Miracle-dz/UniFAR-FTUs huggingface dataset:
Intracellular VHHs to monitor and modulate GPCR signaling

Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010’s. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or β-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery.
Masks, ventilation and exposure time: A web-based calculator of indoor COVID-19 infection risk

Two and half years into the COVID-19 pandemic, there is quite a lot of confusion over public health guidance necessary in order to reduce disease infection risks, from room air ventilation, the use of air cleaners, and type of mask and whether or not to wear a mask. This paper describes the development of a novel web-based calculator for use by the public to assess COVID-19 infection risks between a source and receiver in a typical room. The aim is to inform the disease infection risk in response to varying exposure times, mask-wearing, and viral variant in circulation. The calculator is based on the state-of-the-art research evidence, i.e., a room air ventilation model, mask infiltration efficiencies, room cleaner efficiencies, the quanta emission rates of various viral variants of COVID-19, and the modified Wells Riley equations. The results show that exposure times are critical in determining transmission risk. Masks are important and can reduce infection risk especially over shorter exposure times and for lower source emission quantum. N95 respirators are by far the most effective, especially for Omicron, and the results indicate that N95 respirators are necessary for the more infectious variants. Increasing fresh air ventilation rates from 2ac/h to 6ac/h can have a considerable impact in reducing transmission risk in a well-mixed space. Going from 6 ac/h to 12ac/h is less effective especially at lower exposure times. Venues can be classified in terms of risk, and appropriate high ventilation rates might be recommended for high-risk, speaking loudly and singing, such as classrooms and theatres. However, for low risk, quiet and speaking softly venues, such as offices and libraries, higher ventilation rates may not be required; instead, mechanical ventilation systems in combination with air cleaners can effectively remove small fraction size aerosol particles. The web-based calculator provides an easy-to-use and valuable tool for use in estimating infection risk.
Mental health progress requires causal diagnostic nosology and scalable causal discovery

Nine hundred and seventy million individuals across the globe are estimated to carry the burden of a mental disorder. Limited progress has been achieved in alleviating this burden over decades of effort, compared to progress achieved for many other medical disorders. Progress on outcome improvement for all medical disorders, including mental disorders, requires research capable of discovering causality at sufficient scale and speed, and a diagnostic nosology capable of encoding the causal knowledge that is discovered. Accordingly, the field’s guiding paradigm limits progress by maintaining: (a) a diagnostic nosology (DSM-5) with a profound lack of causality; (b) a misalignment between mental health etiologic research and nosology; (c) an over-reliance on clinical trials beyond their capabilities; and (d) a limited adoption of newer methods capable of discovering the complex etiology of mental disorders. We detail feasible directions forward, to achieve greater levels of progress on improving outcomes for mental disorders, by: (a) the discovery of knowledge on the complex etiology of mental disorders with application of Causal Data Science methods; and (b) the encoding of the etiological knowledge that is discovered within a causal diagnostic system for mental disorders.
Toward learning robust contrastive embeddings for binaural sound source localization

Recent deep neural network based methods provide accurate binaural source localization performance. These data-driven models map measured binaural cues directly to source locations hence their performance highly depend on the training data distribution. In this paper, we propose a parametric embedding that maps the binaural cues to a low-dimensional space where localization can be done with a nearest-neighbor regression. We implement the embedding using a neural network, optimized to map points that are close to each other in the latent space (the space of source azimuths or elevations) to nearby points in the embedding space, thus the Euclidean distances between the embeddings reflect their source proximities, and the structure of the embeddings forms a manifold, which provides interpretability to the embeddings. We show that the proposed embedding generalizes well in various acoustic conditions (with reverberation) different from those encountered during training, and provides better performance than unsupervised embeddings previously used for binaural localization. In addition, the proposed method performs better than or equally well as a feed-forward neural network based model that directly estimates the source locations from the binaural cues, and it has better results than the feed-forward model when a small amount of training data is used. Moreover, we also compare the proposed embedding using both supervised and weakly supervised learning, and show that in both conditions, the resulting embeddings perform similarly well, but the weakly supervised embedding allows to estimate source azimuth and elevation simultaneously.
Traditional Chinese medicine method of tonifying kidney for hypertension: Clinical evidence and molecular mechanisms

