Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease

Preclinical efficacy and safety data in mice provide support for ex vivo β-globin gene correction to treat patients with sickle cell disease. Gene correction for SCD stem cells Sickle cell disease (SCD) is an autosomal recessive disease resulting from a point mutation in the β-globin gene that leads to sickle-shaped red blood cells, pain crises, and decreased life span. Here, Lattanzi et al. studied ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) as a potential cure for SCD. The authors demonstrated 20% gene correction after transplantation of corrected HSPCs into immunodeficient mice, with no evidence of genotoxicity or tumorigenicity. The gene-corrected HSPCs could also be reliably produced at scale. These studies lay the groundwork for a clinical trial of this gene correction strategy in patients with SCD. Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)–mediated HBB gene correction of the SCD-causing mutation in HSPCs. Here, we demonstrate the preclinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (gcHBB-SCD). We achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing. After transplant into immunodeficient NSG mice, 20% gene correction was achieved with multilineage engraftment. The long-term safety, tumorigenicity, and toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity, or tumorigenicity from the engrafted gcHBB-SCD drug product. Together, these preclinical data support the safety, efficacy, and reproducibility of this gene correction strategy for initiation of a phase 1/2 clinical trial in patients with SCD.
Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition

Macrophage depletion by colony-stimulating factor 1 receptor blockade alters extracellular matrix homeostasis and promotes skin edema. Elucidating edema formation Colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising anticancer therapy that depletes macrophages, but treatment is associated with edema. Bissinger et al. studied the changes to the extracellular matrix associated with anti-CSF1R treatment. They found an increase in matrix-modulating proteins and depletion of macrophages in the skin that preceded the deposition of hyaluronan and proteoglycans in mice treated with anti-CSF1R. In patients treated with the CSF1R inhibitor emactuzumab, serum hyaluronan increase was more pronounced in individuals that developed edema. This study helps uncover the mechanisms underlying anti-CSF1R–associated edema formation and suggests that inhibiting matrix-modulating proteins could help combat fluid retention. Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix–remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors.
The Evolution of Romania’s Internal Migration. Findings from the 1977, 1992, 2002 and 2011 Censuses

Abstract Although internal migration has been rather overlooked, both in terms of its magnitude and importance, its ability to reflect socio-economic changes is providing useful insights on the evolution of the Romanian society over the last decades. Based on the analysis of census microdata over the past 4 censuses, some major shifts in the magnitude and patterns in internal migration reveal the fact that characteristics of internal migrants have not only mirrored, but also preceded the changes observed for the total population. Among the most important developments revealed by our analysis have been a slight decrease in migration incidence since 1992, an increase in migrants residing in rural areas, especially in the South region, and a higher incidence among women, perhaps as a counterweight for higher international migration rates among men. Internal migrants’ age profile shows that they are 11 years older than the total population, up from a gap of only 6 years in 1977. Although they tend to be relatively more educated, their advantage has been on a declining trend and, contrary to common perceptions, are less likely to be single. At the county level, data reveals diverging patterns triggered by post-communist development, among which deindustrialization of some countries and strong international migration. These findings help portray the socio-economic changes as revealed by the analysis of census data, and provide any additional feedback to the annual internal migration flow estimates, by assessing the stock of those who moved from their birthplace, and showing how net internal migration patterns have morphed over time, both reflecting and effecting demographic and socioeconomic evolutions of the Romanian society1.
Pharmacological Inhibition of the VCP/Proteasome Axis Rescues Photoreceptor Degeneration in RHOP23H Rat Retinal Explants

Rhodopsin (RHO) misfolding mutations are a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). The most prevalent mutation, RHOP23H, results in its misfolding and retention in the Endoplasmic Reticulum (ER). Under homeostatic conditions, misfolded proteins are selectively identified, retained at the ER, and cleared via ER-associated degradation (ERAD) and/or autophagy. Overload of these degradation processes for a prolonged period leads to imbalanced proteostasis and may eventually result in cell death. ERAD of misfolded proteins like RHOP23H includes the subsequent steps of protein recognition, targeting for ERAD, retrotranslocation, and proteasomal degradation. In the present study, we investigated and compared pharmacological modulation of ERAD at these four different major steps. We show that inhibition of the VCP/proteasome activity favors cell survival and suppresses P23H-mediated retinal degeneration in RHOP23H rat retinal explants. We suggest targeting this activity as a therapeutic approach for patients with currently untreatable adRP.
Evolution of the nitric oxide synthase family in vertebrates and novel insights in gill development

