Miracle-dz/UniFAR-FTUs huggingface dataset:
Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia

Schizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterize a collection of twelve human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.
Cadmium interference with iron sensing reveals transcriptional programs sensitive and insensitive to reactive oxygen species

Iron (Fe) is an essential micronutrient whose uptake is tightly regulated to prevent either deficiency or oxidative stress. Cadmium (Cd) is a non-essential heavy metal that induces both Fe-deficiency and oxidative stress; however, the mechanisms underlying these Cd-induced responses are still elusive. Here we explored Cd-induced Fe-associated responses in wildtype Arabidopsis and opt3-2, a mutant that over-accumulates Fe. Gene expression profiling revealed a large overlap between transcripts induced by Fe-deficiency and Cd exposure in wildtype plants and the opt3 mutant. Interestingly, vascular-localized Fe-responsive genes were found to be highly induced by Cd even in the presence of high Fe and H2O2 levels, suggesting that Cd impairs Fe sensing. It was recently shown that Fe-S cluster-containing proteins AtNEET, play a role in Fe sensing. Our data shows that Cd negatively impacts both the stability and Fe-S transfer activity of AtNEET. Altogether, our data indicate that Fe-deficiency responses are governed by multiple inputs and that a hierarchical regulation of Fe-deficiency responses prevents the induction of specific gene networks when Fe and H2O2 levels are high. Other Cd/Fe-responsive genes however, are insensitive to this negative feedback regulation suggesting that their induction is the result of an impaired Fe sensing as opposed to the traditional view of Cd/Fe uptake competition at the root level. Highlight Cadmium induces an iron-deficiency response often explained by root uptake competition; here we show that Cd also impairs Fe sensing in leaves, even when Fe is in sufficient quantities.
Genome-wide assessment of REST binding profiles reveals distinctions between human and mouse hippocampus

Background The transcriptional repressor, RE1 Silencing Transcription Factor (REST), recognized historically as a master regulator of neuronal gene expression during mouse development, has recently been ascribed roles in human aging and neurodegenerative disorders. However, REST’s role in healthy adult human brain, and how faithfully mouse models reproduce REST function in human brain, is not known. Results Here, we present the first genome-wide binding profile for REST in both mouse and human postnatal hippocampus. We find the majority of REST-bound sites in human hippocampus are unique compared to both mouse hippocampus and to all other reported human ENCODE cell types. Genes associated with unique REST-bound sites include previously unidentified categories related to innate immunity and inflammation signaling, suggesting species specific roles for REST in protecting human brain health. Conclusions Our results suggest newly evolved functions for REST in maintaining human brain health.
Manual Control of Thorny Mimosa (Mimosa invisa) in Cassava (Manihot esculenta)1

The optimum weeding regime for thorny mimosa control in cassava established at 10,000 plants/ha was studied at Ibadan, Nigeria (7°22½′N, 3°50½′ E), a humid tropical environment. The study compared six weeding regimes, each comprising manual removal of thorny mimosa three times at different intervals within 13 wk after planting (WAP). Cassava vegetative growth recovered from thorny mimosa interference when the first weeding occurred within 5 WAP, but interference for more than 5 WAP reduced storage root yield. Allowing thorny mimosa infestation after 11 WAP had no effect on cassava growth or root yield. Manual removal of thorny mimosa at 4, 7, and 11 WAP consistently gave the highest cassava root yield. Nomenclature: Thorny mimosa (or giant sensitive plant), Mimosa invisa Mart. ; cassava, Manihot esculenta Crantz ‘TMS 30572’. Additional index words: Canopy closure, cassava vegetative growth, storage root yield, weed interference. Abbreviations: IAR & T, Institute of Agricultural Research and Training; MAP, months after planting; WAP, weeks after planting.
Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

COVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is an urgent need to find therapeutic agents that can help clear the virus to prevent the severe disease and death. Identifying effective and safer drugs can provide with more options to treat the COVID-19 infections either alone or in combination. Here we performed a high throughput screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic window compared to hydroxychloroquine which had safety index of 22 in similar experiments. Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA approved compounds can provide much needed therapeutic options that we urgently need in the midst of the pandemic.
MDA5 is an essential vita-PAMP sensor necessary for host resistance against Aspergillus fumigatus

