Miracle-dz/UniFAR-FTUs huggingface dataset:
Human concentrations of uric acid scavenges adaptive and maladaptive ROS in isolated rat hearts subjected to ischemic stress.

Uric acid is a purine degradation product but also an important antioxidant and ROS scavenger. Experimental settings that mimic myocardial ischemia-reperfusion have not included uric acid despite that it is always present in human extracellular fluid and plasma. We hypothesized that uric acid has an important role in myocardial ROS scavenging. Here, we tested the cardiac response to uric acid on infarct size following ischemia-reperfusion with and without exacerbated oxidative stress due to acute pressure overload and during preconditioning. We also examined mitochondrial respiration and ROS-induced mitochondrial permeability transition pore opening. Under exacerbated ROS stress induced by high pressure perfusion, uric acid lowered oxidative stress and reduced infarct size. In contrast, uric acid blocked cardioprotection induced by ischemic preconditioning. However, this effect was reversed by probenecid, an inhibitor of cellular uptake of uric acid. In accordance, in intact cardiomyocytes, extracellular uric acid reduced the susceptibility of mitochondria towards opening of the permeability transition pore, suggesting that uric acid may prevent ischemia-reperfusion injury due to scavenging of maladaptive ROS. Moreover, as uric acid also scavenges also adaptive ROS, this may interfere with preconditioning. Altogether, uric acid might be a confounder when translating preclinical experimental results into clinical treatment.
Completeness of obstetric referral letters/notes from subdistrict to district level in three rural districts in Greater Accra region of Ghana: an implementation research using mixed methods

Objective To assess the completeness of obstetric referral letters/notes at the district level of healthcare. Design An implementation research within three districts in Greater Accra region using mixed methods. During baseline and intervention phases, referral processes for all obstetric referrals from lower level facilities seen at the district hospitals were documented including indications for referrals, availability and completeness of referral notes/forms. An assessment of before and after intervention availability and completeness of referral forms was carried out. Focus group discussions, non-participant observations and in-depth interviews with health workers and pregnant women were conducted for qualitative data. Setting Three (3) districts in the Greater Accra region of Ghana. Participants Pregnant women referred from lower levels of care to and seen at the district hospital, health workers within the three districts and pregnant women attending antenatal clinic in the district and their family members or spouses. Intervention An enhanced interfacility referral communication system consisting of training, provision of communication tools for facilities, formation of hospital referral teams and strengthening feedback mechanisms. Outcome Completeness of obstetric referral letters/notes. Results Proportion of obstetric referrals with referral notes improved from 27.2% to 44.3% from the baseline to intervention period. Mean completeness (95% CI) of all forms was 71.3% (64.1% to 78.5%) for the study period, improving from 70.7% (60.4% to 80.9%) to 71.9% (61.1% to 82.7%) from baseline to intervention periods. Health workers reported they do not always provide referral notes and that most referral notes are not completely filled due to various reasons. Conclusions Most obstetric referrals did not have referral notes. The few notes provided were not completely filled. Interventions such as training of health workers, regular review of referral processes and use of electronic records can help improve both the provision of and completeness of the referral notes.
Lymphatic Cannulation for Lymph Sampling and Molecular Delivery

Key Points Lymph carries the “omic,” vesicular, and immune cell signature of the draining organs. Lymph analysis provides precise and “undiluted” biochemical and cellular information. A protocol for lymph collection from mouse and rat lymphatics is reported. Unlike the blood, the interstitial fluid and the deriving lymph are directly bathing the cellular layer of each organ. As such, composition analysis of the lymphatic fluid can provide more precise biochemical and cellular information on an organ's health and be a valuable resource for biomarker discovery. In this study, we describe a protocol for cannulation of mouse and rat lymphatic collectors that is suitable for the following: the “omic” sampling of pre- and postnodal lymph, collected from different anatomical districts; the phenotyping of immune cells circulating between parenchymal organs and draining lymph nodes; injection of known amounts of molecules for quantitative immunological studies of nodal trafficking and/or clearance; and monitoring an organ’s biochemical omic changes in pathological conditions. Our data indicate that probing the lymphatic fluid can provide an accurate snapshot of an organ’s physiology/pathology, making it an ideal target for liquid biopsy.
Within‐person variability in curiosity during daily life and associations with well‐being

