Miracle-dz/UniFAR-FTUs huggingface dataset:
Computational multiplex panel reduction to maximize information retention in breast cancer tissue microarrays

Recent state-of-the-art multiplex imaging techniques have expanded the depth of information that can be captured within a single tissue sample by allowing for panels with dozens of markers. Despite this increase in capacity, space on the panel is still limited due to technical artifacts, tissue loss, and long imaging acquisition time. As such, selecting which markers to include on a panel is important, since removing important markers will result in a loss of biologically relevant information, but identifying redundant markers will provide a room for other markers. To address this, we propose computational approaches to determine the amount of shared information between markers and select an optimally reduced panel that captures maximum amount of information with the fewest markers. Here we examine several panel selection approaches and evaluate them based on their ability to reconstruct the full panel images and information within breast cancer tissue microarray datasets using cyclic immunofluorescence as a proof of concept. We show that all methods perform adequately and can re-capture cell types using only 18 of 25 markers (72% of the original panel size). The correlation-based selection methods achieved the best single-cell marker mean intensity predictions with a Spearman correlation of 0.90 with the reduced panel. Using the proposed methods shown here, it is possible for researchers to design more efficient multiplex imaging panels that maximize the amount of information retained with the limited number of markers with respect to certain evaluation metrics and architecture biases. Author Summary Multiplex tissue imaging techniques utilize large panels of markers that attempt to gather as much information as possible, but increasing the number of stains does come with the downsides of increased autofluorescence and tissue degradation. There exists a theoretical subsampling of markers that is able to recreate the same information as a full panel; therefore, removing the self-correlating information with such a subset would increase the efficiency of the imaging process and maximize the information collected. By selecting an idealized subsample of markers, a deep learning model can be trained to predict the same information as a full dataset with fewer rounds of staining. Here we evaluate several methods of subsample marker selection and demonstrate their ability to reconstruct the full panel’s information.
A phase field system with memory : global existence (Free Boundary Problems)

In the present paper we analyze a phase ﬁeld model with memory: for T > 0, which has been recently proposed [ 29 ] as a phe- nomenological model to describe phase transitions in the presence of slowly relaxing internal variables. The system yields motion by mean curvature with memory under suitable assumptions in a sharp interface limit. In the present pa- per we give a proof of global existence of a weak solution ( u,φ ) ∈ C ([0 ,T ]; L 2 (Ω) × H 1 (Ω)) for (PFM) assuming that Ω is a smooth bounded domain in R n , n = 1 , 2, or 3, the kernels a 1 ,a 2 ∈ L 1 ( R + ) are of positive type, the initial data is in L 2 (Ω) × H 1 (Ω), and the history is in L 1 ( −∞ , 0; H 2 (Ω)) and L 1 ( −∞ , 0; H 3 (Ω)) ∩ L 5 ( −∞ , 0; L 6 (Ω)), respectively. Our methodology combines results from the theory of Volterra in- tegral equations with Galerkin methods and energy estimates. The results presented here were announced in [ 26 ].
Human anti-ACE2 monoclonal antibodies as pan-sarbecovirus prophylactic agents

Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Here, we describe the development of human monoclonal antibodies that bind the ACE2 receptor rather than the viral spike protein. These antibodies block infection by all ACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants. Structural and biochemical analyses revealed that the antibodies target an ACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit ACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology and protect human ACE2 knock-in mice against SARS-CoV-2 infection. Such antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as ACE2-binding sarbecoviruses that might emerge as future pandemic threats.
Haplotype mining panel for genetic dissection and breeding in Eucalyptus

