Miracle-dz/UniFAR-FTUs huggingface dataset:
Synthesis of higher order feature codes through stimulus-specific supra-linear summation

How cortical circuits build representations of complex objects is poorly understood. The massive dimensional expansion from the thalamus to the primary sensory cortex may enable sparse, comprehensive representations of higher order features to facilitate object identification. To generate such a code, cortical neurons must integrate broadly over space, yet simultaneously obtain sharp tuning to specific stimulus features. The logic of cortical integration that may synthesize such a sparse, high dimensional code for complex features is not known. To address this question, we probed the integration and population coding of higher order stimuli in the somatosensory and visual cortices of awake mice using two-photon calcium imaging across cortical layers. We found that somatosensory and visual cortical neurons sum highly specific combinations of sensory inputs supra-linearly, but integrate other inputs sub-linearly, leading to selective responses to higher order features. This integrative process generates a sparse, but comprehensive code for complex stimuli from the earliest stages of cortical processing. These results from multiple sensory modalities imply that input-specific supra-linear summation may represent a widespread cortical mechanism for the synthesis of higher order feature codes. This new mechanism may explain how the brain exploits the thalamocortical expansion of dimensionality to encode arbitrary complex features of sensory stimuli.
Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory programs in cancers

Background Most cancer alterations occur in the noncoding portion of the human genome, which contains important regulatory regions acting as genetic switches to ensure gene expression occurs at correct times and intensities in correct tissues. However, large scale discovery of noncoding events altering the gene expression regulatory program has been limited to a few examples with high recurrence or high functional impact. Results We focused on transcription factor binding sites (TFBSs) that show similar mutation loads than what is observed in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluated the combined effects of transcriptional and post-transcriptional alteration on the dysregulation of the regulatory programs in cancer. The analysis of seven cancer cohorts culminated with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that were associated with a cascading trans-effect deregulation on the cells’ regulatory program. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predicted 17 miRNAs as pan-cancer-associated through deregulation of their target gene networks. Overall, our predictions were enriched for protein-coding and miRNA genes previously annotated as cancer drivers. Functional enrichment analyses highlighted that cis-regulatory mutations are associated with the dysregulation of key pathways associated with carcinogenesis Conclusions These pan-cancer results suggest that our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. It highlights how the gene regulatory program is disrupted in cancer cells by combining transcriptional and post-transcriptional regulation of gene expression.
DeepGANnel: Synthesis of fully annotated single molecule patch-clamp data using generative adversarial networks

Understanding and accurately quantifying ion channel molecule gating in real time is vital for knowledge of cell membrane behaviour, drug discovery and toxicity screening. Doing this with single-molecule resolution first requires the detection of individual protein pore opening and closing transitions and construction of a so-called idealised record which indicates sample-point by samplepoint whether a given molecule is open or closed. Creating this can be difficult, since patch-clamp electrophysiology data can be noisy or contain multiple ion channel molecules. We have recently developed a deep learning model to achieve this called Deep-Channel, but further development is limited by the massive datasets need to train and validate models. In the past, this problem has been tackled by simulation of single molecule activity from Markov models with the addition of pseudo-random noise. In the present report we develop a new method to synthesise raw data, based on generative adversarial networks (GANs). The limitation to direct application of a GAN with this method has been that whilst there are methods to generate classified output image by image, there has been no method to generate an entire timeseries with parallel idealisation, sample-point by sample-point. In this paper, we over-come this problem with DeepGANnel, a model that splits training data raw and parallel idealised data into different rows of image windows and passes these data through a progressive-GAN. This new methodology allows generation of realistic, idealisation synchronised single molecule patch-clamp data, without the biases inherent in pseudorandom simulation methods. This method will be useful for development of single molecule analysis methods and may in the future prove useful for generation of biological models including single molecule resolution stochastic data. The model is easily extendable to other timeseries data requiring parallel labelling, such as labelled ECG.
COMPARATIVE PHENOLOGICAL STUDIES OF TREELET AND SHRUB SPECIES IN TROPICAL WET AND DRY FORESTS IN THE LOWLANDS OF COSTA RICA

