Miracle-dz/UniFAR-FTUs huggingface dataset:
Refined read‐out: The hUHRF1 Tandem‐Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3

UHRF1 is an essential chromatin protein required for DNA methylation maintenance, mammalian development and gene regulation. We investigated the Tandem-Tudor domain (TTD) of human UHRF1 that is known to bind H3K9me2/3 histones and is a major driver of UHRF1 localization in cells. We verified binding to H3K9me2/3 but unexpectedly discovered stronger binding to H3 peptides and mononucleosomes containing K9me2/3 with additional K4me1. We investigated the combined binding of TTD to H3K4me1-K9me2/3 vs. H3K9me2/3, engineered mutants with specific and differential changes of binding, and discovered a novel read-out mechanism for H3K4me1 in an H3K9me2/3 context that is based on the interaction of R207 with the H3K4me1 methyl group and on counting the H-bond capacity of H3K4. Individual TTD mutants showed up to 10,000-fold preference for the double modified peptides, suggesting that after a conformational change, WT TTD could exhibit similar effects. The frequent appearance of H3K4me1-K9me2 regions demonstrated in our TTD pulldown and ChIP-western blot data suggests that it has specific biological roles. Chromatin pull-down of TTD from HepG2 cells and ChIP-seq data of full-length murine UHRF1 correlate with H3K4me1 profiles indicating that the H3K4me1-K9me2/3 interaction of TTD influences chromatin binding of full-length UHRF1. We demonstrated the H3K4me1-K9me2/3 specific binding of UHRF1-TTD to enhancers and promoters of cell-type specific genes, at the flanks of cell-type specific transcription factor binding sites, and provided evidence supporting an H3K4me1-K9me2/3 dependent and TTD mediated down-regulation of these genes by UHRF1, illustrating the physiological function of UHRF1-TTD binding to H3K4me1-K9me2/3 double marks in a cellular context.
Improved modeling of human vision by incorporating robustness to blur in convolutional neural networks

Whenever a visual scene is cast onto the retina, much of it will appear degraded due to poor resolution in the periphery; moreover, optical defocus can cause blur in central vision. However, the pervasiveness of blurry or degraded input is typically overlooked in the training of convolutional neural networks (CNNs). We hypothesized that the absence of blurry training inputs may cause CNNs to rely excessively on high spatial frequency information for object recognition, thereby causing systematic deviations from biological vision. We evaluated this hypothesis by comparing standard CNNs with CNNs trained on a combination of clear and blurry images. We show that blur-trained CNNs outperform standard CNNs at predicting neural responses to objects across a variety of viewing conditions. Moreover, blur-trained CNNs acquire increased sensitivity to shape information and greater robustness to multiple forms of visual noise, leading to improved correspondence with human perception. Our results provide novel neurocomputational evidence that blurry visual experiences are very important for conferring robustness to biological visual systems.
Elucidating the role of muscarinic acetylcholine receptor (mAChR) signaling in efferent mediated responses of vestibular afferents in mammals

The peripheral vestibular system detects head position and movement through activation of vestibular hair cells (HCs) in vestibular end organs. HCs transmit this information to the CNS by way of primary vestibular afferent neurons. The CNS, in turn, modulates HCs and afferents via the efferent vestibular system (EVS) through activation of cholinergic signaling mechanisms. In mice, we previously demonstrated that activation of muscarinic acetylcholine receptors (mAChRs), during EVS stimulation, gives rise to a slow excitation that takes seconds to peak and tens of seconds to decay back to baseline. This slow excitation is mimicked by muscarine and ablated by the non-selective mAChR blockers scopolamine, atropine, and glycopyrrolate. While five distinct mAChRs (M1-M5) exist, the subtype(s) driving EVS-mediated slow excitation remain unidentified and details on how these mAChRs alter vestibular function is not well understood. The objective of this study is to characterize which mAChR subtypes drive the EVS-mediated slow excitation, and how their activation impacts vestibular physiology and behavior. In C57Bl/6J mice, M3mAChR antagonists were more potent at blocking slow excitation than M1mAChR antagonists, while M2/M4 blockers were ineffective. While unchanged in M2/M4mAChR double KO mice, EVS-mediated slow excitation in M3 mAChR-KO animals were reduced or absent in irregular afferents but appeared unchanged in regular afferents. In agreement, vestibular sensory-evoked potentials (VsEP), known to be predominantly generated from irregular afferents, were significantly less enhanced by mAChR activation in M3mAChR-KO mice compared to controls. Finally, M3mAChR-KO mice display distinct behavioral phenotypes in open field activity, and thermal profiles, and balance beam and forced swim test. M3mAChRs mediate efferent-mediated slow excitation in irregular afferents, while M1mAChRs may drive the same process in regular afferents.
Elevator motion of chloride ion transporter SLC26A9 induced by STAS domain

