Miracle-dz/UniFAR-FTUs huggingface dataset:
The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A

Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are a common cause of hereditary Parkinson's disease. LRRK2 regulates various intracellular vesicular trafficking pathways, including endolysosomal degradative events such as epidermal growth factor receptor (EGFR) degradation. Recent studies have revealed that a subset of RAB proteins involved in secretory and endocytic recycling are LRRK2 kinase substrates in vivo. However, the effects of LRRK2-mediated phosphorylation of these substrates on membrane trafficking remain unknown. Here, using an array of immunofluorescence and pulldown assays, we report that expression of active or phosphodeficient RAB8A variants rescues the G2019S LRRK2–mediated effects on endolysosomal membrane trafficking. Similarly, up-regulation of the RAB11–Rabin8–RAB8A cascade, which activates RAB8A, also reverted these trafficking deficits. Loss of RAB8A mimicked the effects of G2019S LRRK2 on endolysosomal trafficking and decreased RAB7A activity. Expression of pathogenic G2019S LRRK2 or loss of RAB8A interfered with EGFR degradation by causing its accumulation in a RAB4-positive endocytic compartment, which was accompanied by a deficit in EGFR recycling and was rescued upon expression of active RAB7A. Dominant-negative RAB7A expression resulted in similar deficits in EGF degradation, accumulation in a RAB4 compartment, and deficits in EGFR recycling, which were all rescued upon expression of active RAB8A. Taken together, these findings suggest that, by impairing RAB8A function, pathogenic G2019S LRRK2 deregulates endolysosomal transport and endocytic recycling events.
Risk of COPD due to indoor air pollution from biomass cooking fuel: a systematic review and meta-analysis

ABSTRACT Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality in developing nations. In this meta-analysis, we aimed to determine the association between indoor air pollution and risk of COPD. Database searches were conducted using indoor air pollution, biomass and COPD related terms to identify relevant articles. The eligible studies were case-control, retrospective cohort, cross-sectional studies and conducted in adults that assessed COPD using any diagnostic criteria. A total of 35 studies with 73,122 participants were included. The pooled analysis showed that exposure to indoor air pollution due to solid biomass fuels increased risk of COPD by 2.65 (95% confidence interval [CI] 2.13–3.31; n = 73,122) and chronic bronchitis by 2.89 (95% CI 2.18–3.82) times more compared to non-biomass fuels. The risk of COPD was higher in Africa region (odds ratio [OR] 3.19), Asia (OR 2.88), South America (OR 2.15), Europe (OR 2.30) and North America (OR 2.14). The results of our meta-analysis indicated that exposure to indoor air pollution due to biomass smoke is strongly associated with COPD. Abbreviations: CS: cross-sectional; CC: case-control; NR: not reported; ATS: American Thoracic Society; BMRC: British Medical Research Council; GOLD: Global Initiative for Obstructive Lung Disease; IAP: indoor air pollution; BMF: biomass fuel; CB: chronic bronchitis; OR: odds ratio; UCI; upper confidence interval; LCI: lower confidence interval; COPD: chronic obstructive pulmonary disease
A Fast Fixed-Point Algorithm for Independent Component Analysis of Complex Valued Signals

Separation of complex valued signals is a frequently arising problem in signal processing. For example, separation of convolutively mixed source signals involves computations on complex valued signals. In this article, it is assumed that the original, complex valued source signals are mutually statistically independent, and the problem is solved by the independent component analysis (ICA) model. ICA is a statistical method for transforming an observed multidimensional random vector into components that are mutually as independent as possible. In this article, a fast fixed-point type algorithm that is capable of separating complex valued, linearly mixed source signals is presented and its computational efficiency is shown by simulations. Also, the local consistency of the estimator given by the algorithm is proved.
The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial: Rationale and design

Rationale In patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting. Aim To investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack. Design The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a randomized, placebo-controlled, double-blind, event-driven study. Patients will be randomized within 24 h of onset of acute ischemic symptoms. THALES is expected to randomize 13,000 at ∼450 sites worldwide, to collect 764 primary outcome events. Study treatments are ticagrelor 180 mg loading dose on day 1, then 90 mg twice daily on days 2–30, or matching placebo. All patients will also receive open-label aspirin 300–325 mg on day 1, then 75–100 mg once daily on days 2–30. Study outcomes The primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event. Discussion The THALES trial will provide important information about the benefits and risks of dual antiplatelet therapy with ticagrelor and aspirin in patients with acute cerebral ischemia in a global setting (funding: AstraZeneca). Clinical Trial Registration URL http://www.clinicaltrials. gov. Unique identifier: NCT03354429.
Establishment of a thalassaemia major quality improvement collaborative in Pakistan

