Miracle-dz/UniFAR-FTUs huggingface dataset:
Irisin Prevents Disuse‐Induced Osteocyte Apoptosis

Previous results showed that intermittently administered irisin improves bone mass in normal mice and prevents the development of disuse‐induced osteoporosis and muscular atrophy in hindlimb‐suspended mice, a murine model able to mimic the absence of mechanical loading. A recent study showed that irisin increases survival of osteocytes acting through integrin αV/β5 receptors. To better understand the action of irisin on these cells, we investigated the downstream signaling cascades in osteocyte‐like cells (MLO‐Y4) treated with recombinant irisin (rec‐irisin) in vitro and we analyzed survival of osteocytes and caspase activation in cortical bone of osteoporotic mice treated with rec‐irisin in vivo. Our results revealed that rec‐irisin activated the MAP kinases Erk1 and Erk2 and increased the expression of the transcription factor Atf4 (2.5‐fold, p < .05) through an Erk‐dependent pathway in osteocytes. Some key genes expressed by MLO‐Y4 cells were modulated by long‐term irisin treatment, either continuously administered or given with intermittent short pulses. Interestingly, Sost mRNA was severely downregulated only upon intermittent irisin administration (10‐fold, p < .001). Furthermore, rec‐irisin upregulated Tfam mRNA (fourfold, p < .05) and Bcl2/Bax ratio (twofold, p < .05) in MLO‐Y4 cells. By detecting caspase‐9 and caspase‐3, we also found that rec‐irisin inhibited apoptosis induced by hydrogen peroxide and dexamethasone, respectively. In cortical bone of unloading C57BL6 mice treated with vehicle (unload‐veh), irisin prevented disuse‐induced reduction of viable osteocytes (+30% versus unload‐veh, p < .05) and increase of empty lacunae (+110% versus unload‐veh, p < .05), as well as caspase‐9 (threefold, p < .05) and caspase‐3 (twofold, p < .05) activations. Our findings revealed underlying mechanisms of irisin action on osteocytes, which increases their functions and exerts anti‐apoptotic effects, confirming that mechanosensor cells of bone are sensitive to the exercise‐mimetic myokine irisin. © 2019 American Society for Bone and Mineral Research.
Focal inputs are a potential origin of local field potential (LFP) in the brain regions without laminar structure

Current sinks and sources spatially separated between the apical and basal dendrites have been believed to be essential in generating local field potentials (LFPs). According to this theory, LFPs would not be large enough to be observed in the regions without laminar structures, such as striatum and thalamus. However, LFPs are experimentally recorded in these regions. We hypothesized that focal excitatory input induces a concentric current sink and source generating LFPs in these regions. In this study, we tested this hypothesis by the numerical simulations of multicompartment neuron models and the analysis of simplified models. Both confirmed that focal excitatory input can generate LFPs on the order of 0.1 mV in a region without laminar structures. The present results suggest that LFPs in subcortical nuclei indicate localized excitatory input.
Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice

Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. We report that aging impairs the expression of Gadd45γ in the hippocampus of cognitively impaired male mice. Mimicking this decrease in young adult male mice led to age-like memory deficits in hippocampus-dependent memory tasks. Gadd45γ reduction impaired the activity of key components of the mitogen-activated protein kinase (MAPK) pathway (p38 and JNK) in mouse hippocampal cultures. Furthermore, we found that activation of downstream targets, such as ATF-2, c-Jun, and CREB (cAMP response element-binding protein), was disrupted. Finally, we showed that Gadd45γ is required for induction of key early- and late-response genes that have been associated with aging. Together, these findings indicate that Gadd45γ expression regulates cognitive abilities and synapse-to-nucleus communication and suggest Gadd45γ dysfunction as a potential mechanism contributing to age-related cognitive impairments. SIGNIFICANCE STATEMENT A high percentage of subjects experience age-related memory loss that burdens daily performance. Although many advances have been made, the precise changes in the brain governing these deficits are unclear. Identifying molecular processes that are required for cognition and are altered during old age is crucial to develop preventive or therapeutic strategies. Here, we show that baseline and learning-induced expression of the growth arrest DNA damage (Gadd45) γ is selectively impaired in the hippocampus of aged mice with cognitive deficits. Next, we show that modeling this impairment in young adult mice with normal cognitive performance disrupts long- and short-term memories in an age-like manner. Finally, we demonstrate that Gadd45γ regulates synapse-to-nucleus communication processes that are needed for plasticity-associated gene expression.
Diphthamide modification of eEF2 is required for gut tumor‐like hyperplasia induced by oncogenic Ras

