Miracle-dz/UniFAR-FTUs huggingface dataset:
Image model embeddings for digital pathology and drug development via self-supervised learning

Whole slide images (WSIs) contain rich pathology information which can be used to diagnose cancer, characterize the tumour microenvironment (TME), assess patient prognosis, and provide insights into the likelihood of whether a patient may respond to a given treatment. However, since WSI availability is generally scarce during early stage clinical trials, the applicability of deep learning models to new and ongoing drug development in early stages is typically limited. WSIs available in public repositories, such as The Cancer Genome Atlas (TCGA), enable an unsupervised pretraining approach to help alleviate data scarcity. Pretrained models can also be utilised for a range of downstream applications such as automated annotation, quality control (QC), and similar image search. In this work we present DIME (Drug-development Image Model Embeddings), a pipeline for training image patch embeddings for WSIs via self-supervised learning. We compare inpainting and contrastive learning approaches for embedding training in the DIME pipeline, and demonstrate state-of-the-art performance at image patch clustering. In addition, we show that the resultant embeddings allow for training effective downstream patch classifiers with relatively few WSIs, and apply this to an AstraZeneca-sponsored phase III clinical trial. We also highlight the importance of effective colour normalisation for implementing histopathology analysis pipelines, regardless of the core learning algorithm. Finally, we show via subjective exploration of embedding spaces that the DIME pipeline clusters interesting histopathological artefacts, suggesting a possible role for the method in QC pipelines. By clustering image patches according to underlying morphopathologic features, DIME supports subsequent qualitative exploration by pathologists and has the potential to inform and expediate biomarker discovery and drug development.
The connection between Rap1 and Talin1 in CD4+ T Lymphocytes

Agonist induced increase in integrin affinity for ligands (activation) plays a pivotal role in T cell trafficking and functions. Activation requires Rap1 GTPase-mediated recruitment of talin1 to the integrins in the plasma membrane. Rap1-interacting adaptor molecule (RIAM) is a Rap1 effector that serves this function in T cells. In addition, Rap1 directly binds to talin1 to enable integrin activation in platelets. Here, we assessed the relative contributions of the Rap1-talin1 interaction and RIAM and provide a complete accounting of the connections between Rap1 and talin1 that support integrin activation in conventional CD4+ (Tconv) and CD25HiFoxp3+CD4+ regulatory T (Treg) cells. Disruption of both Rap1 binding sites in talin1 (talin1 (R35E,R118E)) causes a partial defect in αLβ2, α4β1 and α4β7 integrin activation in both Tconv and Treg cells with resulting defects in T cell homing and functions. Over-expression of RIAM bypasses the integrin activation defect in Tconv cells expressing talin1 (R35E,R118E), indicating that RIAM can substitute for Rap1 binding to talin in integrin activation. Conversely, deletion of RIAM in talin1 (R35E,R118E) Tconv cells abrogates activation of αLβ2, α4β1 and α4β7. RIAM and lamellipodin (LPD) are mammalian members of the MRL protein family; LPD plays a more important role than RIAM in Treg cell integrin activation. Nevertheless, loss of RIAM profoundly exacerbates the defects in Treg cell function caused by the talin1 (R35E,R118E) mutation. Most importantly, deleting both MRL proteins combined with talin1 (R35E,R118E) phenocopies the complete lack of integrin activation observed in Rap1a/b null Treg cells. In sum, these data reveal the functionally significant connections between Rap1 and talin1 that enable αLβ2, α4β1 and α4β7 integrin activation in T cells.
Emotion Down- and Up-Regulation Act on Spatially Distinct Brain Areas: Interoceptive Regions to Calm Down and Other Affective Regions to Amp Up