Hypertension is the most common chronic disease. A large amount of evidence showed that traditional Chinese medicine (TCM) method of tonifying kidney (TK) combined with routine treatment is more effective and safer in the treatment of hypertension. This study integrated meta-analysis, data mining, and network pharmacology to explore the efficacy and potential mechanisms of TK in the treatment of hypertension. Meta-analysis was performed to explore the efficacy and safety of TK combined with routine treatment in the treatment of hypertension. Data mining was used to screen the core herbs of the TK. Network pharmacology was used to predict the antihypertensive mechanism of TK core herbs. A total of 18 studies with 2,024 patients were included in this study. Meta-analysis showed that TK combined with routine treatment was superior to routine treatment alone in lowering blood pressure (systolic and diastolic blood pressures), lowering blood lipids (total cholesterol, triglyceride, low-density lipoprotein cholesterol), improving vascular endothelial functions (nitric oxide, endothelin) and TCM symptoms (headache dizziness, soreness, and weakness of waist and knees). In addition, TK was safe and has no obvious adverse reactions. Data mining showed that the core herbs of TK were Eucommia ulmoides Oliv. (Duzhong), Vitex negundo L. (Huangjing), Taxillus chinensis (DC.) Danser (Sangjisheng), Ligustrum lucidum W.T. Aiton (Nuzhenzi), Astragalus mongholicus Bunge (Huangqi), Rehmannia glutinosa (Gaertn.) DC. (Shudihuang). Network pharmacology predicted that core herbs antihypertensive components were oleanolic acid, ursolic acid, and civetone, and the antihypertensive targets were NOS3, NOS2, MMP9, TNF, PTGS2, HMOX1. In addition, the antihypertensive targets were enriched in cGMP-PKG signaling pathway, calcium signaling pathway, aldosterone-regulated sodium reabsorption, HIF-1 signaling pathway. In conclusion, TK combined with routine treatment for hypertension is effective and safe. The mechanism of TK may be related to GMP-PKG signaling pathway, calcium signaling pathway, aldosterone-regulated sodium reabsorption. On the premise of syndrome differentiation and treatment, it is promising to treat hypertension with TK. Systematic review registration [https://www.crd. york.ac. uk/prospero/], identifier [CRD42022358276].
Cooperation for Public Goods Driven by Noise

Cooperation for public goods poses a dilemma, where individuals are tempted to free ride on others' contributions. Classic solutions involve monitoring, reputation maintenance and costly incentives, but there are important collective actions based on simple and cheap cues only, for example unplanned protests and revolts. This can be explained by an Ising model with the assumption that individuals in uncertain situations tend to conform to the local majority in their network. Among initial defectors, noise such as rumors or opponents' provocations causes some of them to cooperate accidentally. At a critical level of noise, these cooperators trigger a cascade of cooperation. We find an analytic relationship between the phase transition and the asymmetry of the Ising model, which in turn reflects the asymmetry of cooperation and defection. This study thereby shows that in principle, the dilemma of cooperation can be solved by nothing more than a portion of random noise, without rational decision making.
Development of a behavioural intervention for cognitive fatigability in multiple sclerosis: Protocol for a pilot and feasibility study

Background Up to 90% of people with multiple sclerosis (PwMS) subjectively report fatigue as one of their worst symptoms. Fatigability is an objectively measured component of fatigue. Cognitive fatigability (CF) is a breakdown in task performance following sustained cognitive effort. There is a paucity of interventions targeting CF in MS. The prior success of behavioural interventions at improving subjective fatigue suggests that their adaptation may yield similar results for CF. Given the relationship between CF, sleep quality, and mood, a behavioural intervention targeting these factors, such as cognitive behavioural therapy (CBT), is warranted. Given the multidimensional nature of fatigue, a multifaceted approach targeting lifestyle factors and coping (e.g., fatigue management education supplemented by CBT for insomnia and exercise) might prove efficacious. Aim We describe a protocol for a pilot feasibility study to design and implement a multi-dimensional behavioural intervention to improve CF in PwMS. Methods Stage 1: development of a multi-dimensional group-based videoconference-delivered behavioural intervention based on a previously successful fatigue management program for PwMS. A facilitator manual will be drafted. Course material will focus on four themes: body (sleep and physical activity), mood (impact of depression and anxiety), mind (cognitive contributions), and context (pacing and communication). Stage 2: a needs assessment survey will be completed by 100 PwMS for input on what factors are important contributors to their CF. Modifications will be made to the course material and manual. Stage 3: the facilitator-delivered intervention will include 20 PwMS. After baseline assessment, participants will attend weekly 70-min videoconference group sessions for 8 weeks, including homework assignments. Follow-up assessment will re-evaluate outcomes. Stage 4: analysis and dissemination of results. The primary outcome is improvement in CF. Additional feasibility outcomes will determine if a randomized control trial (RCT) is pursued. Stage 5: refine the intervention based on outcomes and feedback from participants. Determining which aspects participants felt were most effective will help inform RCT design. Conclusion The long-term goal is to ensure that PwMS have access to effective interventions in real-world settings to improve quality of life and enhance their ability to participate in cognitively demanding activities that they enjoy.
Physicochemical properties and gel-forming ability changes of duck myofibrillar protein induced by hydroxyl radical oxidizing systems

