Miracle-dz/UniFAR-FTUs huggingface dataset:
Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model

Patients suffering from Autism Spectrum Disorders (ASD) experience disturbed nociception in form of either hyposensitivity to pain or hypersensitivity and allodynia. We have determined that Shank2-KO mice, which recapitulate the genetic and behavioural disturbances of ASD, display increased sensitivity to formalin pain and thermal, but not mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in WT mice but not in Shank2-KO mice. As consequence, nociception projection neurons in lamina I are activated in larger numbers in Shank2-KO mice. Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. Thus, we provide evidence that dysfunction of spinal cord pain processing circuits may underlie the nociceptive phenotypes in ASD patients and mouse models.
BrphyB is critical for rapid recovery to darkness in mature Brassica rapa leaves

Crop biomass and yield are tightly linked to how the light signaling network translates information about the environment into allocation of resources, including photosynthates. Once activated, the phytochrome (phy) class of photoreceptors signal and re-deploy carbon resources to alter growth, plant architecture, and reproductive timing. Brassica rapa has been used as a crop model to test for conservation of the phytochrome–carbon network. B. rapa phyB mutants have significantly decreased or absent CO2-stimulated growth responses in seedlings, and adult plants have reduced chlorophyll levels, photosynthetic rate, stomatal index, and seed yield. Here, we examine the transcriptomic response of adult wild-type and BrphyB leaves to darkening and recovery in light. Three days of darkness was sufficient to elicit a response in wild type leaves suggesting a shift from carbon fixation and nutrient acquisition to active redistribution of cellular resources. Upon a return to light, wild-type leaves appeared to transcriptionally return to a pre-darkness state restoring a focus on nutrient acquisition. Overall, BrphyB mutant plants have a similar response with key differences in genes involved in photosynthesis and light response which deviate from the wild type transcriptional dynamics. Genes targeted to the chloroplast are especially affected. Adult BrphyB mutant plants had fewer, larger chloroplasts, further linking phytochromes, chloroplast development, photosynthetic deficiencies and optimal resource allocation.
Factors Affecting Fine Dexterity: A Structural Equation Modeling Approach

Fine dexterity is one of the most fundamental parts of human factors and ergonomics. The aim of this study was to investigate factors affecting fine dexterity. Gender, age, hand length, grip strength, hand skin temperature, room temperature, and room humidity were analyzed simultaneously to predict fine dexterity by utilizing Structural Equation Modeling (SEM). The results showed that hand skin temperature was the most predicting factor for fine dexterity followed by gender, age, and hand length. Female was found to have better fine dexterity and participants with smaller hand size were also found to have better fine dexterity. In addition, grip strength, room temperature, and room humidity were found not significant predictors for fine dexterity. Interestingly, participants with older age were found had better fine dexterity. The causal relationship derived from SEM could be very significant theoretical foundations which would be beneficial for human factors engineer, hand therapist, and even medical doctors.
Heteroloaous expression of yeast prepro‐a‐factor in rat GH3 cells

