Miracle-dz/UniFAR-FTUs huggingface dataset:
Selection of stimulus parameters for enhancing slow wave sleep events with a Neural-field theory thalamocortical computational model

Slow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates to memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events’ co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0º, 45º, and 90º of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0º stimulation produces better results in the power and number of SO and SP than the rhythmic or aleatory stimulation. On the other hand, stimulating at 45º or 90º change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0º phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work. Author summary During the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus –shape, amplitude, duration, periodicity– would be optimal for increasing the events’ frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.
Co-linear Chaining with Overlaps and Gap Costs

Co-linear chaining has proven to be a powerful heuristic for finding near-optimal alignments of long DNA sequences (e.g., long reads or a genome assembly) to a reference. It is used as an intermediate step in several alignment tools that employ a seed-chain-extend strategy. Despite this popularity, efficient subquadratic-time algorithms for the general case where chains support anchor overlaps and gap costs are not currently known. We present algorithms to solve the co-linear chaining problem with anchor overlaps and gap costs in Õ(n) time, where n denotes the count of anchors. We also establish the first theoretical connection between co-linear chaining cost and edit distance. Specifically, we prove that for a fixed set of anchors under a carefully designed chaining cost function, the optimal ‘anchored’ edit distance equals the optimal co-linear chaining cost. Finally, we demonstrate experimentally that optimal co-linear chaining cost under the proposed cost function can be computed orders of magnitude faster than edit distance, and achieves correlation coefficient above 0.9 with edit distance for closely as well as distantly related sequences.
Rare earth element analysis in natural waters by multiple isotope dilution – sector field ICP-MS

The rare earth elements (REEs) are valuable tracers in the earth, ocean and environmental sciences. Ten out of fourteen stable REEs have two or more isotopes, making them suitable for quantification by isotope dilution. We present a plasma mass spectrometry based multiple isotope dilution method for high precision REE concentration analysis in aqueous media. Key aspects of the method are: (i) flexible spiking of ten REEs via two LREE and HREE mixed spike solutions. (ii) Offline pre-concentration and matrix removal, by ion chromatography for freshwater samples and by iron co-precipitation or ion chromatography with the Nobias™ resin for seawater samples. (iii) High sensitivity detection by sector field-inductively coupled plasma mass spectrometry (SF-ICP-MS). (vi) The use of a desolvation micro-nebulization introduction system to lower polyatomic Ba and LREE-oxide interferences on HREEs. The method is suitable for a range of freshwater to seawater type samples, and was validated against SLRS-4, SLRS-5, and CASS-5 reference materials and two GEOTRACES marine inter-comparison samples. Long-term external precision on all REEs was <2% RSD, except La and Ce. Minimum sample volumes are 1 ml for freshwater and 50 ml for seawater. The multispike SF-ICP-MS method should be of particular interest in exploring subtle variations in aqueous REE fractionation patterns and anomalies in large numbers of samples.
Individual variability in structural brain development from late childhood to young adulthood

A fundamental task in neuroscience is to characterize the brain’s developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.0–26.0 years in 269 participants (149 females) with three time points of data (807 scans), drawn from three longitudinal datasets collected in the Netherlands, Norway, and USA. We further investigated the relationship between overall brain size and developmental changes, as well as how females and males differed in change variability across development. There was considerable individual variability in the magnitude of changes observed for all included brain measures. However, distinct developmental patterns of change were observed for total brain and cortical gray matter, cortical thickness, and white matter surface area, with individuals demonstrating either stability or decreases in early adolescence, then almost universal decreases during mid-to-late adolescence, before returning to more variable patterns in early adulthood. White matter volume demonstrated a similar developmental pattern of variability, but with individuals shifting from increases to a majority stabilizing during mid-to-late adolescence. We observed sex differences in these patterns, and also an association between an individual’s brain size and their overall rate of change. The present study provides new insight as to the amount of individual variance in changes in structural morphometrics from late childhood to early adulthood in order to obtain a more nuanced picture of brain development. The observed individual- and sex-differences in brain changes also highlight the importance of further studying individual variation in developmental patterns in healthy, at-risk, and clinical populations.
The Use of Spectrofluorimetry for Monitoring the Bioaccumulation and the Biotransformation of Polycyclic Aromatic Hydrocarbons in Daphnia magna

