Miracle-dz/UniFAR-FTUs huggingface dataset:
The CovR regulatory network drives the evolution of Group B Streptococcus virulence

Virulence of the neonatal pathogen Group B Streptococcus depends on the master regulator CovR. Inactivation of CovR leads to large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, comparative analyses suggested a plasticity of the CovR signalling pathway in clinical isolates, probably due to the host selective pressure and leading to phenotypic heterogeneity in the bacterial population. Here, we characterize the CovR regulatory network in a strain representative of the hypervirulent lineage responsible of the majority of late-onset meningitidis. Genome-wide binding and transcriptome analysis demonstrated that CovR acts as a direct and global repressor of virulence genes, either as a primary regulator or with specialized co-regulators. Remarkably, CovR directly regulates genes of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, as well as core-genes showing mutational biases in the population. Parallel analysis of the CovR network in a second isolate links strain-specificities to micro-evolutions in CovR-regulated promoters and to broad difference due to variability in CovR activation by phosphorylation. Our results highlight the direct, coordinated, and strain-specific regulation of virulence genes by CovR. This intra-species evolution of the signalling network reshapes bacterial-host interactions, increasing the potential for adaptation and the emergence of clone associated with specific diseases.
A novel allele in the Arabidopsis thaliana MACPF protein CAD1 results in deregulated immune signaling

Immune recognition in plants is governed by two major classes of receptors: pattern recognition receptors (PRRs) and nucleotide-binding leucine-rich repeat receptors (NLRs). Located at the cell surface, PRRs bind extracellular ligands originating from microbes (indicative of ‘non-self’) or damaged plant cells (indicative of ‘infected-self’), and trigger signaling cascades to protect against infection. Located intracellularly, NLRs sense pathogen-induced physiological changes and trigger localized cell death and systemic resistance. Immune responses are under tight regulation in order to maintain homeostasis and promote plant health. In a forward-genetic screen to identify regulators of PRR-mediated immune signaling, we identified a novel allele of the membrane-attack complex and perforin (MACPF)-motif containing protein CONSTITUTIVE ACTIVE DEFENSE 1 (CAD1) resulting from a missense mutation in a conserved N-terminal cysteine. We show that cad1-5 mutants display deregulated immune signaling and symptoms of autoimmunity dependent on the lipase-like protein ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1), suggesting that CAD1 integrity is monitored by the plant immune system. We further demonstrate that CAD1 localizes to both the cytosol and plasma membrane using confocal microscopy and subcellular fractionation. Our results offer new insights into immune homeostasis and provide tools to further decipher the intriguing role of MACPF proteins in plants.
Diet composition, body condition and sexual size dimorphism of the common African toad (Amietophrynus regularis) in urban and agricultural landscape

Land use and land cover change (LULCC) are major drivers of global biodiversity loss. The conversion of natural habitats into human-modified landscapes poses novel and multifaceted environmental stressors to organisms, influencing their ecology, physiology, life history and fitness. Although the effects of LULCC have been studied extensively at the community level, there is scant information about its effect on population and individual characteristics. We assessed the diet composition, body condition, and sexual size dimorphism of the common African toad (Amietophrynus regularis) in urban and agricultural landscape. Diet composition was evaluated using gut content analysis, while body condition was measured using residual mass index. Overall, 935 prey items comprising six classes, at least 18 orders and 31 families were obtained from toads. This broad dietary niche suggested that Amietophrynus regularis is a generalist predator. The family Formicidae was the most consumed prey item, with a frequency of occurrence above 80% at both sites. We found no sex- or habitat-biased dietary partitioning in the toads. A statistically significant positive correlation existed between snout-vent-length (SVL) and diversity of prey items (Pearson’s correlation r = 0.999, p ≤ 0.0001) for toads from farmland, which also had better body conditions. The toads showed female-biased sexual size dimorphism, but males had longer tibio-fibula, radio-ulna, foot, and distal fore limbs. This study is probably the first to assess the diet composition, body condition and sexual size dimorphism of Amietophrynus regularis simultaneously. The ecological, evolutionary and conservation implications of our findings are discussed.
tTARGIT AAVs: A sensitive and flexible method to manipulate intersectional neuronal populations

