Miracle-dz/UniFAR-FTUs huggingface dataset:
Electrostatic and bending energies predict staggering and splaying in nonmuscle myosin II minifilaments

Recent experiments with super-resolution live cell microscopy revealed that nonmuscle myosin II minifilaments are much more dynamic than formerly appreciated, often showing plastic processes such as splitting, concatenation and stacking. Here we combine sequence information, electrostatics and elasticity theory to demonstrate that the parallel staggers at 14.3, 43.2 and 72 nm have a strong tendency to splay their heads away from the minifilament, thus potentially initiating the diverse processes seen in live cells. In contrast, the straight antiparallel stagger with an overlap of 43 nm is very stable and likely initiates minifilament nucleation. Using stochastic dynamics in a newly defined energy landscape, we predict that the optimal parallel staggers between the myosin rods are obtained by a trial-and-error process in which two rods attach and re-attach at different staggers by rolling and zipping motion. The experimentally observed staggers emerge as the configurations with the largest contact times. We find that contact times increase from isoforms C to B to A, that A-B-heterodimers are surprisingly stable and that myosin 18A should incorporate into mixed filaments with a small stagger. Our findings suggest that nonmuscle myosin II minifilaments in the cell are first formed by isoform A and then convert to mixed A-B-filaments, as observed experimentally. Author summary Nonmuscle myosin II (NM2) is a non-processive molecular motor that assembles into minifilaments with a typical size of 300 nm to generate force and motion in the actin cytoskeleton. This process is essential for many cellular processes such as adhesion, migration, division and mechanosensing. Due to their small size below the resolution limit, minifilaments are a challenge for imaging with traditional light microscopy. With the advent of super-resolution microscopy, however, it has become apparent that the formation of NM2-minifilaments is much more dynamic than formerly appreciated. Modeling the electrostatic interaction between the rigid rods of the myosin monomers has confirmed the main staggers observed in experiments, but cannot explain these high dynamics. Here we complement electrostatics by elasticity theory and stochastic dynamics to show that the parallel staggers are likely to splay away from the main axis of the minifilament and that monomers attach and deattach with rolling and zipping motions. Based on the sequences of the different NM2-isoforms, we predict that isoform A forms the most stable homofilaments and that A-B-heterofilaments are also very stable.
Genome Graphs

There is increasing recognition that a single, monoploid reference genome is a poor universal reference structure for human genetics, because it represents only a tiny fraction of human variation. Adding this missing variation results in a structure that can be described as a mathematical graph: a genome graph. We demonstrate that, in comparison to the existing reference genome (GRCh38), genome graphs can substantially improve the fractions of reads that map uniquely and perfectly. Furthermore, we show that this fundamental simplification of read mapping transforms the variant calling problem from one in which many non-reference variants must be discovered de-novo to one in which the vast majority of variants are simply re-identified within the graph. Using standard benchmarks as well as a novel reference-free evaluation, we show that a simplistic variant calling procedure on a genome graph can already call variants at least as well as, and in many cases better than, a state-of-the-art method on the linear human reference genome. We anticipate that graph-based references will supplant linear references in humans and in other applications where cohorts of sequenced individuals are available.
Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

Background DYT1 dystonia is a neurological movement disorder characterized by painful sustained muscle contractions resulting in abnormal twisting and postures. In a subset of patients, it is caused by a loss-of-function mutation (ΔE302/303; or ΔE) in the luminal ATPases associated with various cellular activities (AAA+) protein torsinA encoded by the TOR1A gene. The low penetrance of the ΔE mutation (∼30-40%) suggests the existence of unknown genetic modifiers of DYT1 dystonia. Methods To identify these modifiers, we performed whole exome sequencing of blood leukocyte DNA isolated from two DYT1 dystonia patients, three asymptomatic carriers of the ΔE mutation, and an unaffected adult relative. Results A total of 264 DYT1 dystonia-associated variants (DYT1 variants) were identified in 195 genes. Consistent with the emerging view of torsinA as an important regulator of the cytoskeleton, endoplasmic reticulum homeostasis, and lipid metabolism, we found DYT1 variants in genes that encode proteins implicated in these processes. Moreover, 40 DYT1 variants were detected in 32 genes associated with neuromuscular and neuropsychiatric disorders. Conclusion The DYT1 variants described in this work represent exciting new targets for future studies designed to increase our understanding of the pathophysiology and pathogenesis of DYT1 dystonia.
Low frequency traveling waves in the human cortex coordinate neural activity across spatial scales