Objectives The aim of this study was to establish multidisciplinary care for patients with transfusion-dependent thalassaemia (TDT) by creating a TDT quality improvement (QI) collaborative in a resource-constrained setting. This study presents our initial experience of creating this collaborative, the baseline characteristics of the participants, the proposed QI interventions and the outcome metrics of the collaborative. Design and setting TDT QI collaborative is a database comprising patients with TDT from four centres in Karachi, Pakistan. Study variables included symptoms of cardiac or endocrine dysfunction, physical examination including anthropometry and Tanner staging, chelation therapy, results of echocardiography, T2* cardiac MRI (CMR) and serum ferritin. The main outcome of this collaborative was improvement in TDT-related morbidity and mortality. Interventions addressing the key drivers of outcome were designed and implemented. Results At the time of reporting, the total number of patients in this database was 295. Most patients reported cardiac symptoms corresponding to New York Heart Association class 2. Approximately half (52%, n=153) of the patients demonstrated severe myocardial iron overload (T2* <10 ms). Majority of the patients (58%, n=175) were not on adequate chelation therapy. There was no difference in echocardiographic measures of systolic and diastolic left ventricle among the different spectrums of iron overloaded myocardium. Conclusion Using T2* CMR and endocrine testing, we have identified significant burden of iron siderosis in our patients with TDT. Lack of adequate iron load assessment and standardised management was observed. Interventions designed to target these key drivers of outcome are the unique part of this QI-based TDT registry.
Collaborative Key Exchange System Based on Chinese Remainder Theorem in Heterogeneous Wireless Sensor Networks

IPv6 over Low Power Wireless Personal Area Networks (6LoWPANs), in the next generation of wireless sensor networks, represent an emerging field which can be integrated with Internet technology. Security is one of the most important issues in 6LoWPANs given the vulnerability to security threats from Internet and the inherent constraints such as bandwidth, processing power, memory, and energy. Despite limited resources, data security for nodes adds an additional heavy cost by using various security schemes. Moreover, there is no standard approach to provide the end-to-end security in 6LoWPANs. In this work, we first axed our research to propose a new end-to-end security scheme for IP enabled sensor networks to optimize battery energy consumption and then we adapted the Internet Key Exchange version 2 (IKEv2) to wireless sensor networks while taking into consideration the scarce resources. Hence a novel Cooperative Key Exchange System (CKES) has been proposed in this paper based on Chinese Remainder Theorem (CRT) which has also been implemented in NS2 to analyze energy consumption compared to IKEv2.
Patient satisfaction reporting for patellofemoral arthroplasty is significantly lacking: a systematic review

ABSTRACT Background: Patellofemoral Arthroplasty (PFA) has been shown to be successful in restoring knee function and quality of life in patients with the isolated patellofemoral disease. Patient satisfaction has been suggested as an indicator of the quality of elective orthopedic operations, although there remains no standardized method to collect and evaluate satisfaction. The present study offers a systematic review of the available literature concerning patient satisfaction following PFA to assess common methodologies for reporting patient satisfaction. Methods: A query of the Medline database produced 116 articles that were reviewed for inclusion in the review. The following inclusion criteria were used to identify suitable articles: English language, clinical outcomes study related to PFA, and patient-reported satisfaction as an outcome measure. Results: Seven studies met inclusion criteria and were eligible for review. The highest level of evidence was level-III. The study publication dates ranged from 2009 to 2016, with six published in 2015 & 2016. In total, 320 PFAs were performed on 267 patients. Four articles reported the proportion of included patients who had previous knee surgeries (range: 20–60%). Three studies used ordinal scales to rate patient satisfaction. Four studies (57.1%) reported the numeric proportion of patients satisfied following PFA, which ranged from 76% to 96.5%. Two studies used Visual Analog Scale methods. For these two studies, one of them reported the mean satisfaction score as 7.5/10, and the other reported a median of 90/100. Conclusions: The available literature on patient satisfaction after PFA was found to be limited, with low-quality evidence and variable methodology.
Physics of active emulsions

