Miracle-dz/UniFAR-FTUs huggingface dataset:
Diversification or collapse of self-incompatibility haplotypes as a rescue process

In angiosperm self-incompatibility systems, pollen with an allele matching the pollen recipient at the self-incompatibility locus is rejected. Extreme allelic polymorphism is maintained by frequency-dependent selection favoring rare alleles. However, two challenges limit the spread of a new allele (a tightly linked haplotype in this case) under the widespread “collaborative non-self recognition” mechanism. First, there is no obvious selective benefit for pollen compatible with non-existent stylar incompatibilities, which themselves cannot spread if no pollen can fertilize them. However, a pistil-function mutation complementary to a previously neutral pollen mutation may spread if it restores self-incompatibility to a self-compatible intermediate. Second, we show that novel haplotypes can drive elimination of existing ones with fewer siring opportunities. We calculate relative probabilities of increase and collapse in haplotype number given the initial collection of incompatibility haplotypes and the population gene conversion rate. Expansion in haplotype number is possible when population gene conversion rate is large, but large contractions are likely otherwise. A Markov chain model derived from these expansion and collapse probabilities generates a stable haplotype number distribution in the realistic range of 10–40 under plausible parameters. However, smaller populations might lose many haplotypes beyond those lost by chance during bottlenecks.
Genome wide analysis of gene dosage in 24,092 individuals shows that 10,000 genes modulate cognitive ability

Genomic Copy Number Variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect-size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect-sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVs >50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect-size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of IQ when duplicated or deleted, respectively. Effect-sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect-sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect-size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect-sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways.
Immunity to infections in arboviral vectors by integrated viral sequences: an evolutionary perspective

In the model organism Drosophila melanogaster, the PIWI-interacing RNA pathway contributes in silencing transposable elements (TEs) through smallRNAs (piRNAs), which arise from genomic loci (piRNA clusters) that contain sequences of previously-acquired TEs. As such, they are a functionally-immune archive of previous TE invasions that is passed to the offspring. In the arboviral vector Aedes aegypti, piRNA clusters contain TEs and endogenous viral elements from nonretroviral RNA viruses (nrEVEs) which produce piRNAs, supporting the hypothesis that nrEVEs are heritable immunity effectors. However, direct evidence that nrEVEs mediate adaptive immunity is lacking. Here, by using an analytic approach intersecting population genomics with molecular biology we demonstrate that the composition of piRNA clusters is modular through acquisition and absence of nrEVEs. We show that the genomes of wild-caught mosquitoes have a different set of nrEVEs than those annotated in the reference genome, including population-specific integrations. nrEVEs are not distributed in mosquito genomes only by genetic drift, but some show signs of positive selection. Moreover, by comparing natural mosquito populations expressing or lacking two newly characterised nrEVEs with high sequence complementarity to cell fusing agent virus, we show that nrEVEs confer antiviral immunity in ovaries against the cognate virus. Our results confirm that some nrEVEs have been co-opted for adaptive immunity to viral infections.
Enabling a fast annotation process with the Table2Annotation tool

In semantic annotation, semantic concepts are linked to natural language. Semantic annotation helps in boosting the ability to search and access resources and can be used in information retrieval systems to augment the queries from the user. In the research described in this paper, we aimed to identify ontological concepts in scientific text contained in spreadsheets. We developed a tool that can handle various types of spreadsheets. Furthermore, we used the NCBO Annotator API provided by BioPortal to enhance the semantic annotation functionality to cover spreadsheet data. Table2Annotation has strengths in certain criteria such as speed, error handling, and complex concept matching.
ZNF423 patient variants, truncations, and in-frame deletions in mice define an allele-dependent range of midline brain abnormalities

Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice. AUTHOR SUMMARY Gene identification in rare disorders is typically supported by finding different mutations of the same gene in multiple families with the same disorder. However, causal evidence for any specific mutation found in one or a few related individuals is weaker, especially if the disorder can be caused by any of several genes and the functional effect of the mutation is not certain. Experimental models can be helpful in testing causal effects, but only to the extent that the model is validated to recapitulate one or more aspects of the disorder. We used CRISPR/Cas9-based genome engineering to create a wide range of mutations in mouse Zfp423, whose human cognate is implicated in neurodevelopmental disorders, especially cerebellar vermis hypoplasia and Joubert syndrome. This large collection of animal models shows that both reduced Zfp423 expression, including heterozygosity for loss-of-function mutations, and normally-expressed domain deletions, including specific zinc finger domains, produce measureable abnormalities in midline development. Despite this high level of validation, most patient-derived amino acid substitution variants tested do not produce measureable effects. The single exception is a substitution, H1277Y, that destroys a structural element in the last zinc finger domain and results in dramatic loss of steady-state Zfp423 protein level.
UltraPrep is a scalable, cost-effective, bead-based method for purifying cell free DNA

UltraPrep is an open-source, two-step method for purification of cell-free DNA that entails extraction of total DNA followed by size-selective enrichment of the smaller fragments that are characteristic of DNA originating from fragmentation between nucleosome. The advantages of the method are that it can easily accommodate a wide range of sample input volumes, it relies on simple, magnetic bead-based technology, the yields of cfDNA are directly comparable to the most popular methods for cfDNA purification, and it dramatically reduces the cost of cfDNA isolation relative to currently available commercial methods. We provide a framework for physical and molecular quality analysis of purified cfDNA and demonstrate that the cfDNA generated by UltraPrep meets or exceeds the quality metrics of the most commonly used procedure. Our method removes high molecular weight genomic DNA that can interfere with downstream assay results, thereby addressing one of the primary concerns for preanalytical collection of blood samples.
Dynamic changes in the urine proteome of tumor-bearing mouse models of B16 melanoma and RM-1 prostate cancer

Urine can accumulate changes and reflect early physiological and pathological changes of various diseases, such as tumors. Therefore, urine is an ideal source for identification of early biomarkers. In this study, melanoma and prostate cancer-bearing mouse models were established by subcutaneous injection of B16 and RM-1 cells, respectively. Urine samples were collected at four time points during tumor growth. Based on data-independent acquisition (DIA) technology, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for quantitative analysis. Compared with those before the injection of B16 cells, 38 human homologous differential proteins were identified, and 18 proteins were reported to be related to melanoma. Before the tumor was visible, there were 4 differential proteins, and all were reported to be related to melanoma. Compared with that before the injection of RM-1 cells, a total of 14 human homologous differential proteins were identified, and 9 proteins were reported to be associated with prostate cancer. Before the tumor was palpable, 9 proteins showed significant differences. There were significant differences between the two tumor-bearing models. Through the above experiments and analysis, we found that the urine proteome can reflect the changes in the development and provide early biomarkers of the two tumors and provide clues for the early clinical diagnosis of these diseases.
Multi-organ transcriptomic profiling reveals differential regulation of the immune system among the brain-liver-fats organ network of short-term fasted mice

Different fasting regiments are known to promote health, and chronic immunological disorders and mitigate age-related pathophysiological parameters in animals and humans. Indeed, several clinicals trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis, but the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not-well understood, particularly at a systems/multi-organ level. We investigated the dynamic gene expression patterns associated with periods of STF in nine different mouse organs. First, we identified both unique and shared transcriptional signatures at the organ and systemic levels. Second, we discovered differential temporal effects of STF among organs. Third, using gene ontology enrichment analysis, we identified an organ network, formed by the 63 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown, and perigonadal white adipose tissue, hence we name it the brain-liver-fats organ network. Fourth, we identified that the immune system, dominated by T cell regulation processes, is a central and prominent target of systemic modulations during short-term energy loss in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. In conclusion, our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF and added new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.
The primary donor of far-red Photosystem II: ChlD1 or PD2?

