Miracle-dz/UniFAR-FTUs huggingface dataset:
Aberrant MNX1 expression associated with t(7;12)(q36;p13) pediatric acute myeloid leukemia induces the disease through altering histone methylation

Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome. One of these has a translocation t(7;12)(q36;p13) leading to a MNX1::ETV6 fusion along with high expression of MNX1. Here we identified the transforming event in this AML and possible ways of treatment. Only MNX1 was able to induce AML in mice, with similar gene expression and pathway enrichment to t(7;12) AML patient data. Importantly, this leukemia was only induced in immune incompetent mice using fetal but not adult hematopoietic stem and progenitor cells. The restriction in transforming capacity to cells from fetal liver is in alignment with t(7;12)(q36;p13) AML being mostly seen in infants. Expression of MNX1 led to increased histone 3 lysine 4 mono-, di- and trimethylation, reduction in H3K27me3, accompanied with changes in genome-wide chromatin accessibility and genome expression, likely mediated through MNX1 interaction with the methionine cycle and methyltransferases. MNX1 expression increased DNA damage, depletion of the Lin-/Sca1+/c-Kit+ population and skewing toward the myeloid lineage. These effects, together with leukemia development, was prevented by pretreatment with the S-adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of MNX1 in development of AML with t(7;12), supporting a rationale for targeting MNX1 and downstream pathways.
A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis in KRAS-driven lung cancer

Ferroptosis, a form of non-apoptotic cell death program driven by excessive lipid peroxidation and an important mechanism of tumor suppression, is frequently dysregulated in cancer. However, the mechanisms underlying impaired ferroptosis in oncogene-specific tumors remain poorly understood. Here we report a non- canonical role of lactate dehydrogenase B (LDHB), whose main activity is the conversion of lactate to pyruvate, in protecting KRAS-mutated lung cancer from ferroptosis. Silencing of LDHB impairs intracellular glutathione (GSH) metabolism and drives the hypersensitivity of KRAS-mutant cells to ferroptosis inducers by inhibiting the SLC7A11/GSH/GPX4 axis, a central antioxidant system against lipid peroxidation and ferroptosis by catalyzing GSH synthesis and utilization. Mechanistically, LDHB promotes SLC7A11 expression and GSH biosynthesis, and inhibition of LDHB confers metabolic synthetic lethality with ferroptosis inducers due to increased glutaminolysis and production of reactive oxygen species (ROS) in mitochondria, ultimately triggering ferroptosis of KRAS-driven lung cancer cells. Consequently, combined inhibition of LDHB and SLC7A11 synergistically suppresses tumor growth in multiple KRAS-mutant lung cancer implants and in an autochthonous model of Kras-induced lung adenocarcinoma. Taken together, our results reveal a hitherto unrecognized mechanism of ferroptosis defense by glycolytic LDHB and suggest a new strategy for the treatment of KRAS-dependent lung cancer.
Two disc dynamos with viscous friction and time delay

Abstract Two extensions of the Rikitake model are examined; the first includes viscous friction and the second includes time delay. By use of Liapounov's direct method the viscous system is shown to have an unstable limit cycle associated with two of the three singular points. By numerical integration true ‘reversals of field’ are shown to occur for both the viscous and time delay cases.
STATISTICAL CHARACTERIZATION OF RAY PROPAGATION IN A RANDOM LATTICE

We address the problem of optical propagation in random lattices. This can be relevant in characterizing, among other phenomena, the urban shortwave channels such as those involved in cellular communications. We consider an ensemble of optical rays, generated by an isotropic source, that propagates in a two-dimensional disordered medium whose characteristic parameter is the density of inner square reflectors. The statistical characterization of the propagation mechanism is our aim. In a previous work [ G. Franceschetti , IEEE Trans. Antennas Propag.47(7) (1999)], a quite similar scenario has been considered, with a ray impinging on a semi-infinite layer of reflectors and with a Markov chain formulation. We report the extension of such an approach to the internal-source scenario and point out how the independence assumption of the ray characterization may not lead to particularly accurate results. Therefore we propose a different approach, based solely on the geometry of the random lattice. We exploit the intuition that the relevant geometry in such a propagation problem should be based on the city-block distance rather than on the usual Euclidean distance. This allows us to obtain a simple analytical solution in the form of a parametric family of distribution functions. This basic result is validated by means of computer simulations.
STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as Stat3 deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated Stat3 deletion in 20% of the hematopoietic compartment. Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to Stat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin−ckit+Sca1+ BM cells revealed altered transcriptional responses in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient Lin−ckit+Sca1+ cells accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs. Key Points STAT3 is critical for hematopoietic activity and hematopoietic stem cell maintenance in non-inflammatory conditions STAT3 has a cell-intrinsic role in the suppression of interferon signaling and myeloid-skewed transcription in hematopoietic stem cells
RNAseq reveals that Pseudomonas aeruginosa mounts medium-dependent competitive responses when sensing diffusible cues from Burkholderia cenocepacia

