Miracle-dz/UniFAR-FTUs huggingface dataset:
Multivalency of nucleosome recognition by LEDGF

Abstract Eukaryotic transcription is dependent on specific histone modifications. Their recognition by chromatin readers triggers complex processes relying on the coordinated association of transcription regulatory factors. Although various modification states of a particular histone residue often lead to differential outcomes, it is not entirely clear how they are discriminated. Moreover, the contribution of intrinsically disordered regions outside of the specialized reader domains to nucleosome binding remains unexplored. Here, we report the structures of a PWWP domain from transcriptional coactivator LEDGF in complex with the H3K36 di- and trimethylated nucleosome, indicating that both methylation marks are recognized by PWWP in a highly conserved manner. We identify a unique secondary interaction site for the PWWP domain at the interface between the acidic patch and nucleosomal DNA that might contribute to an H3K36-methylation independent role of LEDGF. We reveal DNA interacting motifs in the intrinsically disordered region of LEDGF that discriminate between the intra- or extranucleosomal DNA but remain dynamic in the context of dinucleosomes. The interplay between the LEDGF H3K36-methylation reader and protein binding module mediated by multivalent interactions of the intrinsically disordered linker with chromatin might help direct the elongation machinery to the vicinity of RNA polymerase II, thereby facilitating productive elongation.
Evaluation of canine and feline leukocyte differential counts obtained with the scil vCell 5 compared to the Advia 2120 hematology analyzer and a manual method

The vCell 5 (scil Animal Care), a point-of-care hematology analyzer (POCA), was recently introduced to veterinary laboratories. This laser- and impedance-based analyzer is capable of providing a CBC with 5-part WBC differential count (Diff) along with WBC cytograms and flags serving as interpretation aids for numerical results. We compared the scil POCA-Diff to reference methods (i.e., manual differential count, Advia 2120 hematology analyzer [Siemens]) for canine and feline blood samples and considered WBC cytograms and flags. Total observed error (TEo), calculated from CV and bias%, was compared to total allowable error (TEa). Data were analyzed before and after a review process (exclusion of flagged and samples with invalid cytograms). For both species, correlation was good-to-excellent (rs = 0.81–0.97) between both analyzers for all variables, except for feline monocytes (rs = 0.21–0.63) and canine monocyte% (rs = 0.50). Smallest biases were seen for neutrophils (dog: −5.7 to 0.8%; cat: 1.5–9.4%) with both reference methods. Quality requirements (TEo < TEa) were fulfilled for canine and feline neutrophils (TEo = 5.3–10.6%, TEa = 15%) and eosinophils (TEo = 67.1–83%, TEa = (90)–50%) considering at least one reference method. Our review process led to mildly higher rs-values for most variables. Although not completely satisfactory, the scil POCA provides reliable results in compliance with ASVCP quality goals for canine and feline neutrophils and eosinophils. Analyzer flag and cytogram analysis served as useful tools for QA, indicating the necessity for manual review of blood smears, and contributed to improvement of scil POCA performance.
3D Printing of Interpenetrating Network Flexible Hydrogels with Enhancement of Adhesiveness

3D printing of hydrogels has been widely explored for the rapid fabrication of complex soft structures and devices. However, using 3D printing to customize hydrogels with both adequate adhesiveness and toughness remains a fundamental challenge. Here, we demonstrate mussel-inspired (polydopamine) PDA hydrogel through the incorporation of a classical double network (2-acrylamido-2-methylpropanesulfonic acid) PAMPS/(polyacrylamide) PAAm to achieve simultaneously tailored adhesiveness, toughness, and biocompatibility and validate the 3D printability of such a hydrogel into customized architectures. The strategy of combining PDA with PAMPS/PAAm hydrogels leads to favorable adhesion on either hydrophilic or hydrophobic surfaces. The hydrogel also shows excellent flexibility, which is attributed to the reversible cross-linking of PDA and PAMPS, together with the long-chain PAAm cross-linking network. Among them, the reversible cross-linking of PDA and PAMPS is capable of dissipating mechanical energy under deformation. Meanwhile, the long-chain PAAm network contributes to maintaining a high deformation capability. We establish a theoretical framework to quantify the contribution of the interpenetrating networks to the overall toughness of the hydrogel, which also provides guidance for the rational design of materials with the desired properties. Our work manifests a new paradigm of printing adhesive, tough, and biocompatible interpenetrating network hydrogels to meet the requirements of broad potential applications in biomedical engineering, soft robotics, and intelligent and superabsorbent devices.
Yersinia deploys type III-secreted effectors to evade caspase-4 inflammasome activation in human cells