Eukaryotic elongation factor 2 (eEF2) undergoes a unique post‐translational modification called diphthamidation. Although eEF2 diphthamidation is highly conserved, its pathophysiological function is still largely unknown. To elucidate the function of diphthamidation in tumor, we examined the involvement of diphthamidation pathway enzyme Dph5 in tumor progression in Drosophila adult gut. Expression of oncogenic RasV12 in gut intestinal stem cells (ISCs) and enteroblasts (EBs) causes hypertrophy and disruption of gut epithelia, and shortened life span. Knockdown of Dph5 ameliorated these pathogenic phenotypes. Dph5 is required for gross translation activation and high dMyc protein level in RasV12 tumor‐like hyperplasia. Transcriptome analysis revealed that Dph5 is involved in the regulation of ribosome biogenesis genes. These results suggest that diphthamidation is required for translation activation partly through the regulation of ribosome biogenesis in Ras‐induced tumor‐like hyperplasia model in Drosophila gut.
Hepatic Transcriptomic Patterns in the Neonatal Rat After Pentabromodiphenyl Ether Exposure

Human exposure to pentabromodiphenyl ether (PBDE) mixture (DE-71) and its PBDE-47 congener can occur both in utero and during lactation. Here, we tested the hypothesis that PBDE-induced neonatal hepatic transcriptomic alterations in Wistar Han rat pups can inform on potential toxicity and carcinogenicity after longer term PBDE exposures. Wistar Han rat dams were exposed to either DE-71 or PBDE-47 daily from gestation day (GD 6) through postnatal day 4 (PND 4). Total plasma thyroxine (T4) was decreased in PND 4 pups. In liver, transcripts for CYPs and conjugation enzymes, Nrf2, and ABC transporters were upregulated. In general, the hepatic transcriptomic alterations after exposure to DE-71 or PBDE-47 were similar and provided early indicators of oxidative stress and metabolic alterations, key characteristics of toxicity processes. The transcriptional benchmark dose lower confidence limits of the most sensitive biological processes were lower for PBDE-47 than for the PBDE mixture. Neonatal rat liver transcriptomic data provide early indicators on molecular pathway alterations that may lead to toxicity and/or carcinogenicity if the exposures continue for longer durations. These early toxicogenomic indicators may be used to help prioritize chemicals for a more complete toxicity and cancer risk evaluation.
The RNA binding protein Quaking represses host interferon response by downregulating MAVS

ABSTRACT Quaking (QKI) is an RNA-binding protein (RBP) involved in multiple aspects of RNA metabolism and many biological processes. Despite a known immune function in regulating monocyte differentiation and inflammatory responses, the degree to which QKI regulates the host interferon (IFN) response remains poorly characterized. Here we show that QKI ablation enhances poly(I:C) and viral infection-induced IFNβ transcription. Characterization of IFN-related signalling cascades reveals that QKI knockout results in higher levels of IRF3 phosphorylation. Interestingly, complementation with QKI-5 isoform alone is sufficient to rescue this phenotype and reduce IRF3 phosphorylation. Further analysis shows that MAVS, but not RIG-I or MDA5, is robustly upregulated in the absence of QKI, suggesting that QKI downregulates MAVS and thus represses the host IFN response. As expected, MAVS depletion reduces IFNβ activation and knockout of MAVS in the QKI knockout cells completely abolishes IFNβ induction. Consistently, ectopic expression of RIG-I activates stronger IFNβ induction via MAVS-IRF3 pathway in the absence of QKI. Collectively, these findings demonstrate a novel role for QKI in negatively regulating host IFN response by reducing MAVS levels.
Does caffeine ingestion before a short-term sprint interval training promote body fat loss?

We investigated the effect of caffeine ingestion combined with a 2-wk sprint interval training (SIT) on training-induced reductions in body adiposity. Twenty physically-active men ingested either 5 mg/kg of cellulose as a placebo (PLA, n=10) or 5 mg/kg of caffeine (CAF, n=10) 60 min before each SIT session (13×30 s sprint/15 s of rest). Body mass and skinfold thickness were measured pre- and post-training. Energy expenditure was measured at rest, during exercise, and 45 min after exercise in the first SIT session. Body fat was similar between PLA and CAF groups at pre-training (P>0.05). However, there was a significant decrease in body fat after training in the CAF group (−5.9±4.2%, P<0.05) but not in PLA (1.5±8.0%, P>0.05). There was no difference in energy expenditure at rest and during exercise between PLA and CAF groups (P>0.05), but the post-exercise energy expenditure was 18.3±21.4% greater in the CAF than in the PLA group (P<0.05). In conclusion, caffeine ingestion before SIT sessions induced a body fat loss that may be associated with higher post-exercise energy expenditure.
Design of Ceramic Packages for Ultrasonically Coupled Implantable Medical Devices