Traveling waves of oscillatory activity are thought to influence neuronal spiking, providing a spatiotemporal frame-work for neural communication. However, no direct link has been established between traveling waves and single unit spiking in humans. We examined traveling waves in the human lateral temporal lobe by using recordings from intracranial electrodes implanted in twenty participants for seizure monitoring as they performed a paired-associates verbal memory task. We observed ubiquitous low frequency traveling waves across the temporal lobe. While wave occurrence in a broad low frequency range did not differ between successful and unsuccessful memory conditions, in a subset of participants with microelectrode recordings, we found that macro-scale waves co-occurred with micro-scale waves, which in turn were temporally locked to single unit spiking. This temporal coordination between traveling waves at different spatial scales and between waves and neuronal spiking in the human brain suggests a role for traveling waves in neural communication.
Analysis of circulating-microRNA expression in lactating Holstein cows under summer heat stress

Korean peninsular weather is rapidly becoming subtropical due to global warming. In summer 2018, South Korea experienced the highest temperatures since the meteorological observations recorded in 1907. Heat stress has a negative effect on Holstein cows, the most popular breed of dairy cattle in South Korea, which is susceptible to heat. To examine physiological changes in dairy cows under heat stress conditions, we analyzed the profiles circulating microRNAs isolated from whole blood samples collected under heat stress and non-heat stress conditions using small RNA sequencing. We compared the expression profiles in lactating cows under heat stress and non-heat stress conditions to understand the regulation of biological processes in heat-stressed cows. Moreover, we measured several heat stress indicators, such as rectal temperature, milk yield, average daily gain, and progesterone concentration. All these assessments showed that pregnant cows were more susceptible to heat stress than non-pregnant cows. Particularly, progesterone concentrations known to have maternal warming effects were at similar levels in non-pregnant cows but significantly increased in pregnant cows under heat stress conditions. The differentially expressed miRNAs and their putative target genes were analyzed in pregnant cows. Interestingly, we found that differentially expressed miRNAs (bta-miR-146b, bta-miR-20b, bta-miR-29d-3p, bta-miR-1246) specifically targeted progesterone biosynthesis (StAR) and the function of corpus luteum-related genes (CCL11, XCL), suggesting that pregnant cows with elevated progesterone concentrations are more susceptible to heat stress. In addition, we found the differential expression of 11 miRNAs (bta-miR-19a, bta-miR-19b, bta-miR-30a-5p, and several from the bta-miR-2284 family) in both pregnant and non-pregnant cows under heat stress conditions. In target gene prediction and gene set enrichment analysis, these miRNAs were found to be associated with the cytoskeleton, cell junction, vasculogenesis, cell proliferation, ATP synthesis, oxidative stress, and immune responses involved in heat response. These miRNAs can be used as potential biomarkers for heat stress.
Methods matter: your measures of explicit and implicit processes in visuomotor adaptation affect your results

Visuomotor rotations are frequently used to study the different processes underlying motor adaptation. Explicit aiming strategies and implicit recalibration are two of these processes. Various methods, which differ in their underlying assumptions, have been used to dissociate the two processes. Direct methods, such as verbal reports, assume explicit knowledge to be verbalizable, where indirect methods, such as the exclusion, assume that explicit knowledge is controllable. The goal of this study was thus to directly compare verbal reporting with exclusion in two different conditions: during consistent reporting and during intermittent reporting. Our results show that our two conditions lead to a dissociation between the measures. In the consistent reporting group, all measures showed similar results. However, in the intermittent reporting group, verbal reporting showed more explicit re-aiming and less implicit adaptation than exclusion. Curiously, when exclusion was measured again, after the end of learning, the differences were no longer apparent. We suspect this may reflect selective decay in implicit adaptation, as has been reported previously. All told, our results clearly indicate that methods of measurement can affect the amount of explicit re-aiming and implicit adaptation that is measured. Since it has been previously shown that both explicit re-aiming and implicit adaptation have multiple components, discrepancies between these different methods may arise because different measures reflect different components.
The coupled dual-oscillator model of wing and haltere motion in flies

