Miracle-dz/UniFAR-FTUs huggingface dataset:
A human meniscus explant model for studying early events in osteoarthritis development by proteomics

Degenerative meniscus lesions have been associated with both osteoarthritis etiology and its progression. We, therefore, sought to establish a human meniscus ex vivo model to study the meniscal response to cytokine treatment using a proteomics approach. Lateral menisci were obtained from five knee‐healthy donors. The meniscal body was cut into vertical slices and further divided into an inner (avascular) and outer region. Explants were either left untreated (controls) or stimulated with cytokines. Medium changes were conducted every 3 days up to Day 21 and liquid chromatography–mass spectrometry was performed at all the time points for the identification and quantification of proteins. Mixed‐effect linear regression models were used for statistical analysis to estimate the effect of treatments versus control on protein abundance. Treatment by IL1ß increased release of cytokines such as interleukins, chemokines, and matrix metalloproteinases but a limited catabolic effect in healthy human menisci explants. Further, we observed an increased release of matrix proteins (collagens, integrins, prolargin, tenascin) in response to oncostatin M (OSM) + tumor necrosis factor (TNF) and TNF+interleukin‐6 (IL6) + sIL6R treatments, and analysis of semitryptic peptides provided additional evidence of increased catabolic effects in response to these treatments. The induced activation of catabolic processes may play a role in osteoarthritis development.
Preparedness to assume professional roles: experiences of recently qualified radiographers: A qualitative study

Recently qualified health workers including radiographers struggle with workplace integration. Similarly, in our local context, undocumented complaints were received from the various heads of departments and radiologists regarding recently qualified radiographers' ability to fully assume their professional roles. In light of the complaints, this study sought to explore and describe the lived experiences of recently qualified radiographers from one local University on their readiness to assume their professional roles.
Drop breakup modelling in turbulent flows

This paper deals with drop and bubble break-up modelling in turbulent flows. We consider the case where the drop/bubble slip velocity is smaller than or of the order of the turbulent velocity scales, or when the drop/bubble deformation is mainly caused by the turbulent stress (atomisation is not addressed here). The deformation of a drop is caused by continuous interactions with turbulent vortices; the drop responds to these interactions by performing shape-oscillations and breaks up when its deformation reaches a critical value. Following these observations, we use a model of forced oscillator that describes the drop deformation dynamics in the flow to predict its break-up probability. Such a model requires a characterization of the shape- oscillation dynamics of the drop. As this dynamics is theoretically known only under restrictive conditions (without gravity, surfactants), CFD two-phase flow simulations, based on the Level-Set and Ghost Fluid methods, are used to determine the interface dynamics in more complex situations: deformation of a drop in the presence of gravity, bubble-vortex interactions. Results are compared with experimental data. The perspectives to apply this model to breakup in emulsification processes are also discussed.
All human social groups are human, but some are more human than others: A comprehensive investigation of the implicit association of “Human” to US racial/ethnic groups

Significance All humans belong to the species Homo sapiens. Yet, throughout history, humans have breathed life into the Orwellian adage that “All [humans] are equal, but some [humans] are more equal than others. ” Here, participants staunchly rejected this adage, with the overwhelming majority of over 61,000 participants reporting that all humans are equally human. However, across 13 experiments, US White participants (and White participants abroad) showed robust evidence of an implicit Human=Own Group association. Conversely, Black, Latinx, and Asian participants in the United States did not demonstrate this bias. These results highlight the tendency among socially dominant groups to reserve the quality Human for their own kind, producing, even in the 21st century, the age-old error of pseudospeciation.
On a question of Gross concerning uniqueness of entire functions

In this paper, we prove that there exist two finite sets S1 (with 1 element) and S2 (with 3 elements) such that any two entire functions f and g satisfying Ef(Sj) = Eg(Sj) for j = 1, 2 must be identical. This answers a question posed by Gross. Examples are provided to show that this result is sharp.
Telomerase-targeted therapies in myeloid malignancies

