Miracle-dz/UniFAR-FTUs huggingface dataset:
Release from cell cycle arrest with Cdk4/6 inhibitors generates highly synchronized cell cycle progression in human cell culture

Each approach used to synchronize cell cycle progression of human cell lines presents a unique set of challenges. Induction synchrony with agents that transiently block progression through key cell cycle stages are popular, but change stoichiometries of cell cycle regulators, invoke compensatory changes in growth rate and, for DNA replication inhibitors, damage DNA. The production, replacement or manipulation of a target molecule must be exceptionally rapid if the interpretation of phenotypes in the cycle under study is to remain independent of impacts upon progression through the preceding cycle. We show how these challenges are avoided by exploiting the ability of the Cdk4/6 inhibitors, palbociclib, ribociclib and abemaciclib to arrest cell cycle progression at the natural control point for cell cycle commitment: the restriction point. After previous work found no change in the coupling of growth and division during recovery from CDK4/6 inhibition, we find high degrees of synchrony in cell cycle progression. Although we validate CDK4/6 induction synchronization with hTERT-RPE-1, A549, THP1 and H1299, it is effective in other lines and avoids the DNA damage that accompanies synchronization by thymidine block/release. Competence to return to cycle after 72 h arrest enables out of cycle target induction/manipulation, without impacting upon preceding cycles.
An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics

The human albumin variant E505Q/T527M/K573P improves pharmacokinetics of protein-based drugs and facilitates transport across mucosal epithelia. Altering albumin for drug delivery Ideally, protein-based biologic drugs could be given transmucosally, rather than intravenously or subcutaneously, but the efficiency of transmucosal drug uptake is poor. Bern et al. designed an albumin protein with three amino acid substitutions, E505Q/T527M/K573P (QMP), improving binding to the neonatal Fc receptor expressed on mucosal epithelial cells. This prevented intracellular degradation and enhanced mucosal uptake of proteins fused to QMP upon intranasal delivery. Activated factor VII was fused to QMP, prolonging half-life without impeding factor VII function in a mouse model of hemophilia B. QMP may be a suitable carrier for biologic drugs but will require further testing in large-animal models. Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.
Effectiveness of pelvic floor muscle training with and without electromyographic biofeedback for urinary incontinence in women: multicentre randomised controlled trial

Abstract Objective To assess the effectiveness of pelvic floor muscle training (PFMT) plus electromyographic biofeedback or PFMT alone for stress or mixed urinary incontinence in women. Design Parallel group randomised controlled trial. Setting 23 community and secondary care centres providing continence care in Scotland and England. Participants 600 women aged 18 and older, newly presenting with stress or mixed urinary incontinence between February 2014 and July 2016: 300 were randomised to PFMT plus electromyographic biofeedback and 300 to PFMT alone. Interventions Participants in both groups were offered six appointments with a continence therapist over 16 weeks. Participants in the biofeedback PFMT group received supervised PFMT and a home PFMT programme, incorporating electromyographic biofeedback during clinic appointments and at home. The PFMT group received supervised PFMT and a home PFMT programme. PFMT programmes were progressed over the appointments. Main outcome measures The primary outcome was self-reported severity of urinary incontinence (International Consultation on Incontinence Questionnaire-urinary incontinence short form (ICIQ-UI SF), range 0 to 21, higher scores indicating greater severity) at 24 months. Secondary outcomes were cure or improvement, other pelvic floor symptoms, condition specific quality of life, women’s perception of improvement, pelvic floor muscle function, uptake of other urinary incontinence treatment, PFMT self-efficacy, adherence, intervention costs, and quality adjusted life years. Results Mean ICIQ-UI SF scores at 24 months were 8.2 (SD 5.1, n=225) in the biofeedback PFMT group and 8.5 (SD 4.9, n=235) in the PFMT group (mean difference −0.09, 95% confidence interval −0.92 to 0.75, P=0.84). Biofeedback PFMT had similar costs (mean difference £121 ($154; €133), −£409 to £651, P=0.64) and quality adjusted life years (−0.04, −0.12 to 0.04, P=0.28) to PFMT. 48 participants reported an adverse event: for 23 this was related or possibly related to the interventions. Conclusions At 24 months no evidence was found of any important difference in severity of urinary incontinence between PFMT plus electromyographic biofeedback and PFMT alone groups. Routine use of electromyographic biofeedback with PFMT should not be recommended. Other ways of maximising the effects of PFMT should be investigated. Trial registration ISRCTN57756448.
Cryopreservation of Shoot Tips from Prunus