The anion exchanger SLC26A9, consisting of the transmembrane (TM) domain and the cytoplasmic STAS domain, plays an essential role in regulating chloride transport across cell membranes. Recent studies have indicated that C-terminal helices block the entrance of the putative ion transport pathway. However, the precise functions of the STAS domain and C-terminal helix, as well as the underlying molecular mechanisms governing the transport process, remain poorly understood. In this study, we performed molecular dynamics simulations of three distinct models of human SLC26A9: full-length (FL), STAS domain removal (ΔSTAS), and C-terminus removal (ΔC), to investigate their conformational dynamics and ion binding properties. Stable binding of ions to the binding sites was exclusively observed in the ΔC model in these simulations. Comparing the FL and ΔC simulations, the ΔC model displayed enhanced motion of the STAS domain. Furthermore, comparing the ΔSTAS and ΔC simulations, the ΔSTAS simulation failed to exhibit stable ion bindings to the sites despite the absence of the C-terminus blocking the ion transmission pathway in both systems. These results suggest that the removal of the C-terminus not only unblocks the access of ions to the permeation pathway but also triggers STAS domain motion, gating the TM domain to promote ions’ entry into their binding site. Further analysis revealed that the asymmetric motion of STAS domain leads to the expansion of the ion permeation pathway within the TM domain, resulting in the stiffening of the flexible TM12 helix near the ion binding site. This structural change in the TM12 helix stabilizes chloride ion binding, which is essential for SLC26A9 elevator motion. Overall, our study provides new insights into the molecular mechanisms of SLC26A9 transport and may pave the way for the development of novel treatments for diseases associated with dysregulated ion transport. SIGNIFICANCE We explored the mechanism by which the human protein SLC26A9 transports chloride in the cell. SLC26A9 is a potential therapeutic target for patients with cystic fibrosis, as by targeting drugs to it, it may be possible to restore chloride ion transport in epithelial cells. To design therapeutic drugs, it is essential to understand how the protein works. Our findings support an elevator-type mechanism, in which chloride ions bind to SLC26A9 inside the cell and are then released by the protein to the extracellular environment. We find that the STAS domain of SLC26A9 has critical roles in binding chloride and induces conformational changes in the transmembrane domain that facilitate chloride transport.
NetVA: An R Package for Network Vulnerability and Influence Analysis

In biological network analysis, identifying key molecules plays a decisive role in the development of potential diagnostic and therapeutic candidates. Among various approaches of network analysis, network vulnerability analysis is quite important, as it assesses significant associations between topological properties and the functional essentiality of a network. Further, some node centralities are also used to screen out key molecules. Among these node centralities, escape velocity centrality (EVC), and its extended version (EVC+) outperform others, viz., Degree, Betweenness, and Clustering coefficient. Keeping this in mind, we aimed to develop a first-of-its-kind R package named NetVA, which analyzes networks to identify key molecular players through network vulnerability and EVC+-based approaches. To demonstrate the application and relevance of our package in network analysis, previously published and publicly available protein-protein interactions (PPIs) data of human breast cancer were analyzed. This resulted in identifying some most important proteins. These included essential proteins, non-essential proteins, hubs, and bottlenecks, which play vital roles in breast cancer development. Thus, the NetVA package, available at https://github.com/kr-swapnil/NetVA with a detailed tutorial to download and use, assists in predicting potential candidates for therapeutic and diagnostic purposes by exploring various topological features of a disease-specific PPIs network.
Salmonella Infantis, the emerging human multidrug resistant pathogen – a One Health perspective