Abstract Human telomeres are tandem arrays that are predominantly composed of 5′-TTAGGG-3′ nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres within rapidly dividing cells and is upregulated across nearly all malignant cells. Accordingly, targeting telomerase to inhibit uncontrolled cell growth has been an area of great interest for decades. In this review, we summarize telomere and telomerase biology because it relates to both physiologic and malignant cells. We discuss the development of telomere- and telomerase-targeted therapeutic candidates within the realm of myeloid malignancies. We overview all mechanisms of targeting telomerase that are currently in development, with a particular focus on imetelstat, an oligonucleotide with direct telomerase inhibitory properties that has advanced the furthest in clinical development and has demonstrated promising data in multiple myeloid malignancies.
Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains

Abstract Background Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease complicated by vast numbers of patient-specific mutations. We explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Methods Hydrogen-deuterium exchange mass spectrometry analysis of conformational dynamics in recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation and amyloidogenic sequence propensity. The results were mapped on the structures of native and fibrillary proteins. Results Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower, suggesting different major factors influencing amyloidogenesis. In 33*01-related amyloid LC, these factors involved destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC stemmed from increased dynamics/exposure of amyloidogenic segments in βC′V and βEV that could initiate aggregation and decreased dynamics/exposure near the Cys23–Cys88 disulfide. Conclusions The results suggest distinct amyloidogenic pathways for closely related LCs and point to the complementarity-defining regions CDR1 and CDR3, linked via the conserved internal disulfide, as key factors in amyloid formation.
In vitro-based prediction of human plasma concentrations of food-related compounds.

Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans, based on the existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies were evaluated. Human-induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIEC) and Caco-2 cells, HepaRG cells, equilibrium dialysis of human plasma, and LLC-PK1 cell monolayer were used to assess the intestinal absorption and availability, hepatic metabolism, unbound plasma fraction, and secretion and reabsorption in renal tubular cells, respectively. After conversion of these parameters into human kinetic parameters, the plasma concentration profiles of these compounds were predicted using in silico methods, and the obtained Cmax values were found to be 0.017-183-times higher than the reported Cmax values. When the in silico-predicted parameters were modified with in vitro data, the predicted Cmax values were almost within 0.1-10-fold because the metabolic activities of hiPSC-SIECs, such as uridine 5'-diphospho-glucuronosyl transferase, were closer to human primary enterocytes. Thus, combining in vitro test results with the plasma concentration simulations resulted in more accurate and transparent predictions of Cmax values of food-related compounds than those obtained using in silico-derived predictions. This method facilitated accurate safety evaluation without the need for animal experiments.
Reliability assessment of systems subject to dependent degradation processes and random shocks

ABSTRACT System failures can be induced either by internal degradation mechanisms or by external causes. In this article, we consider the reliability of systems experiencing both degradation and random shock processes. The dependencies between degradation processes and random shocks and those among the degradation processes are explicitly modeled. The degradation processes of system components are modeled using Multi-State Models (MSMs) and Physics-Based Models (PBMs). The piecewise-deterministic Markov process modeling framework is employed to combine MSMs and PBMs and to incorporate degradation and random shocks dependencies. The Monte Carlo simulation and finite-volume methods are used to compute the system reliability. A subsystem of a residual heat removal system in a nuclear power plant is considered as an illustrative case.
Novel secreted STPKLRR from Vibrio splendidus AJ01 promotes pathogen internalization via mediating tropomodulin phosphorylation dependent cytoskeleton rearrangement

We previously demonstrated that the flagellin of intracellular Vibrio splendidus AJ01 could be specifically identified by tropomodulin (Tmod) and further mediate p53-dependent coelomocyte apoptosis in the sea cucumber Apostichopus japonicus. In higher animals, Tmod serves as a regulator in stabilizing the actin cytoskeleton. However, the mechanism on how AJ01 breaks the AjTmod-stabilized cytoskeleton for internalization remains unclear. Here, we identified a novel AJ01 Type III secretion system (T3SS) effector of leucine-rich repeat-containing serine/threonine-protein kinase (STPKLRR) with five LRR domains and a serine/threonine kinase (STYKc) domain, which could specifically interact with tropomodulin domain of AjTmod. Furthermore, we found that STPKLRR directly phosphorylated AjTmod at serine 52 (S52) to reduce the binding stability between AjTmod and actin. After AjTmod dissociated from actin, the F-actin/G-actin ratio decreased to induce cytoskeletal rearrangement, which in turn promoted the internalization of AJ01. The STPKLRR knocked out strain could not phosphorylated AjTmod and displayed lower internalization capacity and pathogenic effect compared to AJ01. Overall, we demonstrated for the first time that the T3SS effector STPKLRR with kinase activity was a novel virulence factor in Vibrio and mediated self-internalization by targeting host AjTmod phosphorylation dependent cytoskeleton rearrangement, which provided a candidate target to control AJ01 infection in practice.
Astrocytes as master modulators of neural networks: Synaptic functions and disease‐associated dysfunction of astrocytes