The current paper studied factors that effect the cryopreservation of Prunus salicina Lindl in vitro shoot tips.By using simple vitrification technique,factors like,culture time,PVS3 treatment time and cold hardening were all tested,the rapid examination method of shoot tips survival was studied,and a sample procedure was established at last.When shoot tips were excised from healthy in vitro plants of Prunus cultivars,that have been subcultured for 120 d and followed by 5 ℃ cold hardening for 21 d,and precultured with 0.7 mol·L-1 sucrose for 2 d,treated with PVS3 for 100 min before direct plunging into liquid nitrogen,the survival after cryopreservation was higher than 60.0%.
Current Promises and Limitations of Combined Virtual Reality and Functional Magnetic Resonance Imaging Research in Humans: A Commentary on Huffman and Ekstrom (2019)

Abstract Real-world navigation requires movement of the body through space, producing a continuous stream of visual and self-motion signals, including proprioceptive, vestibular, and motor efference cues. These multimodal cues are integrated to form a spatial cognitive map, an abstract, amodal representation of the environment. How the brain combines these disparate inputs and the relative importance of these inputs to cognitive map formation and recall are key unresolved questions in cognitive neuroscience. Recent advances in virtual reality technology allow participants to experience body-based cues when virtually navigating, and thus it is now possible to consider these issues in new detail. Here, we discuss a recent publication that addresses some of these issues (D. J. Huffman and A. D. Ekstrom. A modality-independent network underlies the retrieval of large-scale spatial environments in the human brain. Neuron, 104, 611–622, 2019). In doing so, we also review recent progress in the study of human spatial cognition and raise several questions that might be addressed in future studies.
Effect of Ginger (Zingiber officinale) on Performance and Blood Serum Parameters of Broiler

This study was carried out at the Poultry of Animal Resource, College of Agriculture, Tikrit University. The present study was conducted to explore the usage of different levels of ginger at concentration of 0.1 and 0.2% respectively supplemented to diets on the Performance and blood serum traits of the Broiler Chickens. 180 (ROSS) 3 weeks old broiler chicks raised to 6 weeks of age. The birds were distributed into 3 treatment groups with three replicates per treatment (20 birds per replicate + 10 females). Ginger (Zingiber officinale) was supplemented at the rate 0.1 and 0.2% in the diets to treatments T2 and T3 respectively while treatment one served as control. The result of performance parameter showed significant difference between treatments. However body weight, weight gain, FCR and feed intake showed a significant differences (p<0.05) between T2 (0.1% ginger) and T3 (0.2% ginger) and control. The total protein didn't differ significantly between the treatment groups. Serum cholesterol, triglyceride and glucose level was a significantly lower in the 0.1 and 0.2% of ginger (p<0.05) than control. Findings of the research study indicated that groups receiving ginger at the rate of 0.1 and 0.2% of the diets showed better performance and serum profiles in broiler.
TMLRpred: A machine learning classification model to distinguish reversible EGFR double mutant inhibitors

The EGFR is a clinically important therapeutic drug target in lung cancer. The first‐generation tyrosine kinase inhibitors used in clinics are effective against L858R‐mutated EGFR. However, relapse of the disease due to the presence of resistant mutation (T790M) makes these inhibitors ineffective. This has necessitated the need to identify new potent EGFR inhibitors against the resistant double mutants. Therefore, various machine learning techniques ((instance‐based learner (IBK), naïve Bayesian (NB), sequential minimal optimization (SMO), and random forest (RF)) were employed to develop twelve classification models on three different datasets (high, moderate, and weakly active inhibitors). The models were validated using fivefold cross‐validation and independent validation datasets. It was observed that the random forest‐based models showed best performance. Also, functional groups, PubChem fingerprints, and substructure of highly active inhibitors were compared to inactive to identify structural features which are important for activity. To promote open‐source drug discovery, a tool has been developed, which incorporates the best performing models and allows users to predict the potential of chemical molecules as anti‐TMLR inhibitor. It is expected that the machine learning classification models developed in this study will pave way for identifying novel inhibitors against the resistant EGFR double mutants.
Multitask deep networks with grid featurization achieve improved scoring performance for protein–ligand binding