Objective: Ultrasonic acoustic power transfer is an efficient mechanism for coupling energy to millimeter and sub-millimeter implants in the body. To date, published ultrasonically powered implants have been encapsulated with thin film polymers that are susceptible to well-documented failure modes in vivo, including water penetration and attack by the body. As with all medical implants, packaging with ceramic or metallic materials can reduce water vapor transmission and improve biostability to provide decadal device lifetime. In this paper, we evaluate methods of coupling ultrasonic energy to the interior of ceramic packages. Methods: The classic wave approach and modal expansion are used to obtain analytical expressions for ultrasonic transmission through two different package designs and these approaches are validated experimentally. A candidate package design is demonstrated using alumina packages and titanium lids, designed to be acoustically transparent at ultrasonic frequencies. Results: Bulk modes are shown to be more effective at coupling ultrasonic energy to a piezoelectric receiver than flexural modes. Using bulk modes, packaged motes have an overall link efficiency of roughly 10%, compared to 25% for unpackaged motes. Packaging does not have a significant effect on translational misalignment penalties, but does increase angular misalignment penalties. Passive amplitude-modulated backscatter communication is demonstrated. Conclusion: Thin lids enable the use of ultrasonically coupled devices even with package materials of very different acoustic impedance. Significance: This work provides an analysis and method for designing packages that enable ultrasonic coupling with implantable medical devices, which could facilitate clinical translation.
Change in Meniscal Strain with Anterior Cruciate Ligament Injury and After Reconstruction

Meniscal injury has been well documented in association with injury to the anterior cruciate ligament. The purpose of this study was to evaluate the effect of anterior cruciate ligament transection and reconstruction on meniscal strain. Four differential variable reluctance transducer strain gauges were placed in the medial and lateral menisci of nine cadaveric knees. Each specimen was mounted to a six-degree-of-freedom knee testing device. Testing was conducted with the knee fully extended and at 45° and 90° of flexion, both with and without applied axial load. At each angle of flexion, an anterior and posterior tibial load was applied. Next, the anterior cruciate ligament was transected and the testing sequence was repeated. Finally, the ligament was reconstructed using a central one-third patellar tendon graft and the testing sequence was repeated. The results demonstrated statistically significant increases in meniscal strain in ligament-transected knees compared with intact specimens. A reduction in meniscal strain to a level similar to that detected in the ligament-intact knees was observed after anterior cruciate ligament reconstruction. These results have important clinical implications regarding the potentially deleterious effect of the anterior cruciate ligament-deficient knee on meniscal strain and the potential benefit of anterior cruciate ligament reconstruction.
Standardising Dementia Diagnosis Across Linguistic and Educational Diversity: Study Design of the Indian Council of Medical Research-Neurocognitive Tool Box (ICMR-NCTB)

Abstract Objectives: While the burden of dementia is increasing in low- and middle-income countries, there is a low rate of diagnosis and paucity of research in these regions. A major challenge to study dementia is the limited availability of standardised diagnostic tools for use in populations with linguistic and educational diversity. The objectives of the study were to develop a standardised and comprehensive neurocognitive test battery to diagnose dementia and mild cognitive impairment (MCI) due to varied etiologies, across different languages and educational levels in India, to facilitate research efforts in diverse settings. Methods: A multidisciplinary expert group formed by Indian Council of Medical Research (ICMR) collaborated towards adapting and validating a neurocognitive test battery, that is, the ICMR Neurocognitive Tool Box (ICMR-NCTB) in five Indian languages (Hindi, Bengali, Telugu, Kannada, and Malayalam), for illiterates and literates, to standardise diagnosis of dementia and MCI in India. Results: Following a review of existing international and national efforts at standardising dementia diagnosis, the ICMR-NCTB was developed and adapted to the Indian setting of sociolinguistic diversity. The battery consisted of tests of cognition, behaviour, and functional activities. A uniform protocol for diagnosis of normal cognition, MCI, and dementia due to neurodegenerative diseases and stroke was followed in six centres. A systematic plan for validating the ICMR-NCTB and establishing cut-off values in a diverse multicentric cohort was developed. Conclusions: A key outcome was the development of a comprehensive diagnostic tool for diagnosis of dementia and MCI due to varied etiologies, in the diverse socio-demographic setting of India.
Wearable Sensors for Monitoring Human Motion: A Review on Mechanisms, Materials, and Challenges

The emergence of flexible wearable electronics as a new platform for accurate, unobtrusive, user-friendly, and longitudinal sensing has opened new horizons for personalized assistive tools for monitoring human locomotion and physiological signals. Herein, we survey recent advances in methodologies and materials involved in unobtrusively sensing a medium to large range of applied pressures and motions, such as those encountered in large-scale body and limb movements or posture detection. We discuss three commonly used methodologies in human gait studies: inertial, optical, and angular sensors. Next, we survey the various kinds of electromechanical devices (piezoresistive, piezoelectric, capacitive, triboelectric, and transistive) that are incorporated into these sensor systems; define the key metrics used to quantitate, compare, and optimize the efficiency of these technologies; and highlight state-of-the-art examples. In the end, we provide the readers with guidelines and perspectives to address the current challenges of the field.
Strengthening universal health: development of a nursing and midwifery education quality improvement toolkit