Salmonella Infantis presents an ever-increasing threat to public health due to its spread throughout many countries and association with high levels of antimicrobial resistance (AMR). Whole genome sequences of 5,284 S. Infantis strains from 74 countries, isolated between 1989 and 2020 from a wide variety of sources including humans, animals, and food, were analysed to compare genetic phylogeny, AMR determinants and plasmid presence. The global S. Infantis population structure diverged into three clusters: a North American cluster, European cluster and a global cluster. The levels of AMR varied between the S. Infantis clusters and by isolation source; 73% of poultry isolates had multidrug resistance (MDR) compared to 35% of human isolates. This correlated with plasmid of emerging S. Infantis (pESI) presence; 71% of poultry isolates contained pESI versus 32% of human isolates. This provides important information for public health teams engaged in reducing the spread of this pathogen.
Estimating parameters in discretely, partially observed stochastic differential equations

An approximate maximum likelihood method for direct estimation of embedded parameters in nonlinear, multivariate stochastic differential equations using discrete-time input-output data encumbered with additive measurement noise is proposed. The stochastic differential equations act as the system equation of a continuous-discrete time state space model which is introduced to describe nonlinear, multivariate and quasi-stationary systems. The likelihood is formulated as a function of the embedded parameters of the stochastic state space model, and an Iterated Extended Kalman filter is used in evaluating the likelihood function. A transformation is introduced to remove level effects (state-dependent diffusion terms) in some multivariate SDEs such that the filtering problem may be solved using the IEKF. Monte Carlo simulation of a nonlinear predator-prey system is used to study the statistical properties of the proposed method.
Existence Results of Ordinary Differential Inclusions in Banach Algebra under Weak Topology

The area devoted to the study of differential equations and differential inclusions has received much attention due to the fact that they describe many phenomenons in various fields of applied sciences like physics, control theory, chemistry, biology, and so forth. For some of these applications, one can see [1-8] and the references therein. In most papers, sufficient conditions for the existence of solutions to the corresponding problems are obtained by using classical fixed point theory. We refer, for example, to few studies [9-14]. In this work, we are mainly concerned with the existence results of solutions for the following two-dimensional quadratic problems for ordinary differential inclusion (in short QV P) occurring in some physical and biological problems:
Total Knee Arthroplasty in Patients Over 80 Years of Age

We conducted this study to review the clinical and radiographic outcomes of patients 80 years of age or older who underwent total knee arthroplasty (TKA). We identiﬁed clinical results in 60 patients (66 knees) who had a mean age of 84 years (range, 80 to 95 years) and who underwent TKA. These were compared with a non-age-matched group of 63 patients (66 knees) who had a mean age of 69 years (range, 60 to 79 years). Four patients were lost to follow-up. After a mean 43-month follow-up (range, 24 to 117 months), Knee Society pain and function scores for the study group improved from 53 points (range, 25 to 70 points) and 53 points (range, 40 to 70 points), respectively, to 94 points (range, 75 to 100 points) and 87 points (range, 45 to 100 points). There were no implant failures, 2 surgical complications, and 13 medical complications. In the matching group, there were four surgical complications (two required revision) and two medical complications. There were no radiographic failures or progressive radiolucencies. Although the incidence of medical complications in the perioperative period may be higher, TKA is a safe and effective treatment for refractory joint pain in patients over 80 years of age.
The Impact of Low-Level Moisture Errors on Model Forecasts of an MCS Observed during PECAN