Deep learning‐based methods have been extensively developed to improve scoring performance in structure‐based drug discovery. Extending multitask deep networks in addressing pharmaceutical problems shows remarkable improvements over single task network. Recently, grid featurization has been introduced to convert protein–ligand complex co‐ordinates into fingerprints with the advantage of incorporating inter‐ and intra‐molecular information. The combination of grid featurization with multitask deep networks would hold great potential to boost the scoring performance. We examined the performance of three novel multitask deep networks (standard multitask, bypass, and progressive network) in reproducing the binding affinities of protein–ligand complexes in comparison with AutoDock Vina docking and MM/GBSA method. Among five evaluated methods, progressive network combined with grid featurization provided the best Pearson correlation coefficient (0.74) and least mean absolute average error (0.98) for the overall scoring performance. Moreover, all networks increased screening ability for the re‐docking pose and progressive network even achieved AUC of 0.87 over 0.52 of AutoDock Vina. Our results demonstrated that progressive network combined with grid featurization would be one powerful rescoring approach to strengthen screening results after obtaining protein–ligand complex in the conventional docking software.
The role of psychological attribution in responses to weight stigma

Weight discrimination is associated with numerous negative health consequences. Little is known about early‐stage psychological mechanisms that explain variability in responses to weight discrimination among people with obesity. This study tested the hypothesis that attributing negative social evaluation to one's weight would be associated with stigma‐related stress responses (eg, reduced cognitive functioning and self‐esteem, increased negative affect and cortisol), especially among people who had experienced frequent weight discrimination in the past.
Sonority as a Phonological Cue in Early Perception of Written Syllables in French

Many studies focused on the letter and sound co-occurrences to account for the well-documented syllable-based effects in French in visual (pseudo)word processing. Although these language-specific statistical properties are crucial, recent data suggest that studies that go all-in on phonological and orthographic regularities may be misguided in interpreting how—and why—readers locate syllable boundaries and segment clusters. Indeed, syllable-based effects could depend on more abstract, universal phonological constraints that rule and govern how letter and sound occur and co-occur, and readers could be sensitive to sonority—a universal phonological element—for processing (pseudo)words. Here, we investigate whether French adult skilled readers rely on universal phonological sonority-related markedness continuum across the syllable boundaries for segmentation (e.g., from marked, illegal intervocalic clusters /zl/ to unmarked, legal intervocalic clusters /lz/). To address this question, we ran two tasks with 128 French adult skilled readers using two versions of the illusory conjunction paradigm (Task 1 without white noise; Task 2 with white noise). Our results show that syllable location and segmentation in reading is early and automatically modulated by phonological sonority-related markedness in the absence or quasi-absence of statistical information and does not require acoustic-phonetic information. We discuss our results toward the overlooked role of phonological universals and the over-trusted role of statistical information during reading processes.
Effects of Social Housing Changes on Immunity and Vaccine-Specific Immune Responses in Adolescent Male Rhesus Macaques

Nonhuman primates (NHPs) in research institutions may be housed in a variety of social settings, such as group housing, pair housing or single housing based on the needs of studies. Furthermore, housing may change over the course of studies. The effects of housing and changes in housing on cell activation and vaccine mediated immune responses are not well documented. We hypothesized that animals moved indoors from group to single housing (GH-SH) would experience more stress than those separated from groups into pair housing (GH-PH), or those placed briefly into pair housing and separated 5 weeks later into single housing (GH-PH-SH). We also compared the effects of separation from group to pair housing with the separation from pair to single housing. Eighteen male rhesus macaques were followed over the course of changes in housing condition over 10–14 weeks, as well as prior to and after primary vaccination with a commercially available measles vaccine. We identified two phenotypic biomarkers, namely total CD8 population and proliferating B cells, that differed significantly across treatment groups over time. At 10 weeks post-separation, levels of proliferating B cells were higher in GH-SH subjects compared to GH-PH subjects, and in the latter, levels were lower at 10 weeks than prior to removal from group housing. At 2 weeks post-separation from group to single housing, the frequency of CD8+ T cells was higher in GH-SH subjects compared to one week post separation from pair into single housing in the GH-PH-SH subjects. Comparing the same elapsed time since the most recent separation activated CD20 populations were persistently higher in the GH-SH animals than the GH-PH-SH animals. Housing configuration did not influence vaccine-mediated responses. Overall, our study found benefits of pair housing over single housing, suggesting that perturbations in immune function will be more severe following separation from group to single housing than from pair to single housing, and supporting the use of short-duration pair housing even when animals must subsequently be separated. These findings are useful for planning the housing configurations of research NHPs used for vaccine studies and other studies where immune response is being assessed.
Attractive internuclear force drives the collective behavior of nuclear arrays in Drosophila embryos