Astrocytes are the most abundant glial cell type in the central nervous system and are essential to the development, plasticity, and maintenance of neural circuits. Astrocytes are heterogeneous, with their diversity rooted in developmental programs modulated by the local brain environment. Astrocytes play integral roles in regulating and coordinating neural activity extending far beyond their metabolic support of neurons and other brain cell phenotypes. Both gray and white matter astrocytes occupy critical functional niches capable of modulating brain physiology on time scales slower than synaptic activity but faster than those adaptive responses requiring a structural change or adaptive myelination. Given their many associations and functional roles, it is not surprising that astrocytic dysfunction has been causally implicated in a broad set of neurodegenerative and neuropsychiatric disorders. In this review, we focus on recent discoveries concerning the contributions of astrocytes to the function of neural networks, with a dual focus on the contribution of astrocytes to synaptic development and maturation, and on their role in supporting myelin integrity, and hence conduction and its regulation. We then address the emerging roles of astrocytic dysfunction in disease pathogenesis and on potential strategies for targeting these cells for therapeutic purposes.
Effectiveness of educational video on deaf people’s knowledge and skills for cardiopulmonary resuscitation: a randomized controlled trial

ABSTRACT Objective: To analyze the effectiveness of an educational video on deaf people’s knowledge and skills about cardiopulmonary resuscitation. Method: A randomized trial, carried out at three schools with 113 deaf people (control group = 57 and intervention group = 56). After the pre-test, the control group was exposed to the lecture, while the intervention group was exposed to the video. The post-test occurred immediately after the intervention and was repeated after 15 days. A validated instrument was used, with 11 questions, presented in video/Libras (to enable understanding by deaf people) and in written/printed form (to record the answers). Results: In the analysis of knowledge, the median of correct answers in the pre-test was similar between the groups (p = 0.635), while the intervention group had a higher accuracy in the immediate post-test (p = 0.035) and after 15 days (p = 0.026). In the skill analysis, the median of correct answers in the pre-test was higher in the control group (p = 0.031). There was no difference in the immediate post-test (p = 0.770), and there was a higher accuracy in the intervention group in the post-test after 15 days (p = 0.014). Conclusion: The video proved to be effective in increasing deaf people’s knowledge and skills about cardiopulmonary resuscitation. Brazilian Registry of Clinical Trials: RBR-5npmgj.
The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations.
Modulation of deep neural circuits with sonogenetics

Significance Manipulating specific neural activity by physical intervention is a powerful method to gain causal insight into brain functions and treat brain disorders. Sonogenetics is among the promising modalities being used to stimulate neurons noninvasively in the intact brain. Here, we demonstrate sonogenetics, a noninvasive neural stimulation approach using mechanosensitive ion channels, to control well-defined deep neural circuits and ameliorate parkinsonian motor behaviors through transcranial ultrasound stimulation. This sonogenetic approach may enhance our understanding of cell pathophysiology and lead to the development of unique treatments for neuropsychiatric diseases and nonneural diseases.
Prevalence and factors associated with healthcare avoidance during the COVID-19 pandemic among the Sámi in Sweden: the SámiHET study