RIG-I like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor to activate interferon responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. Herein we demonstrate that MDA5/MAVS signaling was essential for host resistance against pulmonary Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses in mice. Activation of MDA5/MAVS signaling was driven by dsRNA from live A. fumigatus serving as a key vitality-sensing pattern-recognition receptor. Interestingly, induction of type I interferons after A. fumigatus challenge was only partially dependent on MDA5/MAVS signaling, whereas type III interferon expression was entirely dependent on MDA5/MAVS signaling. Ultimately, type I and III interferon signaling drove the expression of CXCL10. Furthermore, the MDA5/MAVS-dependent interferon response was critical for the induction of optimal antifungal neutrophil killing of A. fumigatus spores. In conclusion, our data broaden the role of the RLR family to include a role in regulating antifungal immunity against A. fumigatus. KEY POINTS MDA5 is essential for maintaining host resistance against Aspergillus fumigatus MDA5 serves as a critical vitality sensor after fungal challenge MDA5 is essential for IFNλ expression and anti-fungal neutrophil killing
Terrestrial Activity, Abundance and Species Richness of Amphibians in Managed Forests in South Carolina

Abstract We determined the relative abundance, days of surface activity and indices of species diversity, evenness and richness for amphibians inhabiting three differently managed forests surrounding a Carolina bay in South Carolina following restoration. We collected animals daily for 3 y (Oct. 1993–Sept. 1996) using drift fences with pitfall traps in three forest types: loblolly pine (Pinus taeda), slash pine (P. elliotti) and mixed hardwoods (predominantly oak, Quercus spp. and hickory, Carya spp.). Captured animals were marked and recaptures were recorded but not included in statistical analyses, except in our evaluation of activity. We compared results to those of a more limited study conducted before restoration. Amphibians were significantly more numerous and more active in the mixed hardwood forest than in the pine forest types. However, the hardwood forest had the lowest species diversity in 2 of the 3 y of the study. The slash pine habitat had the highest diversity in all 3 y and for the 3 y combined. Because the evenness index (J′) values differ in step with the species diversity index (H′) it appears that the evenness component of diversity, rather than the richness component, is what is determining H′ variation. A summer subset of these data and summer data from an earlier study of 1977–1978 is in marked contrast with yearlong patterns. For our summer data each forest type had the highest H′ value in one of the years of the study and again the J′ values parallel the differences in H′. Large numbers of southern toads (Bufo terrestris) reduced evenness, and therefore species diversity, for all three habitats particularly the mixed hardwoods where this species was especially abundant. Proportionally lower numbers of B. terrestris in the summer samples increased J′ and H′ indices. Overall lower abundance and H′ values in the summers of 1994–1996 compared with 1977–1978 may be the result of habitat alteration during the restoration of the Carolina bay.
The Bonds between EFL Learners' Perceptions of Classroom Activities, Self-Regulatory Skills, and Language Achievement

This study investigated EFL learners' perceptions of classroom activities, selfregulatory skills, and language achievement. To do so, two samples were utilized; the first sample comprised 155 students studying in the language institutes of Mashhad, and the second one, English learners at a university in this city. For measuring self-regulatory skills, 'Self-Regulation Trait' (SRT) questionnaire designed by Herl et al (1999) was employed. It contained four subscales (planning, monitoring, self-efficacy, and effort). To determine EFL students' classroom perceptions, the study employed the Persian version of the Gentry and Gable‟s (2001) 'Students Perceptions of Classroom Activities' scale translated and validated by Ghanizadeh and Jahedizadeh (2015). The scale measures four perceptions (interest, challenge, choice, and joy). The results indicated that all four perceptions had significant positive correlations with self-regulation. The highest correlations were found between challenge and self-regulation followed by the correlation between choice and self-regulation. Moreover, there were positive associations between language achievement, students' perceptions of classroom activities, and their selfregulation. The results of correlation between perception of choice and the subscales of self-regulation (planning, self-monitoring, effort, self-efficacy) indicted that interest had the highest link with effort; joy had the highest nexus with self-efficacy; choice had the highest association with effort, and challenge had the highest relationship with planning.
On the diversity of chemical power supply as a determinant of biological diversity

