radiofrequency emissions of BMI systems are safe. Here, we describe an approach to generating pre-compliance safety data by simulating the Specific Absorption Rate (SAR) and tissue heating of a multi-layered human head model containing a system of wireless, modular BMIs powered and controlled by an externally worn telemetry unit. We explore a number of system configurations such that our approach can be utilized for similar BMI systems, and our results provide a benchmark for the electromagnetic emissions of similar telemetry units. Our results show that the volume-averaged SAR per 10g of tissue exposed to our telemetry field complies with ICNIRP and IEEE reference levels, and that the maximum temperature increase in tissues was within permissible limits. These results were unaffected by the number of implants in the system model, and therefore we conclude that the electromagnetic emissions our BMI in any configuration are safe.

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With the aim of producing ß cells for replacement therapies to treat diabetes, several protocols have been developed to differentiate human pluripotent stem cells to ß cells via pancreatic progenitors. While in vivo pancreatic progenitors expand throughout development, the in vitro protocols have been designed to make these cells progress as fast as possible to ß cells. Here, we report on a protocol enabling a long-term expansion of human pancreatic progenitors in a defined medium on fibronectin, in the absence of feeder layers. Moreover, through a screening of a polymer library we identify a polymer that can replace fibronectin. Our experiments, comparing expanded progenitors to directly differentiated progenitors, show that the expanded progenitors differentiate more efficiently into glucose-responsive ß cells and produce fewer glucagon-expressing cells. The ability to expand progenitors under defined conditions and cryopreserve them will provide flexibility in research and therapeutic production.

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The sequencing of modern and ancient genomes from around the world has revolutionized our understanding of human history and evolution. However, the problem of how best to characterize ancestral relationships from the totality of human genomic variation remains unsolved. Here, we address this challenge with nonparametric methods that enable us to infer a unified genealogy of modern and ancient humans. This compact representation of multiple datasets explores the challenges of missing and erroneous data and uses ancient samples to constrain and date relationships. We demonstrate the power of the method to recover relationships between individuals and populations as well as to identify descendants of ancient samples. Finally, we introduce a simple nonparametric estimator of the geographical location of ancestors that recapitulates key events in human history.

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