While Cre-dependent viral systems permit the manipulation of many neuron types, some cell populations cannot be targeted by a single DNA recombinase. Although the combined use of Flp and Cre recombinases can overcome this limitation, insufficient recombinase activity can reduce the efficacy of existing Cre+Flp-dependent viral systems. We developed a sensitive dual recombinase-activated viral approach: tTA-driven Recombinase-Guided Intersectional Targeting (tTARGIT) AAVs. tTARGIT AAVs utilize a Flp-dependent tetracycline transactivator (tTA) “Driver” AAV and a tetracycline response element (TRE)-driven, Cre-dependent “Payload” AAV to express the transgene of interest. We employed this system in Slc17a6FlpO;LeprCre mice to manipulate LepRb neurons of the ventromedial hypothalamus (VMH; LepRbVMH neurons) while omitting neighboring LepRb populations. We defined the circuitry of LepRbVMH neurons and roles for these cells in the control of food intake and energy expenditure. Thus, the tTARGIT system mediates robust recombinase-sensitive transgene expression, permitting the precise manipulation of previously intractable neural populations.
A noncanonical FLT3 gatekeeper mutation disrupts gilteritinib binding and confers resistance

The recent FDA approval of the FLT3 inhibitor, gilteritinib, for AML represents a major breakthrough for treatment of FLT3 mutated AML. However, patients only respond to gilteritinib for 6-7 months due to the emergence of drug resistance. Clinical resistance to gilteritinib is often associated with expansion of NRAS mutations, and less commonly via gatekeeper mutations in FLT3, with F691L being the most common. We developed an in vitro model that charts the temporal evolution of resistance to gilteritinib from early microenvironmental-mediated resistance to late intrinsic resistance mutations. Our model system accurately recapitulates the expansion of NRAS mutations and the F691L gatekeeper mutations found in AML patients. As part of this study, we also identified a novel FLT3N701K mutation that also appeared to promote resistance to gilteritinib. Using the Ba/F3 system, we demonstrate that N701K mutations effectively act like a gatekeeper mutation and block gilteritinib from binding to FLT3, thereby promoting resistance. Structural modeling of FLT3 reveals how N701K, and other reported gilteritinib resistance mutations, obstruct the gilteritinib binding pocket on FLT3. Interestingly, FLT3N701K does not block quizartinib binding, suggesting that FLT3N701K mutations are more specific for type 1 FLT3 inhibitors (gilteritinib, midostaurin, and crenolanib). Thus, our data suggests that for the FLT3N701K mutation, switching classes of FLT3 inhibitors may restore clinical response. As the use of gilteritinib expands in the clinic, this information will become critical to define clinical strategies to manage gilteritinib resistance.
Identification and characterization of a biphasic/bidirectional wound-inducible RHA3B gene promoter from Arabidopsis thaliana

Conditional promoters such as wound inducible are important tools for plant biotechnology to selectively express agronomically important genes. From a set of Enhancer trap (DsE-uidA) transposant lines we identified wound inducible ET1075 line by injuring leaf blade and screening for Ds linked GUS gene expression. Earliest GUS stain detected at petiolar region at 2hrs post injury with a progressive attainment of maximum visual intensity between 12 and 24hrs wherein, the transcript expression induced in a bidirectional manner. DsE was found to be inserted in the intergenic region between AT4G35480 and AT4G35490. To find the essential transcriptional regulatory region, deletion constructs comprising upstream sequences of pRHA3B fused to GUS reporter gene were functionally tested in Arabidopsis plants by generating stable transgenics. A 481 bp of upstream sequence from ATG is found to be sufficient to promote wound inducible gene expression. Sequence analysis revealed the presence of several regulatory elements implicated in wound inducible gene expression. Comparative analysis with similar wound inducible promoters revealed the presence of common cis-regulatory elements. This promoter can essentially be used in pest control and in molecular pharming to conditionally express agronomically/commercially important genes in plants. Highlights DsE enhancer trap transposant lines were generated. Identified a novel wound inducible promoter line ET1075. Wound inducible promoter pRHA3B is bidirectional and induces the expression of RHA3B and MRPL11 genes. Wound responsive key cis-elements WRKY, W-box, FORCA are present in the pRHA3B promoter.
Modelling the deathbed of ASF-infected wild boars in South Korea using 2019-2020 national surveillance data