Phase separating systems that are maintained away from thermodynamic equilibrium via molecular processes represent a class of active systems, which we call active emulsions. These systems are driven by external energy input, for example provided by an external fuel reservoir. The external energy input gives rise to novel phenomena that are not present in passive systems. For instance, concentration gradients can spatially organise emulsions and cause novel droplet size distributions. Another example are active droplets that are subject to chemical reactions such that their nucleation and size can be controlled, and they can divide spontaneously. In this review, we discuss the physics of phase separation and emulsions and show how the concepts that govern such phenomena can be extended to capture the physics of active emulsions. This physics is relevant to the spatial organisation of the biochemistry in living cells, for the development of novel applications in chemical engineering and models for the origin of life.
Inferring User Intent using Bayesian Theory of Mind in Shared Avatar-Agent Virtual Environments

We present a real-time algorithm to infer the intention of a user's avatar in a virtual environment shared with multiple human-like agents. Our algorithm applies the Bayesian Theory of Mind approach to make inferences about the avatar's hidden intentions based on the observed proxemics and gaze-based cues. Our approach accounts for the potential irrationality in human behavior, as well as the dynamic nature of an individual's intentions. The inferred intent is used to guide the response of the virtual agent and generate locomotion and gaze-based behaviors. Our overall approach allows the user to actively interact with tens of virtual agents from a first-person perspective in an immersive setting. We systematically evaluate our inference algorithm in controlled multi-agent simulation environments and highlight its ability to reliably and efficiently infer the hidden intent of a user's avatar even under noisy conditions. We quantitatively demonstrate the performance benefits of our approach in terms of reducing false inferences, as compared to a prior method. The results of our user evaluation show that 68.18% of participants reported feeling more comfortable in sharing the virtual environment with agents simulated with our algorithm as compared to a prior inference method, likely as a direct result of significantly fewer false inferences and more plausible responses from the virtual agents.
Tryptophan-Tyrosine Dipeptide, the Core Sequence of β-Lactolin, Improves Memory by Modulating the Dopamine System

Tryptophan-tyrosine (WY)-related peptides including the β-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, β-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.
Patient’s Decisional Control Preferences of a Cohort of Patients With Advanced Cancer Receiving Palliative Care in India

Context: Frequency of passive decisional control preferences (DCPs) has been variably reported but is generally higher among patients living in developing countries. Objectives: This prospective cross-sectional study aimed to determine the frequency of passive DCP among patients with advanced cancer in a tertiary cancer center in India and to identify its association with their sociodemographic and clinical characteristics. Methods: Patients with advanced cancer referred to palliative care (between March and August 2016) underwent assessment of DCP using validated tools including Control Preference Scale, Satisfaction with Decision Scale, and understanding of illness questionnaire. Information regarding patient characteristics including age, gender, education, marital status, employment, Karnofsky Performance Status Scale (KPS), cancer stage and type, and religion were also collected. Descriptive statistics and logistic regression analyses were performed. Results: Median age 48 years, Karnofsky 90, and 55.3% were men. Shared, active (patient prefers to make decision by his or her own), and passive DCP were 20.7%, 26.7%, and 52.7%, respectively (n = 150). A total of 51.3% were satisfied by the way the actual decisions were made. Passive DCP did not vary across regions. Multivariate analysis shows that the active DCP was significantly associated with better KPS (exp B 1.07 [1.01-1.15], P = .03). Conclusions: There are significant differences in DCP with KPS. Patients report a high level of satisfaction with their treatment decision-making process, though they have a poor understanding of their prognosis and goals of care and understand their treatment to be of curative intent. Individualized understanding of DCP and focus on illness understanding may be important for quality care and patient satisfaction outcomes.
Vigilance/Avoidance to Expected and Presented Stimuli in Trauma Survivors: An Eye-Tracking Study

ABSTRACT Attention in trauma-related disorders has been characterized by both vigilance and avoidance of trauma-related or aversive stimuli. This study used eye-tracking technology to investigate how cumulative trauma, as well as hypervigilance and dissociative symptoms, affected attentional patterns to anticipated negative stimuli and actual negative stimuli. A sample of forty-two trauma participants recruited from the community had a choice about where to look on a computer screen knowing which segments of the screen negative stimuli were likely to appear. Participants could look at those stimuli for as long as they chose before pushing a button to move onto the next trial. A measure of hypervigilance predicted looking to quadrants in which a negative stimulus was to appear. Cumulative trauma predicted avoidance of those stimuli. Neither cumulative trauma or symptom profiles predicted how long participants looked at the negative pictures once they were presented. These data suggest that hypervigilance is associated with looking for threats that are not yet present, and that cumulative trauma may be associated with motivation to avoid negative stimuli. The findings are discussed with respect to the characteristics of the sample and the limited dissociative pathology.
The risk of mortality among people with type 2 diabetes in Latin America: A systematic review and meta‐analysis of population‐based cohort studies