Objective: to present the development of a toolkit for education quality improvement in universal health and primary health care, targeting schools of nursing and midwifery in Latin American and Caribbean countries. Methods: an expert work group conducted a systematic literature review, selected key content and completed toolkit drafting, using an iterative consensus approach. International partners reviewed the toolkit. Cognitive debriefing data were analyzed, revisions and new tools were integrated, and the final version was approved. Results: twenty-two articles were identified and mapped as resources. The Model for Improvement, a data-driven approach to performance analysis, was selected for its widespread use and simplicity in carrying out the following steps: 1) organize a team, 2) assess improvement need regarding universal health and primary health care education, 3) set an aim/goal and identify priorities using a matrix, 4) establish metrics, 5) identify change, 6) carry out a series of Plan-Do-Study-Act learning cycles, and 7) sustain change. Conclusions: the Education Quality Improvement Toolkit, developed through stakeholder consensus, provides a systematic, and potentially culturally adaptable approach to improve student, faculty, and program areas associated with universal health coverage and access.
Classification of Cutibacterium acnes at phylotype level by MALDI-MS proteotyping

Cutibacterium acnes is a major commensal human skin bacteria. It is a producer of propionic acids that maintain skin acidic pH to inhibit the growth of pathogens. On the other hand, it is also associated with diseases such as acne vulgaris and sarcoidosis. C. acnes strains have been classified into six phylotypes using DNA-based approaches. Because several characteristic features of C. acnes vary according to the phylotype, the development of a practical method to identify these phylotypes is needed. For rapid identification of phylotypes for C. acnes strains, a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) fingerprinting technique has been applied; however, some phylotypes have not been discriminated. We developed a high-throughput protein purification method to detect biomarker proteins by ultrafiltration. MALDI-MS proteotyping using profiling of identified biomarker peaks was applied for the classification of 24 strains of C. acnes, and these were successfully classified into the correct phylotypes. This is a promising method that allows the discrimination of C. acnes phylotypes independent of a DNA-based approach.
Hepatitis B virus X protein modulates upregulation of DHX9 to promote viral DNA replication

Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver diseases. During the HBV life cycle, HBV hijacks various host factors to assist viral replication. In this research, we find that the HBV regulatory protein X (HBx) can induce the upregulation of DExH‐box RNA helicase 9 (DHX9) expression by repressing proteasome‐dependent degradation mediated by MDM2. Furthermore, we demonstrate that DHX9 contributes to viral DNA replication in dependence on its helicase activity and nuclear localization. In addition, the promotion of viral DNA replication by DHX9 is dependent on its interaction with Nup98. Our findings reveal that HBx‐mediated DHX9 upregulation is essential for HBV DNA replication.
From energy to cellular forces in the Cellular Potts Model: An algorithmic approach

Single and collective cell dynamics, cell shape changes, and cell migration can be conveniently represented by the Cellular Potts Model, a computational platform based on minimization of a Hamiltonian. Using the fact that a force field is easily derived from a scalar energy (F = −∇H), we develop a simple algorithm to associate effective forces with cell shapes in the CPM. We predict the traction forces exerted by single cells of various shapes and sizes on a 2D substrate. While CPM forces are specified directly from the Hamiltonian on the cell perimeter, we approximate the force field inside the cell domain using interpolation, and refine the results with smoothing. Predicted forces compare favorably with experimentally measured cellular traction forces. We show that a CPM model with internal signaling (such as Rho-GTPase-related contractility) can be associated with retraction-protrusion forces that accompany cell shape changes and migration. We adapt the computations to multicellular systems, showing, for example, the forces that a pair of swirling cells exert on one another, demonstrating that our algorithm works equally well for interacting cells. Finally, we show forces exerted by cells on one another in classic cell-sorting experiments.
Early weaning induces short‐ and long‐term effects on pancreatic islets in Wistar rats of both sexes

The World Health Organization recommends exclusive breastfeeding until 6 months of age as an important strategy to reduce child morbidity and mortality. Studies have associated early weaning with the development of obesity and type 2 diabetes in adulthood. In our model, we demonstrated that early weaning leads to increased insulin secretion in adolescent males and reduced insulin secretion in adult offspring. Early weaned males exhibit insulin resistance in skeletal muscle. Early weaning did not change insulin signalling in the muscle of female offspring. Taking into account that insulin resistance is one of the primary factors for the development of type 2 diabetes mellitus, this work demonstrates the importance of breastfeeding in the fight against this disease.