Most habitats on earth are colonized by diverse bacterial communities, offering ample opportunities for inter-species interactions. While competition for space and nutrients might often dominate such interactions, little is known about whether bacteria can sense competitors and mount specific responses to withstand their attacks. The competition-sensing hypothesis proposes that bacteria can do so through nutrient stress and cell damage cues. Here, we conducted a replicated RNAseq-transcriptomic study to test this hypothesis. We exposed Pseudomonas aeruginosa to either its own spent medium or to the supernatant of its competitor Burkholderia cenocepacia. Compared to controls, we detected significant changes in the transcriptome of P. aeruginosa that entail both general responses to spent medium and specific responses to the competitor. Specifically, genes encoding various competitive traits, including the type-VI secretion system, the siderophore pyoverdine, and the toxins phenazines and hydrogen cyanide, were upregulated when exposed to the competitor supernatant. Similarly, several genes coding for stress response and quorum-sensing regulators were overexpressed. Moreover, we found transcriptional responses to vary as a function of iron availability, whereby metabolically more costly responses were launched under iron rich conditions. Altogether, our results reveal nuanced competitive responses of P. aeruginosa when exposed to B. cenocepacia supernatant, integrating both environmental and social cues.
Integrative analysis of in vitro strategies to induce human vascularized cerebral organoids using single-cell RNA sequencing data

Cerebral organoids are three-dimensional in vitro cultured brains that mimic the function and structure of the human brain. One of the major challenges for cerebral organoids is the lack of functional vasculature. Without perfusable vessels, oxygen and nutrient supplies may be insufficient for long-term culture, hindering the investigation of the neurovascular interactions. Recently, several strategies for the vascularization of human cerebral organoids have been reported. However, the generalizable trends and variability among different strategies are unclear due to the lack of a comprehensive characterization and comparison of these vascularization strategies. In this study, we aimed to explore the effect of different vascularization strategies on the nervous system and vasculature in human cerebral organoids. We integrated single-cell RNA sequencing data of multiple vascularized and vascular organoids and fetal brains from publicly available datasets and assessed the protocol-dependent and culture-day-dependent effects on the cell composition and transcriptomic profiles in neuronal and vascular cells. We revealed the similarities and uniqueness of multiple vascularization strategies and demonstrated the transcriptomic effects of vascular induction on neuronal and mesodermal-like cell populations. Moreover, our data suggested that the interaction between neurons and mesodermal-like cell populations is important for the cerebrovascular-specific profile of endothelial-like cells. This study highlights the current challenges to vascularization strategies in human cerebral organoids and offers a benchmark for the future fabrication of vascularized organoids.
CPA-Perturb-seq: Multiplexed single-cell characterization of alternative polyadenylation regulators

Most mammalian genes have multiple polyA sites, representing a substantial source of transcript diversity that is governed by the cleavage and polyadenylation (CPA) regulatory machinery. To better understand how these proteins govern polyA site choice we introduce CPA-Perturb-seq, a multiplexed perturbation screen dataset of 42 known CPA regulators with a 3’ scRNA-seq readout that enables transcriptome-wide inference of polyA site usage. We develop a statistical framework to specifically identify perturbation-dependent changes in intronic and tandem polyadenylation, and discover modules of co-regulated polyA sites exhibiting distinct functional properties. By training a multi-task deep neural network (APARENT-Perturb) on our dataset, we delineate a cis-regulatory code that predicts responsiveness to perturbation and reveals interactions between distinct regulatory complexes. Finally, we leverage our framework to re-analyze published scRNA-seq datasets, identifying new regulators that affect the relative abundance of alternatively polyadenylated transcripts, and characterizing extensive cellular heterogeneity in 3’ UTR length amongst antibody-producing cells. Our work highlights the potential for multiplexed single-cell perturbation screens to further our understanding of post-transcriptional regulation in vitro and in vivo.
Reelin plasma levels predict cognitive decline in Alcohol Use Disorder: peak levels in patients expressing plasma APOE4 protein