AbstractThis article investigates errors in forecasts of the environment near an elevated mesoscale convective system (MCS) in Iowa on 24–25 June 2015 during the Plains Elevated Convection at Night (PECAN) field campaign. The eastern flank of this MCS produced an outflow boundary (OFB) and moved southeastward along this OFB as a squall line. The western flank of the MCS remained quasi stationary approximately 100 km north of the system’s OFB and produced localized flooding. A total of 16 radiosondes were launched near the MCS’s eastern flank and 4 were launched near the MCS’s western flank.Convective available potential energy (CAPE) increased and convective inhibition (CIN) decreased substantially in observations during the 4 h prior to the arrival of the squall line. In contrast, the model analyses and forecasts substantially underpredicted CAPE and overpredicted CIN owing to their underrepresentation of moisture. Numerical simulations that placed the MCS at varying distances too far to the northeast we.
Passive smoking increases platelet thromboxane

Although active smoking is known to enhance platelet thromboxane production, no data on passive smoking are available yet. In an 18 m 3 room, the influence of single and repeated exposure to passive smoke for 60 minutes was assessed in nonsmokers and smokers. Smokers and nonsmokers were matched for sex and age. All the evaluated parameters (plasma TXB2, serum TXB2, malondialdehyde, l 1-dehydro-TXB2, conversion of exogenous arachidonic acid to hydroxy-5,8,10-heptadecatrienoic acid, and TXB 2) were higher in smokers than nonsmokers at baseline conditions, immediately and 6 hours after passive exposure to cigarette smoke. Repeated exposure of nonsmokers rendered their platelets more activated, so they became closer to the behavior of smokers. Contributing to the development of hemostatic imbalance, these results indicate that passive smoking may enhance thromboxane A 2 release from the platelets.
Reactivity of intraosseous femoral head arteries after long term glucocorticoid treatment: An experimental study in immature pigs

In the pathogenesis of steroid induced femoral head necrosis only intraand extravascular factors have been discussed. Vasoreactivity of intraosseous femoral head arteries has not previously been investigated. This study investigates the effect of long term glucocorticoid treatment on reactivity of intraosseous femoral head arteries in a porcine model. From 24 immature female Danish Landrace pigs from 12 litters, 12 animals received 100 mg methylprednisolone (orally) daily for 3 months. Their 12 sister pigs served as controls and received no corticosteroid. After sacrificing the animal, resistance arteries (diameter approximately 250 ~.~m) were isolated from the femoral head epiphyseal cancellous bone and mounted as ring preparations on a small vessel myograph for measurement of isometric force development. The vasocontractory response to increasing doses of noradrenaline was not altered by methytprednisolone treatment. After submaximal precontraction by noradrenaline, vasorelaxation by sodium nitroprusside was not altered by methylprednisolone treatment. Only part of both experimental groups showed vasorelaxation to substance P and increasing doses of bradykinin. Increasing dose of endothelin-1 evoked vasoconstriction in both experimental groups. Sensitivity to endothelin-1 was increased after 3 months of methylprednisolone treatment. The response of isolated intraosseous femoral head arteries to endothelin-1 after tong term glucocorticoid treatment in the pig is enhanced and appears to be unchanged for other physiologic vasoactive substances. Presented in part as a Young Investigator Award Competition of the 42 na Annual World Congress International College of Angiology, San Diego, California, June 2000. The experiment complied with the Danish Law on Animal Experiments and was approved by the Danish Ministry of Justice. Correspondence to: W. Drescher, M.D., A.F. I.C. A. , Department of Orthopaedic Surgery, Aarhus University Hospital, DK-8000 Aarhus C, Denmark Introduction Glucocorticoid treatment is a known etiology for nontraumatic femoral head necrosis, but the pathomechanism of steroid induced femoral head necrosis is still under discussion [15]. It has been shown that short term high dose methylprednisolone treatment reduces bone blood flow in a pig model [4]. Intra[6] and extravascular factors [1,3] have been studied in relation to steroid induced femoral head necrosis. Vasoreactivity of intraosseous femoral head arteries has not previously been investigated [14,21], The aim of this study was to investigate the effect of long term glucocorticoid treatment on vasoreactivity of intraosseous femoral head arteries in a porcine model. Materials and Methods
The Influence of Material and Design on Total Knee Replacement Wear