A rapid and direct spectrofluorimetric method was tested in order to monitor the bioaccumulation of PAHs in Daphnia magna in a control media. After exposure to water containing benzo[ a ]pyrene or fluoranthene, daphnids were put in solvent, sonicated, and filtered. The fluorescence spectrum observed in the filtrate was recorded. Results were compared to HPLC measurements of the same pools of organisms. In fluoranthene experiments, the fluorescence peak of the daphnid extract spectrum was linearly related to the PAH content as measured with HPLC. In benzo[ a ]pyrene experiments, other fluorescent compounds progressively appeared in the sample. They were assumed to be metabolites. A linear regression involving fluorescence intensities at two different wavelengths was necessary for a satisfactory correlation with HPLC measurements. A water extraction was performed to isolate metabolites. None or very few fluoranthene metabolites were isolated in the aqueous phase, whereas increasing benzo[ a ]pyrene metabolites were observed while the exposure time increased.
Strong transgenerational effects but no genetic adaptation in zooplankton 24 years after an abrupt +10°C climate change

The climate is currently warming fast, threatening biodiversity all over the globe. Adaptation is often rapid when the environment changes quickly, but for climate warming very little evidence is available. Here, we investigate the pattern of adaptation to an extreme +10°C climate change in the wild, following the introduction of brine shrimp Artemia franciscana from San Francisco Bay, USA, to Vinh Chau saltern in Vietnam. We use a resurrection ecology approach, hatching diapause eggs from the ancestral population and the introduced population after 13 and 24 years (resp. ~54 and ~100 generations). In a series of coordinated experiments, we determined whether the introduced Artemia show increased tolerance to higher temperatures, and the extent to which genetic adaptation, developmental plasticity, transgenerational effects, and local microbiome differences contributed to this tolerance. We find that introduced brine shrimp do show increased phenotypic tolerance to warming. Yet strikingly, these changes do not have an additive genetic component, are not caused by mitochondrial genetic variation, and are not caused by epigenetic marks set by adult parents exposed to warming. Further, we do not find any developmental plasticity in response to warming, nor any protective effect of heat-tolerant local microbiota. We conclude that the evolution of shrimp’s extreme thermal tolerance is only due to transgenerational (great)grandparental effects, possibly epigenetic marks set by parents who were exposed to high temperatures as juveniles. This finding challenges standard models of genetic and plastic adaptive responses, and our conception of how species may cope with climate warming. Significance statement Adaptation is often rapid when environments change quickly, but for climate warming little evidence is available. Many studies report no genetic responses due to pre-existing plasticity, while others point towards epigenetics and microbiota effects. In this study, we take advantage of a natural experiment to study all of these effects. We use a set of coordinated experiments and a ‘resurrection ecology’ approach, reviving resting eggs of brine shrimp up to100 generations after their introduction from a temperate to a tropical saltern. We find that heat adaptation occurs, but heritability is fully “missing”. Plasticity and microbiota play no role either, indicating that only transgenerational (great)grandmaternal effects are involved. This finding prompts us to reconsider the relative importance of the different possible mechanisms by which phenotypic change can occur, especially in response to temperature variation.
Using host genetics to infer the global spread and evolutionary history of HCV subtype 3a

Studies have shown that HCV subtype 3a had likely been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV subtype 3a from the UK, North America, Australia and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV subtype 3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country and that they were more diverse than viruses from other host ancestries. We also inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America and the Australian continent. This initial spread happened during or soon after the end of the second world war. This was followed by an exponential growth in the effective population size of HCV subtype 3a worldwide and many independent transmissions between the UK, North America and Australian continent. Using both host and virus genomic information can be highly informative in studying the virus epidemic history especially in the context of chronic infections.
Vertical junction Si cells for concentrating photovoltaics

Vertical junction Si cell has shown a potential to operate at high concentrations, mainly the result of reduced series resistance losses due to its low‐current/high‐voltage design, but tests and analyses have so far only shown a modest efficiency of about 20%. We perform a comprehensive optimization study and show that the conversion efficiency of vertical multi‐junction (VMJ) cells can be significantly higher, close to 30% at concentrations of 1000 and higher. Reaching this efficiency requires junction dimensions that are significantly smaller than previous VMJ cells. This may require a different approach in the fabrication process, possibly by using a monolithic method rather than the wafer stacking approach. We also show that increased photoconductivity, which is usually negligible in conventional cells, produces a significant reduction in series resistance at high concentrations making it a significant contributor to the outstanding performance of the VMJ cell at high concentration. Copyright © 2011 John Wiley & Sons, Ltd.
Sorghum pan-genome explores the functional utility to accelerate the genetic gain

