Miracle-dz/UniFAR-FTUs huggingface dataset:
A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity

Psychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. Here, we conducted genome-wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine-induced speed following the second and third administration, we identified a single genome-wide significant QTL on chromosome 11 that peaked near the Cyfip2 locus [LOD = 3.5, 4.2; peak = 21 cM (36 Mb)]. For methamphetamine-induced distance traveled, we identified a single genome-wide significant QTL on chromosome 5 that peaked near a functional intronic indel in Gabra2 that codes for the alpha-2 subunit of the GABA-A receptor [LOD = 5.2; peak = 35 cM (67 Mb)]. Striatal cis-expression QTL mapping corroborated Gabra2 as a functional candidate gene underlying methamphetamine-induced distance traveled. CRISPR/Cas9-mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild-type C57BL/6NJ allele was sufficient to reduce methamphetamine-induced locomotor activity toward the wild-type C57BL/6NJ-like level, thus validating the quantitative trait variant (QTV). These studies demonstrate the power and efficiency of Reduced Complexity Crosses in identifying causal genes and variants underlying complex traits. Functionally restoring Gabra2 expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA-A receptor in psychostimulant addiction-relevant traits. Importantly, our findings have major implications for investigators studying psychostimulants in the C57BL/6J strain - the gold standard strain in biomedical research.
Population genetics of polymorphism and divergence in rapidly evolving populations

In rapidly evolving populations, numerous beneficial and deleterious mutations can arise and segregate within a population at the same time. In this regime, evolutionary dynamics cannot be analyzed using traditional population genetic approaches that assume that sites evolve independently. Instead, the dynamics of many loci must be analyzed simultaneously. Recent work has made progress by first analyzing the fitness variation within a population, and then studying how individual lineages interact with this traveling fitness wave. However, these “traveling wave” models have previously been restricted to extreme cases where selection on individual mutations is either much faster or much slower than the typical coalescent timescale Tc. In this work, we show how the traveling wave framework can be extended to intermediate regimes in which the scaled fitness effects of mutations (Tcs) are neither large nor small compared to one. This enables us to describe the dynamics of populations subject to a wide range of fitness effects, and in particular, in cases where it is not immediately clear which mutations are most important in shaping the dynamics and statistics of genetic diversity. We use this approach to derive new expressions for the fixation probabilities and site frequency spectra of mutations as a function of their scaled fitness effects, along with related results for the coalescent timescale Tc and the rate of adaptation or Muller’s ratchet. We find that competition between linked mutations can have a dramatic impact on the proportions of neutral and selected polymorphisms, which is not simply summarized by the scaled selection coefficient Tcs. We conclude by discussing the implications of these results for population genetic inferences.
Age-related declines in neural distinctiveness correlate across brain areas and result from both decreased reliability and increased confusability

According to the neural dedifferentiation hypothesis, age-related reductions in the distinctiveness of neural representations contribute to sensory, cognitive, and motor declines associated with aging: neural activity associated with different stimulus categories becomes more confusable with age and behavioural performance suffers as a result. Initial studies investigated age-related dedifferentiation in the visual cortex, but subsequent research has revealed declines in other brain regions, suggesting that dedifferentiation may be a general feature of the aging brain. In the present study, we used functional magnetic resonance imaging to investigate age-related dedifferentiation in the visual, auditory, and motor cortices. Participants were 58 young adults and 79 older adults. The similarity of activation patterns across different blocks of the same condition was calculated (within-condition correlation, a measure of reliability) as was the similarity of activation patterns elicited by different conditions (between-category correlations, a measure of confusability). Neural distinctiveness was defined as the difference between the mean within- and between-condition similarity. We found age-related reductions in neural distinctiveness in the visual, auditory, and motor cortices, which were driven by both decreases in within-category similarity and increases in between-category similarity. There were significant positive cross-region correlations between neural distinctiveness in different regions. These correlations were driven by within-category similarities, a finding that indicates that declines in the reliability of neural activity appear to occur in tandem across the brain. These findings suggest that the changes in neural distinctiveness that occur in healthy aging result from changes in both the reliability and confusability of patterns of neural activity
Vertical distribution of micronutrient cations in relation to soil characteristics in lower shiwaliks of solan district in North-West himalayas

