Miracle-dz/UniFAR-FTUs huggingface dataset:
Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.
Multifunctionally-doped PEDOT for organic electrochemical transistors

Organic Electrochemical Transistors (OECTs) are suitable for developing ultra-sensitive bioelectronic sensors. In the organic electrochemical transistors architecture, the source-drain channel is made of a conductive polymer film either cast from a formulated dispersion or electrodeposited from a monomer solution. The commercial poly(3,4-ethylenedioxidethiophene)/poly(styrene sulfonate) (PEDOT:PSS) water dispersion is the workhorse of organic bioelectronics for its high conductance, low impact and ease of processability. In this study, a hybrid organic electrochemical transistors channel fabrication strategy is presented, where electrochemical deposition of a PEDOT/X (with X indicating the counterion) is performed on a dispersion-cast PEDOT:PSS film. Six different counterions where used: X = PSS, Nafion, Hyaluronate, Dextran sulfate, Dexamethasone phosphate and tauroursodeoxycholic acid, each potentially endowing organic electrochemical transistors with additional functions such as ion exchange and pharmacological activity upon release of X. The PEDOT/X-PEDOT:PSS bilayers were characterized by means of electrochemical impedance spectroscopy (EIS), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and focused ion beam tomography combined with scanning electron microscopy (FIB-SEM). In addition, their respective organic electrochemical transistorss were characterized and compared to PEDOT:PSS organic electrochemical transistors. Our results show that the hybrid bilayer strategy is viable to fabricate multifunctional organic electrochemical transistorss with biologically-relevant function, thereby retaining the outstanding figures of merit of commercial PEDOT:PSS.
Evaluating drivers of female dominance in the spotted hyena

Introduction Dominance relationships in which females dominate males are rare among mammals. Mechanistic hypotheses explaining the occurrence of female dominance suggest that females dominate males because (1) they are intrinsically more aggressive or less submissive than males, and/or (2) they have access to more social support than males. Methods Here, we examine the determinants of female dominance across ontogenetic development in spotted hyenas (Crocuta crocuta) using 30 years of detailed behavioral observations from the Mara Hyena Project to evaluate these two hypotheses. Results Among adult hyenas, we find that females spontaneously aggress at higher rates than males, whereas males spontaneously submit at higher rates than females. Once an aggressive interaction has been initiated, adult females are more likely than immigrant males to elicit submission from members of the opposite sex, and both adult natal and immigrant males are more likely than adult females to offer submission in response to an aggressive act. We also find that adult male aggressors are more likely to receive social support than are adult female aggressors, and that both adult natal and immigrant males are 2–3 times more likely to receive support when attacking a female than when attacking another male. Across all age classes, females are more likely than males to be targets of aggressive acts that occur with support. Further, receiving social support does slightly help immigrant males elicit submission from adult females compared to immigrant males acting alone, and it also helps females elicit submission from other females. However, adult females can dominate immigrant males with or without support far more often than immigrant males can dominate females, even when the immigrants are supported against females. Discussion Overall, we find evidence for both mechanisms hypothesized to mediate female dominance in this species: (1) male and female hyenas clearly differ in their aggressive and submissive tendencies, and (2) realized social support plays an important role in shaping dominance relationships within a clan. Nevertheless, our results suggest that social support alone cannot explain sex-biased dominance in spotted hyenas. Although realized social support can certainly influence fight outcomes among females, adult females can easily dominate immigrant males without any support at all.
Acanthamoeba spp. aggregate and encyst on contact lens material increasing resistance to disinfection

