bluuebunny/crossref_metadata_2025_split huggingface dataset:
A roadmap to target interleukin-6 in osteoarthritis
Authors: Wiegertjes Renske , van de Loo Fons A J , Blaney Davidson Esmeralda N 
Published: April 2020

AbstractJoint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g. via induction of matrix-degrading enzymes. However, IL-6 also increases expression of anti-catabolic factors, suggesting a protective role. Until now, this dual role of IL-6 is incompletely understood and may be caused by differential effects of IL-6 classic vs trans-signalling. Here, we review current evidence regarding the role of IL-6 classic- and trans-signalling in local joint pathology of cartilage, synovium and bone. Furthermore, we discuss targeting of IL-6 in experimental OA models and provide future perspective for OA treatment by evaluating currently available IL-6 targeting strategies.
Classification vs diagnostic criteria: the challenge of diagnosing axial spondyloarthritis
Authors: Poddubnyy Denis 
Published: April 2020

Abstract
In recent years, significant progress has been made in improving the early diagnosis of spondyloarthritides (SpA), including axial SpA. Nonetheless, there are still issues related to the application of classification criteria for making the primary diagnosis of SpA in the daily practice. There are substantial conceptional and operational differences between the diagnostic vs classification approach. Although it is not possible to develop true diagnostic criteria for natural reasons as discussed in this review, the main principles of the diagnostic approach can be clearly defined: consider the pre-test probability of the disease, evaluate positive and negative results of the diagnostic test, exclude other entities, and estimate the probability of the disease at the end. Classification criteria should only be applied to patients with an established diagnosis and aimed at the identification of a rather homogeneous group of patients for the conduction of clinical research.
Cannabis Use Linked to Altered Functional Connectivity of the Visual Attentional Connectivity in Patients With Psychosis and Controls
Authors: Sami Musa Basseer , McCutcheon Robert A , Ettinger Ulrich , Williams Steve , Lythgoe Dave , McGuire Philip , Bhattacharyya Sagnik 
Published: April 2020

Abstract

Background
Both chronic cannabis use and psychotic disorders are associated with abnormalities in visual attentional processing. Using functional magnetic resonance imaging (fMRI), we sought to determine whether there would be a difference in functional connectivity in patients and controls with and without a history of cannabis use in the visual and dorsal attention networks.

Methods
Resting-state fMRI data were acquired in patients with early psychosis with (EPC = 29) and without (EPNC = 25); and controls with (HCC = 16) and without (HCNC = 22) cannabis use.

Results
There was a patient effect in both Visual-Dorsal Attention Internetwork (F(1,87) = 5.326, P = .023) and the Visual Network (F(1,87) = 4.044, P = .047) and a cannabis effect in the Dorsal Attention Network (F(1,87) = 4.773, P = .032). These effects were specific to the networks examined with no evidence for significant patient or cannabis effects in other canonical networks. Patients with a history of cannabis use showed increased connectivity in the Dorsal Attention Network (134%, P = .019) and Visual Dorsal Attention Internetwork (285%, P = .036) compared to non-using controls. In the EPC group connectivity of the Visual Network (ρ = 0.379, P = .042) and Visual-Dorsal Attention Internetwork (ρ = 0.421, P = .023) correlated with visual hallucinations which were significantly different from EPNC (P = .011). Dorsal attention network strength correlated with severity of dependence for cannabis (ρ = 0.215, P = .04).

Conclusion
We demonstrate specific cannabis and patient effects in networks associated with visual attentional processing. There is a differential association with hallucinatory symptoms in patients with and without a history of cannabis use. This may indicate that dysconnectivity in these networks serves different roles in the context of cannabis use.
Exploring the effects of Ia reciprocal inhibition on neuromodulatory commands in the human lower limb
Authors: Pearcey Gregory E. P. , Khurram Obaid U. , Beauchamp James A. , Heckman Charles J. 
Published: April 2020