Vertical distribution of available micronutrient cations (Zn, Cu, Fe and Mn) and their relationship with different soil properties were studied in thirty two profiles of eight tentative soil series (Johranpur, Mandhala I, Mandhala II, Mandhala III, Mandhala IV, Majri, Dhaular and Haripur) of Mandhala watershed representing lower Shiwaliks of Solan district in Himachal Pradesh. The contents of available Zn, Cu, Fe and Mn were higher in surface horizons and decreased with depth in most of the soil series and ranged from 0.31 to 4.7, 0.30 to 2.80, 8.2 to 50.2 and 2.7 to 56.4 mg kg−1, respectively. Available Zn was found deficient in 15.2, marginal in 23.7 and sufficient in 61.1% of the studied samples, while Cu, Fe and Mn were sufficient in all the soils. Multiple regression analysis indicated that available Zn, Cu, Fe and Mn were influenced by silt, clay, pH, OC, CEC, BSP and EC to the level of 70.22, 66.00, 75.15 and 85.72%, respectively. However, only BSP, OC, EC, clay and silt contributed significantly towards these micronutrients
Combination and competition between path integration and landmark navigation in the estimation of heading direction

Successful navigation requires the ability to compute one’s location and heading from incoming multisensory information. Previous work has shown that this multisensory input comes in two forms: body-based idiothetic cues, from one’s own rotations and translations, and visual allothetic cues, from the environment (usually visual landmarks). However, exactly how these two streams of information are integrated is unclear, with some models suggesting the body-based idiothetic and visual allothetic cues are combined, while others suggest they compete. In this paper we investigated the integration of body-based idiothetic and visual allothetic cues in the computation of heading using virtual reality. In our experiment, participants performed a series of body turns of up to 360 degrees in the dark with only a brief flash (300ms) of visual feedback en route. Because the environment was virtual, we had full control over the visual feedback and were able to vary the offset between this feedback and the true heading angle. By measuring the effect of the feedback offset on the angle participants turned, we were able to determine the extent to which they incorporated visual feedback as a function of the offset error. By further modeling this behavior we were able to quantify the computations people used. While there were considerable individual differences in performance on our task, with some participants mostly ignoring the visual feedback and others relying on it almost entirely, our modeling results suggest that almost all participants used the same strategy in which idiothetic and allothetic cues are combined when the mismatch between them is small, but compete when the mismatch is large. These findings suggest that participants update their estimate of heading using a hybrid strategy that mixes the combination and competition of cues. Author summary Successful navigation requires us to combine visual information about our environment with body-based cues about our own rotations and translations. In this work we investigated how these disparate sources of information work together to compute an estimate of heading. Using a novel virtual reality task we measured how humans integrate visual and body-based cues when there is mismatch between them — that is, when the estimate of heading from visual information is different from body-based cues. By building computational models of different strategies, we reveal that humans use a hybrid strategy for integrating visual and body-based cues — combining them when the mismatch between them is small and picking one or the other when the mismatch is large.
Taming the massive genome of Scots pine with PiSy50k, a new genotyping array for conifer research

Scots pine (Pinus sylvestris) is the most widespread coniferous tree in the boreal forests of Eurasia and has major economic and ecological importance. However, its large and repetitive genome presents a challenge for conducting genome-wide analyses such as association studies and genomic selection. We present a new 50K SNP genotyping array for Scots pine research, breeding programs, and other applications. To select the SNP set, we first genotyped 480 Scots pine samples on a 407 540 SNP screening array, and identified 47 712 high-quality SNPs for the final array (called ‘PiSy50k’). Here, we provide details of the design and testing, as well as allele frequency estimates from the discovery panel, functional annotation, tissue-specific expression patterns, and expression level information for the SNPs or corresponding genes, when available. We validated the performance of the PiSy50k array using samples from breeding populations from Finland and Scotland. Overall, 39 678 (83.2%) SNPs showed low error rates (mean = 0.92%). Relatedness estimates based on array genotypes were consistent with the expected pedigrees, and the amount of Mendelian error was negligible. In addition, array genotypes successfully discriminate Scots pine populations from different geographic origins. The PiSy50k array will be a valuable tool for future genetic studies and forestry applications. Significance statement Scots pine is an evolutionary, economically and ecologically impressive coniferous species but its gigantic genome has limited studying e.g. the genetic basis of its functional trait variation. We have developed a genotyping array that facilitates Scots pine genetic research and linking its trait variation to genetic polymorphisms and gene expression levels across the genome.
Modeling Adsorption, Conformation, and Orientation of the Fis1 Tail Anchor at the Mitochondrial Outer Membrane