ABSTRACT Yersinia are Gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to inject Yersinia outer proteins into the host cytosol to subvert essential components of innate immune signaling. However, Yersinia virulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection. Yersinia activation and evasion of inflammasomes have been characterized in murine macrophages but remain poorly defined in human cells, particularly intestinal epithelial cells (IECs), a primary site of intestinal Yersinia infection. In contrast to murine macrophages, we find that in both human IECs and macrophages, Yersinia pseudotuberculosis T3SS effectors promote evasion of the caspase-4 inflammasome, which senses cytosolic lipopolysaccharide. The anti-phagocytic YopE and YopH, as well as the translocation regulator YopK, were collectively responsible for evading inflammasome activation, in part by inhibiting Yersinia internalization mediated by YadA and β1-integrin signaling. These data provide insight into the mechanisms of Yersinia-mediated inflammasome activation and evasion in human cells and reveal species-specific differences underlying the regulation of inflammasome responses to Yersinia. IMPORTANCE Yersinia are responsible for significant disease burden in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics (Yersinia pestis plague). Together with rising antibiotic resistance rates, there is a critical need to better understand Yersinia pathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans. Here, we dissect human intestinal epithelial cell and macrophage inflammasome responses to Yersinia pseudotuberculosis. Our findings provide insight into species- and cell type-specific differences in inflammasome responses to Yersinia. Yersinia are responsible for significant disease burden in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics (Yersinia pestis plague). Together with rising antibiotic resistance rates, there is a critical need to better understand Yersinia pathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans. Here, we dissect human intestinal epithelial cell and macrophage inflammasome responses to Yersinia pseudotuberculosis. Our findings provide insight into species- and cell type-specific differences in inflammasome responses to Yersinia.
Five‐year on‐treatment variables‐based PPACS model predicts subsequent hepatocellular carcinoma in entecavir/tenofovir‐treated patients

Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long‐term potent antiviral therapy, models predicting HCC after 5 years of therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4‐fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore, Platelet counts and Prothrombin time at 5 years, Age at baseline and Sex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time‐dependent area under the curve of 0.80 (95% confidence interval, 0.75‐0.85) at 8‐year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (https://ppacs.shinyapps.io/shiny_app_up/).
First principles modeling of mechanical properties of binary alloys containing Ga, Sn, and In for soldering applications

Using density functional theory, the elastic properties of various binary Ga, Sn, and In-based alloys have been calculated to determine their viability as potential replacements for toxic Pb-based solders. Computed quantities such as the bulk K, shear G, and Young’s E moduli were used to evaluate the mechanical behavior of the studied materials. The Pugh ratio γ and Poisson’s ratio ν were utilized to quantify the ductility of the alloys. Through comparative charge density analysis, we illustrated the relationship between the relative charge distributions and the aforementioned ductility metrics. Among the 52 studied alloys, 27 were determined to be stable/metastable at room temperature, and each of these stable/metastable materials are expected to be ductile. To facilitate the discovery and implementation of thermodynamically accessible and ductile solders, this work focuses on the mechanical properties of the alloys expected to be stable/metastable. Based on the cutoff criteria for stability and ductility established at the end of this work ( EForm < 10 meV/atom and γ > 4.00), the α-Ga0.125In0. 875, GaII0.750In0. 250, GaII0.833Sn0. 167 and In0.875Ga0. 125 alloys warrant further study for soldering applications.
A mixture of glyphosate and 2,4‐D herbicides enhances the deleterious reproductive outcomes induced by Western diet in obese male mice

The consumption of Western diet (WD) – enriched in fats and sugars – is associated with overweight, obesity and male reproductive disorders. In addition to WD intake, crops and dairy products display residues of herbicides, including glyphosate and 2,4‐D that are widely applied worldwide. The concomitant exposure to WD and herbicides – mimicking contemporary scenarios – is not fully investigated. Thus, we evaluated the effects of glyphosate and 2,4‐D, alone or in mixture, on WD‐induced alterations in the male genital system. Male C57BL6J mice were submitted to WD (chow containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D‐fructose and D‐glucose) for 6 months. Concomitantly to WD, the animals received glyphosate (0.05, 5, or 50 mg/kg/day), 2,4‐D (0.02, 2 or 20 mg/kg/day) or their mixture (0, 05 + 0.02, 5 + 2, or 50 + 20 mg/kg/day) by intragastrical administration (5×/week). Doses were based on Acceptable Daily Intake (ADIs) or No Observed Adverse Effect Level (NOAEL) values. Herbicide exposure did not alter the WD‐induced obesity, hypercholesterolemia and hyperglycemia. WD induced sperm cell abnormalities, reduced the number, volume and area of Leydig cells, enhanced the frequency of epididymal abnormalities, decreased the proliferation in both germinal and epididymal epithelia, and reduced the number of androgen receptor (AR) positive epididymal cells. Remarkably, the herbicide mixtures promoted such WD‐induced effects: increased the frequency of sperm cell and epididymal abnormalities (absence of sperm, cytoplasmic vacuoles, and clear cell hypertrophy) (5 + 2 and 50 + 20 doses); decreased Leydig cell nuclei volume and area (5 + 2 and 50 + 20 doses), reduced epididymal cell proliferation (all mixtures), and AR expression (50 + 20 dose). In addition, herbicide mixtures reduced serum testosterone levels (5 + 2 and 50 + 20 doses). Our findings indicate that the mixture of glyphosate and 2,4‐D herbicides, mimicking environmentally relevant scenarios, promotes WD‐induced changes in the male genital system.
RNAcode_Web – Convenient identification of evolutionary conserved protein coding regions