The control of normal motor behaviors involves sublime interactions between excitatory, inhibitory and neuromodulatory commands to motoneurons. The effects of altered inhibition on neuromodulatory commands has not received much attention in humans. Yet, motoneuron firing patterns can be readily measured from the muscle fibers they innervate, collectively known as motor units (MUs), due to their one‐to‐one spike ratio. Persistent inward currents (PICs) are reduced with activation of Ia fibers from the antagonist muscle in the decerebrate cat. Here, we set out to explore whether estimated PICs are affected by a tonic vibratory input to antagonist tendons in humans. MU firing patterns of the tibialis anterior (TA), soleus (SOL) and medial gastrocnemius (MG) were discriminated using high‐density surface electromyography array electrodes and a convolutive blind source separation algorithm. PICs were estimated using the paired MU analysis technique, which quantifies discharge rate hysteresis (ΔF) by comparing the onset and offset of a high‐threshold MU with respect to a low‐threshold MU, providing an estimate of neuromodulatory drive to the MU. Participants performed isometric plantarflexion and dorsiflexion triangular ramp contractions to 30% of maximal voluntary contraction with 10 s ascending and descending phases. In half of the trials, we applied vibration (128 Hz) to the distal TA tendon (plantarflexion) or Achilles tendon (dorsiflexion) with a constant force of 15 ± 2 N. There were large decreases in ΔF for both the SOL (31.3 ± 7.94%, p = 0.006, d = 0.81) and MG (31.4 ± 10.36%, p = 0.008, d = 0.9) during plantarflexion contractions with vibration applied to the distal TA tendon, and there was a moderate decrease in ΔF for the TA (10.9 ± 8.79%, p = 0.009, d = 0.63) during dorsiflexion with vibration to the Achilles tendon. These findings suggest that Ia reciprocal inhibition from the antagonist muscle can reduce the discharge rate hysteresis, providing insights about the interactions that occur to produce normal human motor behaviors.Support or Funding InformationThis work was supported by National Institute of Health (NIH) grants R01NS098509‐01 and T32HD007418‐23, and a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellowship.
Vascular Phenotype is Compromised in Dynamically Stiffening Hydrogel
Authors: Schnellmann Rahel , Wei Zhao , Choudhury Mohammad Ikbal , Sun Sean , Gerecht Sharon 
Published: April 2020

Cardiovascular diseases are one of the leading causes of death worldwide with age mediated endothelial dysfunction as one of the major risk factors. Endothelial dysfunction is caused by a variety of reasons, such as oxidative stress, DNA damage and senescence. Although, observations in vivo showed a clear correlation between increased extracellular matrix (ECM) stiffness and morphological changes within the vasculature, the identification of underlying signaling pathways in endothelial cells remains challenging, due to the lack of physiological 3D systems. Here we report the use of a fibrillary hydrogel, composed of hyaluronic acid and collagen I, which is capable of dynamically changing its stiffness along cell culture. This hydrogel allows for the increase in stiffness after the development of a mature vascular network, therefore mimicking the natural process of aging ex vivo. Using this system we found that an increase in ECM stiffness leads to a decrease in vessel length, increase in lumen size and the disassembly of adherence junctions. We further observed that an increase in matrix stiffness leads to changes in cell contractility and pFAK signaling, leading to further increase in matrix stiffness and the disassembly of adherence junctions. Inhibition of cell contractility using blebbistatin partially rescues the vascular morphology and the integrity of adherence junctions.Support or Funding InformationMaryland Stem Cell Fund (RS is MSCRF Fellow)
The Impact of Perinatal Exposure to Inflammation and Hyperoxia on the MicroRNA Profile of the Developing Heart
Authors: Pavlek Leeann , Korada Roopi , Rogers Lynette 
Published: April 2020