Background Human apolipoprotein (APO)-E4 has been related to neuropsychiatric disorders such as Alzheimer’s disease and cognitive decline. Reelin and Clusterin share the VLDLR and ApoER2 receptors with APOE4. Here we checked the role of these components in Alcohol Use Disorder (AUD)-induced cognitive decline. Methods This is a cross-sectional study with AUD-diagnosed patients (DSM-5) (n=24) recruited from an outpatient ‘Alcohol Programme’ and matched controls (n=34). Participants were assessed by the validated ‘Test of Detection of Cognitive Impairment in Alcoholism’ (TEDCA). APOE4 presence in plasma (distinguishing APOE4 carriers and no carriers subjects) and its levels were performed by ‘e4Quant’ technique. The rest of biological markers were tested by Enzyme-Linked Immunosorbent Assay kits. Results Plasma APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively. Quantification analyses revealed that APOE4 reached similar plasma levels in carriers independently if they were AUD subjects or controls. Circulant plasma APOE4 had a negative effect on AUD’s cognition, specifically affecting Memory/Learning (p<0.01, η2=0.15). Plasma Clusterin and Reelin increased in patients but, interestingly, Reelin plasma levels peaked in patients expressing APOE4 (p<0.05, η2=0.09), who showed reduced VLDL and ApoER2 expression in peripheral blood mononuclear cells (PBMCs). Reelin was a good predictor of cognitive loss in patients, accounting for the 42.3% and 54.0% of general intelligence and executive function impairments, respectively. Conclusions Reelin plasma levels are increased in AUD patients who express the APOE4 isoform, predicting cognitive deterioration to a great extent. Remarkably, plasma Reelin helps to differentiate between AUD patients with and without cognitive decline. Significance Statement Finding biological markers that predict a worse evolution in neuropsychiatric disorders may help to assist vulnerable patients appropriately. In this sense, in this study we found a biological marker, Reelin, which is elevated in patients with diagnosis of alcohol use disorder (AUD) that underwent an outpatient treatment. Interestingly, Reelin plasma levels were elevated in patients that also express APOE4, an aberrant protein present only in a small percentage of the population which is related to neuroinflammation and cognitive impairment (i.e. it is involved in Alzheimer’s disease). We observed that Reelin plasma levels negatively correlate with cognitive scores, being Reelin a good predictor of cognitive impairment in patients. These results may have implications for the follow-up of AUD patients in outpatient treatment.
Neural correlates of drinking reduction during cognitive behavioral therapy for alcohol use disorder

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in cognitive control and goal-directed behavior, plays a role behavior change during CBT by facilitating regulation of craving. To examine this, treatment-seeking participants with AUD (N=22) underwent functional MRI scanning both before and after a 12-week single-arm trial of CBT, using a regulation of craving (ROC) fMRI task designed to measure an individual’s ability to control alcohol craving and previously shown to engage the DLPFC. We found that both the number of heavy drinking days (NHDD, the primary clinical outcome) and the self-reported alcohol craving measured during the ROC paradigm were significantly reduced from pre- to post-CBT [NHDD: t=15.69, p<0.0001; alcohol craving: (F(1,21)=16.16; p=0.0006)]. Contrary to our hypothesis, there was no change in regulation effects on self-reported craving over time (F(1,21)=0.072; p=0.79), nor was there was a significant change in regulation effects over time on activity in any parcel. Searching the whole brain for neural correlates of reductions in drinking and craving after CBT, we found a significant 3-way interaction between the effects of cue-induced alcohol craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on NHDD in a parcel corresponding to area 46 of the right DLPFC (ß=-0.37, p=0.046, FDR corrected). Follow-up analyses showed that reductions in cue-induced alcohol craving from pre- to post-CBT were linearly related to reductions in alcohol cue-induced activity in area 46 only among participants who ceased heavy drinking during CBT (r=0.81, p=0.005) but not among those who continued to drink heavily (r=0.28, p=0.38). These results are consistent with a model in which CBT impacts heavy drinking by increasing the engagement of the DLPFC during cue-induced craving.
Benchmarking variational AutoEncoders on cancer transcriptomics data