Yeast pheromone a‐factor is a 13‐amino acid peptide hormone that is synthesized as a part of a larger precursor, prepro‐a‐factor, consisting of a signal peptide and a proregion of 64 amino acids. The carboxy‐terminal half of the precursor contains four tandem copies of mature a‐factor. To investigate the molecular basis of intracellular sorting, proteolytic processing, and storage of the peptide hormone, yeast prepro‐a‐factor precursors were heterologously expressed in rat pituitary GH3 cells. When cells harboring the precursor were metabolically labeled, a species of approximately 27 kD appeared inside the cells. Digestion with peptide: N‐glycosidase F (PNG‐F) shifted the molecular mass to a 19 kD, suggesting that the 27 kD protein was the glycosylated form as in yeast cells. The nascent polypeptide is efficiently targeted to the ER in the GH3 cells, where it undergoes cleavage of its signal peptide and core glycosylation to generate glycosylated pro‐a‐factor. To look at the post ER intracellular processing, the pulse‐labelled cells were chased up to 2 hrs. The nascent propeptides disappeared from the cells at a half life of 30min and only 10–25% of the newly synthesized, unprocessed precursors were stored intracellularly after the 2 h chase. However, about 20% of the pulse‐labeled pro‐a‐factor precursors were secreted into the medium in the pro‐hormone form. With increasing chase time, the intracellular level of propeptide decreased, but the amount of secreted propeptide could not account for the disappearance of intracellular propeptide completely. This disappearance was insensitive to lysosomotropic agents, but was inhibited at 16°C or 20°C, suggesting that the turnover of the precursors was not occurring in the secretory pathway to trans Golgi network (TGN) or dependent on acidic compartments. From these results, it is concluded that a part of these heterologous precursors may be processed at its paired dibasic sites by prohormone processing enzymes located in TGN/secretory vesicles producing small peptides, and that the residual unprocessed precursors may be secreted into the medium rather than degraded intracellularly.
Haplotype tagging reveals parallel formation of hybrid races in two butterfly species

Significance A defining goal in genetics is linking variation in DNA sequence to trait evolution between populations and, ultimately, species. Genome sequencing efficiently captures such variation but typically in millions of tiny fragments that omit haplotype or linkage information. We present “haplotagging,” a simple, rapid linked-read sequencing technique that allows high-throughput sequencing without sacrificing haplotype information. We validated this affordable approach for whole-genome haplotyping in large populations. We used haplotagging to investigate the rise of a novel hybrid morph in parallel hybrid zones of two comimetic Heliconius butterfly species in Ecuador. Our results reveal that strikingly parallel divergences in their genomes produced coordinated shifts in haplotype frequencies across the hybrid zone, giving rise to comimetic hybrid morphs in each species. Genetic variation segregates as linked sets of variants or haplotypes. Haplotypes and linkage are central to genetics and underpin virtually all genetic and selection analysis. Yet, genomic data often omit haplotype information due to constraints in sequencing technologies. Here, we present “haplotagging,” a simple, low-cost linked-read sequencing technique that allows sequencing of hundreds of individuals while retaining linkage information. We apply haplotagging to construct megabase-size haplotypes for over 600 individual butterflies (Heliconius erato and H. melpomene), which form overlapping hybrid zones across an elevational gradient in Ecuador. Haplotagging identifies loci controlling distinctive high- and lowland wing color patterns. Divergent haplotypes are found at the same major loci in both species, while chromosome rearrangements show no parallelism. Remarkably, in both species, the geographic clines for the major wing-pattern loci are displaced by 18 km, leading to the rise of a novel hybrid morph in the center of the hybrid zone. We propose that shared warning signaling (Müllerian mimicry) may couple the cline shifts seen in both species and facilitate the parallel coemergence of a novel hybrid morph in both comimetic species. Our results show the power of efficient haplotyping methods when combined with large-scale sequencing data from natural populations.
Kipa-INIA, new high yield spring bread wheat variety for Chile

Kipa-INIA is a spring wheat variety (Triticum aestivum L.) originated from a cross carried out in the Wheat Plant Breeding Project of the Instituto de Investigaciones Agropecuarias (INIA), in the Centro Regional de Investigacion Quilamapu (36°31’ S; 71°54’ W) in 1993. It has an upright growth habit in the seedling stage. The adult plant is low to medium height and varies between 90 and 95 cm. The spike is white with long awns along its full length. The grain is ovate, white, and vitreous. It was sown in mid-August in the Santa Rosa Experimental Field, Chillan, head emergence occurred 90 to 95 d after sowing, i.e. is 4 to 6 d before ‘Domo-INIA’. On the mean, ‘Kipa-INIA’ sown under irrigation conditions reached a yield of 11.7% higher than the control var. Domo-INIA, and 18.1% higher in dryland soils.
Dependence of the stimulus-driven microsaccade rate signature on visual stimulus polarity