The emerging collective behaviors during embryogenesis play an important role in precise and reproducible morphogenesis. An important question in the study of collective behavior is what rule underlies the emerging pattern. Here we use the Drosophila embryo as a test tube to study this question. We focus on the nuclear array without membrane separation on the embryo periphery from the nuclear cycle (NC) 11 to NC14. After live imaging with light sheet microscopy, we extract the nuclear trajectory, speed, and internuclear distance with an automatic nuclear tracing method. We find that the nuclear speed shows a period of standing waves along the anterior-posterior (AP) axis after each metaphase as the nuclei collectively migrate towards the embryo poles and partially move back. And the maximum nuclear speed dampens by 38% in the second half of the standing wave. Moreover, the nuclear density is 35% higher in the middle than the pole region of the embryo during the S phase of NC11-NC14. To find mechanical rules controlling the collective motion and packing patterns of the nuclear array, we use the deep neural network (DNN) to learn the force field from data. We find two potential strong nuclear-age-dependent force fields, i.e., the repulsive or attractive force field. Simulations with the particle-based model indicate that only if the net internuclear force is attractive and increases with distance, the pseudo-synchronous mitotic wave in a nuclear array with lower nuclear density in embryo poles can drive the collective motion with the damped standing wave of the nuclear speed, and the collective nuclear motion, in turn, maintains the non-uniform nuclear density.
When the ventral visual stream is not enough: A deep learning account of medial temporal lobe involvement in perception

The medial temporal lobe (MTL) supports a constellation of memory-related behaviors. Its involvement in perceptual processing, however, has been subject to an enduring debate. This debate centers on perirhinal cortex (PRC), an MTL structure at the apex of the ventral visual stream (VVS). Here we leverage a deep learning approach that approximates visual behaviors supported by the VVS. We first apply this approach retroactively, modeling 29 published concurrent visual discrimination experiments: Excluding misclassified stimuli, there is a striking correspondence between VVS-modeled and PRC-lesioned behavior, while each are outperformed by PRC-intact participants. We corroborate these results using high-throughput psychophysics experiments: PRC-intact participants outperform a linear readout of electrophysiological recordings from the macaque VVS. Finally, in silico experiments suggest PRC enables out-of-distribution visual behaviors at rapid timescales. By situating these lesion, electrophysiological, and behavioral results within a shared computational framework, this work resolves decades of seemingly inconsistent experimental findings surrounding PRC involvement in perception.
On the Way to Ovules: The Hormonal Regulation of Ovule Development

Abstract This review focuses on the hormonal regulation of ovule development, especially on ovule initiation, patterning, and morphogenesis. Understanding of the genetic and molecular basis of ovule development is essential from both the scientific and economic perspective. The ovule represents an attractive system to study lateral organ development in plants, and, since ovules are the precursors of seeds, full comprehension of this process can be the key to the improvement of crops, especially those depending on high production of seeds and grains. Ovule initiation, patterning, and morphogenesis are governed by complex genetic and hormonal networks involving auxins, cytokinins, brassinosteroids, and gibberellins. These coordinate the determination of the ovule number, size, and shape through the regulation of the number of ovule primordia that arise from the placenta and/or ensuring their correct development into mature functional ovules. Here we summarize the current knowledge of how ovules are formed, paying special attention to the roles of these four plant hormones.
Overcoming barriers to the registration of new varieties

Distinctness, Uniformity and Stability (DUS) is an intellectual property system introduced in 1961 by the International Union for the Protection of New Varieties of Plants (UPOV) for safeguarding the investment and rewarding innovation in developing new plant varieties. Despite the rapid advancement in our understanding of crop biology over the past 60 years, the DUS system has not changed and is still dependent upon a set of morphological traits for testing candidate varieties. As the demand for more plant varieties increases, the barriers to registration of new varieties become more acute and thus require urgent review to the system. To highlight the challenges and remedies in the current system, we evaluated a comprehensive panel of 805 UK barley varieties that span the entire history of DUS testing. Our findings reveal the system deficiencies and provide evidence for a shift towards a robust genomics enabled registration system for new crop varieties.
Permeabilization-free en bloc immunohistochemistry for correlative microscopy

A dense reconstruction of neuronal synaptic connectivity typically requires high-resolution 3D electron microscopy (EM) data, but EM data alone lacks functional information about neurons and synapses. One approach to augment structural EM datasets is with the fluorescent immunohistochemical (IHC) localization of functionally relevant proteins. We describe a protocol that obviates the requirement of tissue permeabilization in thick tissue sections, a major impediment for correlative pre-embedding IHC and EM. We demonstrate the permeabilization-free labeling of neuronal cell types, intracellular enzymes, and synaptic proteins in tissue sections hundreds of microns thick in multiple brain regions while simultaneously retaining the ultrastructural integrity of the tissue. Finally, we explore the utility of this protocol by performing proof-of-principle correlative experiments combining two-photon imaging of protein distributions and 3D electron microscopy.