To improve our understanding of genetic mechanisms underlying complex traits in plants, a comprehensive analysis of gene variants is required. Eucalyptus is an important forest plantation genus that is highly outbred. Trait dissection and molecular breeding in eucalypts currently relies on biallelic SNP markers. These markers fail to capture the large amount of haplotype diversity in these species and thus multi-allelic markers are required. We aimed to develop a gene-based haplotype mining panel for Eucalyptus species. We generated 17 999 oligonucleotide probe sets for targeted sequencing of selected regions of 6 293 genes implicated in growth and wood properties, pest and disease resistance and abiotic stress responses. We identified and phased 195 834 SNPs using a read-based phasing approach to reveal SNP-based haplotypes. A total of 8 915 target regions (at 4 637 gene loci) passed tests for Mendelian inheritance. We evaluated the haplotype panel in four Eucalyptus species (E. grandis, E. urophylla, E. dunnii and E. nitens) to determine its ability to capture diversity across eucalypt species. This revealed an average of 3.13 to 4.52 haplotypes per target region in each species and 33.36% of the identified haplotypes were shared by at least two species. This haplotype mining panel will enable the analysis of haplotype diversity within and between species and provide multi-allelic markers that can be used for genome-wide association studies and gene-based breeding approaches. Significance Statement We developed a haplotype sequencing panel for Eucalyptus targeting 8915 regions at 4637 gene loci associated with growth and wood properties, pest and disease resistance and abiotic stress response providing a genome-wide, multi-allelic, gene centric genotyping resource for eucalypts. We tested the panel in four Eucalyptus species (E. grandis, E. dunnii, E. nitens and E. urophylla) and found an average of 3.65 haplotypes per target region per species, and 9.98 across all four species.
A bioluminescence-based ex vivo burn wound model for real-time assessment of novel antibacterial compounds

The silent pandemic of antibiotic resistance is thriving, prompting the urgent need for the development of new antibacterial drugs. However, within the preclinical pipeline, in vitro screening conditions can differ significantly from the final in vivo settings. To bridge the gap between in vitro and in vivo assays, we developed a pig skin-based bioluminescent ex vivo burn wound infection model, enabling real-time assessment of antibacterials in a longitudinal, non-destructive manner. We provide a proof-of-concept for A. baumannii NCTC13423, a multidrug-resistant clinical isolate, which was equipped with the luxCDABE operon as a reporter using a Tn7-based tagging system. This bioluminescence model provided a linear correlation between the number of bacteria and a broad dynamic range (104 to 109 CFU). This longitudinal model was subsequently validated using a fast-acting enzybiotic as an antibacterial. Since this model combines a realistic, clinically relevant yet strictly controlled environment with real-time measurement of bacterial burden, we put forward this ex vivo model as a valuable tool to assess the preclinical potential of novel antibacterial compounds. Summary statement Here, we demonstrate the potential of a bioluminescence-based ex vivo model for the longitudinal assessment of antibacterials. Moreover, we also provide a proof-of-concept with an engineered lysin.
PyWGCNA: a Python package for weighted gene co-expression network analysis

Motivation Weighted gene co-expression network analysis (WGCNA) is frequently used to identify modules of genes that are co-expressed across many RNA-seq samples. However, the current R implementation is slow, not designed to compare modules between multiple WGCNA networks, and results are hard to interpret and visualize. We introduce the PyWGCNA Python package designed to identify and compare co-expression modules from RNA-seq data. Results We apply PyWGCNA to two distinct datasets of brain bulk RNA-seq from MODEL-AD to identify modules associated with the genotypes. We compare the resulting modules to each other to find modules with significant overlap across the datasets. Availability The PyWGCNA library for Python 3 is available on PyPi at https://pypi.org/project/PyWGCNA and on GitHub at https://github.com/mortazavilab/PyWGCNA.
Invasion of forested areas in Gabon (Central Africa) by the Asian tiger mosquito and the potential consequences from the One Health perspective

Since its first record in urban areas of Central-Africa in 2000s, the invasive mosquito, Aedes albopictus, has continued to spread across the region, including in remote rural areas, and promoted outbreaks of Aedes-borne diseases, such as dengue, chikungunya and Zika. From the One-Health perspective, such invasion might enhance Ae. albopictus interactions with wild animals in forest ecosystems and favor the spillover of zoonotic arboviruses to humans. From 2014 to 2018, we monitored the steady spread of this mosquito species in the wildlife reserve of La Lopé National Park (Gabon), and evaluated the magnitude of its colonization of the rainforest ecosystem using ovitraps, larval surveys, BG-Sentinel traps, and human landing catches following an anthropization gradient. We detected Ae. albopictus in forest galleries up to 15km away from La Lopé village. However, Ae. albopictus was significantly more abundant at anthropogenic sites than in less anthropized areas. The number of eggs laid by Ae. albopictus decreased progressively with the distance from the forest fringe up to 200m inside the forest, showing that its occurrence in forest ecosystems is restricted to anthropized-sylvatic interfaces with dense forest. This suggests that Ae. albopictus may act as bridge vector of zoonotic pathogens between wild and anthropogenic compartments.
Life-course social disparities in body mass index trajectories across adulthood: cohort study evidence from China Health and Nutrition Survey