Abstract The differentiation of regions with coding potential from non-coding regions remains a key task in computational biology. Methods such as RNAcode that exploit patterns of sequence conservation for this task have a substantial advantage in classification accuracy in particular for short coding sequences, compared to methods that rely on a single input sequence. However, they require sequence alignments as input. Frequently, suitable multiple sequence alignments are not readily available and are tedious, and sometimes difficult to construct. We therefore introduce here a new web service that provides access to the well-known coding sequence detector RNAcode with minimal user overhead. It requires as input only a single target nucleotide sequence. The service automates the collection, selection, and preparation of homologous sequences from the NCBI database, as well as the construction of the multiple sequence alignment that are needed as input for RNAcode. The service automatizes the entire pre- and postprocessing and thus makes the investigation of specific genomic regions for previously unannotated coding regions, such as small peptides or additional introns, a simple task that is easily accessible to non-expert users. RNAcode_Web is accessible online at rnacode.bioinf. uni-leipzig.de.
An Extensive-Form Game Paradigm for Visual Field Testing via Deep Reinforcement Learning

Glaucoma is the leading cause of irreversible but preventable blindness worldwide, and visual field testing is an important tool for its diagnosis and monitoring. Testing using standard visual field thresholding procedures is time-consuming, and prolonged test duration leads to patient fatigue and decreased test reliability. Different visual field testing algorithms have been developed to shorten testing time while maintaining accuracy. However, the performance of these algorithms depends heavily on prior knowledge and manually crafted rules that determine the intensity of each light stimulus as well as the termination criteria, which is suboptimal. We leverage deep reinforcement learning to find improved decision strategies for visual field testing. In our proposed algorithms, multiple intelligent agents are employed to interact with the patient in an extensive-form game fashion, with each agent controlling the test on one of the testing locations in the patient's visual field. Through training, each agent learns an optimized policy that determines the intensities of light stimuli and the termination criteria, which minimizes the error in sensitivity estimation and test duration at the same time. In simulation experiments, we compare the performance of our algorithms against baseline visual field testing algorithms and show that our algorithms achieve a better trade-off between estimation accuracy and test duration. By retaining testing accuracy with reduced test duration, our algorithms improve test reliability, clinic efficiency, and patient satisfaction, and translationally affect clinical outcomes.
Planning strategies for robust carbon-ion scanning radiotherapy for stage I esophageal cancer: a retrospective study

Abstract This study aimed to establish a treatment planning strategy with carbon-ion scanning radiotherapy (CIRTs) for stage I esophageal cancer. The clinical data of seven patients treated with CIRTs were used. The setup error and interfractional and intrafractional motion error were analyzed using in-room computed tomography (CT) images for each treatment day. Finally, the planning target volume (PTV) margin was identified according to the accuracy of the treatment system. To ensure robustness against the positional displacements of the target and organs at risk (OAR), the replacement areas were placed as a contour adjacent to the tumor or OAR on the CT-image. The CT values of these areas were replaced by those of the target or OAR. Further, the dose distributions were optimized. Moreover, the variations in the target coverage from the initial plan for each treatment day (ΔV95%) were evaluated. By contrast, the risk of OAR was not evaluated in this study. The setup error was within 1.0 mm. The interfractional and intrafractional target motion errors were 2.8 and 5.0 mm, respectively. The PTV margins were 6.5 and 6.8 mm in the axial and depth directions, respectively. The robustness to target and OAR displacement was evaluated. The results showed that the target coverage with replacement could suppress decreased target coverage more than that without replacement. The PTV determination and replacement methods used in this study improved the target coverage in CIRTs for stage I esophageal cancer. Despite the need for a clinical follow-up, this method may help to improve clinical outcomes.
Differential current source to perform an active common-mode attenuation