Proteins can be targeted to organellar membranes using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained simulations to analyze the adsorption, conformation and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.
The SARS-CoV-2 host cell membrane fusion protein TMPRSS2 is a tumor suppressor and its downregulation correlates with increased antitumor immunity and immunotherapy response in lung adenocarcinoma

Background TMPRSS2 is a host cell membrane fusion protein for SARS-CoV-2 invading human host cells. It also has an association with cancer, particularly prostate cancer. However, its association with lung cancer remains insufficiently explored. Thus, an in-depth investigation into the association between TMPRSS2 and lung cancer is significant, considering that lung cancer is the leading cause of cancer death and that the lungs are the primary organ SARS-CoV-2 attacks. Methods Using five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, cancer-associated pathways, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we validated the findings from the bioinformatics analysis by performing in vitro experiments with the human LUAD cell line A549 and in vivo experiments with mouse tumor models. We also validated our findings in LUAD patients from Jiangsu Cancer Hospital, China. Results TMPRSS2 expression levels were negatively correlated with the enrichment levels of CD8+ T and NK cells and immune cytolytic activity in LUAD, which represent antitumor immune signatures. Meanwhile, TMPRSS2 expression levels were negatively correlated with the enrichment levels of CD4+ regulatory T cells and myeloid-derived suppressor cells and PD-L1 expression levels in LUAD, which represent antitumor immunosuppressive signatures. However, TMPRSS2 expression levels showed a significant positive correlation with the ratios of immune-stimulatory/immune-inhibitory signatures (CD8+ T cells/PD-L1) in LUAD. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory signatures than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with elevated activities of many oncogenic pathways in LUAD, including cell cycle, mismatch repair, p53, and extracellular matrix (ECM) signaling. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor advancement, and worse survival in LUAD. In vitro and in vivo experiments validated the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1. Conclusions TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a connection between lung cancer and pneumonia caused by SARS-CoV-2 infection.
Unrevealing water and carbon relations during and after heat and hot drought stress in Pinus sylvestris

Forests are increasingly affected by heatwaves, often co-occurring with drought, with consequences for water and carbon (C) cycling. However, our ability to project the resilience of trees to an intensification of hot droughts remains limited. Here, we used single tree cuvettes (n=18) allowing us to investigate transpiration (E), net assimilation (Anet), root respiration (Rroot) and stem diameter change in Scots pine seedlings during gradually intensifying heat or drought-heat stress (max. 42°C), and post-stress. Further, we assessed indicators of stress impacts and recovery capacities. Under heat stress, well-watered seedlings prevented overheating of leaves effectively via increased E, while under drought-heat leaf temperatures increased to 46°C. However, leaf electrolyte leakage was negligible, but F’v/F’m declined alongside Anet moderately in heat but strongly in drought-heat seedlings, in which respiration exceeded C uptake. Further, the decrease of needle water potential (ψNeedle) to −2.7 MPa and relative needle water content (RWCNeedle) under drought-heat reflected a decline of leaf hydraulic conductance (KLeaf) by 90% and stem hydraulic conductivity (KS) by 25%. Alongside, we observed pronounced stem diameter shrinkage. Heat stress alone resulted in low functional impairment and all measured parameters recovered fast. In contrast, larger impacts following combined heat and drought led to the incomplete recovery of KLeaf and KS. Despite Anet tended to be reduced albeit F’v/F’m had recovered, the seedlings’ net C balance reached control values 2 d after stress release and stem growth rates exceeded control rates in the 2nd week post-stress. This indicates that a new equilibrium of C uptake and release was maintained at the tree level, slowly supporting regaining of stress-induced losses. In summary, we highlight that under moderate heatwaves with low functional impairment, recovery is fast in Scots pine, while in combination with drought hydraulic and thermal stress are intensified, resulting in functional damage and delayed recovery processes. The incomplete recovery of hydraulic conductance indicates limited water transport capacities that could become critical under repeated heat events.
Nuclear and plastid phylogenomic analyses provide insights into the reticulate evolution, species delimitation and biogeography of the Sino-Japanese disjunctive Diabelia (Caprifoliaceae)