Sorghum (Sorghum bicolor L.) is one of the most important food crops in the arid and rainfed production ecologies. It is a part of resilient farming and is projected as a smart crop to overcome the food and nutritional challenges in the developing world. The development and characterisation of the sorghum pan-genome will provide insight into genome diversity and functionality, supporting sorghum improvement. We built a sorghum pan-genome using reference genomes as well as 354 genetically diverse sorghum accessions belonging to different races. We explored the structural and functional characteristics of the pan-genome and explain its utility in supporting genetic gain. The newly-developed pan-genome has a total of 35,719 genes, a core genome of 16,821 genes and an average of 32,795 genes in each cultivar. The variable genes are enriched with environment responsive genes and classify the sorghum accessions according to their race. We show that 53% of genes display presence-absence variation, and some of these variable genes are predicted to be functionally associated with drought traits. Using more than two million SNPs from the pan-genome, association analysis identified 398 SNPs significantly associated with important agronomic traits, of which, 92 were in genes. Drought gene expression analysis identified 1,788 genes that are functionally linked to different conditions, of which 79 were absent from the reference genome assembly. This study provides comprehensive genomic diversity resources in sorghum which can be used in genome assisted crop improvement.
Integrated analysis of the methylome and transcriptome of twin almonds (Prunus dulcis [Mill.] D.A.Webb) reveals genomic features associated with non-infectious bud failure

Almond (Prunus dulcis [Mill.] D.A.Webb) exhibits an age-related disorder called non-infectious bud-failure (BF) affecting vegetative bud development and nut yield. The underlying cause of BF remains unknown but is hypothesized to be associated with heritable epigenetic mechanisms. To address this disorder and its epigenetic components, we utilized a monozygotic twin study model profiling genome-wide DNA methylation and gene expression in two sets of twin almonds discordant for BF-exhibition. Analysis of DNA methylation patterns show that BF-exhibition and methylation, namely hypomethylation, are not independent phenomena. Transcriptomic data generated from the twin pairs also shows genome-wide differential gene expression associated with BF-exhibition. After identifying differentially methylated regions (DMRs) in each twin pair, a comparison revealed 170 shared DMRs between the two twin pairs. These DMRs and the associated genetic components may play a role in BF-exhibition. A subset of 52 shared DMRs are in close proximity to genes involved in meristem maintenance, cell cycle regulation, and response to heat stress. Annotation of specific genes included involvement in processes like cell wall development, calcium ion signaling, and DNA methylation. Results of this work support the hypothesis that BF-exhibition is associated with hypomethylation in almond, and identified DMRs and differentially expressed genes can serve as potential biomarkers to assess BF-potential in almond germplasm. Our results contribute to an understanding of the contribution of epigenetic disorders in agricultural performance and biological fitness of perennials. II. Significance This study examines epigenetic components underlying noninfectious bud failure, an aging-related disorder affecting almond. Results from this work contribute to our understanding of the implications of DNA methylation on agricultural production, namely perennial fruit and nut production, due to effects on growth, development, and reproduction. Describing the methylome of discordant, monozygotic twin almonds enables the study of genomic features underlying noninfectious bud failure in this economically important crop.
Neuronal Switching between Single- and Dual-Network Activity via Modulation of Intrinsic Membrane Properties