BackgroundSeveral cardiac‐specific microRNAs (miRs) are involved in the embryonic and postnatal development of the heart, with alterations in normal expression implicated in multiple disease states. This research aims to understand the impact of exposure to maternal systemic inflammation and/or postnatal hyperoxia on the microRNA profile of the developing heart using a murine model. MiRs‐1 and ‐133 are involved early in cardiac embryogenesis and regulate the transformation of mesoderm into cardiomyocytes. MiR‐195 regulates the cell cycle and proliferation of cardiomyocytes. MiRs‐208a, ‐208b, and ‐499 regulate the differential expression of myosin heavy chain isoforms, which contribute to myocardial contractile strength and energy consumption.MethodsPregnant C3H/HeN mice were injected on embryonic day 16 (E16) intraperitoneal lipopolysaccharide (LPS) to induce maternal inflammation or saline. Offspring were euthanized on E18 or postnatal day 1 (P1). Other offspring were placed into room air or 85% oxygen for 7 days after birth before euthanizing on P7. RT‐PCR was used to analyze expression of microRNA‐1, ‐133, ‐195, ‐208a, ‐208b, and ‐499. Results were normalized to expression of U6.ResultsAt E18 with exposure to LPS, no differences in expression were detected for miR‐1, ‐ 133, ‐195, ‐208, or 499. Exposure to LPS at P1 led to upregulation of miR‐208a (3‐fold; p=0.032) and miR‐208b (10‐fold; p=0.032), but no differences in expression of miR‐1, ‐133, ‐ 195, or ‐499. Upregulation of miR‐208a (4‐fold; p=0.006) and miR‐208b (7‐fold; p=0.047) persisted in hearts exposed to LPS/O2 at P7. No changes in expression of miR‐1, ‐133, ‐195, or ‐ 499 were detected in samples exposed to LPS and/or hyperoxia at P7.ConclusionsPerinatal exposure to inflammation and hyperoxia led to upregulation of miR‐208a and miR‐208b expression in heart tissue from samples at P1 and P7. No changes in expression of miR‐208a and ‐208b were detected in embryonic heart samples. Perinatal exposure to inflammation and hyperoxia did not alter expression of miR‐1, ‐133, ‐195, or ‐499 at any timepoint.Support or Funding InformationAmerican Academy of Pediatrics Marshall Klaus Perinatal Research Award (Pavlek)
The Effects of Chemotherapeutic Agents and a Mitochondrial Antioxidant on the Brain Transcriptome and Cognitive Function
Authors: Cavalier Alyssa N. , Clayton Zachary , Wahl Devin , Seals Douglas , LaRocca Thomas 
Published: April 2020

Cancer is the second leading cause of death in the United States, and over one‐third of patients will receive chemotherapy. One of most frequently reported side effects of chemotherapy is decreased cognitive function, commonly known as “chemobrain.” The underlying biological mechanisms of chemobrain are unclear, but could involve mitochondrial dysfunction and oxidative stress, which have been implicated in peripheral tissues, and could therefore be a therapeutic target. To investigate this possibility in the brain, we measured cognitive function and transcriptome changes by RNA‐seq in mice treated with doxorubicin, a common chemotherapy agent (single intraperitoneal injection, 10mg/kg, at 4 months old), or with doxorubicin plus the mitochondrial antioxidant, MitoQ (250 μM in drinking water for 4 weeks). We observed marked behavioral differences in doxorubicin‐treated mice, such as decreased overall exploration time in the novel object recognition test (NOR, an index of learning/memory). Despite these differences, we observed a trend towards reduced learning/memory (NOR) with doxorubicin treatment compared to sham. MitoQ did not prevent this; however, in RNA‐seq data, we found that doxorubicin increased expression of 127 genes and decreased expression of 154 genes (p < 0.01 vs. sham). These genes corresponded to ~80 transcriptional modules (FDR < 0.01), which were enriched for gene ontology terms related to synaptic transmission/plasticity, learning/memory, neurogenesis and neurotransmitter processing. MitoQ prevented most of these transcriptome changes (31 upregulated and 101 downregulated genes, p < 0.01 vs. sham) which corresponded to expression of only 16 transcriptional modules (none specifically related to brain function). Thus, our results suggest that MitoQ may have potential as a treatment for chemobrain at the biological level; however, its effects on brain/cognitive function require further investigation.Support or Funding InformationAG060302
Characterization of MC903 induced Atopic Dermatitis‐like skin inflammation in mice
Authors: Chu Katharine , Su Zhi , Wetter Joseph , Namovic Marian , Leys Laura , Wang Yibing , Honore Prisca , McGaraughty Steve 
Published: April 2020