電圧制御電流源であって、浮動負荷の為の差動電流源として動作し、或いは負荷の一端が接地されているときには、接地負荷電流源として動作するもの、を提供する。 差動電流源としての動作と、接地電流源としての動作の切替は自動であり、またこれは、電流源と負荷との間の有効なリード抵抗にも対応している。 更に、接地負荷が無ければ、本回路は、アクティブフィードバックを用いて負荷上のコモンモード電圧を低減するアクティブコモンモード減衰をも提供する。
Organizational benefits of neurodiversity: Preliminary findings on autism and the bystander effect

Although the bystander effect is one of the most important findings in the psychological literature, researchers have not explored whether autistic individuals are prone to the bystander effect. The present research examines whether autistic employees are more likely to report issues or concerns in an organization's systems and practices that are inefficient or dysfunctional. By bringing attention to these issues, autistic employees may foster opportunities to improve organizational performance, leading to the development of a more adaptive, high performing, and ethical culture. Thirty‐three autistic employees and 34 nonautistic employees completed an online survey to determine whether employees on the autism spectrum (1) are more likely to report they would voice concerns about organizational dysfunctions, (2) are less likely to report they were influenced by the number of other witnesses to the dysfunction, (3) if they do not voice concerns, are more likely to acknowledge the influence of other people on the decision, (4) are less likely to formulate “elaborate rationales” for their decisions to intervene or not, and (5) whether any differences between autistic and nonautistic employees with regards to the first two hypotheses, intervention likelihood and degree of influence, are moderated by individual differences in camouflaging. Results indicate that autistic employees may be less susceptible to the bystander effect than nonautistic employees. As a result, autistic employees may contribute to improvements in organizational performance because they are more likely to identify and report inefficient processes and dysfunctional practices when they witness them. These preliminary findings suggesting potential benefits of neurodiversity in the workplace are promising. However, further research is required.
Jasmonates, gibberellins, and powdery mildew modify cell cycle progression and evoke differential spatiotemporal responses along the barley leaf

Abstract Barley (Hordeum vulgare) is an important cereal crop, and its development, defence, and stress responses are modulated by different hormones including jasmonates (JAs) and the antagonistic gibberellins (GAs). Barley productivity is severely affected by the foliar biotrophic fungal pathogen Blumeria hordei. In this study, primary leaves were used to examine the molecular processes regulating responses to methyl-jasmonate (MeJA) and GA to B. hordei infection along the leaf axis. Flow cytometry, microscopy, and spatiotemporal expression patterns of genes associated with JA, GA, defence, and the cell cycle provided insights on cell cycle progression and on the gradient of susceptibility to B. hordei observed along the leaf. Notably, the combination of B. hordei with MeJA or GA pre-treatment had a different effect on the expression patterns of the analysed genes compared to individual treatments. MeJA reduced susceptibility to B. hordei in the proximal part of the leaf blade. Overall, distinctive spatiotemporal gene expression patterns correlated with different degrees of cell proliferation, growth capacity, responses to hormones, and B. hordei infection along the leaf. Our results highlight the need to further investigate differential spatial and temporal responses to pathogens at the organ, tissue, and cell levels in order to devise effective disease control strategies in crops.
An Initial Exploration: Learning to Generate Realistic Audio for Silent Video

Generating realistic audio effects for movies and other media is a challenging task that is accomplished today primarily through physical techniques known as Foley art. Foley artists create sounds with common objects (e.g., boxing gloves, broken glass) in time with video as it is playing to generate captivating audio tracks. In this work, we aim to develop a deep-learning based framework that does much the same - observes video in it's natural sequence and generates realistic audio to accompany it. Notably, we have reason to believe this is achievable due to advancements in realistic audio generation techniques conditioned on other inputs (e.g., Wavenet conditioned on text). We explore several different model architectures to accomplish this task that process both previously-generated audio and video context. These include deep-fusion CNN, dilated Wavenet CNN with visual context, and transformer-based architectures. We find that the transformer-based architecture yields the most promising results, matching low-frequencies to visual patterns effectively, but failing to generate more nuanced waveforms.
A second-order length-preserving and unconditionally energy stable rotational discrete gradient method for Oseen-Frank gradient flows

We present a second-order strictly length-preserving and unconditionally energy-stable rotational discrete gradient (Rdg) scheme for the numerical approximation of the Oseen-Frank gradient flows with anisotropic elastic energy functional. Two essential ingredients of the Rdg method are reformulation of the length constrained gradient flow into an unconstrained rotational form and discrete gradient discretization for the energy variation. Besides the well-known mean-value and Gonzalez discrete gradients, we propose a novel Oseen-Frank discrete gradient, specifically designed for the solution of Oseen-Frank gradient flow. We prove that the proposed Oseen-Frank discrete gradient satisfies the energy difference relation, thus the resultant Rdg scheme is energy stable. Numerical experiments demonstrate the efficiency and accuracy of the proposed Rdg method and its capability for providing reliable simulation results with highly disparate elastic coefficients.