Understanding biological diversity and the mechanisms of the Sino-Japanese disjunctions are major challenges in eastern Asia biogeography. The Sino-Japanese flora has been broadly studied as an ideal model for plant phylogeography. Diabelia (Caprifoliaceae) is an East Asian genus, with a disjunctive distribution across the Sino-Japanese region. However, relationships within Diabelia remain elusive. In this study, we reconstructed the phylogeny of Diabelia and inferred historical biogeography and evolutionary patterns based on nuclear and plastid sequences from target enrichment and genome skimming approaches, respectively. We found that the main clades within Diabelia were discordant between nuclear and plastid trees. Both nuclear and plastid phylogenetic analyses supported five main clades: D. serrata, D. tetrasepala, D. sanguinea, D. spathulata var. stenophylla and D. spathulata var. spathulata. Species network analyses revealed that Diabelia tetrasepala is likely the result of a hybridization event. Divergence time estimation and ancestral area reconstructions showed that Diabelia originated in Japan during the early Miocene, with subsequent vicariance and dispersal events between Japan and Korea, and between Japan and China. Overall, our results support the division of Diabelia into five main clades and the recognition of five species in the genus. This research provides new insights in the species delimitation and speciation processes of taxonomically complex lineages such as Diabelia.
Is Algorithm Comprehension Different from Program Comprehension?

At the beginning of their undergraduate studies, computer science students are exposed to introductory programming, discrete mathematics, and algorithms. A large body of literature has studied how such students comprehend programs. Much less attention has been paid to understanding how students comprehend algorithms, i.e., representations of problem-solving processes accompanied by proofs of their properties. To investigate whether algorithm comprehension is under-researched or whether we can simply transfer results from program comprehension (and, possibly, proof comprehension) to the domain of algorithms, we conducted a larger study following a Grounded-Theory approach. For this study, we worked with twelve participants with varying degrees of prior knowledge regarding algorithms, from technically no prior knowledge to advanced graduate students pursuing a doctoral degree in algorithms-related fields. In this paper, we report on the analysis and interpretation of interview data focused on exploring potential differences between program comprehension and algorithm comprehension. Our analyses and interpretations revealed both similarities and differences between program comprehension and algorithm comprehension: Unsurprisingly, we found that aspects known from program comprehension, e.g., using top-down approaches or utilizing prior knowledge of programming plans, can be found in algorithm comprehension as well. However, some of these aspects manifest themselves in notably different details or are influenced by, e.g., the wording of a proof. Most interesting, we found that novice and advanced students alike benefit from switching between reading the representation of the program-solving process and the accompanying proofs. We present qualitative results illustrating both similarities and differences between program comprehension and algorithm comprehensions and offer first explanations for these.
Training Accelerator for Two Means Decision Tree

Decision trees (DTs) are profusely used in machine learning (ML) applications on account of their fast execution and high interpretability. As DT training is time-consuming, in this brief, we proposed a hardware training accelerator to speedup the training process. The proposed training accelerator is implemented on the field-programmable gate array (FPGA) having a maximum operating frequency of 62 MHz. The proposed architecture uses a combination of parallel execution for training time reduction and pipelined execution to minimize resource consumption. For a given design, the proposed hardware implementation is found to be at least $14\times $ faster than the C-based software implementation. Moreover, the proposed architecture can be easily retrained for the next set of data using a single RESET signal. This on-the-go training makes the hardware versatile for any kind of application.