Understanding how environmental factors shape biological communities is a fundamental problem in microbial ecology. Patterns of microbial diversity have been characterized across a wide range of different environmental settings, but the mechanisms generating these patterns remain poorly understood. Here, we use mathematical modelling to investigate fundamental connections between chemical power supply to a system and its biological diversity and community structure. We reveal a strong mechanistic coupling between biological diversity and the diversity of chemical power supply, but also find that different properties of power supply, such as substrate fluxes and flow and Gibbs energies of reactions, affect community structure in fundamentally different ways. Moreover, we show how simple connections between power supply and growth can give rise to complex patterns of biodiversity across physicochemical gradients, such as pH gradients. Our findings demonstrate the importance of taking into account energy fluxes in order to reveal fundamental connections between community structure and environmental variability, and to obtain a better understanding of microbial population dynamics and diversity in natural environments.
Reduced neuronal value signals in monkey orbitofrontal cortex during relative reward-specific satiety

Reward-specific satiety changes the subjective value of one reward relative to other rewards. Two-dimensional indifference curves (IC) capture relative reward-specific values of two-component choice options according to Revealed Preference Theory. Any change of reward value would be captured by specific IC distortions. We estimated two-dimensional ICs from stochastic choice and found that natural on-going consumption of two liquid rewards led to characteristic IC changes indicative of relative value reduction of specific rewards, suggesting reward-specific satiety. Licking changes confirmed the satiety in a mechanism-independent manner. Neuronal reward signals in monkey orbitofrontal cortex (OFC) followed the specific IC distortions and indicated value changes compatible with relative reward-specific satiety. A neuronal classifier predicted well the value changes inferred from the altered behavioral choices. These results demonstrate that neuronal signals in OFC reflect the altered subjective value of selectively sated rewards during economic choice.
Distinct mechanisms underlie the subsynaptic mobility of presynaptic metabotropic glutamate receptor types to tune receptor activation

Presynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission in the brain. However, the mechanisms that control the subsynaptic distribution and mobility of these receptors to contribute to their function are poorly understood. Here, using super-resolution microscopy and single-molecule tracking, we provide novel insights in the molecular mechanisms that control the spatial distribution and mobility of presynaptic mGluRs. We demonstrate that mGluR2 localizes diffusely along the axon and boutons and is highly mobile, while mGluR7 is immobilized specifically at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Indeed, we found that the positioning of mGluR2 is modulated by intracellular interactions. In contrast, immobilization of mGluR7 at the active zone is mediated by its extracellular domain that interacts in trans with the postsynaptic adhesion molecule ELFN2. Moreover, we found that receptor activation or changing synaptic activity does not alter the surface mobility of presynaptic mGluRs. Additionally, computational modeling of presynaptic mGluRs activity revealed that the precise subsynaptic localization of mGluRs determines their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.
Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia

The clinically approved drugs ticagrelor and oseltamivir fortify a pathway of platelet-mediated immunity to clear staphylococcal bacteremia in mice. Promoting platelet persistence Blood infection by Staphylococcus aureus (SA) can be fatal. Sun et al. found that lowered platelet counts associated with mortality in a cohort of patients with bacteremia, and pinpointed SA-induced desialylation and hepatic clearance of platelets as the cause. This reduction in circulating platelets was counteracted by either of two approved drugs, the sialidase inhibitor oseltamivir or ticagrelor, an inhibitor of platelet receptor P2Y12, leading to improved outcomes in a mouse model of SA-induced bacteremia. This study supports the possibility of repurposing two clinically prescribed drugs against bloodstream infection by SA. Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin–mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.
Feeding and Development of Cydia pomonella (Lepidoptera: Tortricidae) Larvae on Apple Leaves