Far-red light (FRL) Photosystem II (PSII) isolated from Chroococcidiopsis thermalis is studied using parallel analyses of low-temperature absorption, circular dichroism (CD) and magnetic circular dichroism (MCD) spectroscopies in conjunction with fluorescence measurements. This extends earlier studies (Nurnberg et al 2018 Science 360 (2018) 1210-1213). We confirm that the chlorophyll absorbing at 726 nm is the primary electron donor. At 1.8 K efficient photochemistry occurs when exciting at 726 nm and shorter wavelengths; but not at wavelengths longer than 726 nm. The 726 nm absorption peak exhibits a 21 ± 4 cm−1 electrochromic shift due to formation of the semiquinone anion, QA•-. Modelling indicates that no other FRL pigment is located among the 6 central reaction center chlorins: PD1, PD2 ChlD1, ChlD2, PheoD1 and PheoD2. Two of these chlorins, ChlD1 and PD2, are located at a distance and orientation relative to QA•- so as to account for the observed electrochromic shift. Previously, ChlD1 was taken as the most likely candidate for the primary donor based on spectroscopy, sequence analysis and mechanistic arguments. Here, a more detailed comparison of the spectroscopic data with exciton modelling of the electrochromic pattern indicates that PD2 is at least as likely as ChlD1 to be responsible for the 726 nm absorption. The correspondence in sign and magnitude of the CD observed at 726 nm with that predicted from modelling favors PD2 as the primary donor. The pros and cons of PD2 vs ChlD1 as the location of the FRL-primary donor are discussed. TOC Graphic Highlights Primary Donor confirmed at 726 nm Determination of far-red chl pigment Qy excitation positions, widths, CD and MCD amplitudes Quantification of electrochromic shifts and QA•- photoconversion yield Electrochromic shift consistent with primary donor at either ChlD1 or PD2 The CD amplitude favors the primary donor at PD2
Equine Facial Action Coding System for determination of pain-related facial responses in videos of horses

During the last decade, pain scales including facial expressions as indicators of pain have been developed for horses, mostly relying on direct observations or inspection of images. Despite differences in the research conditions and methodology the different scales focus on the same regions of the face, corresponding to moveable facial muscles related to the ears, eyes, nostrils, lips and chin. However, a detailed comparison of the facial activities occurring during pain is not possible. We used a Facial Action Coding System modified for horses to code and analyse video recordings from an earlier study of acute short-term experimental pain and from clinical cases with and without pain. We demonstrated for the first time EquiFACS based changes to pain in video of horses, using traditional statistical methods based on frequency, and novel analyses based on sliding observation windows and co-occurrence of facial actions. The most prominent differences of the experimental horses were related to the lower face actions chin raiser and nostril dilator, while less prominent, but significantly more frequent actions were related to the eye region, inner brow raiser (AU101), increased eye white (AD1), half blink (AU47), and ear rotator (EAD104). Ears forward (EAD101) and eye blink (AU145) were not associated to pain. Based on this we selected the two lower face actions for analysis of the clinical videos, and found that their co-occurrence within a window of 10 to 15 second gave 100% positive predictive values, as compared to the rating from three expert pain raters. Using our developed co-occurrence analyses we were surprised to detect that the chance of identifying three or more of the facial actions related to pain in 0.04 second sequence, corresponding to one frame, was below 3%, indicating that use of randomly selected images for pain scoring may be a very insensitive method.
Intravital imaging of mouse embryos

A window to the embryo Mammalian embryonic development is a complex process, continuously changing in space and time. Q. Huang et al. designed an abdominal window to image mouse embryos in utero from embryonic day 9.5 to birth. Using this technique, they visualized dynamic activities during embryonic organ formation, including neurotransmission and cell division in the brain, autophagy in the retina, viral gene delivery, and placental drug transfer. They also tracked diverging fates of human and mouse neural crest cells in interspecies chimeras. Science, this issue p. 181 An abdominal window enables real-time imaging of live mouse embryos from embryonic day 9.5 to birth. Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing embryo from embryonic day 9.5 to birth. This removable intravital window allowed manipulation and high-resolution imaging. In live mouse embryos, we observed transient neurotransmission and early vascularization of neural crest cell (NCC)–derived perivascular cells in the brain, autophagy in the retina, viral gene delivery, and chemical diffusion through the placenta. We combined the imaging window with in utero electroporation to label and track cell division and movement within embryos and observed that clusters of mouse NCC-derived cells expanded in interspecies chimeras, whereas adjacent human donor NCC-derived cells shrank. This technique can be combined with various tissue manipulation and microscopy methods to study the processes of development at unprecedented spatiotemporal resolution.
Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulphate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.
Maternal phylogenetic relationships and genetic variation among rare similar phenotype donkey breeds

