Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data ...to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4
T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.
Conversation between two people involves subtle nonverbal coordination in addition to speech. However, the precise parameters and timing of this coordination remain unclear, which limits our ability ...to theorize about the neural and cognitive mechanisms of social coordination. In particular, it is unclear if conversation is dominated by synchronization (with no time lag), rapid and reactive mimicry (with lags under 1 s) or traditionally observed mimicry (with several seconds lag), each of which demands a different neural mechanism. Here we describe data from high-resolution motion capture of the head movements of pairs of participants (
n
= 31 dyads) engaged in structured conversations. In a pre-registered analysis pathway, we calculated the wavelet coherence of head motion within dyads as a measure of their nonverbal coordination and report two novel results. First, low-frequency coherence (0.2–1.1 Hz) is consistent with traditional observations of mimicry, and modeling shows this behavior is generated by a mechanism with a constant 600 ms lag between leader and follower. This is in line with rapid reactive (rather than predictive or memory-driven) models of mimicry behavior, and could be implemented in mirror neuron systems. Second, we find an unexpected pattern of lower-than-chance coherence between participants, or hypo-coherence, at high frequencies (2.6–6.5 Hz). Exploratory analyses show that this systematic decoupling is driven by fast nodding from the listening member of the dyad, and may be a newly identified social signal. These results provide a step towards the quantification of real-world human behavior in high resolution and provide new insights into the mechanisms of social coordination.
The high viral diversity of HIV-1 is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far ...immunization strategies have failed to efficiently elicit bNAbs. To overcome these obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (MAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive MAbs were isolated using antigen-specific single B-cell sorting. Four of these MAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing MAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles, and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B-neutralizing MAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer-dissociating bNAbs.
Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic, and 1.7 million people still get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing MAbs, combined with detailed characterization of the neutralization epitope, can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination.
Aims
This study aimed to: (a) determine adherence rates to oral anticoagulants in atrial fibrillation patients with a high risk for thromboembolic events postradiofrequency ablation; (b) evaluate ...patients’ knowledge and perceptions towards oral anticoagulants; and (c) explore the impact of patients’ knowledge and perceptions on treatment adherence.
Background
Atrial fibrillation is a common arrhythmia associated with an increased risk of developing thromboembolic events such as stroke. Although adherence to oral anticoagulants is crucial to prevent such complications, the relationship between adherence, knowledge and patient perceptions is poorly understood in patients with atrial fibrillation at high risk for thromboembolic events after radiofrequency ablation.
Design
A cross‐sectional observational survey study was performed in a single centre.
Methods
The levels of adherence, knowledge, and perception towards oral anticoagulants were assessed using the 8‐item Morisky Medication Adherence Scale, Knowledge of Oral Anticoagulation Tool, Perception of Anticoagulant Treatment Questionnaire and Benefit‐Risk Perception Tool, respectively. Results from these self‐reported tools were analysed descriptively. A multivariable binary logistic regression model was used to identify factors associated with levels of adequate adherence.
Results
Adequate treatment adherence was found in three‐quarters of patients. The total mean knowledge score was low. Participants expressed high ease of use and low burden of treatment. Higher total knowledge and satisfaction scores were significant factors associated with higher levels of adherence.
Conclusion
There remains a huge unmet need to follow‐up and educate patients with atrial fibrillation, focusing on good knowledge and correct perception of the advantages and disadvantages of oral anticoagulants. Our results suggest that increased knowledge and satisfaction rates might have a positive impact on adherence to oral anticoagulants.