This paper focuses on the changes of physicochemical properties and gel-forming ability of duck myofibrillar proteins (DMPs) induced using hydroxyl radical oxidizing systems. DMPs were firstly extracted and then oxidized at various H2O2 concentrations (0, 4, 8, and 12 mmol/L) using Fenton reagent (Fe3+-Vc-H2O2) to generate hydroxyl radicals, and the effects of hydroxyl radical oxidation on the physicochemical changes and heat-induced gel-forming capacity of DMPs were analyzed. We observed obvious increases in the carbonyl content (p < 0.05) and surface hydrophobicity of DMPs with increasing of H2O2 concentrations (0–12 mmol/L). In contrast, the free thiol content (p < 0.05) and water retention ability of DMPs decreased with increasing H2O2 concentrations (0–12 mmol/L). These physicochemical changes suggested that high concentrations of hydroxyl radicals significantly altered the biochemical structure of DMPs, which was not conducive to the formation of a gel mesh structure. Furthermore, the gel properties were reduced based on the significant decrease in the water holding capacity (p < 0.05) and increased transformation of immobilized water of the heat-induced gel to free water (p < 0.05). With the increase of H2O2 concentrations, secondary structure of proteins analysis results indicated α-helix content decreased significantly (p < 0.05), however, random coil content increased (p < 0.05). And more cross-linked myosin heavy chains were detected at higher H2O2 concentrations groups through immunoblot analysis (p < 0.05). Therefore, as H2O2 concentrations increased, the gel mesh structure became loose and porous, and the storage modulus and loss modulus values also decreased during heating. These results demonstrated that excessive oxidation led to explicit cross-linking of DMPs, which negatively affected the gel-forming ability of DMPs. Hence, when processing duck meat products, the oxidation level of meat gel products should be controlled, or suitable antioxidants should be added.
The effect of landmark visualization in mobile maps on brain activity during navigation: A virtual reality study

The frequent use of GPS-based navigation assistance is found to negatively affect spatial learning. Displaying landmarks effectively while providing wayfinding instructions on such services could facilitate spatial learning because landmarks help navigators to structure and learn an environment by serving as cognitive anchors. However, simply adding landmarks on mobile maps may tax additional cognitive resources and thus adversely affect cognitive load in mobile map users during navigation. To address this potential issue, we set up the present study experimentally to investigate how the number of landmarks (i.e., 3 vs. 5 vs. 7 landmarks), displayed on a mobile map one at a time at intersections during turn-by-turn instructions, affects spatial learning, cognitive load, and visuospatial encoding during map consultation in a virtual urban environment. Spatial learning of the environment was measured using a landmark recognition test, a route direction test, and Judgements of Relative Directions (JRDs). Cognitive load and visuospatial encoding were assessed using electroencephalography (EEG) by analyzing power modulations in distinct frequency bands as well as peak amplitudes of event-related brain potentials (ERPs). Behavioral results demonstrate that landmark and route learning improve when the number of landmarks shown on a mobile map increases from three to five, but that there is no further benefit in spatial learning when depicting seven landmarks. EEG analyses show that relative theta power at fronto-central leads and P3 amplitudes at parieto-occipital leads increase in the seven-landmark condition compared to the three- and five-landmark conditions, likely indicating an increase in cognitive load in the seven-landmark condition. Visuospatial encoding indicated by greater theta ERS and alpha ERD at occipital leads with a greater number of landmarks on mobile maps. We conclude that the number of landmarks visualized when following a route can support spatial learning during map-assisted navigation but with a potential boundary—visualizing landmarks on maps benefits users’ spatial learning only when the number of visualized landmarks shown does not exceed users’ cognitive capacity. These results shed more light on neuronal correlates underlying cognitive load and visuospatial encoding during spatial learning in map-assisted navigation. Our findings also contribute to the design of neuro-adaptive landmark visualization for mobile navigation aids that aim to adapt to users’ cognitive load to optimize their spatial learning in real time.
Extracellular vesicle-derived miRNAs improve stem cell-based therapeutic approaches in muscle wasting conditions

Skeletal muscle holds an intrinsic capability of growth and regeneration both in physiological conditions and in case of injury. Chronic muscle illnesses, generally caused by genetic and acquired factors, lead to deconditioning of the skeletal muscle structure and function, and are associated with a significant loss in muscle mass. At the same time, progressive muscle wasting is a hallmark of aging. Given the paracrine properties of myogenic stem cells, extracellular vesicle-derived signals have been studied for their potential implication in both the pathogenesis of degenerative neuromuscular diseases and as a possible therapeutic target. In this study, we screened the content of extracellular vesicles from animal models of muscle hypertrophy and muscle wasting associated with chronic disease and aging. Analysis of the transcriptome, protein cargo, and microRNAs (miRNAs) allowed us to identify a hypertrophic miRNA signature amenable for targeting muscle wasting, consisting of miR-1 and miR-208a. We tested this signature among others in vitro on mesoangioblasts (MABs), vessel-associated adult stem cells, and we observed an increase in the efficiency of myogenic differentiation. Furthermore, injections of miRNA-treated MABs in aged mice resulted in an improvement in skeletal muscle features, such as muscle weight, strength, cross-sectional area, and fibrosis compared to controls. Overall, we provide evidence that the extracellular vesicle-derived miRNA signature we identified enhances the myogenic potential of myogenic stem cells.
Tuberculosis and COVID-19 co-infection in Serbia: Pandemic challenge in a low-burden country