Atopic Dermatitis (AD) is a chronic inflammatory skin disease that affects both adults and children worldwide. Symptoms of AD, such as recurrent dry, scaly lesions and intensive pruritus, can become an enormous burden to patients and their caregivers. Animal models are needed to better understand the pathophysiology of AD and for evaluating novel therapeutics. Topically applying MC903 (calcipotriol) on mouse skin has been reported to capture key features associated with AD. In the current study, we conducted a comprehensive characterization of MC903 induced ear skin inflammation in the mouse. An 11 day time course revealed skin thickening starting as early as day 4 and significantly progressing up to day 10. This chronicity was mirrored by increased transepidermal water loss in the ear skin. Histologically, hypervascularization, spongiosis, strong immune cell infiltration and epidermal hyperplasia were observed. The animals also manifested pruritic behaviors. The skin expression of Type 2 and other inflammatory cytokines such as IL‐4, IL‐5, IL‐31, TSLP (peak day 4), IL‐1β, IFNγ, TNFα were typically elevated by day 7 and further increased to day 10. Most of these endpoints were attenuated by administration of a selective JAK1 inhibitor (ABT‐317) or a steroid (Dexamethasone). The observations further the understanding of the utility of MC903 as a preclinical model for AD.Support or Funding Information
Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Identification and Functional Validation of the miRNAs and their Targets, which are Essential to the Induction of Neointimal Hyperplasia
Authors: Kim Yerin 
Published: April 2020

Angioplasty and stent procedures for widening the narrowed artery of atherosclerosis can cause restenosis by damaging endothelial cells. The main reason for this phenomenon is the migration and proliferation of vascular smooth muscle cells toward the intimal layer, which is called neointimal hyperplasia. After the function of miRNA, which is cell‐specific and fine‐tunes the translation of several mRNA targets, was known, several studies have identified miRNAs that affect arterial restenosis to overcome the limits of the previous drugs. However, most of the studies focused on one miRNA each. Therefore, it is necessary to ensure which of the individually studied miRNAs play a more important role at the beginning of restenosis. We should also ensure that there are any unknown miRNAs associated with restenosis regulation. In this study, we used the rat balloon injured carotid artery model to identify the entire differentially expressed (DE)‐miRNAs and DE‐mRNAs in the early stages of restenosis, through small RNA sequencing and total RNA sequencing, respectively. Among the DE‐miRNAs which show the same results in small RNA sequencing and RT‐qPCR, we focus on the rat, human conserved miRNAs with the largest change in expression (> 5 fold). The conserved DE‐miRNAs included previously well‐known miRNAs, such as miR‐221 and miR‐21, but also miRNAs, which show more change in expression but still unknown. By performing in vivo and in vitro functional assays, we were able to identify several undiscovered miRNAs that are effective in the cellular functions associated with the suppression of neointimal hyperplasia. Next, among the DE‐mRNAs identified by total RNA sequencing, we selected the predicted targets of the miRNAs through the target prediction databases (Targetscan, miRDB, miRmap). Also, we selected mRNAs functionally in context with the miRNAs by using the Gene Ontology (GO) term of the expected targets. We used RT‐qPCR to double‐check the changes in expression of these filtered targets and to confirm whether these predicted targets are actual targets for miRNAs. For the mRNA with the greatest variation, we performed luciferase assay to check whether the mRNA is a direct target of the miRNA. Additional functional assays were used to determine whether the target mRNA plays a central role in the progression of the neointimal hyperplasia.In summary, we identified entire miRNAs and their target mRNAs that are important for restenosis control. Through this study, we expect to utilize diverse miRNAs for the diagnosis and therapy of restenosis.Support or Funding InformationThis study was supported by the grant from the National Research Foundation of Korea (2018029571)
Quantitative Proteomic Profile of Caribbean Hispanics with Resistance to Clopidogrel
Authors: Santiago-Cartagena Ednalise , Cantres Yadira , Carrasquillo Kelvin , Moneró Mariangeli , Meléndez Loyda , Roche Abiel , Duconge Jorge 
Published: April 2020