SUMMARY (1) During 1970-73, marked individuals of 154 treelet and shrub species at a Wet forest site and 95 species at a Dry forest site in Costa Rica were observed regularly at 4- to 6-week intervals for changes in leafing, flowering and fruiting. (2) All the shrubs in the Wet forest were evergreen. New leaves were produced continually throughout the year by half the species, although this behaviour was more pronounced in species of secondary forest (87%0). For the community as a whole, leaf production was equable throughout the year. (3) About half of the treelets and shrubs in the Dry forest were deciduous. Hill forest treelets and shrubs produced most leaves at the beginning of the wet season, Riparian forest treelets and shrubs had a peak in leaf production near the end of the wet season, and leafing of species of secondary forest was continuous throughout the wet season. Most treelets and shrubs were bare or dormant during the dry season. Leaf loss was greatest during February. (4) There were no consistent peaks of flowering for treelet and shrub species in the Wet forest, but flowering levels tended to be greatest in the first half of each year. (4) Continuous flowering was rare among Wet forest treelets and shrubs, being characteristic of only a few species of secondary forest. Most Wet forest treelets and shrubs (64%) had several flowering episodes each year, with the episodes separated by 3-5-month intervals. Species with only a single brief synchronous flowering period were rare. (6) By contrast, flowering amongst Dry forest treelets and shrubs showed a pronounced seasonal pattern. The Hill forest treelet and shrub community had a sharp peak of flowering at the beginning of the wet season, while, in contrast, the Riparian forest treelet and shrub community had its major flowering at the end of the wet season. Most Dry forest species flowered synchronously once or twice each year. (7) There was a weak tendency for maximum fruiting of Wet forest shrubs in the second half of each year. A short period of fruit maturation (4 months) was shown by most Wet forest treelets and shrubs, although one species had a fruit maturation time of 27 months. Ten species of Wet forest treelets and shrubs flowered at least once during the study, but failed to produce fruit.
Identification of regulatory microRNAs for hypoxia induced coagulation mechanism by In-silico analysis

Background Hypoxia (oxygen deprivation) is known to induce a prothrombotic state by activating the process of coagulation. Hypoxia inducible factor (HIF), is a major transcription factor involved in cellular response to low oxygen tension. MicroRNAs (miRNAs) are non-coding regulatory sequences capable of post-translational modification of multiple genes. Present study aimed to identify common regulatory miRNAs of HIF gene family and coagulation pathway by In-silico approach in order to understand the molecular mechanism underlying the process of hypoxia induced coagulation. Methods HIF family and Coagulation pathway genes along with their receptors and mediators were enlisted after comprehensive literature review. Thorough search of three highly cited database was done to identify the miRNAs targeting these genes. The extracted miRNA list was then prioritized on the basis of number and functional relevance of genes targeted. The target genes of all prioritized miRNAs were listed and subjected to followed by gene ontology (GO) study and pathway analysis. Result Present In-silico analysis identified five candidate miRNAs, viz., hsa-mir-4433a-3p, hsa-mir-4667-5p, hsa-mir-6735-5p, hsa-mir-6777-3p and hsa-mir-6815-3p that co-regulate genes of HIF family and coagulation pathway. GO and pathway analysis revealed that genes regulated by these five microRNAs, predominantly modulate genes facilitating coagulation and hypoxic response. Conclusion We identified five key microRNAs involved in body’s response to hypoxia and potentially involved in the blood coagulation cascade as well. These five candidate miRNAs may serve as putative epigenetic biomarkers and therapeutic targets to modulate the process of hypoxia induced coagulation.
bioPROTACs establish RAS as a degradable target and provide novel RAS biology insights

Mutations to RAS proteins (H-, N-, and K-RAS) are amongst the most common oncogenic drivers and tumors harboring these lesions are some of the most difficult to treat. Although the recently discovered covalent small molecules against the KRASG12C mutant have shown promising efficacy against lung cancers, traditional barriers remain for drugging the more prevalent KRASG12D and KRASG12V mutants. Targeted degradation has emerged as an attractive alternative approach but for KRAS, identification of the required high-affinity ligands continues to be a challenge. Another significant hurdle is the discovery of a hybrid molecule that appends an E3 ligase-recruiting moiety in a manner that satisfies the precise geometries required for productive polyubiquitin transfer while maintaining favorable drug-like properties. As a tool to gain insights into the advantages and feasibility of KRAS targeted-degradation, we applied the bioPROTAC approach. This workflow centers on the intracellular expression of a chimeric protein consisting of a high-affinity target-binding domain fused to an engineered E3 ligase adapter. We generated a series of anti-RAS bioPROTACs that span different RAS isoform/nucleotide-state specificities and leverage different E3 ligases. Overall, our results provide definitive evidence for the degradability of RAS proteins. We further elucidate the functional consequences of RAS degradation, the susceptibility and degradation kinetics of various mutant KRAS, and the prevalence of different nucleotide-states in WT and mutant KRAS. Finally, if delivery challenges can be addressed, anti-RAS bioPROTACs will be exciting candidates for clinical development.
Comparison of Different Protocols for Control of the Red Imported Fire Ant, Solenopsis invicta Buren (Hymenoptera: Formicidae), in Orange County, California, Including a List of Co-occurring Ants

