Miracle-dz/UniFAR-FTUs huggingface dataset:
Highly disordered histone H1−DNA model complexes and their condensates

Significance DNA is a stiff polymer that is condensed in vivo by polyamines and cationic proteins, many of which are intrinsically disordered. In eukaryotes, where DNA is packaged as chromatin, condensation of internucleosomal (linker) DNA is effected by the C-terminal tail of histone H1. Its structure and DNA binding are poorly understood, as is the link between H1 phosphorylation and chromatin structural changes during the cell cycle. Here we present a model system, with which we show that H1 binds tightly to DNA but retains a high level of disorder. Phase-separated condensates form, containing higher-order structures that are highly sensitive to the phosphorylation state of H1, suggesting a mechanism by which condensation of the chromatin fiber and other assemblies might be regulated. Disordered proteins play an essential role in a wide variety of biological processes, and are often posttranslationally modified. One such protein is histone H1; its highly disordered C-terminal tail (CH1) condenses internucleosomal linker DNA in chromatin in a way that is still poorly understood. Moreover, CH1 is phosphorylated in a cell cycle-dependent manner that correlates with changes in the chromatin condensation level. Here we present a model system that recapitulates key aspects of the in vivo process, and also allows a detailed structural and biophysical analysis of the stages before and after condensation. CH1 remains disordered in the DNA-bound state, despite its nanomolar affinity. Phase-separated droplets (coacervates) form, containing higher-order assemblies of CH1/DNA complexes. Phosphorylation at three serine residues, spaced along the length of the tail, has little effect on the local properties of the condensate. However, it dramatically alters higher-order structure in the coacervate and reduces partitioning to the coacervate phase. These observations show that disordered proteins can bind tightly to DNA without a disorder-to-order transition. Importantly, they also provide mechanistic insights into how higher-order structures can be exquisitely sensitive to perturbation by posttranslational modifications, thus broadening the repertoire of mechanisms that might regulate chromatin and other macromolecular assemblies.
Can Nuts Mitigate Malnutrition in Older Adults? A Conceptual Framework

The proportion of adults aged over 60 years in the world is expected to reach 20% by the year 2050. Ageing is associated with several physiological changes that increase the risk of malnutrition among this population. Malnutrition is characterized by deficiencies or insufficiencies of macro- and micronutrients. Malnutrition has detrimental effects on the health, wellbeing, and quality of life in older adults. Nuts are rich in energy, unsaturated fats, and protein, as well as other nutrients that provide a range of health benefits. While the effects of nuts on overnutrition have been studied extensively, very few studies have been specifically designed to understand the role of nuts in mitigating undernutrition in the elderly. Therefore, this review explores the potential role of nuts in improving the nutritional status of older adults who are at risk of undernutrition. Several properties of whole nuts, some of which appear important for addressing overnutrition, (e.g., hardness, lower-than-expected nutrient availability, satiety-enhancing effects) may limit their effectiveness as a food to combat undernutrition. However, we propose that modifications such as transforming the physical form of nuts, addressing the timing of nut ingestion, and introducing variety may overcome these barriers. This review also discusses the feasibility of using nuts to prevent and reverse undernutrition among older adults. We conclude with a recommendation to conduct clinical studies in the future to test this conceptual framework.
Advances and challenges in recombinant Mycobacterium bovis BCG-based HIV vaccine development: lessons learned

ABSTRACT Introduction: Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome, tuberculosis, and malaria are responsible for most human deaths produced by infectious diseases worldwide. Vaccination against HIV requires generation of memory T cells and neutralizing antibodies, mucosal immunity, and stimulation of an innate immune responses. In this context, the use of Mycobacterium bovis bacillus Calmette–Guérin (BCG) as a live vaccine vehicle is a promising approach for T-cell induction. Areas covered: In this review, we provide a comprehensive summary of the literature regarding immunogenicity studies in animal models performed since 2005. Furthermore, we provide expert commentary and 5-year view on how the development of potential recombinant BCG-based HIV vaccines involves careful selection of the HIV antigen, expression vectors, promoters, BCG strain, preclinical animal models, influence of preexisting immunity, and safety issues, for the rational design of recombinant BCG:HIV vaccines to prevent HIV transmission in the general population. Expert commentary: The three critical issues to be considered when developing a rBCG:HIV vaccine are codon optimization, antigen localization, and plasmid stability in vivo. The use of integrative expression vectors are likely to improve the mycobacterial vaccine stability and immunogenicity to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective responses shortly following birth.
Towards Two-Dimensional Sequence to Sequence Model in Neural Machine Translation