Microsaccades have a steady rate of occurrence during maintained gaze fixation, which gets transiently modulated by abrupt sensory stimuli. Such modulation, characterized by a rapid reduction in microsaccade frequency followed by a stronger rebound phase of high microsaccade rate, is often described as the microsaccadic rate signature, owing to its stereotyped nature. Here we investigated the impacts of stimulus polarity (luminance increments or luminance decrements relative to background luminance) and size on the microsaccadic rate signature. We presented brief visual flashes consisting of large or small white or black stimuli over an otherwise gray image background. Both large and small stimuli caused robust early microsaccadic inhibition, but only small ones caused a subsequent increase in microsaccade frequency above baseline microsaccade rate. Critically, small black stimuli were always associated with stronger modulations in microsaccade rate after stimulus onset than small white stimuli, particularly in the post-inhibition rebound phase of the microsaccadic rate signature. Because small stimuli were also associated with expected direction oscillations to and away from their locations of appearance, these stronger rate modulations in the rebound phase meant higher likelihoods of microsaccades opposite the black flash locations relative to the white flash locations. Our results demonstrate that the microsaccadic rate signature is sensitive to stimulus polarity, and they point to dissociable neural mechanisms underlying early microsaccadic inhibition after stimulus onset and later microsaccadic rate rebound at longer times thereafter. These results also demonstrate early access of oculomotor control circuitry to sensory representations, particularly for momentarily inhibiting saccade generation. New and noteworthy Microsaccades are small saccades that occur during gaze fixation. Microsaccade rate is transiently reduced after sudden stimulus onsets, and then strongly rebounds before returning to baseline. We explored the influence of stimulus polarity (black versus white) on this “rate signature”. We found that small black stimuli cause stronger microsaccadic modulations than white ones, but primarily in the rebound phase. This suggests dissociated neural mechanisms for microsaccadic inhibition and subsequent rebound in the microsaccadic rate signature.
A Genetic Algorithm for Optimizing Parameters for Ant Colony Optimization Solving Capacitated Vehicle Routing Problems

This paper discusses the combined application of two metaheuristic algorithms, a Genetic Algorithm (GA) and Ant Colony Optimization (ACO). The GA optimizes ACO parameters to find the optimal parameter settings automatically to solve a given Capacitated Vehicle Routing Problem (CVRP). The research design and the implemented prototype for this experiment are explained in detail and test results are presented. Optimal ACO parameters for the different CVRP are computed and analyzed and the reasonability of the proposed GA-ACO algorithm to solve CVRP is discussed.
Beyond the connectome: A map of a brain architecture derived from whole-brain volumetric reconstructions

Animal nervous system organization is crucial for all body functions and its disruption can manifest in severe cognitive and behavioral impairment. This organization relies on features across scales, from nano-level localization of synapses, through multiplicities of neuronal morphologies and their contribution to circuit organization, to the high level stereotyped connections between different regions of the brain. The sheer complexity of this organ means that to date, we have yet to reconstruct and model the structure of a complete nervous system that is integrated across all these scales. Here, we present a complete structure-function model of the nematode C. elegans main neuropil, the nerve ring, which we derive by integrating the volumetric reconstruction from two animals with corresponding synaptic and gap junctional connectomes. Whereas previously the nerve ring was considered a densely packed tract of axons, we uncover internal organization into 5 functional bundles and show how they spatially constrain and support the synaptic connectome. We find that the C. elegans connectome is not invariant, but that a precisely wired core circuit is embedded in a background of variable connectivity, and propose a corresponding reference connectome for the core circuit. Using this reference, we show that the architecture of the C. elegans brain can be viewed as a modular Residual Network that supports sensory computation and integration, sensory-motor convergence, and brain-wide coordination. Thesendings point to scalable and robust features of brain organization that are likely universal across phyla.
KARYOTYPES OF FIVE PLANT SPECIES WITH DISJUNCT DISTRIBUTIONS IN VIRGINIA AND THE CAROLINAS

