Miracle-dz/UniFAR-FTUs huggingface dataset:
Cooperativity of myosin II motors in the non-regulated and regulated thin filaments investigated with high-speed AFM

Skeletal myosins II are non-processive molecular motors, that work in ensembles to produce muscle contraction while binding to the actin filament. Although the molecular properties of myosin II are well known, there is still debate about the collective work of the motors: is there cooperativity between myosin motors while binding to the actin filaments? In this study, we used high-speed AFM to evaluate this issue. We observed that the initial binding of small arrays of myosin heads to the non-regulated actin filaments did not affect the cooperative probability of subsequent bindings to neighboring sites and did not lead to an increase in the fractional occupancy of the actin binding sites. These results suggest that myosin motors are independent force generators when connected in small arrays, and that the binding of one myosin does not alter the kinetics of other myosins. In contrast, the probability of binding of myosin heads to regulated thin filaments under activating conditions (at high Ca2+ concentration and with 2 μM ATP) was increased with the initial binding of one myosin, leading to a larger occupancy of neighboring available binding sites. The result suggests that myosin cooperativity is defined by the activation status of the thin filaments. eLife digest Muscle contraction is the result of large ensembles of the molecular motor myosin II working in coordination while attached to actin. Myosin II produces the power stroke, responsible for force generation. In this paper, we used High-Speed Atomic Force Microscopy (HS-AFM) to determine the potential cooperativity between myosin motors bound to non-regulated and regulated thin filaments. Based on the direct visualization of myosin-actin interaction, probability of myosin binding, and the myosin fractional occupancy of binding sites along non-regulated and regulated actin filaments, our results show no cooperative effects over ∼100 nm of the actin filament length. In contrast, there is myosin cooperativity within the activated thin filament, that induces a high affinity of myosin heads to the filaments. Our results support the independent behaviour of myosin heads while attached to actin filaments, but a cooperative behavior when attached to regulated thin filaments.
A Pan-Pneumovirus vaccine based on immunodominant epitopes of the fusion protein

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two leading causes of severe respiratory infections in children, the elderly, and immunocompromised patients. The fusion (F) protein is the major target of neutralizing antibodies. Recent developments in stabilizing the pre-fusion conformation of the F proteins, and identifying immunodominant epitopes that elicit potent neutralizing antibodies have led to testing of numerous pre-fusion RSV F-based vaccines in clinical trials. We designed and tested the immunogenicity and protective efficacy of a chimeric fusion protein that contains immunodominant epitopes of RSV F and hMPV F (RHMS-1). RHMS-1 has several advantages over vaccination with pre-fusion RSV F or hMPV F, including a focus on recalling B cells to the most important protective epitopes and the ability to induce protection against two viruses with a single antigen. RHMS-1 was generated as a trimeric recombinant protein, and negative-stain EM analysis demonstrated the protein resembles the pre-fusion conformation. Probing of RHMS-1 antigenicity using a panel of RSV and hMPV F-specific monoclonal antibodies (mAbs) revealed the protein retains features of both viruses, including the pre-fusion site Ø epitope of RSV F. BALB/c mice immunized with RHMS-1 had serum binding and neutralizing antibodies to both viruses. RHMS-1 vaccinated mice challenged with RSV or hMPV had undetectable virus in lung homogenates for both viruses, in contrast to RSV F or hMPV F vaccinated mice, which had detectable virus for hMPV and RSV, respectively. Overall, this study demonstrates protection against two viruses with a single antigen and supports further testing of RHMS-1 in additional pre-clinical animal models. Significance Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two Pneumoviruses that cause substantial respiratory tract infections in young children, the elderly, and immunocompromised adults. Yet vaccines against either of them are still unavailable. Multiple promising vaccine designs based on the fusion proteins of RSV and hMPV have been tested, but none of them can induce cross-protective antibody responses despite their similar structures and closely related amino acid sequence identity. Here, we report a vaccine candidate, RHMS-1, which combines the immunodominant epitopes of the RSV and hMPV fusion proteins into a single antigen. RHMS-1 maintains the immunological features of both RSV F and hMPV F, which can be recognized by epitope-specific mAbs and human B cells pre-exposed to RSV or hMPV. Furthermore, this is the first immunogen that induced potent cross-neutralizing antibodies and protected mice from RSV and hMPV challenge. Our results suggest RHMS-1 is a promising Pan-Pneumovirus vaccine.
Loss of intracerebellar heterogeneity and selective vulnerability in Spinocerebellar ataxia type 1 neurodegeneration