Maternal inheritance is an indispensable aspect in donkey rare breed population biodiversity management and breeding programs. It is a challenge to characterize breeds genetic inheritance using morphology and historical records, we study mtDNA, to overcome those limitations. The mitochondrial DNA (mtDNA) sequencing is a highly informative system to investigate maternal lineages and breed linkage such as molecular evolution and phylogenetic relationships. Martina Franca, Ragusano, Pantesco and Catalonian donkey mtDNA sequencing analyses were used to study intraspecific genetic diversity and population structure, and to reconstruct phylogenetic relations among these geographically isolated breeds. A wide lost in variability among all breeds emerged. In this scenario, the primeval haplotypes, higher haplogroups variability and larger number of maternal lineages are preserved in Martina Franca and Ragusano. Accordingly, a putative pivotal role in the phyletic relationship is likely for such breeds. Given the level of endangerment undergone by these breeds, some actions are necessary to ensure their longtime survival and conservation. Improving the reproduction and management of existing populations, clarifying their historic interactions by studying the genetic status of their populations, extending and improving monitoring maternal lineages represent valid options.
Lectin-like Intestinal Defensin Inhibits 2019-nCoV Spike binding to ACE2

The burgeoning epidemic caused by novel coronavirus 2019 (2019-nCoV) is currently a global concern. Angiotensin-converting enzyme-2 (ACE2) is a receptor of 2019-nCoV spike 1 protein (S1) and mediates viral entry into host cells. Despite the abundance of ACE2 in small intestine, few digestive symptoms are observed in patients infected by 2019-nCoV. Herein, we investigated the interactions between ACE2 and human defensins (HDs) specifically secreted by intestinal Paneth cells. The lectin-like HD5, rather than HD6, bound ACE2 with a high affinity of 39.3 nM and weakened the subsequent recruitment of 2019-nCoV S1. The cloak of HD5 on the ligand-binding domain of ACE2 was confirmed by molecular dynamic simulation. A remarkable dose-dependent preventive effect of HD5 on 2019-nCoV S1 binding to intestinal epithelial cells was further evidenced by in vitro experiments. Our findings unmasked the innate defense function of lectin-like intestinal defensin against 2019-nCoV, which may provide new insights into the prevention and treatment of 2019-nCoV infection.
Size-dependent eco-evolutionary feedback loops in exploited ecosystems

Current empirical observations largely suggest a body downsizing in response to harvesting, associated with population declines and decreased harvesting yields. These changes are often construed as direct consequences of harvest selection, where smaller-bodied, early reproducing individuals are immediately favoured. Harvesting and evolution of body size however alter many ecological aspects, affecting for instance competitive and trophic interactions. Such changes reshape the fitness landscape thereby altering the subsequent evolution of body size. Predicting these changes in fitness landscapes, and from there the productivity and dynamics of harvested populations, requires accounting for a constant interplay between ecological and evolutionary changes termed eco-evolutionary feedback loops (EEFLs). We analyze scenarios under which EEFLs acting at the population or community levels either oppose or magnify harvest-induced body downsizing. Opposing EEFLs favour body-size stasis but erode genetic variability and associated body-size evolvability, and may ultimately impair population persistence. In contrast, synergistic EEFLs initially favour population persistence and preserve body-size evolvability, but drive fast evolution towards smaller body sizes and increase the probability for trophic feedbacks that may ultimately lead to population collapse. EEFLs imply that reduced ecological effects of harvesting also produce smaller evolutionary changes, and thus pave the way towards a convergence of the ecological and evolutionary perspectives on harvest management. We advocate for a better consideration of natural selection which effects, we believe, should be integrated among default a priori assumption in studies of harvested populations.