This work investigates an alternative model for neural machine translation (NMT) and proposes a novel architecture, where we employ a multi-dimensional long short-term memory (MDLSTM) for translation modelling. In the state-of-the-art methods, source and target sentences are treated as one-dimensional sequences over time, while we view translation as a two-dimensional (2D) mapping using an MDLSTM layer to define the correspondence between source and target words. We extend beyond the current sequence to sequence backbone NMT models to a 2D structure in which the source and target sentences are aligned with each other in a 2D grid. Our proposed topology shows consistent improvements over attention-based sequence to sequence model on two WMT 2017 tasks, German<->English.
Angiotensin-(1-7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice.

Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1-7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1-7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1-7) mas receptor antagonist A779 (400 or 800 ng·kg-1·min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 ( n = 6-13/group). Captopril reduced body weight (28 ± 2 vs. 41 ± 2 g saline; P = 0.001), lowered systolic BP (109 ± 6 vs. 144 ± 7 mmHg saline; P = 0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31 ± 4 vs. 16 ± 2 mg·kg-1·min-1 saline; P = 0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23 ± 2 mg·kg-1·min-1; P = 0.042), with no effect on body weight (32 ± 2 g; P = 0.441) or BP (111 ± 7 mmHg; P = 0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1-7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.
Image Segmentation using Unsupervised Watershed Algorithm with an Over-segmentation Reduction Technique

Image segmentation is the process of partitioning an image into meaningful segments. The meaning of the segments is subjective due to the definition of homogeneity is varied based on the users perspective hence the automation of the segmentation is challenging. Watershed is a popular segmentation technique which assumes topographic map in an image, with the brightness of each pixel representing its height, and finds the lines that run along the tops of ridges. The results from the algorithm typically suffer from over segmentation due to the lack of knowledge of the objects being classified. This paper presents an approach to reduce the over segmentation of watershed algorithm by assuming that the different adjacent segments of an object have similar color distribution. The approach demonstrates an improvement over conventional watershed algorithm.
Reliability and Validity of the Trauma Symptom Checklist for Children and Trauma Symptom Checklist for Young Children Screeners in a Clinical Sample

ABSTRACT This study reports on the reliability and validity for two measures developed for screening of symptoms in child sexual abuse (CSA)—the Trauma Symptom Checklist for Children-Screening Form (TSCC-SF) and the Trauma Symptom Checklist for Young Children-Screening Form (TSCYC-SF). The sample of 200 children and caregivers received outpatient treatment. Internal consistencies ranged from an alpha of 0.79–0.85. Concurrent validity was demonstrated by correlations with the TSCC and TSCYC. The TSCC-SF General Trauma (GT) was only correlated Child Behavior Checklist (r = .236 for the Anxious Depressed Scale with the TSCC GT; however, all Child Behavior Checklist scales correlated with the TSCYC GT ranging from .422 to .692, and with the SC with r = .713), and the Children’s Attributional and Perceptual Scale. Findings support reliability and validity reported elsewhere. The TSCC-SF and TSCYC-SF show promise for screening and triage of CSA victims in many settings.
Early hematoma retraction in intracerebral hemorrhage is uncommon and does not predict outcome

Background Clot retraction in intracerebral hemorrhage (ICH) has been described and postulated to be related to effective hemostasis and perihematoma edema (PHE) formation. The incidence and quantitative extent of hematoma retraction (HR) is unknown. Our aim was to determine the incidence of HR between baseline and time of admission. We also tested the hypothesis that patients with HR had higher PHE volume and good prognosis. Methods This was a retrospective single-centre study in which serial planimetric volume measurements of the total hematoma volume (parenchymal (IPH) and intraventricular (IVH)) and PHE were performed in ICH patients with baseline non-contrast computed tomography (CT) completed within 6 hours of onset and follow-up CT 24 (±12) hours from symptom onset. HR was defined as a decrease in volume of >3ml or >15%, and hematoma expansion (HE) as an increase of >6ml or >30%. All other patients were categorized as stable hematoma (HS). Good outcome was defined as modified Rankin Scale (mRS) 0–2 at 90 days. Results A total of 136 patients (mean age = 69.3±13.39 years, 58.1% male) were included. Median (interquartile range) baseline total hematoma volume was 14.96 (7.80, 31.88) ml. HR >3ml and >15% occurred in 6 (4.4%) and 8 (5.9%) patients, respectively. Neither definition of HR was associated with follow-up PHE (p>0.297) or good outcome (p>0.249). IVH was the only independent predictor of HR (p<0.0241). Conclusions Early HR is rare and associated with IVH, but not with PHE or clinical outcome. There was no relationship between HR, PHE, and patient prognosis. Therefore, HR is unlikely to be a useful endpoint in clinical ICH studies.
Homo- and Heteroclinic Connections in the Planar Solar-Sail Earth-Moon Three-Body Problem