Regional heterogeneity of neurons and glia is a key feature of the brain, yet the effect of disease on heterogeneity and its relationship with selective neuronal vulnerability remains poorly understood. Using region-specific RNA sequencing, we identified a large number of differentially expressed genes (DEGs) across distinct regions of the cerebellar cortex, supporting the notable intrinsic regional transcriptional heterogeneity of the healthy cerebellum. Further, we used fiber photometry to identify regional physiological differences in the activity of Purkinje cells (PCs) during self-motivated, unrestrained walking and non-walking states. In the inherited cerebellar neurodegenerative disease Spinocerebellar ataxia type 1 (SCA1), patients exhibit preferential degeneration of the posterior cerebellum, suggesting regionally selective vulnerability. We demonstrated that in a mouse model of SCA1 the Purkinje cells and glia residing in the posterior vermis of cerebellum also undergo earlier and more severe pathology. Intriguingly, the intrinsic transcriptional heterogeneity of anterior and posterior cerebellum seen in healthy mice was diminished in SCA1 mice. This disruption was also demonstrated via fiber photometry, where we found notable impacts in PC activity in the posterior cerebellum as well as loss of regional differences in PC activity during self-motivated, unrestrained walking, and non-walking states in SCA1 mice. Our findings indicate regionally distinct mechanisms of pathogenesis across cerebellar regions that result in reduced intracerebellar heterogeneity.
Trunk Neural Crest Migratory Position and Asymmetric Division Predict Terminal Differentiation

The generation of complex structures during embryogenesis requires the controlled migration and differentiation of cells from distant origins. How migration and differentiation are coordinated and impact each other to form functional structures is not fully understood. Neural crest cells migrate extensively giving rise to many cell types. In the trunk, neural crest migrate collectively forming chains comprised of cells with distinct migratory identities: one leader cell at the front of the group directs migration, while followers track the leader forming the body of the chain. Herein we analysed the relationship between trunk neural crest migratory identity and terminal differentiation. We found that trunk neural crest migration and fate allocation is coherent. Leader cells that initiate movement give rise to the most distal derivativities. Interestingly, the asymmetric division of leaders separates migratory identity and fate. The distal daughter cell retains the leader identity and clonally forms the Sympathetic Ganglia. The proximal sibling migrates as a follower and gives rise to Schwann cells. The sympathetic neuron transcription factor phox2bb is strongly expressed by leaders from early stages of migration, suggesting that specification and migration occur concomitantly and in coordination. Followers divide symmetrically and their fate correlates with their position in the chain.
The Ankyrin Repeat Protein RARP-1 Is a Periplasmic Factor That Supports Rickettsia parkeri Growth and Host Cell Invasion

Rickettsia spp. are obligate intracellular bacterial pathogens that pose a growing threat to human health. Nevertheless, their strict reliance on a host cell niche has hindered investigation of the molecular mechanisms driving rickettsial infection. ABSTRACT Rickettsia spp. are obligate intracellular bacterial pathogens that have evolved a variety of strategies to exploit their host cell niche. However, the bacterial factors that contribute to this intracellular lifestyle are poorly understood. Here, we show that the conserved ankyrin repeat protein RARP-1 supports Rickettsia parkeri infection. Specifically, RARP-1 promotes efficient host cell entry and growth within the host cytoplasm, but it is not necessary for cell-to-cell spread or evasion of host autophagy. We further demonstrate that RARP-1 is not secreted into the host cytoplasm by R. parkeri. Instead, RARP-1 resides in the periplasm, and we identify several binding partners that are predicted to work in concert with RARP-1 during infection. Altogether, our data reveal that RARP-1 plays a critical role in the rickettsial life cycle. IMPORTANCE Rickettsia spp. are obligate intracellular bacterial pathogens that pose a growing threat to human health. Nevertheless, their strict reliance on a host cell niche has hindered investigation of the molecular mechanisms driving rickettsial infection. This study yields much-needed insight into the Rickettsia ankyrin repeat protein RARP-1, which is conserved across the genus but has not yet been functionally characterized. Earlier work had suggested that RARP-1 is secreted into the host cytoplasm. However, the results from this work demonstrate that R. parkeri RARP-1 resides in the periplasm and is important both for invasion of host cells and for growth in the host cell cytoplasm. These results reveal RARP-1 as a novel regulator of the rickettsial life cycle.
Engineered Cell Membrane-Derived Nanocarriers: The Enhanced Delivery System for Therapeutic Applications