Abstract Objective Curiosity promotes engagement in novel situations and the accruement of resources that promote well‐being. An open question is the extent to which curiosity lability, the degree to which curiosity fluctuates over short timescales, impacts well‐being. Method We use data from a 21‐day daily diary as well as trait measures in 167 participants (mean age = 25.37 years, SD = 7.34) to test (a) the importance of curiosity lability for depression, flourishing, and life satisfaction, (b) day‐to‐day associations among curiosity and happiness, depressed mood, anxiety, and physical activity, and (c) the role of day's mood as a mediator between physical activity and curiosity. Results We observe positive associations among curiosity lability and depression, as well as negative associations among curiosity lability and both life satisfaction and flourishing. Curiosity is higher on days of greater happiness and physical activity, and lower on days of greater depressed mood. We find evidence consistent with day's depressed mood and happiness being mediators between physical activity and curiosity. Conclusions Greater consistency in curiosity is associated with well‐being. We identify several potential sources of augmentation and blunting of curiosity in daily life and provide support for purported mechanisms linking physical activity to curiosity via mood.
Plasma Levels of Soluble PD-L1 Correlate With Tumor Regression in Patients With Lung and Gastric Cancer Treated With Immune Checkpoint Inhibitors

Background/Aim: Cancer immune therapy by immune checkpoint inhibitors (ICIs) is a promising therapeutic strategy for various cancer types. Among ICIs, anti-programmed cell death protein-1 (PD1) and anti-programmed death-ligand 1 (PD-L1) antibodies have shown a remarkable clinical benefit. The present study aimed to address the functional and clinical significance of serum levels of soluble PD-L1 (sPD-L1) in patients. Materials and Methods: A total of 21 patients, 11 with NSCLC, nine with gastric cancer and one with bladder cancer, who underwent anti-PD-1 therapy were evaluated for sPD-L1 concentration by ELISA analyses at diagnosis and after treatment. Results: Pretreatment levels of sPD-L1 in patients who received ICIs were not remarkably correlated with the overall survival of these patients (r=0.3394, p=0.1323). Reduction of plasma sPD-L1 level was significantly correlated with tumor regression in patients administered four cycles of treatment (p<0.05). Conclusion: sPD-L1 might be derived and secreted from tumors and might be useful to identify primary responders to ICIs at a relatively early treatment timepoint.
Risperidone Ameliorates Prefrontal Cortex Neural Atrophy and Oxidative/Nitrosative Stress in Brain and Peripheral Blood of Rats with Neonatal Ventral Hippocampus Lesion

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ. SIGNIFICANCE STATEMENT Prefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.
Keratinocyte Carcinoma and Risk for Another Type of Cancer: Assessment of a Dose-response Relationship

Background/Aim: Keratinocyte carcinoma (KC) is a marker of increased risk of other cancer types. To assess if this association exhibits a dose-response relationship, a case-control study was carried out. Patients and Methods: This was a clinic-based study of cases with KC plus another type of cancer matched by age, race (all Caucasian), sex and histologic type to controls with KC only (n=48 matched pairs). Results: Compared with the KC only group, those with KC plus another cancer had a mean number of lesions that were 43%, 35%, and 41% greater for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and total KC, respectively. The odds ratio (OR) of developing another type of cancer increased from 1.0 to 1.09 (95% confidence interval (CI)=0.23-5.13) to 2.12 (95%CI=0.50-9.08) according to whether the patient had zero, one, or ≥two BCC lesions; for SCC, the corresponding ORs were 1.0, 1.24 (95%CI=0.48-3.24), and 1.39 (95%CI=0.29-6.61). Conclusion: A dose-response relationship seems to exist between the number of skin lesions and the risk of another type of cancer, but the lack of statistical significance weakens this evidence.
A Target-Detecting Visual Neuron in the Dragonfly Locks on to Selectively Attended Targets

