Miracle-dz/UniFAR-FTUs huggingface dataset:
Formulative Study and Intracellular Fate Evaluation of Ethosomes and Transethosomes for Vitamin D3 Delivery

In this pilot study, ethosomes and transethosomes were investigated as potential delivery systems for cholecalciferol (vitamin D3), whose deficiency has been correlated to many disorders such as dermatological diseases, systemic infections, cancer and sarcopenia. A formulative study on the influence of pharmaceutically acceptable ionic and non-ionic surfactants allowed the preparation of different transethosomes. In vitro cytotoxicity was evaluated in different cell types representative of epithelial, connective and muscle tissue. Then, the selected nanocarriers were further investigated at light and transmission electron microscopy to evaluate their uptake and intracellular fate. Both ethosomes and transethosomes proven to have physicochemical properties optimal for transdermal penetration and efficient vitamin D3 loading; moreover, nanocarriers were easily internalized by all cell types, although they followed distinct intracellular fates: ethosomes persisted for long times inside the cytoplasm, without inducing subcellular alteration, while transethosomes underwent rapid degradation giving rise to an intracellular accumulation of lipids. These basic results provide a solid scientific background to in vivo investigations aimed at exploring the efficacy of vitamin D3 transdermal administration in different experimental and pathological conditions.
A Potential Role for HUWE1 in Modulating Cisplatin Sensitivity

Cisplatin is a widely used antineoplastic agent, whose efficacy is limited by primary and acquired therapeutic resistance. Recently, a bladder cancer genome-wide CRISPR/Cas9 knock-out screen correlated cisplatin sensitivity to multiple genetic biomarkers. Among the screen’s top hits was the HECT domain-containing ubiquitin E3 ligase (HUWE1). In this review, HUWE1 is postulated as a therapeutic response modulator, affecting the collision between platinum-DNA adducts and the replication fork, the primary cytotoxic action of platins. HUWE1 can alter the cytotoxic response to platins by targeting essential components of the DNA damage response including BRCA1, p53, and Mcl-1. Deficiency of HUWE1 could lead to enhanced DNA damage repair and a dysfunctional apoptotic apparatus, thereby inducing resistance to platins. Future research on the relationship between HUWE1 and platins could generate new mechanistic insights into therapy resistance. Ultimately, HUWE1 might serve as a clinical biomarker to tailor cancer treatment strategies, thereby improving cancer care and patient outcomes.
Unveiling the Antifouling Performance of Different Marine Surfaces and Their Effect on the Development and Structure of Cyanobacterial Biofilms

Since biofilm formation by microfoulers significantly contributes to the fouling process, it is important to evaluate the performance of marine surfaces to prevent biofilm formation, as well as understand their interactions with microfoulers and how these affect biofilm development and structure. In this study, the long-term performance of five surface materials—glass, perspex, polystyrene, epoxy-coated glass, and a silicone hydrogel coating—in inhibiting biofilm formation by cyanobacteria was evaluated. For this purpose, cyanobacterial biofilms were developed under controlled hydrodynamic conditions typically found in marine environments, and the biofilm cell number, wet weight, chlorophyll a content, and biofilm thickness and structure were assessed after 49 days. In order to obtain more insight into the effect of surface properties on biofilm formation, they were characterized concerning their hydrophobicity and roughness. Results demonstrated that silicone hydrogel surfaces were effective in inhibiting cyanobacterial biofilm formation. In fact, biofilms formed on these surfaces showed a lower number of biofilm cells, chlorophyll a content, biofilm thickness, and percentage and size of biofilm empty spaces compared to remaining surfaces. Additionally, our results demonstrated that the surface properties, together with the features of the fouling microorganisms, have a considerable impact on marine biofouling potential.
3D-Printed Micro-Tweezers with a Compliant Mechanism Designed Using Topology Optimization

