Miracle-dz/UniFAR-FTUs huggingface dataset:
Exploring the Contribution of Proprioceptive Reflexes to Balance Control in Perturbed Standing

Humans control balance using different feedback loops involving the vestibular system, the visual system, and proprioception. In this article, we focus on proprioception and explore the contribution of reflexes based on force and length feedback to standing balance. In particular, we address the questions of how much proprioception alone could explain balance control, and whether one modality, force or length feedback, is more important than the other. A sagittal plane neuro-musculoskeletal model was developed with six degrees of freedom and nine muscles in each leg. A controller was designed using proprioceptive reflexes and a dead zone. No feedback control was applied inside the dead zone. Reflexes were active once the center of mass moved outside the dead zone. Controller parameters were found by solving an optimization problem, where effort was minimized while the neuro-musculoskeletal model should remain standing upright on a perturbed platform. The ground was perturbed with random square pulses in the sagittal plane with different amplitudes and durations. The optimization was solved for three controllers: using force and length feedback (base model), using only force feedback, and using only length feedback. Simulations were compared to human data from previous work, where an experiment with the same perturbation signal was performed. The optimized controller yielded a similar posture, since average joint angles were within 5 degrees of the experimental average joint angles. The joint angles of the base model, the length only model, and the force only model correlated weakly (ankle) to moderately with the experimental joint angles. The ankle moment correlated weakly to moderately with the experimental ankle moment, while the hip and knee moment were only weakly correlated, or not at all. The time series of the joint angles showed that the length feedback model was better able to explain the experimental joint angles than the force feedback model. Changes in time delay affected the correlation of the joint angles and joint moments. The objective of effort minimization yielded lower joint moments than in the experiment, suggesting that other objectives are also important in balance control, which cause an increase in effort and thus larger joint moments.
Characterization and Validation of a Chronic Model of Cyclophosphamide-Induced Interstitial Cystitis/Bladder Pain Syndrome in Rats

Interstitial cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease characterized by visceral pain and voiding symptoms. IC/BPS is still an unsolved enigma with ineffective diagnosis criteria and treatment. A main limitation in IC/BPS understanding is the lack of appropriate preclinical model. Cyclophosphamide (CYP) is commonly used as an experimental model for IC/BPS in rodent. However, the proposed models are very aggressive, contrasting with what occurs in clinic, and often associated with severe toxicity and high mortality rate. In addition, visceral pain, the hallmark symptom of IC/BPS, has been validated in only few of them. In this study, we developed a chronic model of CYP-induced IC/BPS in female rat. In our protocol, no severe weight loss occurred and the survival rate was 100%. In accordance to human pathology, chronic CYP-injected rats developed severe painful behavior whereas only sparse inflammation was observed. Inflammatory response was characterized by bladder edema and focal urothelial damage but absence of massive infiltrate. This chronic model showed persistent symptoms indicative for a central sensitization mechanism. We further demonstrate that CYP-induced chronic visceral pain was significantly reduced by curative treatment with clinically relevant compounds (gabapentin, ibuprofen, and Ialuril®). We therefore developed and validated a rat model of chronic cystitis that shares strong similarity with human non-ulcerative IC/BPS features without overtly affecting the animal health. This model will thus provide mechanistic insights of the disease and help to evaluate therapeutic agents for IC/BPS.
Psychosocial Functioning, BMI, and Nutritional Behaviors in Women at Cardiovascular Risk

Psychosocial factors such as depression, anxiety, and stress are associated with increased cardiovascular risk. Health behaviors may play a role in this relationship, as individuals experiencing elevated levels of anxiety, stress, and/or depression may be less likely to engage in risk-reducing behaviors such as diet and exercise. Some evidence suggests that this relationship is particularly relevant for women. This study explored the relationship between levels of anxiety, depression, stress, and specific nutritional behaviors in a sample of 187 women at cardiovascular risk. BMI was explored as a possible moderator of these relationships. Higher levels of depression in patients with high BMI was associated with increased fruit consumption, whereas this was not seen in highly depressed patients with normal BMI. The reverse pattern was seen for consumption of sweet drinks. Anxiety was found to have a complex relationship with consumption of sweetened drinks and white bread, with higher consumption at moderately elevated levels of anxiety and reduced consumption at the highest levels. Possible interpretations of these findings, as well as their implications for lifestyle interventions with this population are discussed. These findings suggest a number of questions for further research.
Determinants of Willingness to Pay for Health Insurance in Germany—Results of the Population-Based Health Study of the Leipzig Research Centre for Civilization Diseases (LIFE-Adult-Study)