Introduction COVID-19 and tuberculosis (TB) represent global threats to the public health system. The impact of COVID-19 on TB results in a reduction in the number of notified TB cases, delayed diagnosis and treatment, and increased case fatality and mortality rates. The aim of the study was to analyze the TB/COVID-19 co-infected cohort in Serbia as a low-burden country and compare it to the global TB/COVID-19 cohort. Methods A retrospective analysis was done on 53 TB and COVID-19 co-infected patients treated in COVID hospital “Batajnica” in Belgrade and Special Hospital for Pulmonary Diseases “Ozren” Sokobanja in the period from 6 March 2020 to 1 April 2022. A comparative analysis with the global cohort published recently was also performed. Results TB/COVID-19 cohort in Serbia included significantly fewer migrants and diabetes cases, but more cases with chronic respiratory diseases compared to the global. Descriptive analysis of TB cases in the Serbian TB/COVID-19 cohort showed fewer cases diagnosed with sputum smear and Gene Xpert/HAIN, fewer EPTB and mono-resistant cases, and more cases diagnosed with solid culture, unilateral pulmonary infiltrate (with bilateral cavity lesions), and bilateral pulmonary infiltrate (no cavities) compared to TB/COVID-19 cases worldwide. Nasal congestion and fever were more common COVID-19 symptoms in the global cohort. Radiology was more commonly used for the diagnosis of COVID-19 in Serbia. Typical bilateral ground opacities were less common among Serbian patients. Serbian patients spent fewer days in the hospital and achieved a higher PCR conversion rate and TB treatment success rate. Conclusion The Serbian TB/COVID-19 cohort achieved a higher treatment success rate compared to the global cohort. Encouraging vaccination against SARS-CoV-2 for people with a current or past TB disease, as well as rapid diagnosis and targeted treatment of TB in highly specialized pulmonology institutions, presents key points to avoid excessive morbidity and mortality.
Social comparison effects on students’ cognitive anxiety, self-confidence, and performance in Chinese composition writing

Social comparison is a mind-altering determinant that affects students’ learning behavior. To understand the effect, three instructional approaches to teaching Chinese writing skills were designed and implemented in this study: (1) The No Comparison Group (NCG): students were asked to complete compositions on their own; (2) The Upward Comparison Group (UCG): superior composition examples were provided and the students were asked to write compositions on the same topics; and (3) The Downward Comparison Group (DCG): inferior examples were provided for students to critique. Taiwanese junior high school ninth graders participated in three groups, and wrote compositions on six themes. The results revealed that the Chinese composition writing (CCW) skills of the students in the UCG and DCG improved significantly more than those of the students in the NCG. Composition-prompted cognitive anxiety in the DCG declined substantially. The results imply that adopting upward and downward comparisons for students to practice Chinese composition is worth adopting in writing lessons.
The presence of diabetic retinopathy closely associated with the progression of non-alcoholic fatty liver disease: A meta-analysis of observational studies

Background and Objective: Although growing evidence indicates that non-alcoholic fatty liver disease is related to diabetic retinopathy (DR), research results significantly vary. Therefore, we conducted a meta-analysis to assess the association between the progression of non-alcoholic fatty liver disease and the onset of DR. Methods: PubMed, Embase, and Cochrane databases were searched until 7 November 2021. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association. Results: We identified 18 studies involving 12,757 patients. The pooled effect assessment showed that liver fibrosis was positively correlated with DR (OR = 1.69, 95%CI 1.30–2.20; p < 0.0001); non-alcoholic fatty liver disease was not associated with the risk of DR (OR = 1.15, 95%CI 0.75-1.76; p = 0.51); non-alcoholic fatty liver disease was positively correlated with DR in patients with type 1 diabetes (OR = 2.96, 95%CI 1.48–5.94; p = 0.002). In patients with type 2 diabetes, there was no association between non-alcoholic fatty liver disease and DR (OR = 0.92, 95%CI 0.59–1.43; p = 0.70). Subgroup analysis showed no correlation in both Asian and Caucasian races. Conclusion: There is a significant correlation between liver fibrosis and DR. This suggests that the ocular examination of DR could be helpful in predicting whether patients with non-alcoholic fatty liver disease would progress to liver fibrosis.