This paper explores the existence of homo- and heteroclinic connections between solar-sail periodic orbits in the planar Earth-Moon circular restricted three-body problem. The existence of such connections has been demonstrated to great extent for the planar and spatial classical (no-solar sail) three-body problem, but remains unexplored for the inclusion of a solar-sail induced acceleration. Similar to the search for homo-and heteroclinic connections in the classical case, this paper uses the tools and techniques of dynamical systems theory, in particular trajectories along the unstable and stable manifolds, to generate these connections. However, due to the time dependency introduced by the solar-sail induced acceleration, common methods and techniques to find homo- and heteroclinic connections (e.g., using the Jacobi constant and applying spatial Poincare sections) do not necessarily apply. The aim of this paper is therefore to gain an understanding of the extent to which these tools do apply, define new tools (e.g., solar-sail assisted manifolds, temporal Poincare sections, and a genetic algorithm approach), and ultimately find the sought for homo- and heteroclinic connections. As a starting point of such an investigation, this paper focuses on the planar case, in particular on the search for homo- and heteroclinic connections between three specific solar-sail Lyapunov orbits (two at the L1 point and one at the L2 point) that all exist for the same near-term solar-sail technology. The results of the paper show that, by using a simple solar-sail steering law, where a piece-wise constant sail attitude is applied in the unstable and stable solar-sail manifold trajectories, homo- and heteroclinic connections exist for these three solar-sail Lyapunov orbits. The remaining errors on the position and velocity at linkage of the stable and unstable manifold trajectories are less than 10 km and 1 m/s. Future studies can apply the tools and techniques developed in this paper to extend the search for homo- and heteroclinic connections to other solar-sail Lyapunov orbits in the Earth-Moon system (e.g., for different solar-sail technology), to other planar solar-sail periodic orbits, and ultimately also to the spatial, three-dimensional case.
SPIGAN: Privileged Adversarial Learning from Simulation

Deep Learning for Computer Vision depends mainly on the source of supervision.Photo-realistic simulators can generate large-scale automatically labeled syntheticdata, but introduce a domain gap negatively impacting performance. We propose anew unsupervised domain adaptation algorithm, called SPIGAN, relying on Sim-ulator Privileged Information (PI) and Generative Adversarial Networks (GAN). We use internal data from the simulator as PI during the training of a target tasknetwork. We experimentally evaluate our approach on semantic segmentation. Wetrain the networks on real-world Cityscapes and Vistas datasets, using only unla-beled real-world images and synthetic labeled data with z-buffer (depth) PI fromthe SYNTHIA dataset. Our method improves over no adaptation and state-of-the-art unsupervised domain adaptation techniques.
Multi-agent Deep Reinforcement Learning for Zero Energy Communities

A Zero Energy Building (ZEB) has its net energy usage over a period of one year as zero, i.e., its energy use is not larger than its overall renewables generation. A collection of such ZEBs forms a Zero Energy Community (ZEC). This paper addresses the problem of energy sharing in such a community. This is different from previously addressed energy sharing between buildings as our focus is on the improvement of community energy status, while traditionally research focused on reducing losses due to transmission and storage, or achieving economic gains. We model this problem in a multi-agent environment and propose a Deep Reinforcement Learning (DRL) based solution. Results indicate that with time buildings learn to collaborate and learn a policy comparable to the optimal policy, which in turn improves the ZEC's energy status. Buildings with no renewables preferred to request energy from their neighbours rather than from the supply grid.
Application of Neurokinin-1 Receptor in Targeted Strategies for Glioma Treatment. Part I: Synthesis and Evaluation of Substance P Fragments Labeled with 99mTc and 177Lu as Potential Receptor Radiopharmaceuticals

Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. The aim of this work was to study physico-chemical and biological properties of different SP analogues labeled with technetium-99m and lutetium-177 radionuclides. The synthesized compounds were characterized in vitro by partition coefficients (logP) and their stability was investigated in various physiological solutions. Biological properties (Kd, Bmax) were characterized using the U373 MG cell line. The obtained lipophilicity values of the [99mTc]NS3/CN-SP and [177Lu]DOTA-SP radiobioconjugates were in the range of −0.3 to +0.6 and −2.5 to −5.0, respectively. The studied radiobioconjugates were stable in PBS buffer and CSF, as well as in 10 mM histidine and/or cysteine solutions whereas in human serum showed enzymatic biodegradation. [177Lu]DOTA-[Thi8,Met(O2)11]SP(1–11), [177Lu]DOTA-SP(4–11) and [177Lu]DOTA-[Thi8,Met(O2)11]SP(5–11) radiobioconjugates bound specifically to NK-1 receptors expressed on glioblastoma cells with affinity in the nanomolar range. To conclude, the shorter analogues of SP can be used as vectors, nevertheless they still do not fulfil all requirements for preparations in nuclear medicine.
Investigation of activation mechanism and conformational stability of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxybenzamide and N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide in the: active site of p300 histone acetyl transferase enzyme by molecular dynamics and binding free

Abstract The CBP (CREB-binding protein) and p300 are related to transcriptional coactivator family and are involved in several post-translational modifications, in which the acetylation is an important factor because it commences the transcription process. Experimental studies report that CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide) and CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxybenzamide) are good activators of p300 HAT enzyme, but yet, the molecular mechanism of their activation is not explored. The present study pertains to determine the intermolecular interactions, stability and binding free energy of CTB and CTPB from the molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. The docking studies of the molecules reveal that the docking score of CTPB (−15.64 kcal/mol) is higher than that of CTB (−12.30 kcal/mol); on the contrary, CTB forms a strong interaction with the key residues of catalytic site (Tyr1467 and Trp1436) compared with CTPB. The MD simulation shows the stability of both molecules in the active site of p300 and their interactions. Furthermore, both docking and MD simulation studies of CTB confirm that it forms expected key interactions and retain the interactions with the active site amino acid residues of p300 when compared with CTPB. For this reason, the CTB recruits more acetyl-CoA in the active site of p300 compared with CTPB; it leads to activate the acetylation process; hence, CTB may be a best activator than CTPB. The binding free energy value of CTPB (−24.79 2.38 kcal/mol) is higher when compared with that of CTB (−12.14 1.30 kcal/mol) molecule; perhaps, the interaction of pentadecyl chain of CTPB with p300, whereas in CTB, such a group is absent. Communicated by Ramaswamy H. Sarma
Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation

Neurons of the CNS elaborate highly branched dendritic arbors that host numerous dendritic spines, which serve as the postsynaptic platform for most excitatory synapses. The actin cytoskeleton plays an important role in dendrite development and spine formation, but the underlying mechanisms remain incompletely understood. Tropomodulins (Tmods) are a family of actin-binding proteins that cap the slow-growing (pointed) end of actin filaments, thereby regulating the stability, length, and architecture of complex actin networks in diverse cell types. Three members of the Tmod family, Tmod1, Tmod2, and Tmod3 are expressed in the vertebrate CNS, but their function in neuronal development is largely unknown. In this study, we present evidence that Tmod1 and Tmod2 exhibit distinct roles in regulating spine development and dendritic arborization, respectively. Using rat hippocampal tissues from both sexes, we find that Tmod1 and Tmod2 are expressed with distinct developmental profiles: Tmod2 is expressed early during hippocampal development, whereas Tmod1 expression coincides with synaptogenesis. We then show that knockdown of Tmod2, but not Tmod1, severely impairs dendritic branching. Both Tmod1 and Tmod2 are localized to a distinct subspine region where they regulate local F-actin stability. However, the knockdown of Tmod1, but not Tmod2, disrupts spine morphogenesis and impairs synapse formation. Collectively, these findings demonstrate that regulation of the actin cytoskeleton by different members of the Tmod family plays an important role in distinct aspects of dendrite and spine development. SIGNIFICANCE STATEMENT The Tropomodulin family of molecules is best known for controlling the length and stability of actin myofilaments in skeletal muscles. While several Tropomodulin members are expressed in the brain, fundamental knowledge about their role in neuronal function is limited. In this study, we show the unique expression profile and subcellular distribution of Tmod1 and Tmod2 in hippocampal neurons. While both Tmod1 and Tmod2 regulate F-actin stability, we find that they exhibit isoform-specific roles in dendrite development and synapse formation: Tmod2 regulates dendritic arborization, whereas Tmod1 is required for spine development and synapse formation. These findings provide novel insight into the actin regulatory mechanisms underlying neuronal development, thereby shedding light on potential pathways disrupted in a number of neurological disorders.