There has been a rapid development of biomimetic platforms using cell membranes as nanocarriers to camouflage nanoparticles for enhancing bio-interfacial capabilities. Various sources of cell membranes have been explored for natural functions such as circulation and targeting effect. Biomedical applications of cell membranes-based delivery systems are expanding from cancer to multiple diseases. However, the natural properties of cell membranes are still far from achieving desired functions and effects as a nanocarrier platform for various diseases. To obtain multi-functionality and multitasking in complex biological systems, various functionalized modifications of cell membranes are being developed based on physical, chemical, and biological methods. Notably, many research opportunities have been initiated at the interface of multi-technologies and cell membranes, opening a promising frontier in therapeutic applications. Herein, the current exploration of natural cell membrane functionality, the design principles for engineered cell membrane-based delivery systems, and the disease applications are reviewed, with a special focus on the emerging strategies in engineering approaches.
Human Growth Factor/Immunoglobulin Complexes for Treatment of Myocardial Ischemia-Reperfusion Injury

Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48–72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.
Use of Virtual Reality in Psychiatric Diagnostic Assessments: A Systematic Review

Background Technological developments such as Virtual reality (VR) provide new opportunities to extend and innovate mental healthcare. VR as a tool for clinical assessment has been described as promising, as it can enable real-time assessment within real-like environments or contexts as opposed to self-report and behavioral tasks in laboratory settings. Objective With this systematic review we aimed to provide an overview of recent studies using VR in the assessment of psychiatric disorders. Methods A systematic search was performed using Pubmed, Embase, PsycInfo, and Web of Science between 2016 and 2020. Studies were included if they used immersive VR, concerned assessment of psychiatric symptoms/disorders, and included adult patients with psychiatric disorders. Results The search resulted in 3,163 potentially eligible articles, from which a total of 27 studies fulfilled inclusion criteria. Most studies considered anxiety (n = 7), addictive, (n = 7), or psychotic disorders (n = 5). Regarding ADHD (n = 3), PTSD (n = 3), and pedophilic disorder (n = 1), a few studies had been performed since 2016. The majority of the included studies compared patient groups to healthy control groups. Discussion Recent studies on VR-assisted psychiatric assessments have been conducted to validate VR environments, to assess symptoms for diagnostics or therapy goals, search for biomarkers, and to gain knowledge on psychiatric disorders. VR tasks were able to detect some difference between patient and healthy control groups, mainly with regard to self-report measures. Despite previous, promising prospects, the use of VR as a tool in clinical assessments must still be considered as a field in need of continued developments and evaluations. Systematic Review Registration www.crd. york.ac. uk/prospero, identifier: CRD42021233772.
Outward Appearance or Inward Significance? On Experts' Perspectives When Studying and Solving Water Scarcity

In the first decade of the 21st century, a water harvesting approach based on contour trenches—ditches to catch runoff—from Kenya was proposed as groundwater recharge technology in a semi-arid area in Ninh Phuoc district, Vietnam. In order to modify this solutions to tackle water scarcity, hydrological conditions at the site needed to be known. For such small-scale interventions, finding the most suitable set of (cheap and quick) efforts to study local hydrology is not easy. After our own study, we explored how different experts evaluated the chosen approach. The results from this evaluation suggest that different perspective for appropriate hydrological research can be found within a group of experts. This finding—in line with anthropologically inspired science studies—suggests that integrating different perspectives from stakeholders when working on suitable solutions in real-life water scarcity situations needs to be complemented with attention for different perspectives on the underlying hydrological processes and how they are to be studied. We discuss how this notion on the multiple perspectives intrinsic to hydrological research can be fruitfully included when developing water interventions.
Incongruence in Lighting Impairs Face Identification

The effect of uniform lighting on face identity processing is little understood, despite its potential influence on our ability to recognize faces. Here, we investigated how changes in uniform lighting level affected face identification performance during face memory tests. Observers were tasked with learning a series of faces, followed by a memory test where observers judged whether the faces presented were studied before or novel. Face stimuli were presented under uniform bright or dim illuminations, and lighting across the face learning and the memory test sessions could be the same (“congruent”) or different (“incongruent”). This led to four experimental conditions: (1) Bright/Dim (learning bright faces, testing on dim faces); (2) Bright/Bright; (3) Dim/Bright; and (4) Dim/Dim. Our results revealed that incongruent lighting levels across sessions (Bright/Dim and Dim/Bright) significantly reduced sensitivity (d’) to faces and introduced conservative biases compared to congruent lighting levels (Bright/Bright and Dim/Dim). No significant differences in performance were detected between the congruent lighting conditions (Bright/Bright vs. Dim/Dim) and between the incongruent lighting conditions (Bright/Dim vs. Dim/Bright). Thus, incongruent lighting deteriorated performance in face identification. These findings implied that the level of uniform lighting should be considered in an illumination-specific face representation and potential applications such as eyewitness testimony.
Leaf Functional Traits of Two Species Affected by Nitrogen Addition Rate and Period Not Nitrogen Compound Type in a Meadow Grassland