Type 2 diabetes mellitus (T2DM) is associated with a high mortality risk, although the magnitude of this association remains unknown in Latin America (LA). We aimed to assess the strength of the association between T2DM and all‐cause and cause‐specific mortality in population‐based cohort studies in LA.
Increased ventromedial prefrontal cortex activity and connectivity predict poor sertraline treatment outcome in late‐life depression

Previous studies of imaging predictors on acute treatment response in late‐life depression (LLD) demonstrated that poor response to selective serotonin reuptake inhibitors (SSRIs) is associated with pre‐treatment low functional connectivity (FC) within executive control network and high FC within default‐mode network including the ventromedial prefrontal cortex (vmPFC). However, there is less research in regional resting‐state functional activity that explains FC changes related to SSRI response.
Parenting × Brain Development interactions as predictors of adolescent depressive symptoms and well-being: Differential susceptibility or diathesis-stress?

Abstract It is unclear how individual differences in parenting and brain development interact to influence adolescent mental health outcomes. This study examined interactions between structural brain development and observed maternal parenting behavior in the prediction of adolescent depressive symptoms and psychological well-being. Whether findings supported diathesis-stress or differential susceptibility frameworks was tested. Participants completed observed interactions with their mothers during early adolescence (age 13), and the frequency of positive and aggressive maternal behavior were coded. Adolescents also completed structural magnetic resonance imaging scans at three time points: mean ages 13, 17, and 19. Regression models analyzed interactions between maternal behavior and longitudinal brain development in the prediction of late adolescent (age 19) outcomes. Indices designed to distinguish between diathesis-stress and differential susceptibility effects were employed. Results supported differential susceptibility: less thinning of frontal regions was associated with higher well-being in the context of low levels of aggressive maternal behavior, and lower well-being in the context of high levels of aggressive maternal behavior. Findings suggest that reduced frontal cortical thinning during adolescence may underlie increased sensitivity to maternal aggressive behavior for better and worse and highlight the importance of investigating biological vulnerability versus susceptibility.
The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3

The nucleus is enclosed by the inner nuclear membrane (INM) and the outer nuclear membrane (ONM). While the ONM is continuous with the endoplasmic reticulum (ER), the INM is independent and separates the nucleoplasm from the ER lumen. To maintain INM homeostasis, proteins mislocalized to the INM are degraded by the ER-associated protein degradation (ERAD) pathway. However, the mechanism for turnover of resident INM proteins is less clear. Here we show that the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, regulates the degradation of Mps3, a conserved integral protein of the INM. Turnover of Mps3 requires the ubiquitin-conjugating enzymes Ubc7 and Ubc6, but not the three known ERAD ubiquitin ligases, Doa10, Hrd1, and the Asi1-Asi3 complex. Using a genetic approach, we have found that Cdh1, a coactivator of APC/C, modulates Mps3 stability. APC/C controls Mps3 degradation through Mps3’s N-terminus, which resides in the nucleoplasm and possesses two putative APC/C-dependent destruction motifs. Accumulation of Mps3 at the INM impairs nuclear morphological changes and cell division. Our findings therefore reveal an unexpected mechanism of APC/C-mediated protein quality control at the INM that coordinates nuclear morphogenesis and cell-cycle progression.
3D-printed β-TCP bone tissue engineering scaffolds: Effects of chemistry on in vivo biological properties in a rabbit tibia model

In this study, the effects of 3D-printed SiO_2 and ZnO-doped tricalcium phosphate (TCP) scaffolds with interconnected pores were evaluated on the in vivo bone formation and healing properties of a rabbit tibial defect model. Pure and doped TCP scaffolds were fabricated by a ceramic powder-based 3D printing technique and implanted into critical sized rabbit tibial defects for up to 4 months. In vivo bone regeneration was evaluated using chronological radiological examination, histological evaluations, SEM micrographs, and fluorochrome labeling studies. Radiograph results showed that Si/Zn-doped samples had slower degradation kinetics than the pure TCP samples. 3D printing of TCP scaffolds improved bone formation. The addition of dopants in the TCP scaffolds improved osteogenic capabilities when compared to the pure scaffolds. In summary, our findings indicate that the addition of dopants to the TCP scaffolds enhanced bone formation and in turn leading to accelerated healing.