In September 2019, African swine fever (ASF) was reported in South Korea for the first time. Since then, more than 651 ASF cases in wild boars and 14 farm outbreaks have been notified in the country. The purpose of this study was to characterize the spatial distribution of ASF-positive wild boar carcasses to identify the risk factors associated with the presence of ASF and number of ASF-positive wild boar carcasses in the affected areas. To achieve this objective, we divided the study into two periods (October 2, 2019, to January 19, 2020, and January 19 to April 28, 2020) and aggregated the number of reported ASF-positive carcasses into a regular grid of hexagons. To account for imperfect detection, we adjusted spatial zero-inflated Poisson regression models to the number of ASF-positive wild boar carcasses per hexagons. During the first study period, only proximity to North Korea was identified as a risk factor for the presence of African swine fever virus (ASFV). In addition, there were more reports in the affected hexagons with a high habitat suitability for wild boar, low heat load index (HLI), and high human density. During the second study period, proximity to an ASF-positive carcass reported during the first period was the only significant risk factor for the presence of ASF-positive carcasses. Additionally, high HLI and low elevation were associated with an increased number of ASF-positive carcasses reported in the affected hexagons. Although the proportion of ASF-affected hexagons increased from 0.06 (95% credible interval [CrI]: 0.05-0.07) to 0.09 (95% CrI: 0.08-0.10), the probability of reporting ASF-affected hexagons increased substantially from 0.49 (95% CrI: 0.41-0.57) to 0.73 (95% CrI: 0.66-0.81) between the two study periods. These results can be used to further advance risk-based surveillance.
Estimating the fundamental niche: accounting for the uneven availability of existing climates in the calibration area

Studies that question important conceptual and methodological aspects of the field of ecological niche modeling (and species distribution modeling) have cast doubts on whether it is possible to estimate the fundamental niche of a species using presence-only data. The main limitation in niche estimation is that presence data come from the realized niche, which is only a subset of the fundamental niche. Most of the existing methods lack the ability to overcome this limitation and therefore fit niches that resemble the realized niche. To obtain a more accurate estimate of the fundamental niche, we propose using the geographic region that is accessible to a species (based on its dispersal ability) to determine a sampling distribution, in environmental space, from which we can quantify the likelihood of observing a particular environmental combination in a sample of presence points. We incorporate this sampling distribution into a multivariate normal model (i.e., a Mahalanobis distance model) by creating a weight function that modifies the probabilities of observing different environmental combinations in a sample of presences. This modification accounts for the uneven availability of environmental conditions. We show that the parameters of this weighted-normal model can be approximated with a maximum likelihood estimation approach; and then used to draw ellipsoids (confidence regions) that represent the fundamental niche of the species. We illustrate the application of our model with two worked examples. First, we use presence data for an invasive species and an accessible area that includes only its native range to evaluate whether the fitted model predicts confirmed establishments of the species outside its native range. Second, we use presence data for closely related species with known accessible areas to demonstrate how the different dispersal abilities of the species constrain a classic Mahalanobis distance model. Overall, we show that accounting for the distribution of environmental conditions that are accessible to a species indeed affects the estimation of the ellipsoids used to model its fundamental niche.
NOMIS: Quantifying morphometric deviations from normality over the lifetime of the adult human brain

We present NOMIS (https://github.com/medicslab/NOMIS), a comprehensive open MRI tool to assess morphometric deviation from normality in the adult human brain. Based on MR anatomical images from 6,909 cognitively healthy individuals aged 18-100 years, we modeled 1,344 measures computed using the open access FreeSurfer pipeline, considering account personal characteristics (age, sex, intracranial volume) and image quality (resolution, contrast-to-noise ratio and surface reconstruction defect holes), and providing expected values for any new individual. Then, for each measure, the NOMIS tool was built to generate Z-score effect sizes denoting the extent of deviation from the normative sample. Depending on the user need, NOMIS offers four versions of Z-score adjusted on different sets of variables. While all versions consider head size and image quality, they can also incorporate age and/or sex, thereby facilitating multi-site neuromorphometric research across adulthood.
Intelligence and academic performance: Is it all in your head?

Academic performance relies, in part, on intelligence; however, intelligence quotient (IQ) is limited in predicting academic success. Furthermore, while the search for the biological seat of intelligence predates neuroscience itself, its findings remain conflicting. Here, we assess the interplay between IQ, academic performance, and brain connectivity with behavioral and functional MRI data collected from undergraduate students as they completed an active learning or lecture-based semester-long university physics course. IQ (i.e., full-scale WAIS scores) increased significantly pre-to post-instruction, were associated with physics knowledge and reasoning measures, but were unrelated to overall course grade. IQ was related to brain connectivity during physics-related cognition, but connectivity did not mediate IQ’s association with task performance. These relations depended on students’ sex and instructional environment, providing evidence that physics classroom environment and pedagogy may have a gendered influence on students’ performance. Discussion focuses on opportunities to improve physics reasoning skills for all students.
Correlated variance in simultaneous inductively coupled plasma atomic-emission spectrometry: its causes and correction by a parameter-related internal standard method