The development of handling technology for microscopic biological samples such as cells and spheroids has been required for the advancement of regenerative medicine and tissue engineering. In this study, we developed micro-tweezers with a compliant mechanism to manipulate organoids. The proposed method combines high-resolution microstereolithography that uses a blue laser and topology optimization for shape optimization of micro-tweezers. An actuation system was constructed using a linear motor stage with a force control system to operate the micro-tweezers. The deformation of the topology-optimized micro-tweezers was examined analytically and experimentally. The results verified that the displacement of the tweezer tip was proportional to the applied load; furthermore, the displacement was sufficient to grasp biological samples with an approximate diameter of several hundred micrometers. We experimentally demonstrated the manipulation of an organoid with a diameter of approximately 360 µm using the proposed micro-tweezers. Thus, combining microstereolithography and topology optimization to fabricate micro-tweezers can be potentially used in modifying tools capable of handling various biological samples.
A Kalman Filter for Multilinear Forms and Its Connection with Tensorial Adaptive Filters †

The Kalman filter represents a very popular signal processing tool, with a wide range of applications within many fields. Following a Bayesian framework, the Kalman filter recursively provides an optimal estimate of a set of unknown variables based on a set of noisy observations. Therefore, it fits system identification problems very well. Nevertheless, such scenarios become more challenging (in terms of the convergence and accuracy of the solution) when the parameter space becomes larger. In this context, the identification of linearly separable systems can be efficiently addressed by exploiting tensor-based decomposition techniques. Such multilinear forms can be modeled as rank-1 tensors, while the final solution is obtained by solving and combining low-dimension system identification problems related to the individual components of the tensor. Recently, the identification of multilinear forms was addressed based on the Wiener filter and most well-known adaptive algorithms. In this work, we propose a tensorial Kalman filter tailored to the identification of multilinear forms. Furthermore, we also show the connection between the proposed algorithm and other tensor-based adaptive filters. Simulation results support the theoretical findings and show the appealing performance features of the proposed Kalman filter for multilinear forms.
Genomic and immunogenic changes of Piscine novirhabdovirus (Viral Hemorrhagic Septicemia Virus) over its evolutionary history in the Laurentian Great Lakes

A unique and highly virulent subgenogroup (-IVb) of Piscine novirhabdovirus, also known as Viral Hemorrhagic Septicemia Virus (VHSV), suddenly appeared in the Laurentian Great Lakes, causing large mortality outbreaks in 2005 and 2006, and affecting >32 freshwater fish species. Periods of apparent dormancy have punctuated smaller and more geographically-restricted outbreaks in 2007, 2008, and 2017. In this study, we conduct the largest whole genome sequencing analysis of VHSV-IVb to date, evaluating its evolutionary changes from 48 isolates in relation to immunogenicity in cell culture. Our investigation compares genomic and genetic variation, selection, and rates of sequence changes in VHSV-IVb, in relation to other VHSV genogroups (VHSV-I, VHSV-II, VHSV-III, and VHSV-IVa) and with other Novirhabdoviruses. Results show that the VHSV-IVb isolates we sequenced contain 253 SNPs (2.3% of the total 11,158 nucleotides) across their entire genomes, with 85 (33.6%) of them being non-synonymous. The most substitutions occurred in the non-coding region (NCDS; 4.3%), followed by the Nv- (3.8%), and M- (2.8%) genes. Proportionally more M-gene substitutions encoded amino acid changes (52.9%), followed by the Nv- (50.0%), G- (48.6%), N- (35.7%) and L- (23.1%) genes. Among VHSV genogroups and subgenogroups, VHSV-IVa from the northeastern Pacific Ocean has shown the fastest substitution rate (2.01x10-3), followed by VHSV-IVb (6.64x10-5) and by the VHSV-I, -II and-III genogroups from Europe (4.09x10-5). A 2016 gizzard shad (Dorosoma cepedianum) from Lake Erie possessed the most divergent VHSV-IVb sequence. The in vitro immunogenicity analysis of that sample displayed reduced virulence (as did the other samples from 2016), in comparison to the original VHSV-IVb isolate (which had been traced back to 2003, as an origin date). The 2016 isolates that we tested induced milder impacts on fish host cell innate antiviral responses, suggesting altered phenotypic effects. In conclusion, our overall findings indicate that VHSV-IVb has undergone continued sequence change and a trend to lower virulence over its evolutionary history (2003 through present-day), which may facilitate its long-term persistence in fish host populations.
Assistance in dying: Conditions for international comparison