A B S T R A C T Five species (Actaea pachypoda, Aralia nudicaulis, Cornus alternifolia, Panax quinquefolius, and Symplocarpus foetidus) display a disjunct distribution between the Mountains and Piedmont in North Carolina, South Carolina, and Virginia. The Piedmont populations are small and have apparently been isolated from the Mountain populations for several thousand years. Karyotype differences among populations were found only in A. pachypoda, and even in this species the differences were slight. The absence of population differences in four species, and the moderate differentiation found in A. pachypoda, indicate considerable cytological stability in these species. SEVERAL SMALL ISOLATED populations of plants not usually found east of the Appalachian Mountains in the southeastern United States occur in the Piedmont and Coastal Plain of Virginia, North Carolina, and South Carolina. Because of the size and isolation of these populations, they may now be, or are, in the process of becoming genetically differentiated from the Mountain populations. Plants of a given species are morphologically
Development of new cowpea (Vigna unguiculata) mutant genotypes, analysis of their agromorphological variation, genetic diversity and Population structure

Cowpea is one of the most important legume grain in the SubSaharian region of Africa used for human consumption and animal feeding but its production is hampered by biotic and abiotic constraints raising the need to broaden its genetic basis. For this purpose, the seeds of two cowpea varieties Melakh and Yacine were respectively irradiated with 300 and 340 Gy. The developed mutant populations were agromorphologically characterized from M5 to M7 while the genetic diversity of the last were evaluated using 13 ISSR markers. Based on agromorphological characterization, variation of flower color, pod length, seed coat color and seed weight with respectively 78.01, 68.29, 94.48 and 57.58% heritability were recorded in the mutant lines. PCA analyses allowed to identify the elite mutants based on their agromorphological traits while Pearson’s correlation results revealed a positive correlation between yield component traits. Three subpopulations were identified through STRUCTURE analyses but assignment of the individuals in each group was improved using DAPC. Analysis of Molecular Variance revealed that the majority (85%) of the variance rather existed within group than among (15%) group. Finally, our study allowed to select new promising mutant genotypes which could be tested for multi local trials to evaluate their agronomic performance.
Microstructural integrity of the major nuclei of the thalamus in Parkinson’s disease

Background Previous research has shown an association between thalamus and cognition in Parkinson’s disease (PD). Objectives To investigate the microstructural integrity of the nuclei of the thalamus and relationship with cognition. Methods Level II Movement Disorder Society Task Force Criteria characterised patients with Parkinson’s disease as cognitively normal (PDN, n=51); with mild cognitive impairment (PD-MCI, n=16) or with dementia (PDD, n=15). Twenty-three healthy control subjects were included for comparison. A k-means clustering approach segmented the thalamus into regions representing nine major nuclei. Volume, fractional anisotropy and mean diffusivity of nuclei were compared between cognitive groups and the relationship with cognitive domain z-scores investigated using hierarchical Bayesian regression models. Results There was an overall progressive increase in mean diffusivity as cognition deteriorated (PDN: 1.4 µm2/s (95% uncertainty interval [0.2, 2.7]), PDMCI: 2.4 µm2/s [0.8,4.0], PDD: 4.5 µm2/s [2.8, 6.3]). The largest increase was in the lateral dorsal nucleus (PDN: 0.3 µm2/s [-6.7, 7.2], PDMCI: 5.4 µm2/s [-4.7, 16.1], PDD: 14.8 µm2/s [5.0, 25.0]). Fractional anisotropy showed minimal change between cognitive groups (PDN: 0.001 [-0.005, 0,007], PDMCI: −0.005 [-0.013, 0.003], PDD: −0.005 [-0.014, 0.003]). Increase in mean diffusivity of the thalamus is associated with a global decline in cognition, the magnitude of the effect was greatest in lateral dorsal nucleus. Fractional anisotropy only showed evidence of a relationship with cognitive domain scores in the lateral dorsal nucleus. Conclusions The relationship between lateral dorsal nucleus integrity and cognitive changes is likely due to its primary connectivity with frontal and temporal regions.
Moyamoya Disease-Associated RNF213 Alleles Encode Dominant Negative Alleles That Globally Impair Ubiquitylation