Plasticity of plant functional traits plays an important role in plant growth and survival under changing climate. However, knowledge about how leaf functional traits respond to the multi-level N addition rates, multiple N compound and duration of N application remains lacking. This study investigated the effects of 2-year and 7-year N addition on the leaf functional traits of Leymus chinensis and Thermopsis lanceolata in a meadow grassland. The results showed that the type of N compounds had no significant effect on leaf functional traits regardless of duration of N application. N addition significantly increased the leaf total N content (LN) and specific leaf area (SLA), and decreased the leaf total P content (LP) and leaf dry matter content (LDMC) of the two species. Compared with short-term N addition, long-term N addition increased LN, LP, SLA, and plant height, but decreased the LDMC. In addition, the traits of the two species were differentially responsive to N addition, LN and LP of T. lanceolata were consistently higher than those of L. chinensis. N addition would make L. chinensis and T. lanceolata tend to “quick investment-return” strategy. Our results provide more robust and comprehensive predictions of the effects of N deposition on leaf traits.
A Case-Control Study of the Dose-Response Relationship Between Thrombin Activatable Fibrinolysis Inhibitor and Acute Myocardial Infarction

Background Acute myocardial infarction (AMI) is considered an acute coronary syndrome (ACS), which is caused by the death of myocardial cells after prolonged ischemia, and there is a high risk of sudden death during AMI. Therefore, the purpose of this study is to explore the relationship between thrombin activatable fibrinolysis inhibitor (TAFI) and AMI and provide evidence for their association and potentially the prevention of AMI. Methods There were 228 subjects included in this retrospective study, which included 78 AMI patients and 150 controls. The immune turbidimetry was used to measure TAFI concentration in the serum. Mann–Whitney U test was used to compare serum TAFI levels. The logistic regression analysis was used to construct a model of influencing factors of AMI. The dose-response relationship between serum TAFI level and AMI was explored by using the restricted cubic spline (RCS) functions combined with logistic regression analysis. Results The serum TAFI levels of the AMI group were higher than the control group’s (P = 0.003). The risk of AMI in the high-TAFI level group was 2.24 times higher than the low-TAFI level group (P = 0.007) and it was 2.74 times higher after adjustment of other risk factors (P = 0.025). According to the dose-response curve, the risk of AMI increased significantly with an increase of serum TAFI concentration (P = 0.0387). Conclusion Acute myocardial infarction patients had higher serum TAFI levels, and TAFI was an independent risk factor for AMI patients. Serum TAFI levels demonstrated a dose- dependent response to the risk of AMI. Our study provides evidence that TAFI could be used for risk stratification of AMI patients.
Relationship Between Dry Eye Disease and Emotional Disorder: The Mediating Effect of Health Anxiety

Objective This study aims to investigate the relationship between dry eye disease (DED) and anxiety, as well as DED and depression. Additionally, the influence of health anxiety (HA) on this relationship was determined. Methods A total of 206 patients with DED were recruited from Tianjin Medical University Eye Hospital clinic and surveyed using demographic questionnaires, the Ocular Surface Disease Index (OSDI), Hospital Anxiety and Depression Scale (HADS), and Short Health Anxiety Inventory (SHAI). Additionally, they were examined using Keratograph 5M and assessed for DED by corneal fluorescein staining. Regression analysis and the bootstrap method were used to investigate the influence of HA on the relationship between DED and emotional disorders. Results Among the 206 patients with DED, 52 (25.24%) and 56 (27.18%) patients showed depression and anxiety, respectively. The OSDI score and HA were positively correlated with depression and anxiety (P < 0.01). The direct effects of OSDI on depression and anxiety were significant (95% confidence interval [CI]: 0.017–0.069; 0.008–0.060). Additionally, the bootstrap test showed significant mediating effects of HA (95% CI: 0.001–0.016; 0.003–0.021). The results suggested that the severity of DED symptoms, as measured by the OSDI score, affected anxiety and depression by a direct and an indirect pathway mediated by HA. Conclusions We found a significant correlation between DED and anxiety and depression. Moreover, HA was a mediator of the relationship between DED symptoms and anxiety and depression.