Deep generative models, such as variational autoencoders (VAE), have gained increasing attention in computational biology due to their ability to capture complex data manifolds which subsequently can be used to achieve better performance in downstream tasks, such as cancer type prediction or subtyping of cancer. However, these models are difficult to train due to the large number of hyperparameters that need to be tuned. To get a better understanding of the importance of the different hyperparameters, we examined six different VAE models when trained on TCGA transcriptomics data and evaluated on the downstream task of cluster agreement with cancer subtypes. We studied the effect of the latent space dimensionality, learning rate, optimizer and initialization on the quality of subsequent clustering of the TCGA samples. We found β-TCVAE and DIP-VAE to have a good performance, on average, despite being more sensitive to hyperparameters selection. Based on these experiments, we derived recommendations for selecting the different hyperparameters settings. In addition, we examined whether the learned latent spaces capture biologically relevant information. Hereto, we correlated the different representations with various data characteristics such as age, days to metastasis, immune infiltration, and mutation signatures. We found that for all models the latent factors, in general, do not uniquely correlate with one of the data characteristics even for models specifically designed for disentanglement.
Cognitive relevance of an evolutionarily new and variable prefrontal structure 2

25 Identifying structural-functional correspondences is a major goal among biologists. In 26 neurobiology, recent findings identify relationships between performance on cognitive tasks and 27 the presence or absence of small, shallow indentations, or sulci, of the human brain. Here, we 28 tested if the presence or absence of one such sulcus, the paraintermediate frontal sulcus (pimfs- 29 v) in lateral prefrontal cortex, was related to relational reasoning in young adults from the Human 30 Connectome Project (ages 22-36). After manually identifying 2,877 sulci across 144 hemispheres, 31 our results indicate that the presence of the pimfs-v in the left hemisphere was associated with a 32 21-34% higher performance on a relational reasoning task. These findings have direct 33 developmental and evolutionary relevance as recent work shows that the presence or absence 34 of the pimfs-v is also related to reasoning performance in a pediatric cohort, and that the pimfs-v 35 is exceedingly rare in chimpanzees. Thus, the pimfs-v is a novel developmental, cognitive, and 36 evolutionarily relevant feature that should be considered in future studies examining how the 37 complex relationships among multiscale anatomical and functional features of the brain give rise 38 to abstract thought. 39
Mesoscale Frequencies and Seasonal Snowfalls for Different Types of Lake Michigan Snow Storms

Abstract Members of the Cloud Physics Laboratory, University of Chicago, have identified three different mesoscale organization patterns of lake-effect snow storms over Lake Michigan: multiple wind-parallel bands, single midlake bands, and single shoreline bands. For the 70 snowfall seasons ending with 1980/81, Braham and Dungey estimated that lake-effect snows contributed 8% of the total snowfall along the west shore of the lake, and 39% along the east shore. In the present study daily GOES satellite images and daily snowfall records are used to find the seasonal snowfall in four geographical area from each type of lake-effect storm and from nonlake-effect storms, for the snowfall seasons 1978/79 and 1979/80. Over the two seasons, 176 snowfall days were identified. Of these, 52% were nonlake-effect and 48% were lake-effect days. Of the 84 lake-effect days, 51% had wind-parallel bands, 22% had midlake bands, 2% had shoreline bands, and 25% had undetermined lake-effect cloud types. Along the west shore of .
In-group Social Conformity Updates the Neural Representation of Facial Attractiveness

People readily change their behavior to comply with the public. However, to which extent they will internalize the social influence remains elusive. In this pre-registered electroencephalogram (EEG) study, we employed a facial attractiveness social learning paradigm to investigate how learning from one’s in-group or out-group members would change attractiveness perception and neural representation. We found that participants changed their explicit attractiveness ratings to both in-group and out-group influences, i.e., public compliance. We next quantified the neural representational similarities of learned faces with prototypical attractive faces during a face perception task without overt social influence and intentional evaluation. We found that the neural representation of facial attractiveness changed only when participants learned from their in-group members, and among those who perceived tighter social norms. These findings provided novel knowledge on how group affiliations and individual differences modulate the impact of social influence on the internalization of social influence. Statement of Relevance Evolutionary-wise, following the crowd is important given its survival benefits. However, blind compliance with group opinions can also result in immoral decisions when group influence is toxic. Therefore, the crucial question is: To what extent, in which context, and for which population do individuals internalize social influence? We found that while people complied with opinions from both in- and out-group members, they only internalized such social influence from their in-group members, as evidenced by updated neural representations even when social influence was no longer present, and when the intentional evaluation was not required. This neural internalization effect was particularly pronounced among those who perceived tighter social norms. Our study suggests that in-group social influence is internalized and explains why in-group social influence is hard to eliminate afterward.