Objective: To investigate which factors are associated with the willingness to pay (WTP) for health insurance. Methods: The analysis (n = 1,248 individuals) is based on data of a large population-based study—the Health Study of the Leipzig Research Centre for Civilization Diseases (LIFE-Adult-Study). With regard to WTP for health insurance, a contingent valuation method with a payment card was used. Several explanatory variables were included. For example, personality factors (in terms of agreeableness, conscientiousness, extraversion, neuroticism, and openness to experience) were assessed using the NEO-16 Adjective Measure. Results: Average WTP for health insurance per month equaled about €240 which corresponds to ~14% of household net equivalent income. Multiple regressions showed that an increased WTP was associated with lower age (β = −1.7, p < 0.001), higher (log) household net equivalent income (β = 153.6, p < 0.001), higher social support (β = 2.0, p < 0.05), and private health insurance (β = 131.1, p < 0.001). Furthermore, an increased WTP for health insurance was associated with higher openness to experience (β = 10.1, p < 0.05), whereas it was not associated with agreeableness, conscientiousness, extraversion, and neuroticism. Conclusion: The quite large amount of average WTP for health insurance may suggest that individuals accept current contributions to health insurances and would probably accept higher contributions. While previous studies mainly focused on individuals in late life, we identified a link between socioeconomic, health-related factors, and personality factors (in terms of openness to experience) and WTP in the general adult population.
Crystal structure of a YeeE/YedE family protein engaged in thiosulfate uptake

The crystal structure of YeeE shows a sophisticated hourglass shape for thiosulfate uptake. We have demonstrated that a bacterial membrane protein, YeeE, mediates thiosulfate uptake. Thiosulfate is used for cysteine synthesis in bacteria as an inorganic sulfur source in the global biological sulfur cycle. The crystal structure of YeeE at 2.5-Å resolution reveals an unprecedented hourglass-like architecture with thiosulfate in the positively charged outer concave side. YeeE is composed of loops and 13 helices including 9 transmembrane α helices, most of which show an intramolecular pseudo 222 symmetry. Four characteristic loops are buried toward the center of YeeE and form its central region surrounded by the nine helices. Additional electron density maps and successive molecular dynamics simulations imply that thiosulfate can remain temporally at several positions in the proposed pathway. We propose a plausible mechanism of thiosulfate uptake via three important conserved cysteine residues of the loops along the pathway.
Intravascular Polarimetry: Clinical Translation and Future Applications of Catheter-Based Polarization Sensitive Optical Frequency Domain Imaging

Optical coherence tomography (OCT) and optical frequency domain imaging (OFDI) visualize the coronary artery wall and plaque morphology in great detail. The advent of these high-resolution intracoronary imaging modalities has propelled our understanding of coronary atherosclerosis and provided enhanced guidance for percutaneous coronary intervention. Yet, the lack of contrast between distinct tissue types and plaque compositions impedes further elucidation of the complex mechanisms that contribute to acute coronary syndrome (ACS) and hinders the prospective identification of plaques susceptible to rupture. Intravascular polarimetry with polarization-sensitive OFDI measures polarization properties of the coronary arterial wall using conventional intravascular imaging catheters. The quantitative polarization metrics display notable image contrast between several relevant coronary plaque microstructures that are difficult to identify with conventional OCT and OFDI. Tissues rich in collagen and smooth muscle cells exhibit birefringence, while lipid and macrophages cause depolarization. In this review, we describe the basic principles of intravascular polarimetry, discuss the interpretation of the polarization signatures, and outline promising avenues for future research and clinical implications.
Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

The pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is unknown. In this study, we test the hypothesis that hypermobility, signs of intracranial hypertension (IH), and craniocervical obstructions may be overrepresented in patients with ME/CFS and thereby explain many of the symptoms. Our study is a retrospective, cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS as defined by the Canada Consensus Criteria. The first 272 patients with ME/CFS were invited to participate, and 229 who provided prompt informed consent were included. Hypermobility was assessed using the Beighton Score. IH was assessed indirectly by the quotient of the optic nerve sheet diameter (ONSD)/eyeball transverse diameter on both sides as measured on magnetic resonance imaging (MRI) of the brain. We also included assessment of cerebellar tonsil position in relation to the McRae line, indicating foramen magnum. Craniocervical obstructions were assessed on MRI of the cervical spine. Allodynia was assessed by quantitative sensory testing (QST) for pain in the 18 areas indicative of fibromyalgia syndrome (FMS). A total of 190 women, mean age 45 years, and 39 males, mean age 44 years, were included. Hypermobility was identified in 115 (50%) participants. MRI of the brain was performed on 205 participants of whom 112 (55%) had an increased ONSD and 171 (83%) had signs of possible IH, including 65 (32%) who had values indicating more severe states of IH. Cerebellar tonsils protruding under the McRae line into the foramen magnum were identified in 115 (56%) of the participants. MRI of the cervical spine was performed on 125 participants of whom 100 (80%) had craniocervical obstructions. Pain at harmless pressure, allodynia, was found in 96% of the participants, and FMS was present in 173 participants or 76%. Compared to a general population, we found a large overrepresentation of hypermobility, signs of IH, and craniocervical obstructions. Our hypothesis was strengthened for future studies on the possible relation between ME/CFS symptoms and hypermobility, IH, and craniocervical obstructions in a portion of patients with ME/CFS. If our findings are confirmed, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
The roles of large (L) gene of parainfluenza virus 5 in the host signaling pathways