Introduction Acanthamoeba keratitis is often caused when Acanthamoeba contaminate contact lenses and infect the cornea. Acanthamoeba is pervasive in the environment as a motile, foraging trophozoite or biocide-resistant and persistent cyst. As contact lens contamination is a potential first step in infection, we studied Acanthamoeba’s behavior and interactions on different contact lens materials. We hypothesized that contact lenses may induce aggregation, which is a precursor to encystment, and that aggregated encystment would be more difficult to disinfect than motile trophozoites. Methods Six clinically and/or scientifically relevant strains of Acanthamoeba (ATCC 30010, ATCC 30461, ATCC 50370, ATCC 50702, ATCC 50703, and ATCC PRA-115) were investigated on seven different common silicone hydrogel contact lenses, and a no-lens control, for aggregation and encystment for 72 h. Cell count and size were used to determine aggregation, and fluorescent staining was used to understand encystment. RNA seq was performed to describe the genome of Acanthamoeba which was individually motile or aggregated on different lens materials. Disinfection efficacy using three common multi-purpose solutions was calculated to describe the potential disinfection resistance of trophozoites, individual cysts, or spheroids. Results Acanthamoeba trophozoites of all strains examined demonstrated significantly more aggregation on specific contact lens materials than others, or the no-lens control. Fluorescent staining demonstrated encystment in as little as 4 hours on contact lens materials, which is substantially faster than previously reported in natural or laboratory settings. Gene expression profiles corroborated encystment, with significantly differentially expressed pathways involving actin arrangement and membrane complexes. High disinfection resistance of cysts and spheroids with multi-purpose solutions was observed. Discussion Aggregation/encystment is a protective mechanism which may enable Acanthamoeba to be more disinfection resistant than individual trophozoites. This study demonstrates that some contact lens materials promote Acanthamoeba aggregation and encystment, and Acanthamoeba spheroids obstruct multi-purpose solutions from disinfecting Acanthamoeba.
Dynamic regulation and key roles of ribonucleic acid methylation

Ribonucleic acid (RNA) methylation is the most abundant modification in biological systems, accounting for 60% of all RNA modifications, and affects multiple aspects of RNA (including mRNAs, tRNAs, rRNAs, microRNAs, and long non-coding RNAs). Dysregulation of RNA methylation causes many developmental diseases through various mechanisms mediated by N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), 5-hydroxymethylcytosine (hm5C), and pseudouridine (Ψ). The emerging tools of RNA methylation can be used as diagnostic, preventive, and therapeutic markers. Here, we review the accumulated discoveries to date regarding the biological function and dynamic regulation of RNA methylation/modification, as well as the most popularly used techniques applied for profiling RNA epitranscriptome, to provide new ideas for growth and development.
Images of bodies in mass and social media and body dissatisfaction: The role of internalization and self-discrepancy

Introduction The study examines the influence on body dissatisfaction of viewed images of bodies transmitted over mass media and social media, as mediated by the internalization of body ideals through media and self-discrepancy (the difference between the perceived actual self and the perceived ideal self). Method In this study, the images of bodies individuals view in their everyday media diet are estimated using a newly developed pictorial scale for women (thinness) and men (muscularity). For participants, the perceived body image is formed through mass media (magazines, TV) and social media (Facebook, YouTube, Instagram, and Snapchat). The self-discrepancy theory is then used to explain the effect of images of bodies in the media on the internalization of these body ideals and body dissatisfaction. Results Results show that Facebook and YouTube shape body ideals perceived to be prevalent in the media, negatively influencing internalization and self-discrepancy. Self-discrepancy, in turn, increases body dissatisfaction. However, for males, the perceived body ideals in the media did not affect body dissatisfaction, internalization, or self-discrepancy. Discussion These results emphasize the importance of combining and comparing mass and social media and differentiating between female and male concerns regarding body image.
The role of SWI/SNF chromatin remodelers in the repair of DNA double strand breaks and cancer therapy

Switch/Sucrose non-fermenting (SWI/SNF) chromatin remodelers hydrolyze ATP to push and slide nucleosomes along the DNA thus modulating access to various genomic loci. These complexes are the most frequently mutated epigenetic regulators in human cancers. SWI/SNF complexes are well known for their function in transcription regulation, but more recent work has uncovered a role for these complexes in the repair of DNA double strand breaks (DSBs). As radiotherapy and most chemotherapeutic agents kill cancer cells by inducing double strand breaks, by identifying a role for these complexes in double strand break repair we are also identifying a DNA repair vulnerability that can be exploited therapeutically in the treatment of SWI/SNF-mutated cancers. In this review we summarize work describing the function of various SWI/SNF subunits in the repair of double strand breaks with a focus on homologous recombination repair and discuss the implication for the treatment of cancers with SWI/SNF mutations.
The des-Arg9-bradykinin/B1R axis: Hepatic damage in COVID-19