The mechanics of Dipteran thorax is dictated by a network of exoskeletal linkages which, when deformed by flight muscles, generate coordinated wing movements. In Diptera, forewings power flight, whereas hindwings have evolved into specialized halteres which provide rapid mechanosensory feedback for flight stabilization. Although actuated by independent muscles, wing-haltere motion is precisely phase-coordinated at high frequencies. Because wingbeat frequency is a product of wing-thorax resonance, wear-and-tear of wings or thorax should impair flight ability. Here, we show that wings and halteres are independently-driven, linked, coupled oscillators. We systematically reduced wing length in flies and observed how wing-haltere synchronization was affected. The wing-wing system is a strongly-coupled oscillator, whereas wing-haltere system is weakly-coupled through mechanical linkages which synchronize phase and frequency. Wing-haltere link is unidirectional; altering wingbeat frequency affects haltere frequency, but not vice-versa. Exoskeletal linkages are thus key morphological features of Dipteran thorax, ensuring robust wing-haltere synchrony despite wing damage.
African swine fever virus-like integrated elements in a soft tick genome – an ancient virus vector arms race?

Background African swine fever virus (ASFV) is the only known DNA-arbovirus and a most devastating suid pathogen that, originating from a sylvatic cycle in Africa, has spread to eastern Europe and recently reached western Europe and Asia, leading to a socio-economic crisis of global proportion. However, since neither closely related viruses nor integrated viral elements have yet been identified, ASFV evolution remains a mystery. Results Here, we show that soft ticks of the Ornithodoros moubata group, the natural arthropod vector of ASFV, harbour African swine fever virus-like integrated (ASFLI)-elements corresponding to up to 10% (over 20 kb) of the ASFV genome. Through orthologous dating and molecular clock analyses, we provide data suggesting that integration occurred over 1.47 million years ago. Furthermore, our data indicate that these elements, showing high sequence identities to modern ASFV, are maintained in the tick genome to protect the tick from infection with specific ASFV-strains through RNA interference. Conclusion We suggest that this mechanism of protection, shaped through many years of co-evolution, is part of an evolutionary virus-vector “arms race”, a finding that has not only high impact on our understanding of the co-evolution of viruses with their hosts but also provides a glimpse into the evolution of ASFV.
Untangling intelligence, psychopathy, antisocial personality disorder, & conduct problems: A meta-analytic review

Abstract Substantial research has investigated the association between intelligence and psychopathic traits. The findings to date have been inconsistent and have not always considered the multi-dimensional nature of psychopathic traits. Moreover, there has been a tendency to confuse psychopathy with other closely related, clinically significant disorders. The current study represents a meta-analysis conducted to evaluate the direction and magnitude of the association of intelligence with global psychopathy, as well as its factors and facets, and related disorders (Antisocial Personality Disorder, Conduct Disorder, and Oppositional Defiant Disorder). Our analyses revealed a small, significant, negative relationship between intelligence and total psychopathy (r = -.07, p = .001). Analysis of factors and facets found differential associations, including both significant positive (e.g., interpersonal facet) and negative (e.g., affective facet) associations, further affirming that psychopathy is a multi-dimensional construct. Additionally, intelligence was negatively associated with Antisocial Personality Disorder (r = -.13, p = .001) and Conduct Disorder (r = -.11, p = .001), but positively with Oppositional Defiant Disorder (r = .06, p = .001). There was significant heterogeneity across studies for most effects, but the results of moderator analyses were inconsistent. Finally, bias analyses did not find significant evidence for publication bias or outsized effects of outliers.
Robust HIV-1 replication in the absence of integrase function

Integration of the proviral DNA intermediate into the host cell genome represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that HIV-1 mutants lacking functional integrase can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1. In these cells, HIV-1 forms episomal DNA circles, analogous to Hepatitis B virus covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. This rescue correlates with the loss of inhibitory epigenetic marks, and the acquisition of activating marks, on histones bound to unintegrated HIV-1 DNA. Thus retroviral DNA integration may have evolved, at least in part, as a mechanism to avoid the epigenetic silencing of extrachromosomal viral DNA by host innate antiviral factors. Significance While retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks, and the recruitment of NF-kB/Rel proteins, to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic IN- HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV.
Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

The World Health Organization has recently declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 infection. One major immunological question is concerning the antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or immunized mice. Our results show that while cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses is rare, indicating the presence of non-neutralizing antibody response to conserved epitopes in the spike. Whether these non-neutralizing antibody responses will lead to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding the antigenicity differences between SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine development.
MITRAGYNA SPECIOSA-INDUCED HEPATOTOXICITY-TREATED EFFECTIVELY BY PIPER BETLE: SCOPE AS A FUTURE ANTIDOTE