The innate immune responses play critical roles in combating viral infection. A key feature of this response is production of type I interferons (IFNs) which induce an antiviral and anti-proliferative state in the cells. This process requires activation of transcription factors, such as nuclear factor-κB (NF-κB) and interferon regulatory factor3 (IRF-3). It has been reported that paramyxovirus infection can activate expression of cytokines such as IFN-β, a type I IFN. However, the mechanism of the activation by virus is not well understood. The cytoplasmic viral sensors, the RNA helicases, RIG-I or MDA5, play critical roles in induction of interferon signaling through detection of specific viral components in the infected cells. However, the origin and molecular identity of these viral RNA ligands is not well characterized. Intriguingly, viruses have strategies to evade this host defense response. This interplay between innate immunity and virus infections, is not only crucial to understand virus-host relationships, but also may lead to development of novel antiviral therapeutics. In this work, we have studied the activation and modulation of innate immune responses by viruses, focusing on the NF-κB and the interferon signaling pathways using parainfluenza virus 5 (PIV5), a prototypical paramyxovirus as our model system. Paramyxoviruses are enveloped nonsegmented negative stranded (NNS) RNA viruses that include many important human and animal pathogens. PIV5 is a poor inducer of the antiviral responses. However, a recombinant PIV5 lacking the conserved region of the V iv protein (rPIV5VΔC) activates expression of cytokines IFN-β and IL-6 through a NF-κB
Bacteriophage Protects Against Aerococcus viridans Infection in a Murine Mastitis Model

Bovine mastitis, an inflammatory disease that occurs frequently in early lactation or the dry period, is primarily caused by bacterial infections. There is growing evidence that Aerococcus viridans (A. viridans) is becoming an important cause of bovine mastitis. The treatment of bovine mastitis is primarily based on antibiotics, which not only leads to a large economic burden but also the development of antibiotic resistance. On the other hand, bacteriophages present a promising alternative treatment strategy. The object of this study was to evaluate the potential of a previously isolated A. viridans phage vB_AviM_AVP (AVP) as an anti-mastitis agent in an experimental A. viridans-induced murine mastitis model. A. viridans N14 was isolated from the milk of clinical bovine mastitis and used to establish a mastitis model in mice. We demonstrated that administration of phage AVP significantly reduced colony formation by A. viridans and alleviated damage to breast tissue. In addition, reduced inflammation was indicated by decreased levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and myeloperoxidase (MPO) activity in the phage-treated group compared to those in the phosphate buffered saline (PBS)-treated group. To the best of our knowledge, this report is the first to show the potential use of phages as a treatment for A. viridans-induced mastitis.
Radioactive Beams in Particle Therapy: Past, Present, and Future

Heavy ion therapy can deliver high doses with high precision. However, image guidance is needed to reduce range uncertainty. Radioactive ions are potentially ideal projectiles for radiotherapy because their decay can be used to visualize the beam. Positron-emitting ions that can be visualized with PET imaging were already studied for therapy application during the pilot therapy project at the Lawrence Berkeley Laboratory, and later within the EULIMA EU project, the GSI therapy trial in Germany, MEDICIS at CERN, and at HIMAC in Japan. The results show that radioactive ion beams provide a large improvement in image quality and signal-to-noise ratio compared to stable ions. The main hindrance toward a clinical use of radioactive ions is their challenging production and the low intensities of the beams. New research projects are ongoing in Europe and Japan to assess the advantages of radioactive ion beams for therapy, to develop new detectors, and to build sources of radioactive ions for medical synchrotrons.
TRAP-based allelic translation efficiency imbalance analysis to identify genetic regulation of ribosome occupancy in specific cell types in vivo