Patients infected by the SARS-CoV-2 virus are commonly diagnosed with threatening liver conditions associated with drug-induced therapies and systemic viral action. RNA-Seq data from cells in bronchoalveolar lavage fluid from COVID-19 patients have pointed out dysregulation of kallikrein-kinin and renin-angiotensin systems as a possible mechanism that triggers multi-organ damage away from the leading site of virus infection. Therefore, we measured the plasma concentration of biologically active peptides from the kallikrein-kinin system, bradykinin and des-Arg9-bradykinin, and liver expression of its proinflammatory axis, bradykinin 1 receptor (B1R). We measured the plasma concentration of bradykinin and des-Arg9-bradykinin of 20 virologically confirmed COVID-19 patients using a liquid chromatography-tandem mass spectrometry-based methodology. The expression of B1R was evaluated by immunohistochemistry from post-mortem liver specimens of 27 COVID-19 individuals. We found a significantly higher blood level of des-Arg9-bradykinin and a lower bradykinin concentration in patients with COVID-19 compared to a healthy, uninfected control group. We also observed increased B1R expression levels in hepatic tissues of patients with COVID-19 under all hepatic injuries analyzed (liver congestion, portal vein dilation, steatosis, and ischemic necrosis). Our data indicate that des-Arg9-bradykinin/B1R is associated with the acute hepatic dysfunction induced by the SARS-CoV-2 virus infection in the pathogenesis of COVID-19.
An Illustration of a Pitfall in Estimating the Effects of Aggregate Variables on Micro Unit

Many economic researchers have attempted to measure the effect of aggregate market or public policy variables on micro units by merging aggregate data with micro observations by industry, occupation, or geographical location, then using multiple regression or similar statistical models to measure the effect of the aggregate variable on the micro units. The methods are usually based upon the assumption of independent disturbances, which is typically not appropriate for data from populations with grouped structure. Incorrectly using ordinary least squares can lead to standard errors that are seriously biased downward. This note illustrates the danger of spurious regression from this kind of misspecification, using as an example a wage regression estimated on data for individual workers that includes in the specification aggregate regressors for characteristics of geographical states. Copyright 1990 by MIT Press.
HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others – ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs.
The calibration of esophageal pressure by proper esophageal balloon filling volume: A clinical study

Background Esophageal pressure (Pes) can be used as a reliable surrogate for pleural pressure, especially in critically ill patients requiring personalized mechanical ventilation strategies. How to choose the proper esophageal balloon filling volume and then find the optimal value of esophageal pressure remains a challenge. The study aimed to assess the feasibility of catheters for Pes monitoring in mechanically ventilated patients. Materials and methods Twelve patients under pressure-controlled mechanical ventilation were included in this study. Raw esophageal pressure was recorded at different balloon filling volumes. Then, the P-V curves were determined. VWORK was the intermediate linear section on the end-expiratory P-V curve, and VBEST was the filling volume providing the maximum difference between Pes at end-inspiration and end-expiration. The raw value of Pes was recorded, and the calibrated values of Pes were calculated by calculating the esophageal wall pressure (Pew) and esophageal elastance (Ees). Results Twenty-four series of Pes measurements were performed. The mean VMIN and VMAX were 2.17 ± 0.49 ml (range, 1.0–3.0 ml) and 6.79 ± 0.83 ml (range, 5.0–9.0 ml), respectively, whereas VBEST was 4.69 ± 0.16 ml (range, 2.0–8.0 ml). Ees was 1.35 ± 0.51 cm H2O/ml (range, 0.26–2.38 cm H2O/ml). The estimated Pew at VBEST was 3.16 ± 2.19 cm H2O (range, 0–7.97 cm H2O). Patients with a body mass index (BMI) ≥ 25 kg/m2 had a significantly lower VMAX (5.88 [5.25–6] vs. 7.25 [7–8] ml, p = 0.006) and a significantly lower VBEST (3.69 [2.5–4.38] vs. 5.19 [4–6] ml, p = 0.036) than patients with a BMI < 25 kg/m2. Patients with positive end-expiratory pressure (PEEP) ≥ 10 cm H2O had a lower VMIN and VBEST than patients with PEEP < 10 cm H2O, P > 0.05. Patients in the supine position had a higher esophageal pressure than those in the prone position with the same balloon filling volume. Conclusions Calibration of esophageal pressure to identify the best filling volume of esophageal balloon catheters is feasible. The esophageal pressure can be influenced by BMI, PEEP, and position. It is necessary to titrate the optimal inflation volume again when the PEEP values or the positions change.
Applying muscle synergy analysis to forearm high-density electromyography of healthy people