目标
本研究旨在:(a)确定在射频消融术后易患血栓的房颤患者口服抗凝血剂的依从率;(b)评估患者对口服抗凝血剂的了解和认知;以及(c)探讨患者的了解和认知对治疗依从性的影响。
背景
房颤是一种常见的心律失常,与中风等患血栓的风险增加有关。尽管坚持口服抗凝血剂对于预防这种并发症非常重要,但对射频消融术后易患血栓的房颤患者的依从性、了解和患者认知之间的关系却知之甚少。
设计
进行了单中心横断面观察性调查研究。
方法
对口服抗凝血剂的依从性、了解和认识水平进行了评估,分别采用了8条目Morisky服药依从性量表、口服抗凝治疗工具知识、抗凝治疗问卷的看法和利弊认知工具。对这些自我报告工具的结果进行了描述性分析。同时,采用了多变量二元逻辑回归模型来确定与适当依从性水平相关的因素。
结果
在四分之三的患者中发现有适当的治疗依从性。总平均了解评分较低。受试者表现出了对治疗的高度接受和较低的心理负担。此外,较高的了解和满意度总分是与更高的依从性水平相关的重要因素。
结论
仍有大量未被满足的需求,需要对房颤患者进行随访和教育,以便患者良好了解和正确认识口服抗凝血剂的优缺点。研究结果表明,增加的了解和满意度可能对口服抗凝血剂的依从性有积极的影响。
The structural design, control system, and integrated biofeedback for a wearable exoskeletal robot for upper extremity stroke rehabilitation are presented. Assisted with clinical evaluation, ...designers, engineers, and scientists have built a device for robotic assisted upper extremity repetitive therapy (RUPERT). Intense, repetitive physical rehabilitation has been shown to be beneficial overcoming upper extremity deficits, but the therapy is labor intensive and expensive and difficult to evaluate quantitatively and objectively. The RUPERT is developed to provide a low cost, safe and easy-to-use, robotic-device to assist the patient and therapist to achieve more systematic therapy at home or in the clinic. The RUPERT has four actuated degrees-of-freedom driven by compliant and safe pneumatic muscles (PMs) on the shoulder, elbow, and wrist. They are programmed to actuate the device to extend the arm and move the arm in 3-D space. It is very important to note that gravity is not compensated and the daily tasks are practiced in a natural setting. Because the device is wearable and lightweight to increase portability, it can be worn standing or sitting providing therapy tasks that better mimic activities of daily living. The sensors feed back position and force information for quantitative evaluation of task performance. The device can also provide real-time, objective assessment of functional improvement. We have tested the device on stroke survivors performing two critical activities of daily living (ADL): reaching out and self feeding. The future improvement of the device involves increased degrees-of-freedom and interactive control to adapt to a user's physical conditions.
•We use VR technology to create an immersive environment that simulates social interaction between a human participant and a virtual human.•We model two types of head nodding on the virtual ...character, namely mimicry head nods and fast nods.•We present a study that investigates the role of head nodding in social interaction, where we find a positive impact of naturalistic nodding.•We obtained implicit and explicit measures showing that participants liked and trusted the nodding variant of the virtual character.
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Nonverbal communication is an important part of human communication, including head nodding, eye gaze, proximity and body orientation. Recent research has identified specific patterns of head nodding linked to conversation, namely mimicry of head movements at 600 ms delay and fast nodding when listening. In this paper, we implemented these head nodding behaviour rules in virtual humans, and we tested the impact of these behaviours, and whether they lead to increases in trust and liking towards the virtual humans. We use Virtual Reality technology to simulate a face-to-face conversation, as VR provides a high level of immersiveness and social presence, very similar to face-to-face interaction. We then conducted a study with human-subject participants, where the participants took part in conversations with two virtual humans and then rated the virtual character social characteristics, and completed an evaluation of their implicit trust in the virtual human. Results showed more liking for and more trust in the virtual human whose nodding behaviour was driven by realistic behaviour rules. This supports the psychological models of nodding and advances our ability to build realistic virtual humans.
Aluminum oxide (Al
2
O
3
) is an emerging material in integrated photonics. It exhibits a very broad transparency window from the UV to the mid-IR, very low propagation losses and a high solubility ...for rare-earth ions leading to optical gain in different spectral ranges. Al
2
O
3
can be deposited by different wafer-level deposition techniques, including atomic layer deposition and reactive magnetron sputtering, being compatible with the monolithic integration onto passive integrated photonics platforms, such as Si
3
N
4
, to which it provides optical amplification and lasing. When deposited at low temperatures, it is also compatible with integration onto CMOS chips. In this review, the state-of-the-art on the deposition, integration and device development in this photonic platform is described.
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices ...to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI < 18.5 kg/m
) or obese (BMI ≥ 30 kg/m
) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
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