Abstract This special issue of Death Studies interrogates conditions for conducting international comparisons of assistance in dying regimes, and of related discourses and practices. To do so, it provides comparative social sciences and humanities perspectives on assistance in dying. In this editorial introduction, we first trace the origin of this special issue to the symposium held in 2018 in Lausanne, Switzerland. We then offer a short exploration of how assistance in dying regimes have been compared in the literature. Finally, we identify key conditions for conducting international comparisons of assistance in dying based on the articles presented in this issue of Death Studies.
Stacked Biocomposite Screws in a Single-Stage Revision Anterior Cruciate Ligament Reconstruction Has Acceptable Fixation Strength in a Porcine Cadaveric Model

Background: Stacked screws is a commonly used technique in single-stage revision anterior cruciate ligament (ACL) reconstruction in the setting of bone loss, but there are limited data to support its use. Hypothesis: Two configurations of a biocomposite stacked screws construct have similar fixation strength and linear stiffness as a primary ACL reconstruction construct in a biomechanical model. Study Design: Controlled laboratory study. Methods: A total of 30 porcine legs were divided into 3 groups. Group 1 underwent primary ACL reconstruction with a patellar tendon graft fixed into the femur, with an 8-mm biocomposite interference screw of beta-tricalcium phosphate and poly lactide-co-glycolide. For a revision ACL reconstruction model, groups 2 and 3 had bone tunnels created and subsequently filled with 12-mm biocomposite screws. New bone tunnels were drilled through the filler screw and the surrounding bone, and the patellar bone plug was inserted. Group 2 was fixed with 8-mm biocomposite screws on the side of the graft opposite the filler screw, while group 3 had the interference screw interposed between the graft and the filler screw. The construct was loaded at 1.5 mm/s in line with the tunnel until failure. Load to failure, linear stiffness, and mode of failure were recorded. Results: The mean pullout strength for groups 1, 2, and 3 was 626 ± 145 N, 653 ± 152 N, and 720 ± 125 N, respectively (P = .328). The mean linear stiffness of the construct in groups 1, 2, and 3 was 71.4 ± 9.9 N/mm, 84.1 ± 11.1 N/mm, and 82.0 ± 10.8 N/mm, respectively. Group 2 was significantly stiffer than group 1 (P = .037). Conclusion: Two configurations of a biocomposite stacked screws construct for a single-stage revision ACL reconstruction in the setting of bone loss show a similar fixation strength and linear stiffness to a primary ACL reconstruction at time zero in a porcine model. Clinical Relevance: In the setting of bone loss from tunnel malpositioning, a single-stage revision ACL reconstruction using a stacked screws construct may provide adequate fixation strength and linear stiffness.
Identification of key immune regulatory genes in HIV–1 Progression