Abstract We present leaf consumption, maximum body weight, head capsule width, and testicular ultrastructure of four sequential instars in codling moth reared solely on apple leaves of Honeycrisp variety. The developmental parameters for Cydia pomonella (L.) larvae fed on leaves are compared with those reared on artificial diet. Head capsules in the second, third, and fourth instars reared on leaves were significantly smaller than those in larvae fed artificial diet. Maximum body weights were significantly lower in all instars fed leaves compared with larvae fed artificial diet. More than 60% of larvae fed leaves molted to the third instar, and ≈3% entered the fifth instar, but none pupated, demonstrating an inability to fully compensate for the reduced nutritive value of a leaf-based diet. A study of testicular ultrastructure revealed that feeding codling moth larvae exclusively on apple leaves allowed formation of testes, but also triggered an intense, abnormal autophagocytosis that caused premature senescence of this tissue.
Formal Query Building with Query Structure Prediction for Complex Question Answering over Knowledge Base

Formal query building is an important part of complex question answering over knowledge bases. It aims to build correct executable queries for questions. Recent methods try to rank candidate queries generated by a state-transition strategy. However, this candidate generation strategy ignores the structure of queries, resulting in a considerable number of noisy queries. In this paper, we propose a new formal query building approach that consists of two stages. In the first stage, we predict the query structure of the question and leverage the structure to constrain the generation of the candidate queries. We propose a novel graph generation framework to handle the structure prediction task and design an encoder-decoder model to predict the argument of the predetermined operation in each generative step. In the second stage, we follow the previous methods to rank the candidate queries. The experimental results show that our formal query building approach outperforms existing methods on complex questions while staying competitive on simple questions.
Towards Fully 8-bit Integer Inference for the Transformer Model

8-bit integer inference, as a promising direction in reducing both the latency and storage of deep neural networks, has made great progress recently. On the other hand, previous systems still rely on 32-bit floating point for certain functions in complex models (e.g., Softmax in Transformer), and make heavy use of quantization and de-quantization. In this work, we show that after a principled modification on the Transformer architecture, dubbed Integer Transformer, an (almost) fully 8-bit integer inference algorithm Scale Propagation could be derived. De-quantization is adopted when necessary, which makes the network more efficient. Our experiments on WMT16 En<->Ro, WMT14 En<->De and En->Fr translation tasks as well as the WikiText-103 language modelling task show that the fully 8-bit Transformer system achieves comparable performance with the floating point baseline but requires nearly 4x less memory footprint.
Unsupervised Multilingual Alignment using Wasserstein Barycenter

We study unsupervised multilingual alignment, the problem of finding word-to-word translations between multiple languages without using any parallel data. One popular strategy is to reduce multilingual alignment to the much simplified bilingual setting, by picking one of the input languages as the pivot language that we transit through. However, it is well-known that transiting through a poorly chosen pivot language (such as English) may severely degrade the translation quality, since the assumed transitive relations among all pairs of languages may not be enforced in the training process. Instead of going through a rather arbitrarily chosen pivot language, we propose to use the Wasserstein barycenter as a more informative ``mean'' language: it encapsulates information from all languages and minimizes all pairwise transportation costs. We evaluate our method on standard benchmarks and demonstrate state-of-the-art performances.
Comparison of arterial wave intensity analysis by pressure–velocity and diameter–velocity methods in a virtual population of adult subjects

Pressure–velocity-based analysis of arterial wave intensity gives clinically relevant information about the performance of the heart and vessels, but its utility is limited because accurate pressure measurements can only be obtained invasively. Diameter–velocity-based wave intensity can be obtained noninvasively using ultrasound; however, due to the nonlinear relationship between blood pressure and arterial diameter, the two wave intensities might give disparate clinical indications. To test the magnitude of the disagreement, we have generated an age-stratified virtual population to investigate how the two dominant nonlinearities viscoelasticity and strain-stiffening cause the two formulations to differ. We found strong agreement between the pressure–velocity and diameter–velocity methods, particularly for the systolic wave energy, the ratio between systolic and diastolic wave heights, and older subjects. The results are promising regarding the introduction of noninvasive wave intensities in the clinic.