Background The social disparities in obesity may originate in early life and adult social class. There are various developmental trajectories of overweight/obesity in adulthood. It is unclear how the intergenerational mobility of socioeconomic status influences adult overweight/obesity in China. Methods We used longitudinal data from ten waves of the China Health and Nutrition Survey (CHNS) between 1989 and 2015 for our analysis. The group-based trajectory modeling was used to identify BMI trajectories in adulthood. Multinomial logistic regression was adopted to assess the associations between SES and adult BMI trajectories. Results Among a total of 3,138 participants, three latent clusters, including normal-stable BMI (51.4%), progressive overweight group (39.8%), and progressive obesity group (8.8%), were identified. High father’s occupational position, high participants’ occupation position and educational attainment, respectively, were associated with greater obesity risk. Compared to a stable low life course SES trajectory, a stable high life course SES trajectory was associated with a 2.35-fold risk of obesity, and upward and downward social mobility trajectories increased the risk for overweight/obesity. Individuals in the highest relative to the lowest life course cumulative socioeconomic score group had around twice risk of obesity. Conclusions The results emphasize the role of the high SES in early life and life-course SES accumulation, in the obesity intervention in China. Funding All the work was supported by the National Natural Science Foundation of China (Grant Nos. 72174167, 81602928) and Natural Science Foundation of Shaanxi (2021JM-031).
Integrity of membrane fluidity and fatty acid environment are necessary for Ebola virus VP40 assembly and release of viral particles

Plasma membrane (PM) domains and order phases have been shown to play a key role in the assembly, release, and entry of several lipid-enveloped viruses. In the present study, we provide a mechanistic understanding of the Ebola virus (EBOV) matrix protein VP40 interaction with PM lipids and their effect on VP40 oligomerization, a crucial step for viral assembly and budding. VP40 matrix formation is sufficient to induce changes in the PM fluidity. We demonstrate that the distance between the lipid headgroups, the fatty acid tail saturation and the order between the two leaflets are important factors for the stability of VP40 binding and oligomerization at the PM. Use of FDA-approved drugs (dibucaine, propranolol and trifluoperazine) to fluidize the plasma membrane, destabilizes the viral matrix assembly leading to a reduction in budding efficiency. Lastly, we show that VP40 can tether and cluster lipid vesicles upon protein enrichment at the membrane. This is a new characteristic of the protein, and it opens the door to new avenues of exploration to deepen our understanding of VP40 host interactions and EBOV assembly. Indeed, our findings support a complex assembly mechanism of the EBOV viral matrix that reaches beyond lipid headgroup specificity using ordered PM lipid regions independent of cholesterol.
Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase

The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural constraints on the kinase domain holding it in a catalytically non-permissive state. The transition between inactive and active conformation is known to be largely regulated by the phosphorylation state of key tyrosines 416 and 527. Here we identified that phosphorylation of tyrosine 90 reduces binding affinity of the SH3 domain to its interacting partners, opens the Src structure, and renders Src catalytically active. This is accompanied by an increased affinity to the plasma membrane, decreased membrane motility and slower diffusion from focal adhesions. Phosphorylation of tyrosine 90 controlling SH3-medited intramolecular inhibitory interaction, analogical to tyrosine 527 regulating SH2-C-terminus bond, enables SH3 and SH2 domains to serve as cooperative but independent regulatory elements. This mechanism allows Src to adopt several distinct conformations of varying catalytic activities and interacting properties, enabling it to operate not as a simple switch but as a tunable regulator functioning as a signaling hub in a variety of cellular processes.
Dynamic control of eye-head gaze shifts by a spiking neural network model of the superior colliculus