Nitric oxide (NO) is an ancestral key signaling molecule essential for life and has enormous versatility in biological systems, including cardiovascular homeostasis, neurotransmission, and immunity. Although our knowledge of nitric oxide synthases (Nos), the enzymes that synthesize NO in vivo, is substantial, the origin of a large and diversified repertoire of nos gene orthologs in fish with respect to tetrapods remains a puzzle. The recent identification of nos3 in the ray-finned fish spotted gar, which was considered lost in the ray-finned fish lineage, changed this perspective. This prompted us to explore nos gene evolution and expression in depth, surveying vertebrate species representing key evolutionary nodes. This study provides noteworthy findings: first, nos2 experienced several lineage-specific gene duplications and losses. Second, nos3 was found to be lost independently in two different teleost lineages, Elopomorpha and Clupeocephala. Third, the expression of at least one nos paralog in the gills of developing shark, bichir, sturgeon, and gar but not in arctic lamprey, suggest that nos expression in this organ likely arose in the last common ancestor of gnathostomes. These results provide a framework for continuing research on nos genes’ roles, highlighting subfunctionalization and reciprocal loss of function that occurred in different lineages during vertebrate genome duplications.
Willingness to Pay in the Human Brain: A fMRI Activation Likelihood Estimation Meta-analysis

The neural substrate of willingness to pay (WTP) ultimately supports human economic exchange activities and plays a crucial role in daily life. This paper aimed to identify the neural basis of WTP for food and nonfood, as well as the brain regions related to real and hypothetical WTP choices. We found the human brain centers of WTP by performing an activation likelihood estimation (ALE) meta-analysis (27 experiments, 796 subjects) on the existing neuroimaging studies. The conjunction analysis revealed that WTP for food and nonfood engaged a common cluster in the paracingulate and cingulate gyrus, revealing a common reward circuit in the brain. The frontal medial cortex and paracingulate gyrus were particularly activated by WTP for nonfood. Furthermore, the left caudate, left thalamus, angular gyrus and supramarginal gyrus (subregions of inferior parietal lobule) were more convergently activated by hypothetical WTP choice. Our findings support the idea that a common currency representation in the brain and reward-specific neural basis. Results also provide evidence of neural representations of the hypothetical bias.
A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s ataxia

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction. Teaser Reduction of Cu1+ production by histone H3 restores cellular deficiencies caused by insufficient supply of iron-sulfur clusters.
Metacommunity dynamics and the spurious detection of species associations in co-occurrence analyses: patch disturbance matters

Many methods attempt to detect species associations from co-occurrence patterns. Such associations are then typically used to infer inter-specific interactions. However, correlation is not equivalent to interaction. Habitat heterogeneity and out-of-equilibrium colonization histories are acknowledged to cause species associations even when inter-specific interactions are absent. Here we show how classical metacommunity dynamics, within a homogeneous habitat at equilibrium, can also lead to statistical associations. This occurs even when species do not interact. All that is required is patch disturbance (i.e. simultaneous extinction of several species in a patch) a common phenomenon in a wide range of real systems. We compare direct tests of pairwise independence, matrix permutation approaches and joint species distribution modelling. We use mathematical analysis and example simulations to show that patch disturbance leads all these methods to produce characteristic signatures of spurious association from “null” co-occurrence matrices. Including patch age (i.e. the time since the last patch disturbance event) as a covariate is necessary to resolve this artefact. However, this would require data that very often are not available in practice for these types of analyses. We contend that patch disturbance is a key (but hitherto overlooked) factor which must be accounted for when analysing species co-occurrence.
In silico study for decoding the correlated role of MCM7 gene in progression of breast cancer and Alzheimer’s disorder