For practical purposes the precision of inductively coupled plasma atomic-emission spectrometry (ICP-AES) is limited by medium-term changes of sensitivity, i.e., those occurring on a time scale shorter than the period between calibration adjustments. For any ICP-AES it is this longer term lack of reproducibility that limits its capacity to match other multi-element methods (such as X-ray fluorecence) for high precision analysis.This paper describes the application of principal components analysis to show that more than 90% of the total variance in routine analysis by ICP-AES is not random but multi-element correlated and therefore potentially correctable. Ten possible causes of this variation are quantified in terms of their particular multi-element respose “signatures”. Comparison of the ten signatures suggests that only two signatures predominate, despite being produced by seven apparently independent instrumental parameters.A new method of improving the medium-term precision of ICP-AES is described in which the variation from the two predominating signatures on all analytes is removed by use of the parameter-related internal standard method (PRISM). Two internal standard elements are chosen each of which responds significantly to only one of the two predominating signatures. Two instrumental parameters, forward power and nebuliser uptake rate, are varied separately. In each instance the response of each analyte is related to corresponding variation of the appropriate internal standard. For subsequent routine analysis a straightforward mathematical correction is then applied to each analyte using the measured function relating that analyte with both internal standards.
Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or “IC”) is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a “leaky gut” phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.
A behavioral paradigm for cortical control of a robotic actuator by freely moving rats in a one-dimensional two-target reaching task

Controlling the trajectory of a neuroprosthetic device to reach multiple targets is a commonly used brain-machine interface (BMI) task in primates and has not been available for rodents yet. Here, we describe a novel experimental paradigm which enables this task for rats in one-dimensional space for reaching two distant targets depending on their limited cognitive and visual capabilities compared to primates. An online transform was used to convert the activity of a pair of primary motor cortex (M1) units into two robotic actions. The rats were shaped to adapt to the transform and direct the robotic actuator toward the selected target by modulating the activity of the M1 neurons. All three rats involved in the study were capable of achieving randomly selected targets with at least 78% accuracy. A total of 9 out of 16 pairs of units examined were eligible for exceeding this success criterion. Two out of three rats were capable of reversal learning, where the mapping between the activity of the unit pairs and the robotic actions were reversed. The present work is the first demonstration of trajectory-based control of a neuroprosthetic device by rodents to reach two distant targets using visual feedback. The paradigm introduced here may be used as a cost-effective platform for elucidating the information processing principles in the neural circuits related to neuroprosthetic control and for studying the performance of novel BMI technologies using freely moving rats.
Modulation of auditory responses by visual inputs in the mouse auditory cortex

So far, our understanding on the role of the auditory cortex (ACX) in processing visual information has been limited to infragranular layers of the ACX, which have been shown to respond to visual stimulation. Here, we investigate the neurons in supragranular layers of the mouse ACX using 2-photon calcium imaging. Contrary to previous reports, here we show that more than 20% of responding neurons in layer2/3 of the ACX respond to full-field visual stimulation. These responses occur by both excitation and hyperpolarization. The primary ACX (A1) has a greater proportion of visual responses by hyperpolarization compared to excitation likely driven by inhibitory neurons of the infragranular layers of the ACX rather than local layer 2/3 inhibitory neurons. Further, we found that more than 60% of neurons in the layer 2/3 of A1 are multisensory in nature. We also show the presence of multisensory neurons in close proximity to exclusive auditory neurons and that there is a reduction in the noise correlations of the recorded neurons during multisensory presentation. This is evidence in favour of deep and intricate visual influence over auditory processing. The results have strong implications for decoding visual influences over the early auditory cortical regions. Significance statement To understand, what features of our visual world are processed in the auditory cortex (ACX), understanding response properties of auditory cortical neurons to visual stimuli is important. Here, we show the presence of visual and multisensory responses in the supragranular layers of the ACX. Hyperpolarization to visual stimulation is more commonly observed in the primary ACX. Multisensory stimulation results in suppression of responses compared to unisensory stimulation and an overall decrease in noise correlation in the primary ACX. The close-knit architecture of these neurons with auditory specific neurons suggests the influence of non-auditory stimuli on the auditory processing.