The alteration of gene expression due to variations in the sequences of transcriptional regulatory elements has been a focus of substantial inquiry in humans and model organisms. However, less is known about the extent to which natural variation contributes to post-transcriptional regulation. Allelic Expression Imbalance (AEI) is a classical approach for studying the association of specific haplotypes with relative changes in transcript abundance. Here, we piloted a new TRAP based approach to associate genetic variation with transcript occupancy on ribosomes in specific cell types, to determine if it will allow examination of Allelic Translation Imbalance (ATI), and Allelic Translation Efficiency Imbalance, using as a test case mouse astrocytes in vivo. We show that most changes of the mRNA levels on ribosomes were reflected in transcript abundance, though ∼1.5% of transcripts have variants that clearly alter loading onto ribosomes orthogonally to transcript levels. These variants were often in conserved residues and altered sequences known to regulate translation such as upstream ORFs, PolyA sites, and predicted miRNA binding sites. Such variants were also common in transcripts showing altered abundance, suggesting some genetic regulation of gene expression may function through post-transcriptional mechanisms. Overall, our work shows that naturally occurring genetic variants can impact ribosome occupancy in astrocytes in vivo and suggests that mechanisms may also play a role in genetic contributions to disease.
Single-pixel epiretinal stimulation with a wide-field and high-density retinal prosthesis for artificial vision

Retinal prostheses hold the promise of restoring artificial vision in profoundly and totally blind people. However, a decade of clinical trials highlighted quantitative limitations hampering the possibility to reach this goal. A key obstacle to suitable retinal stimulation is the ability to independently activate retinal neurons over a large portion of the subject’s visual field. Reaching such a goal would significantly improve the perception accuracy in the users of retinal implants, along with their spatial cognition, attention, ambient mapping and interaction with the environment. Here we show a wide-field, high-density and high-resolution photovoltaic epiretinal prosthesis for artificial vision. The prosthesis embeds 10,498 physically and functionally independent photovoltaic pixels allowing for both wide retinal coverage and high-resolution stimulation. Single-pixel illumination reproducibly induced network-mediated responses from retinal ganglion cells at safe irradiance levels. Furthermore, the prosthesis enables a sub-receptive field response resolution for retinal ganglion cells having a dendritic tree larger than the pixel’s pitch. This approach could allow the restoration of mid-peripheric artificial vision in patients with retinitis pigmentosa.
Binary decision between asymmetric and symmetric cell division is defined by the balance of PAR proteins in C. elegans embryos

Coordination between cell differentiation and proliferation during development requires the balance between asymmetric and symmetric modes of cell division. However, the cellular intrinsic cue underlying the binary choice between these two division modes remains elusive. Here we show evidence in Caenorhabditis elegans that the invariable lineage of the division modes is programmed by the balance between antagonizing complexes of partitioning-defective (PAR) proteins. By uncoupling unequal inheritance of PAR proteins from that of fate determinants during zygote division, we demonstrated that changes in the balance between PAR-2 and PAR-6 are sufficient to re-program the division modes from symmetric to asymmetric and vice versa in two-cell stage embryos. The division mode adopted occurs independently of asymmetry in cytoplasmic fate determinants, cell-size asymmetry, and cell-cycle asynchrony between the sister cells. We propose that the balance between antagonizing PAR proteins represents an intrinsic self-organizing cue for binary specification of the division modes during development.
Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease. Characterizing PDAC by mRNA profiling remains particularly challenging. Previously identified bulk expression subtypes were influenced by contaminating stroma and have not yet informed clinical management, whereas single cell RNA-seq (scRNA-seq) of fresh tumors under-represented key cell types. Here, we developed a robust single-nucleus RNA-seq (snRNA-seq) technique for frozen archival PDAC specimens and used it to study both untreated tumors and those that received neoadjuvant chemotherapy and radiotherapy (CRT). Gene expression programs learned across untreated malignant cell and fibroblast profiles uncovered a clinically relevant molecular taxonomy with improved prognostic stratification compared to prior classifications. Moreover, in the increasingly-adopted neoadjuvant treatment context, there was a depletion of classical-like phenotypes in malignant cells in favor of basal-like phenotypes associated with TNF-NFkB and interferon signaling as well as the presence of novel acinar and neuroendocrine classical-like states, which may be more resilient to cytotoxic treatment. Spatially-resolved transcriptomics revealed an association between malignant cells expressing these basal-like programs and higher immune infiltration with increased lymphocytic content, whereas those exhibiting classical-like programs were linked to sparser macrophage-predominant microniches, perhaps pointing to susceptibility to distinct therapeutic strategies. Our refined molecular taxonomy and spatial resolution can help advance precision oncology in PDAC through informative stratification in clinical trials and insights into differential therapeutic targeting leveraging the immune system.