To reorient gaze (the eye in space) towards a target can be achieved by infinitely many combinations of eye- and head movements. However, behavioral measurements show that the primate gaze-control system selects specific contributions of eye- and head to the saccade, which depend on the initial eye-in-head orientation. Single-unit recordings in the primate superior colliculus (SC) during head-unrestrained gaze shifts have further suggested that cells may encode the instantaneous trajectory of a desired straight gaze path in a feedforward way by the total cumulative number of spikes in the neural population, and that the instantaneous gaze kinematics are determined by the neural firing rates. The recordings also indicated that the latter depended strongly on the initial eye position as well. We recently proposed a conceptual model that accounts for many of the observed properties of eye-head gaze shifts and on the potential role of the SC. Here, we extend and test the model by incorporating a spiking neural network of the SC motor map, the output of which drives the eye-head motor control circuitry by linear cumulative summation of individual spike effects of each recruited SC neuron. We propose a simple neural mechanism on SC cells that explains the modulatory influence of feedback from an initial eye-in-head position signal on their spiking activity. The same signal also determines the onset delay of the head movement with respect to the eye. The downstream eye- and head burst generators were taken to be linear, as our earlier work had suggested that much of the nonlinear kinematics of saccadic eye movements may be due to neural encoding at the collicular level, rather than at the brainstem. We show that the spiking activity of the SC population drives gaze to the intended target location within a dynamic local gaze-velocity feedback circuit that yields realistic eye- and head-movement kinematics and dynamic SC gaze-movement fields.
Reprograming human fibroblasts into Sertoli cells: a tool for personalized medicine

Disorders/Differences of Sex Development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry. We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells. The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model.
The Moderating Influence of Acute Stress in the Relationship between Impulsivity and Reward Processing

Previous studies have shown that acute stress and impulsivity can directly impair reward sensitivity and performance on a response inhibition task. This study attempted to validate the Maastritch Acute Stress Task (MAST) as an effective stressor and to demonstrate that acute interfered with performance on reward processing and response inhibition tasks. The study also explored acute stress as the moderator of reward sensitivity on trait and behavioural impulsivity. The study confirmed that the MAST was an effective stressor, however, the MAST neither altered reward processing or response inhibition. For individuals who scored high on behavioural impulsivity (not trait impulsivity) the stressor reduced reward sensitivity and the ability to discriminate stimuli in the probabilistic reward task. The results showed the interaction of stress and impulsivity and its influence on reward processing which contributes to our understanding of how these variables may affect basic motivational processes underlying both normal and
Cloning and Expression Pattern of a Gene Encoding an a -Xylosidase Active against Xyloglucan Oligosaccharides from Arabidopsis 1

An a -xylosidase active against xyloglucan oligosaccharides was purified from cabbage ( Brassica oleracea var. capitata) leaves. Two peptide sequences were obtained from this protein, the N-terminal and an internal one, and these were used to identify an Arabidopsis gene coding for an a -xylosidase that we propose to call AtXYL1 . It has been mapped to a region of chromosome I between markers at 100.44 and 107.48 cM. AtXYL1 comprised three exons and encoded a peptide that was 915 amino acids long, with a potential signal peptide of 22 amino acids and eight possible N -glycosylation sites. The protein encoded by AtXYL1 showed the signature regions of family 31 glycosyl hydrolases, which comprises not only a -xylosidases, but also a -glucosidases. The a -xylosidase activity is present in apoplastic extractions from Arabidopsis seedlings, as suggested by the deduced signal peptide. The first eight leaves from Arabidopsis plants were harvested to analyze a -xylosidase activity and AtXYL1 expression levels. Both increased from older to younger leaves, where xyloglucan turnover is expected to be higher. When this gene was introduced in a suitable expression vector and used to transform Saccharomyces cerevisiae , significantly higher a -xylosidase activity was detected in the yeast cells. a -Glucosidase activity was also increased in the transformed cells, although to a lesser extent. These results show that AtXYL1 encodes for an apoplastic a -xylosidase active against xyloglucan oligosaccharides that probably also has activity against p -nitrophenyl- a - d -glucoside.