Abstract. The Orange County Vector Control District treats infestations of red imported fire ants, Solenopsis invicta Buren, with two granular baits, Amdro Pro and Distance, at residences with the ant. Some treatments are subcontracted to pestmanagement professionals who received red imported fire ant certification by the Orange County Vector Control District. During this study, we compared four treatment protocols and assessed their efficacy at suppressing red imported fire ants. At the first post-treatment survey at 3 months, homes in three of the protocols received a single treatment of Amdro Pro. Homes in two of the protocols subsequently received either one follow-up treatment with Distance at 3 months or two follow-up treatments with Distance at 3 and 6 months, respectively. Homes in the fourth protocol received a single treatment of a 50:50 mixture of Amdro Pro and Distance. Most reinfestation by red imported fire ants occurred within the first 3 months after the initial treatment, with failure ranging from 29–40%. Although the failure rate was slightly higher for the treatment with the mixture compared to Amdro Pro alone (40 versus 33%, respectively), failure rates did not differ significantly between these treatments. Thereafter and until 9 months later, treatment failures were <10% among residences without red imported fire ants at 3 months. The differences among the protocols were not significant for any of the time periods. At 9 months, there was a small increase in failures compared to 6 months, indicating more red imported fire ants had moved in from surrounding areas or the original colonies were starting to recover. Additional treatments would be necessary to maintain a low level of infestation. We also recorded the identification and frequency of other ant species seen at homes inspected for red imported fire ants.
Habitat Selection and Site Fidelity of Cope's Gray Treefrog (Hyla chrysoscelis) at the Aquatic-Terrestrial Ecotone

Abstract Wetlands are essential breeding sites for many amphibians. The importance of terrestrial habitat for many aquatic-breeding amphibian species is well known, although often understudied and understated. This study examined the recapture rates, habitat use, and site fidelity of Cope's Gray Treefrogs (Hyla chrysoscelis) within and surrounding a wetland for 15 months. Using visible implant elastomer and visible implant alpha tags, we tracked individuals as they used a grid of 110 PVC pipes as refugia. PVC pipe refugia allow treefrogs to be sampled when not actively calling or breeding. We captured 82 individual frogs a total of 141 times (59 recaptures). Treefrogs occupied pipes every month except during winter (December, January, and February). Recapture rates decreased during the breeding season (May, June, and July). Preferred pipes were in terrestrial habitat or close to trees instead of in aquatic habitat devoid of trees. Treefrogs displayed high site fidelity; only three frogs were recaptured in pipes different from those in which they were originally captured. Our results suggest that H. chrysoscelis select terrestrial habitat adjacent to wetlands and have high site fidelity, which could have important implications for the conservation of treefrogs and other wetland-breeding amphibians.
Evaluating the appropriate oral lipid tolerance test model for investigating plasma triglyceride elevation in mice

The oral lipid tolerance test (OLTT) has been known to assess intestinal fat metabolism and whole-body lipid metabolism, but rodent models for OLTT are not yet established. Differences in OLTT methodology preclude the generation of definitive results, which may cause some confusion about the anti-hypertriglyceridemia effects of the test materials. To standardize and generate more appropriate methodology for the OLTT, we examined the effects of mice strain, dietary lipid sources, fasting period, and gender on lipid-induced hypertriglyceridemia in mice. First, lipid-induced hypertriglyceridemia was more strongly observed in male ddY mice than in C57BL/6N or ICR mice. Second, the administration of olive and soybean oils remarkably repressed lipid-induced hypertriglyceridemia in male ddY mice. Third, fasting period before the OLTT largely affected the plasma triglyceride elevation. Fasting for 12 h, but less than 48 h, provoked lipid-induced hypertriglyceridemia in male ddY mice. Fourth, we explored the suppressive effects of epigallocatechin gallate (EGCG), a green tea polyphenol, on lipid-induced hypertriglyceridemia. The administration of 100 mg/kg of EGCG suppressed lipid-induced hypertriglyceridemia and intestinal lipase activity in male ddY mice after 12 h fasting. Fifth, EGCG-induced suppressive effects were observed after lipid-induced hypertriglyceridemia was triggered in male mice. Lastly, lipid-induced hypertriglyceridemia could be more effectively induced in mice fed a high-fat diet for 1 week before the OLTT. These findings indicate that male ddY mice after 12 h fasting displayed marked lipid-induced hypertriglyceridemia in response to soybean oil and, hence, may be a more appropriate OLTT model.
Succinate Accumulation Links Mitochondrial MnSOD Depletion to Aberrant Nuclear DNA Methylation and Altered Cell Fate