Prior studies on emotion regulation identified a set of brain regions specialized for generating and controlling affect. Researchers generally agree that when up- and down-regulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating areas. However, the assumption that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We call this assumption the ‘affective dial hypothesis. ’ Our study tested this hypothesis by examining the overlap between the sets of regions activated during up-regulation and those deactivated during down-regulation in a large number of participants (N=105). We found that up- and down-regulation both recruit regulatory regions such as the inferior frontal gyrus and dorsal anterior cingulate gyrus but act on distinct affect-generating regions. While up-regulation increases BOLD signal in regions associated with emotion such as the amygdala, anterior insula, striatum and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity such as periventricular white matter, down-regulation decreases signal in regions receiving interoceptive input such as the posterior insula and postcentral gyrus. These findings indicate that up- and down-regulation do not generally exert opposing effects on the same affect-generating regions. Instead, they target different brain circuits. Significance Statement Many contexts require modulating one’s own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: that both emotion up- and down-regulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation differ more than previously appreciated for up- versus down-regulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention.
Effects of memantine and high dose vitamin D on gait in the APP/PS1 mouse model of Alzheimer’s disease following vitamin D deprivation

Background Altered gait is a frequent feature of Alzheimer’s disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods Male APPswe/PS1dE9 mice were split into four groups (n=14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. The VitD− group remained on this deficient diet for the rest of the study. At month 9, the remaining two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait performance was assessed at months 6, 9, 12, and 15. Results Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p<0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p<0.01), while mice treated with memantine and vitamin D did not (p=0.21). Conclusion Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.
Genomic Heritability: A Ragged Diagonal Between Bias and Variance

Many important traits in plants, animals, and microbes are polygenic and are therefore difficult to improve through traditional marker-assisted selection. Genomic prediction addresses this by enabling the inclusion of all genetic data in a mixed model framework. The main method for predicting breeding values is genomic best linear unbiased prediction (GBLUP), which uses the realized genomic relationship or kinship matrix (K) to connect genotype to phenotype. The use of relationship matrices allows information to be shared for estimating the genetic values for observed entries and predicting genetic values for unobserved entries. One of the key parameters of such models is genomic heritability , or the variance of a trait associated with a genome-wide sample of DNA polymorphisms. Here we discuss the relationship between several common methods for calculating the genomic relationship matrix and propose a new matrix based on the average semivariance that yields accurate estimates of genomic variance in the observed population regardless of the focal population quality as well as accurate breeding value predictions in unobserved samples. Notably, our proposed method is highly similar to the approach presented by Legarra (2016) despite different mathematical derivations and statistical perspectives and only deviates from the classic approach presented in VanRaden (2008) by a scaling factor. With current approaches, we found that the genomic heritability tends to be either over- or underestimated depending on the scaling and centering applied to the marker matrix (Z), the value of the average diagonal element of K, and the assortment of alleles and heterozygosity (H) in the observed population and that, unlike its predecessors, our newly proposed kinship matrix KASV yields accurate estimates of in the observed population, generalizes to larger populations, and produces BLUPs equivalent to common methods in plants and animals.
The anterior paired lateral neuron normalizes odour-evoked activity at the mushroom body calyx

To identify and memorize discrete but similar environmental inputs, the brain needs to distinguish between subtle differences of activity patterns in defined neuronal populations. The Kenyon cells of the Drosophila adult mushroom body (MB) respond sparsely to complex olfactory input, a property that is thought to support stimuli discrimination in the MB. To understand how this property emerges, we investigated the role of the inhibitory anterior paired lateral neuron (APL) in the input circuit of the MB, the calyx. Within the calyx, presynaptic boutons of projection neurons (PNs) form large synaptic microglomeruli (MGs) with dendrites of postsynaptic Kenyon cells (KCs). Combining EM data analysis and in vivo calcium imaging, we show that APL, via inhibitory and reciprocal synapses targeting both PN boutons and KC dendrites, normalizes odour-evoked representations in MGs of the calyx. APL response scales with the PN input strength and is regionalized around PN input distribution. Our data indicate that the formation of a sparse code by the Kenyon cells requires APL-driven normalization of their MG postsynaptic responses. This work provides experimental insights on how inhibition shapes sensory information representation in a higher brain centre, thereby supporting stimuli discrimination and allowing for efficient associative memory formation.
The transposition rate has little influence on equilibrium copy numbers of the P-element