Single nucleotide polymorphisms (SNPs) in RNF213, which encodes a 591kDa protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, Moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of RNF213, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily be explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3-ligase activity have remained unclear. We found that the RING domain of RNF213 uses the E2-conjugating enzyme UBE2D2 to catalyze predominantly K6-dependent poly-ubiquitination events comprising a mixture of typical and atypical ubiquitin linkages. MMD-associated SNPs encode proteins with decreased E3-ligase activity and the most frequent MMD allele, RNF213R4810K, is a dominant negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated RNF213 SNPs do not affect ATPase activity. We propose that decreased RNF213 E3-ligase activity is central to MMD pathogenesis.
Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is critical for cell volume control, but its broader physiological functions remain under investigation. Recent studies in the field indicate that Lrrc8a disruption in brain astrocytes reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against cerebral ischemia. In the present work, we generated the brain-wide conditional LRRC8A knock-out mice (LRRC8A bKO) using NestinCre-driven Lrrc8aflox/flox excision in neurons, astrocytes, and oligodendroglia. LRRC8A bKO animals were born close to the expected Mendelian ratio and developed without overt histological abnormalities, but, surprisingly, all died between 5 and 9 weeks of age with a seizure phenotype, which was confirmed by video and EEG recordings. Brain slice electrophysiology detected changes in the excitability of pyramidal cells and modified GABAergic inputs in the hippocampal CA1 region of LRRC8A bKO. LRRC8A-null hippocampi showed increased immunoreactivity of the astrocytic marker GFAP, indicating reactive astrogliosis. We also found decreased whole-brain protein levels of the GABA transporter GAT-1, the glutamate transporter GLT-1, and the astrocytic enzyme glutamine synthetase. Complementary HPLC assays identified reduction in the tissue levels of the glutamate and GABA precursor glutamine. Together, these findings suggest that VRAC provides vital control of brain excitability in mouse adolescence. VRAC deletion leads to a lethal phenotype involving progressive astrogliosis and dysregulation of astrocytic uptake and supply of amino acid neurotransmitters and their precursors.
Assessment of NR4A Ligands that Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1

Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a potential drug target for neurological disorders including Alzheimer’s and Parkinson’s diseases. Previous studies identified small molecule modulators of NR4A nuclear receptors including Nurr1 and Nur77/NR4A1; it remains unclear whether these ligands affect Nurr1 through direct binding or indirect non-binding mechanisms. We assessed a panel of twelve ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and binding to the Nurr1 ligand-binding domain (LBD). Most of the NR4A ligands show Nurr1-independent effects on transcription in a cell type-specific manner, suggesting they may function through binding to effector proteins whose downstream activities influence Nurr1 function. Protein NMR spectroscopy structural footprinting data show that 4-amino-7-chloroquinoline derivatives (amodiaquine and chloroquine) and cytosporone B directly bind the Nurr1 LBD. In contrast, other NR4A ligands including commercially available compounds such as C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, and TMPA do not bind the Nurr1 LBD. Interestingly, previous crystal structures indicate that cytosporone B analogs bind to surface pockets in the Nur77 LBD, but protein NMR data indicate cytosporone B likely binds to the Nurr1 orthosteric pocket. These findings should influence medicinal chemistry efforts that desire to optimize Nurr1-binding ligands as opposed to ligands that function through binding to Nurr1 effector proteins.