Breast cancer and Alzheimer’s disease (AD) are two of the progressive and detrimental disorders affecting large population around the globe. While the chemotherapy of breast cancer is well established and enriched, the AD still lacks it due to unrecognized peripheral biomarkers for detection and targeted therapy. This study aimed to identify common molecular signature markers in breast cancer (grade 1, 2, and 3) and AD for the diagnosis and prognosis. We used two microarray datasets (GSE42568, GSE33000) respectively for both disorders that led to identification of two common differentially expressed genes (DEGs), namely MCM7 and CD209, as common players in both these two conditions. While the pattern of expression of CD209 gene running upregulated in both disorders, the MCM7 showed unusual contrary in its pattern of expression. The expression of MCM7 is downregulated in breast cancer but upregulated in AD. Gene set and protein overrepresentation analysis, protein-protein interaction (PPI), and protein subcellular localizations analyses of this underrated MCM7 gene was performed with further prediction and validation of its structure. The findings may pave the way in designing therapeutic approaches to ameliorate AD.
Label2label: training a neural network to selectively restore cellular structures in fluorescence microscopy

Fluorescence microscopy is an essential tool in cell biology to visualise the spatial distribution of proteins that dictates their role in cellular homeostasis, dynamic cellular processes, and dysfunction during disease. However, unspecific binding of the antibodies that are used to label a cellular target often leads to high background signals in the images, decreasing the contrast of a cellular structure of interest. Recently, convolutional neural networks (CNNs) have been successfully employed for denoising and upsampling in fluorescence microscopy, but current image restoration methods cannot correct for background signals originating from the label. Here, we report a new method to train a CNN as content filter for non-specific signals in fluorescence images that does not require a clean benchmark, using dual-labelling to generate the training data. We name this method label2label (L2L). In L2L, a CNN is trained with image pairs of two non-identical labels that target the same cellular structure of interest. We show that after L2L training a network restores images not only with reduced image noise but also label-induced unspecific fluorescence signal in images of a variety of cellular structures, resulting in images with enhanced structural contrast. By implementing a multi-scale structural similarity loss function, the performance of the CNN as a content filter is further enhanced, for example, in STED images of caveolae. We show evidence that, for this loss function, sample differences in the training data significantly decrease so-called hallucination effects in the restorations that we otherwise observe when training the CNN with images of the same label. We also assess the performance of a cycle generative adversarial network as a content filter after L2L training with unpaired image data. Lastly, we show that a CNN can be trained to separate structures in superposed fluorescence images of two different cellular targets, allowing multiplex imaging with microscopy setups where the number of excitation sources or detectors is limited.
An Overlapping Community Detection Approach in Ego-Splitting Networks Using Symmetric Nonnegative Matrix Factorization

Overlapping clustering is a fundamental and widely studied subject that identifies all densely connected groups of vertices and separates them from other vertices in complex networks. However, most conventional algorithms extract modules directly from the whole large-scale graph using various heuristics, resulting in either high time consumption or low accuracy. To address this issue, we develop an overlapping community detection approach in Ego-Splitting networks using symmetric Nonnegative Matrix Factorization (ESNMF). It primarily divides the whole network into many sub-graphs under the premise of preserving the clustering property, then extracts the well-connected sub-sub-graph round each community seed as prior information to supplement symmetric adjacent matrix, and finally identifies precise communities via nonnegative matrix factorization in each sub-network. Experiments on both synthetic and real-world networks of publicly available datasets demonstrate that the proposed approach outperforms the state-of-the-art methods for community detection in large-scale networks.
Phosphorus Compounds of Natural Origin: Prebiotic, Stereochemistry, Application