The invasion of transposable elements (TEs) in mammals and invertebrates, is likely stopped by piRNAs that emerge after insertion of the TE into a piRNA cluster (the trap model). It remains, however, still unclear which factors influence the dynamics of TE invasions. The activity of the TE (i.e. transposition rate) is one of the frequently discussed key factors. Here we take advantage of the temperature-dependent activity of the P-element, a widely studied eukaryotic TE, to test how TE activity affects the dynamics of a TE invasion. Taking advantage of the temperature-specific activity of the P-element, we monitored its invasion dynamics in experimental Drosophila simulans populations at hot and cold culture conditions. Despite marked differences in transposition rates, the P-element reached very similar copy numbers at both temperatures. The reduction of the insertion rate upon approaching the copy number plateau was accompanied by the emergence of similar amounts of piRNAs against the P-element at both temperatures. Interestingly, the ping-pong cycle, which degrades TE transcripts, becomes only active after the copy number has reached the plateau. We show that the P-element abundance is an order of magnitude lower and fewer P-element insertions in piRNA clusters were observed than expected under the trap model. We conclude that the transposition rate has at the most only a minor influence on TE abundance, but other factors, such as paramutations or selection against TE insertions are shaping the TE composition of organism.
Controlling fibroblast fibrinolytic activity allows for the bio-engineering of stable connective tissue equivalents

In tissue engineering, cell origin is important to ensure outcome quality. However, the impact of the cell type chosen for seeding in a biocompatible matrix has been less investigated. Here, we investigated the capacity of primary and immortalized fibroblasts of distinct origins to degrade a gelatin/alginate/fibrin (GAF)-based biomaterial. We further established that fibrin was targeted by degradative fibroblasts through the secretion of fibrinolytic matrix-metalloproteinases (MMPs) and urokinase, two types of serine protease. Finally, we demonstrated that besides aprotinin, specific targeting of fibrinolytic MMPs and urokinase led to cell-laden GAF stability for at least several days. These results support the use of specific strategies to tune fibrin-based biomaterials degradation over time. It emphasizes the need to choose the right cell type and further bring targeted solutions to avoid the degradation of fibrin-containing hydrogels or bioinks.
Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase

The pairing of homologous chromosomes (homologs) in meiosis is essential for distributing the correct numbers of chromosomes into haploid gametes. In budding yeast, pairing depends on the formation of 150-200 Spo11-mediated double-strand breaks (DSBs) that are distributed among 16 homolog pairs, but it is not known if all, or only a subset of these DSBs, contribute to the close juxtaposition of homologs. Having established a system to measure the position of fluorescently tagged chromosomal loci in 3D space over time, we analyzed locus trajectories to determine how frequently, and how long, loci spend colocalized or apart. Continuous imaging revealed highly heterogeneous cell-to-cell behavior of foci, with the majority of cells exhibiting a “mixed” phenotype where foci move into and out of proximity, even at late stages of prophase, suggesting that the axial structures of the synaptonemal complex may be more dynamic than anticipated. The observed plateaus of the mean-squared change in distance (MSCD) between foci informed the development of a biophysical model of two diffusing polymers that captures the loss of centromere linkages as cells enter meiosis, nuclear confinement, and the formation of Spo11-dependent linkages. The predicted number of linkages per chromosome in our theoretical model closely approximates the small number (~2-4) of estimated synapsis-initiation sites, suggesting that excess DSBs have negligible effects on the overall juxtaposition of homologs. These insights into the dynamic in-terchromosomal behavior displayed during homolog pairing demonstrate the power of combining time-resolved in vivo analysis with modeling at the granular level. Significance Statement Essential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process is the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent “pairing” of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study is the first to provide observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.
Refining the Assessment of Entitlement in Romantic Relationships: The Sense of Relational Entitlement Scale—Revised (SRE-R)