Objective: Consumption of Mitragyna speciosa (MS) leads to various toxicities including hepatotoxicity. Piper betle (PB) is a herb that possesses various therapeutic properties. The aim of the present study was to examine the protective effect of PB methanol extract (PBME) on MS-induced hepatotoxicity which could pave the way for any future antidote. Methods: Twenty-four male Sprague–Dawley rats were randomized into control and experimental groups. The control group was further divided into the negative (G-T80) and positive (G-PB) control groups. The G-T80 group (n=6) received oral gavage of the vehicle, 15% Tween 80. The G-PB group (n=6) received PBME 200 mg/kg/day, orally. The experimental group was divided into two groups, i.e., The G-MS and G-MS (PB) groups. The G-MS group (n=6) received only MS methanol extract (MSME) 500 mg/kg/day, while the G-MS (PB) group (n=6) received MSME with concomitant treatment with PBME. Results: Histopathology examination of the G-T80 and G-PB groups showed normal histology of the liver. The G-MS group showed liver injury features such as microvesicular steatosis, ballooning degeneration, acidophilic bodies, scattered focal necrosis, fibrous portal expansion, bridging fibrosis, sinusoidal congestion, and dilatation. These features were fewer in the G-MS (PB) group which received concomitant treatment with PBME. Conclusion: Administration of PBME exerted a protective effect against MS-induced hepatotoxicity. Future clinical trials using PB as an antidote may help in combating MS-induced hepatoxicity.
Developing a Model of Community of Practice Among Health Informatics Professionals in South and Southeast Asia

There is still debate on whether communities of practice (COP) can be formed or created. Many have claimed that they provide a venue to share knowledge which translates to action. In South and Southeast Asia, international development partners have invested in many capacity building initiatives to set-up and/or improve eHealth implementations in countries. While interest and resources for this increase, many challenges are still left unresolved due to repeated mistakes and undocumented experiences. The Asia eHealth Information Network (AeHIN) is a community of health informatics professionals organised to share knowledge and improve the use of ICT in health systems strengthening. Objectives : This study examined how AeHIN emerged as a knowledge sharing platform, identified best practices it adopted, and developed a model that could sustain itself as a COP. Methods : A sociometric survey was used to map knowledge sharing connections of pioneer members with interviews to substantiate findings and a 20-hour participant observation to triangulate data . UCINET 6 . 0 was used to analyse social network data while qualitative data were coded . Results : Defining roles of health informatics professionals inside the COP influences the type of information, resources, and capacities that can enter a network. The nature of its subgroups determines potentials and barriers to the network . Twelve best practices were identified to sustain a health informatics COP . It is recommended that a learning network is an appropriate model for this type of COP and an understanding of country - specific political structure is important to support participation . Conclusion : AeHIN is a COP model whose activities have a life of their own . While some prove successful, others die down or are discontinued . This unique design proved to be fitting for a group of health informatics professionals as it accommodates success and failures crucial for project implementations .
Auditory-Vestibulomotor Temporal Processing and Crossmodal Plasticity for Musical Rhythm in the Early Blind

The auditory dorsal stream (ADS) is a cortical brain network responsible for sensorimotor control and integration, including spatiotemporal processing. Although spatiotemporal movement of the head and body involves input from the vestibular system, and despite the wealth of evidence for the strong coupling between the vestibular and visual systems, very little is known about how vestibular information is integrated with auditory-motor inputs in the ADS. There is also no evidence addressing to what extent auditory-vestibulomotor integration is affected by early visual deprivation. Using functional magnetic resonance imaging and motion capture technology we show that in a task of sensorimotor temporal processing (‘feeling the beat’), the ADS includes an extension to parietoinsular vestibular cortex (PIVC) and to subcortical regions including basal ganglia and vestibular cerebellum. This circuit is engaged after sensorimotor synchronization training, during beat recognition, and is preserved in the early blind. The strength of activation of PIVC in the early blind correlates with a measure of lifetime physical spatial activity, suggesting that experience with vestibular stimulation via physical spatial activities might compensate for any negative effects of early blindness, and thus reinforcing the potential beneficial effects of mobility training. Finally, rhythmic entrainment provides an effective tool for studying auditory-vestibulomotor integration and music appreciation, and for developing music- and movement-based interventions for early blind individuals.