Oscillatory networks underlie rhythmic behaviors (e.g., walking, chewing) and complex behaviors (e.g., memory formation, decision-making). Flexibility of oscillatory networks includes neurons switching between single- and dual-network participation, even generating oscillations at two distinct frequencies. Modulation of synaptic strength can underlie this neuronal switching. Here we ask whether switching into dual-frequency oscillations can also result from modulation of intrinsic neuronal properties. The isolated stomatogastric nervous system of male Cancer borealis crabs contains two well-characterized rhythmic feeding-related networks (pyloric, ∼1 Hz; gastric mill, ∼0.1 Hz). The identified modulatory projection neuron MCN5 causes the pyloric-only lateral posterior gastric (LPG) neuron to switch to dual pyloric/gastric mill bursting. Bath applying the MCN5 neuropeptide transmitter Gly1-SIFamide only partly mimics the LPG switch to dual activity because of continued LP neuron inhibition of LPG. Here, we find that MCN5 uses a cotransmitter, glutamate, to inhibit LP, unlike Gly1-SIFamide excitation of LP. Thus, we modeled the MCN5-elicited LPG switching with Gly1-SIFamide application and LP photoinactivation. Using hyperpolarization of pyloric pacemaker neurons and gastric mill network neurons, we found that LPG pyloric-timed oscillations require rhythmic electrical synaptic input. However, LPG gastric mill-timed oscillations do not require any pyloric/gastric mill synaptic input and are voltage-dependent. Thus, we identify modulation of intrinsic properties as an additional mechanism for switching a neuron into dual-frequency activity. Instead of synaptic modulation switching a neuron into a second network as a passive follower, modulation of intrinsic properties could enable a switching neuron to become an active contributor to rhythm generation in the second network. SIGNIFICANCE STATEMENT Neuromodulation of oscillatory networks can enable network neurons to switch from single- to dual-network participation, even when two networks oscillate at distinct frequencies. We used small, well-characterized networks to determine whether modulation of synaptic strength, an identified mechanism for switching, is necessary for dual-network recruitment. We demonstrate that rhythmic electrical synaptic input is required for continued linkage with a “home” network, whereas modulation of intrinsic properties enables a neuron to generate oscillations at a second frequency. Neuromodulator-induced switches in neuronal participation between networks occur in motor, cognitive, and sensory networks. Our study highlights the importance of considering intrinsic properties as a pivotal target for enabling parallel participation of a neuron in two oscillatory networks.
Drug Conjugates of Antagonistic RSPO4 Mutant For Simultaneous Targeting of LGR4/5/6 for Cancer Treatment

LGR4-6 (Leucine-rich repeating containing, G-protein-coupled receptors 4, 5, and 6) are three related receptors with distinct roles in organ development and stem cell survival. All three receptors are upregulated in gastrointestinal cancers to different levels, and LGR5 has been shown to be enriched in cancer stem cells. Antibody-drug conjugates (ADCs) targeting LGR5 showed robust antitumor effect in vivo but could not eradicate tumors due to plasticity of LGR5-positive cancer cells. As LGR5-negative cells often express LGR4 or LGR6 or both, we reasoned that simultaneous targeting of all three LGRs may provide a more effective approach. R-spondins (RSPOs) bind to LGR4-6 with high affinity and potentiate Wnt signaling. We identified an RSPO4 mutant (Q65R) that retains potent LGR binding but no longer potentiates Wnt signaling. The RSPO4 mutant was fused to the N-terminus of human IgG1-Fc to create a peptibody which was then conjugated with cytotoxins monomethyl auristatin or duocarmycin by site-specific conjugation. The resulting peptibody drug conjugates (PDCs) showed potent cytotoxic effects on cancer cell lines expressing any LGR in vitro and suppressed tumor growth in vivo without inducing intestinal enlargement or other adverse effects. These results suggest that RSPO-derived PDCs may provide a novel approach to the treatment of cancers with high LGR expression.
The C. elegans DAF-19M module: a shift from general ciliogenesis to ciliary and behavioral specialization

In animals, cilia are important for the interaction with environments and the proper function of tissues and organs. Understanding the distinctive identities of each type of ciliated cell is essential for therapeutic solutions for ciliopathies, complex disorders with impairments of various organs caused by defective cilia development and function. Here, we report a regulatory module consisting of a cascade of transcription factors and their target genes that confer the cell type-specific ciliary identities on the IL2 ciliated neurons in C. elegans. We found that DAF-19M, isoform of the sole C. elegans RFX transcription factor DAF-19, through X-box promoter motif variants, heads a regulatory module in IL2 neurons, comprising the core target genes klp-6 (kinesin), osm-9 (TRP channel), and cwp-4 (novel); under the overall control of terminal selector proteins UNC-86 and CFI-1. Considering the conservation of this DAF-19M module in IL2 neurons for nictation, a dauer larva-specific behavior, and in male-specific neurons for mating behavior, we propose the existence of an evolutionarily adaptable, hard-wired genetic module for distinct behaviors that share the feature “recognizing the environment. ”