Objective: A subjective sense of entitlement is strongly evoked in the context of romantic relationships. A pathological sense of entitlement results from believing a partner should fulfill all one’s needs and wishes (inflated) or that the expression of genuine needs is illegitimate (restricted). This study aimed to validate a revised, improved version of the Sense of Relational Entitlement scale entitled the Sense of Relational Entitlement scale—Revised (SRE-R). We hypothesized it would have good factor structure and convergent validity, and that attachment dimensions and relationship indices would predict both inflated and restricted subscales. Method: The SRE-R was completed by 854 Israeli adults (8.3% males) aged 31.94 ± 8.02. A subset (n = 629) also completed measures of attachment (ECR-S) and 447 completed measures of relational authenticity, pathological concern, and relational obsessions and compulsions. Results: CFA confirmed two factors, inflated and restricted sense of relational entitlement. Relational obsessive-compulsive symptoms and pathological concern predicted an inflated sense of entitlement, and attachment avoidance, pathological concern, and authenticity in relationships predicted a restricted sense of entitlement. Discussion: The SRE-R is a valid and useful tool to assess sense of entitlement in romantic relationships and should be examined in diverse samples and cultures.
relA Inactivation Converts Sulfonamides Into Bactericidal Compounds

Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting relA in Escherichia coli and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When E. coli ∆relA was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against E. coli O157 ∆relA in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them.
Influence of the Environment on the Distribution and Quality of Gentiana dahurica Fisch.

Gentiana dahurica Fisch. is a characteristic medicinal plant found in Inner Mongolia, China. To meet the increase in market demand and promote the development of medicinal plant science, we explored the influence of the environment on its distribution and the quantity of its active compounds (loganic acid and 6’-O-β-D-glucosylgentiopicroside) to find suitable cultivation areas for G. dahurica. Based on the geographical distribution of G. dahurica in Inner Mongolia and the ecological factors that affect its growth, identified from the literature and field visits, a boosted regression tree (BRT) was used to model ecologically suitable areas in the region. The relationship between the content of each of active compound in the plant and ecological factors was also established for Inner Mongolia using linear regression. The results showed that elevation and soil type had the most significant influence on the distribution of G. dahurica—their relative contribution was 30.188% and 28.947%, respectively. The factors that had the greatest impact on the distribution of high-quality G. dahurica were annual precipitation, annual mean temperature, and temperature seasonality. The results of BRT and linear regression modeling showed that suitable areas for high-quality G. dahurica included eastern Ordos, southern Baotou, Hohhot, southern Wulanchabu, southern Xilin Gol, and central Chifeng. However, there were no significant correlations between the contents of loganic acid and 6’-O-β-D-glucosylgentiopicroside and the ecological factors. This study explored the influence of the environment on the growth and quantity of active compounds in G. dahurica to provide guidance for coordinating the development of medicinal plant science.
Template-free synthesis of mesoporous α-Fe2O3 nanoflowers with short charge-carrier diffuse distance for superior photocatalysis

Abstract In this work, well-shaped monodisperse mesoporous α-Fe2O3 nanoflowers were prepared by a facile template-free solvothermal route. The α-Fe2O3 nanoflowers with size of ~80 nm composed of nanobranches with width of ~10 nm. Contributed by the short charge-carrier diffuse distance of thin branches, the as-prepared mesoporous α-Fe2O3 nanoflowers possess notably higher phtotocatalytic activity in comparison with non-porous samples, commercial α-Fe2O3 and TiO2 by a model organic dye degradation reaction of Rhodamine B. The kinetic constant of mesoporous α-Fe2O3 nanoflowers for Rhodamine B degradation is about twice that of the non-porous materials and 10 times that of commercial α-Fe2O3 photocatalyst. Therefore, a simple method is developed to access the highly active mesoporous α-Fe2O3 nanoflowers, and the as-prepared material is potential to be used in photocatalysis or solar energy harvest.