Previous studies showed that human cell line HEK293 lacking mitochondrial superoxide dismutase (MnSOD) exhibited decreased succinate dehydrogenase (SDH) activity, and mice lacking MnSOD displayed significant reductions in SDH and aconitase activities. Since MnSOD has significant effects on SDH activity, and succinate is a key regulator of TET enzymes needed for proper differentiation, we hypothesized that SOD2 loss would lead to succinate accumulation, inhibition of TET activity, and impaired erythroid precursor differentiation. To test this hypothesis, we genetically disrupted the SOD2 gene using the CRISPR/Cas9 genetic strategy in a human erythroleukemia cell line (HEL 92.1.7) capable of induced differentiation toward an erythroid phenotype. Cells obtained in this manner displayed significant inhibition of SDH activity and ~10-fold increases in cellular succinate levels compared to their parent cell controls. Furthermore, SOD2−/− cells exhibited significantly reduced TET enzyme activity concomitant with decreases in genomic 5-hmC and corresponding increases in 5-mC. Finally, when stimulated with δ-aminolevulonic acid (δ-ALA), SOD2−/− HEL cells failed to properly differentiate toward an erythroid phenotype, likely due to failure to complete the necessary global DNA demethylation program required for erythroid maturation. Together, our findings support the model of an SDH/succinate/TET axis and a role for succinate as a retrograde signaling molecule of mitochondrial origin that significantly perturbs nuclear epigenetic reprogramming and introduce MnSOD as a governor of the SDH/succinate/TET axis.
13 C-NMR Studies on Lactate Metabolism in a Porcine Gut Microbial Ecosystem

Lactate is seldom detected as a major acid in the hindgut because it is a typical intermediate metabolite and is converted to a short-chain fatty acid (SCFA) by lactate-utilizing bacteria. Lactate becomes a key metabolite in the large intestine when lactogenic and bifidogenic dietary supplements are fed to animals. If lactate-utilizers are eliminated, lactate will be accumulated. Accumulation of lactate in hindgut might be responsible for diarrhoea caused by short-bowel syndrome, dyspepsia, and antibiotic treatments. Thus, the lactate metabolism in the hindgut ecosystem is important. l -[3- 13 C]-lactate fermentation was studied in a pig in vitro model using 13 C-NMR. Pig cecal digesta were diluted with four weights of an anaerobic phosphate buffer containing 13 C-labeled lactate. The mixture was incubated for 24 h at 37°C with gentle shaking. A portion of the culture was sampled periodically and analysed for SCFA. [3- 13 C] propionate, [2- 13 C] acetate, [2- 13 C] propionate, [2- 13 C] butyrate, and [4- 13 C] butyrate were produced from [3- 13 C]-Lactate in decreasing order. The importance of an acrylate pathway in propionate formation was evidenced by the predominant [3- 13 C] propionate formation. An equal production of [2- 13 C] butyrate and [4- 13 C] butyrate, as well as a negligible production of [3- 13 C] butyrate, indicated that extra non-labeled acetate is required for butyrate synthesis. 13 C-labelled butyrate, together with the detection of [2- 13 C] valerate, suggested the important role for Megasphaera elsdenii in lactate utilization in the system.
LMTK1, a Novel Modulator of Endosomal Trafficking in Neurons

Neurons extend long processes known as axons and dendrites, through which they communicate with each other. The neuronal circuits formed by the axons and dendrites are the structural basis of higher brain functions. The formation and maintenance of these processes are essential for physiological brain activities. Membrane components, both lipids, and proteins, that are required for process formation are supplied by vesicle transport. Intracellular membrane trafficking is regulated by a family of Rab small GTPases. A group of Rabs regulating endosomal trafficking has been studied mainly in nonpolarized culture cell lines, and little is known about their regulation in polarized neurons with long processes. As shown in our recent study, lemur tail (former tyrosine) kinase 1 (LMTK1), an as yet uncharacterized Ser/Thr kinase associated with Rab11-positive recycling endosomes, modulates the formation of axons, dendrites, and spines in cultured primary neurons. LMTK1 knockdown or knockout (KO) or the expression of a kinase-negative mutant stimulates the transport of endosomal vesicles in neurons, leading to the overgrowth of axons, dendrites, and spines. More recently, we found that LMTK1 regulates TBC1D9B Rab11 GAP and proposed the Cdk5/p35-LMTK1-TBC1D9B-Rab11 pathway as a signaling cascade that regulates endosomal trafficking. Here, we summarize the biochemical, cell biological, and physiological properties of LMTK1.
Artificial Neural Networks Accurately Predict Language Processing in the Brain

The ability to share ideas through language is our species’ signature cognitive skill, but how this feat is achieved by the b rain 2 remains unknown. Inspired by the success of artificial neural networks (ANNs) in explaining neural responses in perceptual tasks 3 (Kell et al., 2018; Khaligh-Razavi & Kriegeskorte, 2014; Schrimpf et al., 2018; Yamins et al., 2014; Zhuang et al., 2017), we here