In the last few decades, application of DNA microarray technology has sprung up as a powerful technique for discovering stage specific changes in expression pattern of a disease progression. Human Immunodeficiency Virus (HIV) infection causes Acquired Immunodeficiency Syndrome (AIDS) which is one of the most devastating diseases affecting humankind. Here, we have proposed a framework to examine the difference among microarray gene expression data of uninfected and three different HIV–1 infection stages using module preservation statistics. Initially, we detected differentially expressed genes among all the stages and identified coexpression modules by using topological overlap as a dissimilarity measure. To examine relationship among co-expression modules, we have compiled a module eigenegene network for each sample category which models similarity among all coexpression modules. To further examine the network, we have found clusters in it which are termed as ‘meta-modules’. Different module preservation statistics with two composite statistics: “Zsummary” and “MedianRank” are utilized to examine changes in structure of coexpression modules. We have applied our proposed methodology to discover modular changes between uninfected and acute samples, acute and chronic samples, chronic and AIDS samples. We have found several interesting results on preservation characteristics of gene modules across different stages. Some genes are identified to be preserved in a pair of stages while alter their characteristics across other stages. We further validated the obtained results using permutation test and classification techniques. Biological significance of the obtained modules have been examined using gene ontology and pathway based analysis. Additionally, we have detected key immune regulatory hub genes in the associated protein-protein interaction networks (PPINs) of the differentially expressed genes (DEGs) using twelve topological and centrality analysis methods. Moreover, we have analyzed the key immune regulatory genes which interacts with HIV-1 proteins inside the preserved and perturbed meta-modules across different HIV-1 stages and thus likely to act as potential biomarkers in HIV–1 progression.
Systematic analysis of the ubiquitome in mouse testis

A growing body of evidence now supports the fact that protein ubiquitination is an important modification during the regulation of spermatogenesis. However, little is known about the ubiquitome of the testis. In this study, we created a large‐scale mouse testis ubiquitome profile using di‐glycine remnant antibodies and mass spectrometry and identified a total of 14,219 ubiquitination sites in 4217 proteins. Bioinformatics and phenotypic analyses showed that the ubiquitinated proteins were closely related to meiosis and spermiogenesis. And 512 ubiquitination regulatory enzymes were identified in testis that can exert regulatory functions over ubiquitination: the homologous to E6AP C‐terminus (HECT) and multi‐subunit RING‐finger type E3 ligases were significantly enriched. In addition, we identified 22 new ubiquitination sites on testicular histones and 146 ubiquitinated epigenetic factors, thus demonstrating that ubiquitination plays an important role in epigenetic regulation. Collectively, this in‐depth characterization of the ubiquitome in mouse testis could provide a rich resource for further studies of regulatory events at the protein level during spermatogenesis. All MS data are available via ProteomeXchange with the identifier PXD025866.
Liebau density vector: a new approach to characterize lone electron pairs in mullite-type materials

Abstract The bismuth 6s2 lone electron pair (LEP) in mullite-type Bi2M4O9/10 (where M = Al, Fe, or Mn) was characterized by means of several parameters derived from experimental and theoretical calculations. The Wang-Liebau eccentricity (WLE) parameter proved to be very useful to quantify the stereochemical activity of the LEPs. Calculations of electronic distributions (three-dimensional charge density difference isosurfaces) were used as independent measurements, which validated the relevance of the WLE parameter for the characterization and quantification of LEPs. The distribution of the Bi 6s2 electrons around the nucleus was evaluated and the maximum of electron density calculated. The spatial orientation of this electron density with respect to the nucleus is expressed as “Liebau density vector”. Therefore, this vector is ascribed to be a key result of this work as a proof that the purely geometrically defined Wang-Liebau vector indeed points towards the maximum electron density of the LEP. The LEP stereochemical activity was studied in terms of the type of structure (Bi2M4O9 or Bi2M4O10) and the nature of M. The effect of exchanging bismuth by lanthanum as well as the relative stabilities of Bi2M4O9 or Bi2M4O10 structures were calculated and discussed.
Mergeomics 2.0: a web server for multi-omics data integration to elucidate disease networks and predict therapeutics