The resistance to clopidogrel increases the risk of ischemic events in adults with coronary artery disease. This resistance varies with ethnicity, genetic, and many other clinical variables. Proteomic data from studies on Caribbean Hispanic (CH) patients treated with clopidogrel that have developed resistance has not yet been conducted. Thus, this is the first study performed on patients from the Caribbean region that also uses a cutting‐edge proteomic approach to a Precision Medicine application. A 10‐plex tandem mass tag labeling quantitative proteomic analysis was performed on plasma proteins isolated from CH patients treated with clopidogrel. Plasma samples from 6 patients were divided into two groups: non‐responder (High P2Y12 reaction units (PRU) ≥230) and responder (Low PRU <230). Both groups were compared with cardiovascular patients under other treatments. A total of 201 proteins were identified in the plasma. For the non‐responder group, 74 proteins were significantly down‐regulated, and 22 proteins were up‐regulated. Conversely, 55 proteins were significantly down‐regulated, whereas 28 proteins were up‐regulated in the responder group. Bioinformatic analysis showed that 8 of the regulated proteins were associated to the blood coagulation system pathway, and 5 proteins were associated with Intrinsic prothrombin activation pathway. Also, some of the significantly regulated proteins participate in two interaction networks associated with Acute coronary syndrome and Acute myocardial infarction. The proteomic analysis demonstrates differences in protein abundance regarding clopidogrel responses. These findings are expected to provide preliminary evidence on early expression of novel biomarkers in CH cardiovascular patients with resistance to clopidogrel.Support or Funding InformationThis study was supported by grant # 2U54 MD007600‐31 and Research Supplement to Promote Diversity in Health‐Related Research from NIMHD, NIH (CCRHD‐RCMI Program at UPR MSC).
Cardiovascular Effects of Three Distinct Anesthetic Approaches in Rats
Authors: Barboza Amanda Rosanna Alves , Silva Luiz Eduardo Virgílio , Salgado Helio Cesar , Jr Rubens Fazan 
Published: April 2020

It is well known that anesthesia affects hemodynamics and leads to marked changes in neurohumoral modulation of the cardiovascular system, affecting results obtained in research protocols conducted during anesthesia. We evaluated the effect of three distinct anesthetic agents on arterial pressure (AP), heart rate (HR), and their variability indexes before and during anesthesia in rats. Conscious freely moving Wistar rats, previously instrumented with catheters in the femoral artery, had their AP recorded during 30 min. Following they were anesthetized with ketamine/xylazine (KX: 50/10 mg/kg, ip, N=7), urethane (URE: 1 g/kg, ip, N=7) or inhalation of isoflurane (ISO: 3–5%, N=10) and the AP recording was maintained for the next 30 min. At the onset of anesthesia with KX, the animals showed a marked rise in AP (D 47±2 mmHg) that slowly returned to normal values within 30 min. URE did not affect AP, while ISO caused a pressure drop of 16±1 mmHg. Overall blood pressure variability, measured by the standard deviation of systolic pressure values, was reduced during anesthesia with KX (D ‐ 1.9±0.5 mmHg) or URE (D −2.3±0.3 mmHg) but was not affected by inhalation of ISO. Likewise, the power of systolic AP spectra, an index of sympathetic vascular modulation, was markedly decreased by anesthesia with KX or URE (D −6.6±1.3 and −4.7±0.6 mmHg2, respectively) but not with ISO. Bradycardia (D −64±10 bpm) and an increase in HR (D 85±12 bpm) were caused by anesthesia with KX and URE, respectively. Inhalation of ISO had no effect on HR. Overall HR variability, measured by the standard deviation of normal cardiac intervals (SDNN), was markedly reduced by all anesthetic agents studied (D −1.1 to −2.0 ms for the three agents used). Spectral analysis showed that low‐frequency power of pulse interval (PI) spectra was decreased during anesthesia with KX (D −10±1 nu) or URE (D −11±3 nu). At the same time, it was not affected by the inhalation of ISO. The high‐frequency power of PI spectra was found reduced during anesthesia with the tree agents used (D −7.7 to −3.1 ms2). Multiscale entropy, an index of complexity of HR variability, showed that anesthesia with KX or URE, but not with ISO, decreased HR complexity at lower scales (1–6). At higher scales (7–20) entropy was markedly decreased by the three anesthetic agents studied. Our results revealed that, despite its hemodynamical effects, anesthesia decreases cardiovascular modulation. However, the inhalation of ISO is the anesthetic approach that preserves the most the characteristics of AP and HR variability, suggesting that this is the anesthesia that has less effect on cardiac and vascular modulation.Support or Funding InformationSupported by FAPESP and CNPq