Introduction Muscle synergy is regarded as a motor control strategy deployed by the central nervous system (CNS). Clarifying the modulation of muscle synergies under different strength training modes is important for the rehabilitation of motor-impaired patients. Methods To represent the subtle variation of neuromuscular activities from the smaller forearm muscles during wrist motion, we proposed to apply muscle synergy analysis to preprocessed high-density electromyographic data (HDEMG). Here, modulation of muscle synergies within and across the isometric and isotonic training modes for strengthening muscles across the wrist were investigated. Surface HDEMGs were recorded from healthy subjects (N = 10). Three different HDEMG electrode configurations were used for comparison and validation of the extracted muscle synergies. The cosine of principal angles (CPA) and the Euclidian distance (ED) between synergy vectors were used to evaluate the intra- and inter-mode similarity of muscle synergies. Then, how the activation coefficients modulate the excitation of specific synergy under each mode was examined by pattern recognition. Next, for a closer look at the mode-specific synergies and the synergies shared by the two training modes, k-means clustering was applied. Results We observed high similarity of muscle synergies across different tasks within each training mode, but decreased similarity of muscle synergies across different training modes. Both intra- and intermode similarity of muscle synergies were consistently robust to electrode configurations regardless of the similarity metric used. Discussion Overall, our findings suggest that applying muscle synergy analysis to HDEMG is feasible, and that the traditional muscle synergies defined by whole-muscle components may be broadened to include sub-muscle components represented by the HDEMG channels. This work may lead to an appropriate neuromuscular analysis method for motor function evaluation in clinical settings and provide valuable insights for the prescription of rehabilitation training therapies.
Accounting for the valley of recovery during post-stroke rehabilitation training via a model-based analysis of macaque manual dexterity

Background True recovery, in which a stroke patient regains the same precise motor skills observed in prestroke conditions, is the fundamental goal of rehabilitation training. However, a transient drop in task performance during rehabilitation training after stroke, observed in human clinical outcome as well as in both macaque and squirrel monkey retrieval data, might prevent smooth transitions during recovery. This drop, i.e., recovery valley, often occurs during the transition from compensatory skill to precision skill. Here, we sought computational mechanisms behind such transitions and recovery. Analogous to motor skill learning, we considered that the motor recovery process is composed of spontaneous recovery and training-induced recovery. Specifically, we hypothesized that the interaction of these multiple skill update processes might determine profiles of the recovery valley. Methods A computational model of motor recovery was developed based on a state-space model of motor learning that incorporates a retention factor and interaction terms for training-induced recovery and spontaneous recovery. The model was fit to previously reported macaque motor recovery data where the monkey practiced precision grip skills after a lesion in the sensorimotor area in the cortex. Multiple computational models and the effects of each parameter were examined by model comparisons based on information criteria and sensitivity analyses of each parameter. Result Both training-induced and spontaneous recoveries were necessary to explain the behavioral data. Since these two factors contributed following logarithmic function, the training-induced recovery were effective only after spontaneous biological recovery had developed. In the training-induced recovery component, the practice of the compensation also contributed to recovery of the precision grip skill as if there is a significant generalization effect of learning between these two skills. In addition, a retention factor was critical to explain the recovery profiles. Conclusions We found that spontaneous recovery, training-induced recovery, retention factors, and interaction terms are crucial to explain recovery and recovery valley profiles. This simulation-based examination of the model parameters provides suggestions for effective rehabilitation methods to prevent the recovery valley, such as plasticity-promoting medications, brain stimulation, and robotic rehabilitation technologies.