Abstract The Mergeomics web server is a flexible online tool for multi-omics data integration to derive biological pathways, networks, and key drivers important to disease pathogenesis and is based on the open source Mergeomics R package. The web server takes summary statistics of multi-omics disease association studies (GWAS, EWAS, TWAS, PWAS, etc.) as input and features four functions: Marker Dependency Filtering (MDF) to correct for known dependency between omics markers, Marker Set Enrichment Analysis (MSEA) to detect disease relevant biological processes, Meta-MSEA to examine the consistency of biological processes informed by various omics datasets, and Key Driver Analysis (KDA) to identify essential regulators of disease-associated pathways and networks. The web server has been extensively updated and streamlined in version 2.0 including an overhauled user interface, improved tutorials and results interpretation for each analytical step, inclusion of numerous disease GWAS, functional genomics datasets, and molecular networks to allow for comprehensive omics integrations, increased functionality to decrease user workload, and increased flexibility to cater to user-specific needs. Finally, we have incorporated our newly developed drug repositioning pipeline PharmOmics for prediction of potential drugs targeting disease processes that were identified by Mergeomics. Mergeomics is freely accessible at http://mergeomics.research. idre.ucla. edu and does not require login.
Dynamic Amyloid PET: Relationships to 18F-Flortaucipir Tau PET Measures

Visual Abstract Measuring amyloid and predicting tau status using a single amyloid PET study would be valuable for assessing brain AD pathophysiology. We hypothesized that early-frame amyloid PET (efAP) correlates with the presence of tau pathology because the initial regional brain concentrations of radioactivity are determined primarily by blood flow, which is expected to be decreased in the setting of tau pathology. Methods: The study included 120 participants (63 amyloid-positive and 57 amyloid-negative) with dynamic 18F-florbetapir PET and static 18F-flortaucipir PET scans obtained within 6 mo of each other. These subjects were predominantly cognitively intact in both the amyloid-positive (63%) and the amyloid-negative (93%) groups. Parameters for efAP quantification were optimized for stratification of tau PET positivity, assessed by either a tauopathy score or Braak regions. The ability of efAP to stratify tau positivity was measured using receiver-operating-characteristic analysis of area under the curve (AUC). Pearson r and Spearman ρ were used for parametric and nonparametric comparisons between efAP and tau PET, respectively. Standardized net benefit was used to evaluate improvement in using efAP as an additional copredictor over hippocampal volume in predicting tau PET positivity. Results: Measuring efAP within the hippocampus and summing the first 3 min of brain activity after injection showed the strongest discriminative ability to stratify for tau positivity (AUC, 0.67–0.89 across tau PET Braak regions) in amyloid-positive individuals. Hippocampal efAP correlated significantly with a global tau PET tauopathy score in amyloid-positive participants (r = −0.57, P < 0.0001). Compared with hippocampal volume, hippocampal efAP showed a stronger association with tau PET Braak stage (ρ = −0.58 vs. −0.37) and superior stratification of tau PET tauopathy score (AUC, 0.86 vs. 0.66; P = 0.002). Conclusion: Hippocampal efAP can provide additional information to conventional amyloid PET, including estimation of the likelihood of tau positivity in amyloid-positive individuals.
ApodNet: Learning for High Frame Rate Synthetic Transmit Aperture Ultrasound Imaging

Two-way dynamic focusing in synthetic transmit aperture (STA) beamforming can benefit high-quality ultrasound imaging with higher lateral spatial resolution and contrast resolution. However, STA requires the complete dataset for beamforming in a relatively low frame rate and transmit power. This paper proposes a deep-learning architecture to achieve high frame rate STA imaging with two-way dynamic focusing. The network consists of an encoder and a joint decoder. The encoder trains a set of binary weights as the apodizations of the high-frame-rate plane wave transmissions. In this respect, we term our network ApodNet. The decoder can recover the complete dataset from the acquired channel data to achieve dynamic transmit focusing. We evaluate the proposed method by simulations at different levels of noise and in-vivo experiments on the human biceps brachii and common carotid artery. The experimental results demonstrate that ApodNet provides a promising strategy for high frame rate STA imaging, obtaining comparable lateral resolution and contrast resolution with four-times higher frame rate than conventional STA imaging in the in-vivo experiments. Particularly, ApodNet improves contrast resolution of the hypoechoic targets with much shorter computational time when compared with other high-frame-rate methods in both simulations and in-vivo experiments.