ABSTRACT The aim of this population-based cross-sectional study was to assess the prevalence of healthcare avoidance during the COVID-19 pandemic and its associated factors among the Sámi population in Sweden. Data from the “Sámi Health on Equal Terms” (SámiHET) survey conducted in 2021 were used. Overall, 3,658 individuals constituted the analytical sample. Analysis was framed using the social determinants of health framework. The association between healthcare avoidance and several sociodemographic, material, and cultural factors was explored through log-binomial regression analyses. Sampling weights were applied in all analyses. Thirty percent of the Sámi in Sweden avoided healthcare during the COVID-19 pandemic. Sámi women (PR: 1.52, 95% CI: 1.36–1.70), young adults (PR: 1.22, 95% CI:1.05–1.47), Sámi living outside Sápmi (PR: 1.17, 95% CI: 1.03–1.34), and those having low income (PR: 1.42, 95% CI:1.19–1.68) and experiencing economic stress (PR: 1.48, 95% CI: 1.31–1.67) had a higher prevalence of healthcare avoidance. The pattern shown in this study can be useful for planning future pandemic responses, which should address healthcare avoidance, particularly among the identified vulnerable groups, including the active participation of the Sámi themselves.
Continuous Glucose Monitoring in Children and Adolescents with Congenital Adrenal Hyperplasia

Objective: Patients with congenital adrenal hyperplasia (CAH) require lifelong therapy with glucocorticoids to suppress androgen excess and substitute for deficient cortisol. An important aspect of care is the prevention of metabolic sequelae. In infants, potentially lethal nocturnal hypoglycaemia has been described. In adolescence, visceral obesity, hypertension, hyperinsulinism and insulin resistance are reported. To date, systematic studies of glucose profiles in this age group with CAH are lacking. Methods: This was a monocentric, prospective, observational study to determine the glucose profiles under different treatment regimens in a cohort of young patients with CAH. The continuous glucose monitoring device used was the latest generation FreeStyle Libre 3® sensor in blinded mode. Therapeutic and auxological data were obtained. Results: The cohort consisted of 10 children/adolescents with a mean age of 11 years. Three patients exhibited morning fasting hyperglycaemia. Overall, 6 out of 10 patients had unacceptably few total values in the desired range of 70-120 mg/dL. Tissue glucose values above 140-180 mg/dL were found in 5 of 10 patients. The mean value for glycosylated haemoglobin for the cohort was of 5.8%. All pubertal adolescents with reverse circadian regimens had significantly higher glucose levels at night. Two adolescents showed asymptomatic nocturnal hypoglycaemia. Conclusion: Most of the patients exhibited abnormalities in glucose metabolism. Two-thirds had elevated total 24h glucose values outside the age-appropriate reference values. Thus, this aspect may need to be addressed early in life by adjusting the doses, treatment regimen or dietary measures. Consequently, reverse circadian therapy regimens should be critically indicated and closely monitored due to the potential metabolic risk.
Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors

Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gβ5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/– Gnb5fl/fl mice but not in Rgs9-Cre+/– Gnb5fl/fl mice, suggesting that Gβ5 might specifically regulate mechanical pain in regulator of G protein signaling 7–positive (Rgs7+) cells. Additionally, Gβ5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gβ5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein–coupled receptor Mrgprd agonist β-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/– Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.
Shorter TR combined with finer atlas positively modulate topological organization of brain network: A resting state fMRI study

ABSTRACT Background: The use of shorter TR and finer atlases in rs-fMRI can provide greater detail on brain function and anatomy. However, there is limited understanding of the effect of this combination on brain network properties. Methods: A study was conducted with 20 healthy young volunteers who underwent rs-fMRI scans with both shorter (0.5s) and long (2s) TR. Two atlases with different degrees of granularity (90 vs 200 regions) were used to extract rs-fMRI signals. Several network metrics, including small-worldness, Cp, Lp, Eloc, and Eg, were calculated. Two-factor ANOVA and two-sample t-tests were conducted for both the single spectrum and five sub-frequency bands. Results: The network constructed using the combination of shorter TR and finer atlas showed significant enhancements in Cp, Eloc, and Eg, as well as reductions in Lp and γ in both the single spectrum and subspectrum (p < 0.05, Bonferroni correction). Network properties in the 0.082–0.1 Hz frequency range were weaker than those in the 0.01–0.082 Hz range. Conclusion: Our findings suggest that the use of shorter TR and finer atlas can positively affect the topological characteristics of brain networks. These insights can inform the development of brain network construction methods.