Organophosphorus compounds play a vital role as nucleic acids, nucleotide coenzymes, metabolic intermediates and are involved in many biochemical processes. They are part of DNA, RNA, ATP and a number of important biological elements of living organisms. Synthetic compounds of this class have found practical application as agrochemicals, pharmaceuticals, bioregulators, and othrs. In recent years, a large number of phosphorus compounds containing P-O, P-N, P-C bonds have been isolated from natural sources. Many of them have shown interesting biological properties and have become the objects of intensive scientific research. Most of these compounds contain asymmetric centers, the absolute configurations of which have a significant effect on the biological properties of the products of their transformations. This area of research on natural phosphorus compounds is still little-studied, that prompted us to analyze and discuss it in our review. Moreover natural organophosphorus compounds represent interesting models for the development of new biologically active compounds, and a number of promising drugs and agrochemicals have already been obtained on their basis. The review also discusses the history of the development of ideas about the role of organophosphorus compounds and stereochemistry in the origin of life on Earth, starting from the prebiotic period, that allows us in a new way to consider this most important problem of fundamental science.
R2-Cosmology and New Windows for Superheavy Dark Matter

Evolution and heating of the universe in R2-modified gravity are considered. It is shown that the universe’s history can be separated into four different epochs: (1) inflation, (2) heating due to curvature oscillations (scalaron decay), (3) transition to matter dominated period, and (4) conventional cosmology governed by General Relativity. Cosmological density of dark matter (DM) particles for different decay channels of the scalaron is calculated. The bounds on the masses of DM particles are derived for the following dominant decay modes: to minimally coupled scalars, to massive fermions, and to gauge bosons.
Addressing Health Literacy as a Foundation for Effective and Equitable Health Communication

Abstract Health behaviors contribute heavily to health outcomes and play a role in health disparities. To develop health education programming that is equitably accessible, health communicators in clinical and public health settings will be optimally positioned for success when they use a combination of strategies in the development and implementation of programming. Those strategies include use of health behavior theory to select content, plain language communication techniques to address limited health literacy, and a dissemination strategy designed to reach those who need information most but are often difficult to reach.
The Roles of Culture in Online User Reviews: An Empirical Investigation

Abstract Electronic word-of-mouth (eWOM) is a prominent source of information that significantly influences consumer purchase decisions. Recent literature has extensively explored the impact of eWOM on consumers-generated reviews and purchase decisions. However, few studies have analyzed the role of culture on eWOM. We use a novel dataset of Airbnb eWOM messages in order to empirically extend the findings by Banerjee and Chai (2019). We find that the sentiment of individualistic customers is worse than that of their collectivistic counterparts when both groups experience the same level of negative disconfirmations. Furthermore, guests from a relatively more distant culture rely less on heuristics. In particular, quality signals, such as the “superhost” status, are more influential to consumers from a less distant cultural background.
A Brief Introduction to the Principle and Application of Nuclear Magnetic Resonance Cryoporometry

Nuclear magnetic resonance cryoporometry is a novel method to characterize pore size distribution,combining NMR spectroscopy and the theory of phase transition of restricted materials which was studied by Gibbs,Thomson,etc.Due to the different phase transition point of restricted liquid within pores of various size,the pore size distribution can be derived via obtaining the liquid phase′s signal intensity as a function of the temperature by NMR.Compared with traditional methods of pore characterizing,it has some unique advantages.The method has been well studied abroad,while the studies are barely found in china.Through summarizing the foreign references,the theory,experiment method,research progress are briefly introduced and the application in cementitious materials is simply analyzed.
KRRecover: An Auto-Recovery Tool for Hijacked Devices and Encrypted Files by Ransomwares on Android

Ransomwares on Android have become a challenging threat, performing tasks such as hijacking screen resources, locking devices, and encrypting files. Even worse, with the evolution of ransomwares, many ransomwares can disable USB interfaces of mobile devices. It is difficult for users to recover their devices or decrypt files with the help of other equipment and gives monetary damages to victims. In this paper, we analyse the symmetry between the ransom behaviours and the source code of screen resource hijacked ransomwares, devices locked ransomwares and files encrypted ransomwares. We also propose strategies of recovering hijacked resources, recovering hijacked devices and decrypting encrypted files. To protect mobile devices and private files from ransomwares, we design and implement an automatic recovery application—KRRecover—which is used to recover the hijacked devices and decrypt encrypted files on Android.