It is difﬁcult for surgeons to make the decision on which design or material to use given the different options available. Marketing claims and direct-to-consumer advertising certainly complicate this further. One company may claim a higher percentage of wear reduction with their bearing surfaces compared with those of another manufacturer. If the percentage of wear reduction is lower, it is unclear as to whether this creates a more effective technology for reducing wear in the clinical situation. The relative contribution and relationship of design and materials to wear performance must be considered before making that important judgment. To examine the overall inﬂuence of implant design on wear reduction, a knee simulator study was undertaken. This simulator study compared the Oxinium Genesis II system with the Triathlon Conventional and Triathlon X3 knee systems under physiologic stair-climb loading and motion proﬁles. This allows a similar comparison of material effect within one design but also a global comparison across designs. Test results show the Triathlon Conventional and Triathlon X3 knee systems have superior wear resistance compared with that of the Genesis II Oxinium system under stair-climbing simulation. This ﬁnding indicates that implant design plays a more signiﬁcant role in knee wear reduction than material. Although material technology may improve a given knee system’s ability to wear, design geometry has a ﬁrst-order effect and should be addressed before materials. This study represents an effort to differentiate design effect from two different approaches to material enhancement. The results of this study support the predominance of design in knee replacement wear performance. Ultimately, only clinical evidence such as published studies or outcomes reported in the available joint registries will establish whether any material or design can achieve a 30-year outcome.
Meniscus Repair and Transplantation Techniques

Modern meniscal repair incorporates multiple techniques and adjunctive measures. The classic inside-out repair remains the gold standard and is most appropriate for a bucket-handle type tear of the medial or lateral meniscus. The all-inside technique has gained in popularity recently and has outcomes that approach those of the inside-out repair with decreased morbidity but increased cost. The choice of this technique is most appropriate for small tears requiring few sutures to repair. Outside-in repair can also be employed and is preferred for anterior horn tears. Surgeons may use a hybrid technique that incorporates all techniques in some challenging cases. Meniscal debridement is used for degenerative tears that are not amenable to repair. Meniscal transplantation is an option for symptomatic meniscal deficiency in young, active patients. This article discusses the technical considerations for meniscal debridement, repair, and transplantation.
The effect of explanations on mathematical reasoning tasks

ABSTRACT Studies in mathematics education often point to the necessity for students to engage in more cognitively demanding activities than just solving tasks by applying given solution methods. Previous studies have shown that students that engage in creative mathematically founded reasoning to construct a solution method, perform significantly better in follow up tests than students that are given a solution method and engage in algorithmic reasoning. However, teachers and textbooks, at least occasionally, provide explanations together with an algorithmic method, and this could possibly be more efficient than creative reasoning. In this study, three matched groups practiced with either creative, algorithmic, or explained algorithmic tasks. The main finding was that students that practiced with creative tasks did, outperform the students that practiced with explained algorithmic tasks in a post-test, despite a much lower practice score. The two groups that got a solution method presented, performed similarly in both practice and post-test, even though one group got an explanation to the given solution method. Additionally, there were some differences between the groups in which variables predicted the post-test score.
Does Knee Replacement Surgery Lead to Chronic Limb Ischemia?

Total knee replacement (TKR) may be associated with chronic limb ischemia (CLI) due to arterial injury intraoperatively. The aim of this study was to determine the incidence of CLI after TKR surgery. Patients who received a unilateral TKR in 2003–2004 were identiﬁed from our database. Patients with diabetes mellitus and preexisting peripheral arterial disease were excluded. Patient assessment was by collection of demographic details, completion of the Oxford Knee Score, Short Form-12 Health Survey, and King’s College Hospital’s Vascular Quality of Life Questionnaire, and measurement of the ankle brachial pressure index (ABPI). Of the 209 eligible patients, 86 (41%) participated (median age, 73 years; 50% male). Five (5.8%) patients had a reduced ABPI compared with population norms of 4.6 to 7%. Patients with reduced ABPI measurements had higher Oxford Knee Scores, but no relationships between other variables were demonstrated. TKR surgery does not appear to increase the risk of CLI.