The visual world projects a complex and rapidly changing image onto the retina of many animal species. This presents computational challenges for those animals reliant on visual processing to provide an accurate representation of the world. One such challenge is parsing a visual scene for the most salient targets, such as the selection of prey amid a swarm. The ability to selectively prioritize processing of some stimuli over others is known as 'selective attention'. We recently identified a dragonfly visual neuron called 'Centrifugal Small Target Motion Detector 1′ (CSTMD1) that exhibits selective attention when presented with multiple, equally salient targets. Here we conducted in vivo, electrophysiological recordings from CSTMD1 in wild-caught male dragonflies (Hemicordulia tau), while presenting visual stimuli on an LCD monitor. To identify the target selected in any given trial, we uniquely modulated the intensity of the moving targets (frequency tagging). We found that the frequency information of the selected target is preserved in the neuronal response, while the distracter is completely ignored. We also show that the competitive system that underlies selection in this neuron can be biased by the presentation of a preceding target on the same trajectory, even when it is of lower contrast than an abrupt, novel distracter. With this improved method for identifying and biasing target selection in CSTMD1, the dragonfly provides an ideal animal model system to probe the neuronal mechanisms underlying selective attention. SIGNIFICANCE STATEMENT We present the first application of frequency tagging to intracellular neuronal recordings, demonstrating that the frequency component of a stimulus is encoded in the spiking response of an individual neuron. Using this technique as an identifier, we demonstrate that CSTMD1 'locks on' to a selected target and encodes the absolute strength of this target, even in the presence of abruptly appearing, high-contrast distracters. The underlying mechanism also permits the selection mechanism to switch between targets mid-trial, even among equivalent targets. Together, these results demonstrate greater complexity in this selective attention system than would be expected in a winner-takes-all network. These results are in contrast to typical findings in the primate and avian brain, but display intriguing resemblance to observations in human psychophysics.
Prospective Memory Predictions in Aging: Increased Overconfidence in Older Adults

ABSTRACT Introduction: This study investigated whether young and older adults can predict their future performance on an event-based prospective memory (PM) task. Methods: Metacognitive awareness was assessed by asking participants to give judgments-of-learning (JOLs) on an item-level for the prospective (remembering that something has to be done) and retrospective (remembering what to do) PM component. In addition, to explore possible age differences in the ability to adapt predictions to the difficulty of the task, encoding time and the relatedness between the prospective and the retrospective PM component were varied. Results: Results revealed that both age groups were sensitive to our task manipulations and adapted their predictions appropriately. Moreover, item-level JOLs indicated that for the retrospective component, young and older adults were equally accurate and slightly overconfident. For the prospective component, predictions were fairly accurate in young adults, while older adults were overconfident. Thus, results suggest that general overconfidence is increased in older adults and concerns both components of PM. Discussion: Findings regarding the conceptual differences between the prospective and retrospective components of a PM task, as well as the link between aging and metamemory in PM are discussed.
MUC1-C Activates The NuRD Complex To Drive Dedifferentiation of Triple-Negative Breast Cancer Cells.

The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4 and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic MUC1-C protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C->MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and post-transcriptionally induced CHD4 expression in basal- but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3 and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells.
Effect of Implant Neck Design on Primary and Secondary Implant Stability in the Posterior Maxilla: A prospective randomized controlled study.

OBJECTIVE To compare the early changes in implant stability of Implants with different neck design during the first 3 months of healing in the posterior maxilla. MATERIALS AND METHODS Patients were randomized to receive triangular neck implant (test), or round neck implant (control). Resonance frequency analysis (ISQ) measurements were obtained at surgery and at 2, 4, 7, 14, 21, 28, 45, 60 and 90 days following implant placement. Non-parametric statistic was used for data analysis. RESULTS 32 patients were included (17 test, 15 controls). Initial ISQ values of the test implants were high (mean 68.4, SD=8.4), and increased over time (mean 74.4, SD=6.0). Control implants presented a statistically significant higher initial ISQ value at implant placement (mean 76.9, SD=8.7) which was maintained over the healing period (mean 77.6, SD=3.6) with no significant changes between time intervals. After 6 weeks of healing, both implants displayed comparable ISQ values with no differences between the groups. All implants exhibited a decrease in stability on day 2 and 21 post-placement. All round-neck implants used and 82% of the triangular-neck implants showed initial ISQ values above the suggested threshold for immediate loading (>60). CONCLUSIONS Implant neck design plays a role in implant primary stability in the posterior maxilla. Both implant show high primary stability, with significantly higher values for the round neck. However, these differences disappeared after 6 weeks of healing. While primary implant stability is partially governed by implant neck design, the role of this result is negligible for the achievement of secondary stability.
Periodontal regeneration using bone morphogenetic protein 2 incorporated biomimetic calcium phosphate in conjunction with barrier membrane: A pre‐clinical study in dogs

Abstract Aim To evaluate the effect of bone morphogenetic protein 2 (BMP‐2) incorporated biomimetic calcium phosphate (BMP‐2/BioCaP) in conjunction with barrier membrane on periodontal regeneration in chronic periodontitis experimental model. Material and Methods Chronic periodontitis experimental model with critical‐sized supra‐alveolar defects was created in 15 dogs’ mandibles. After the initial periodontal therapy, the defects were randomly assigned to the following groups: (a) control; (b) barrier membrane; (c) deproteinized bovine bone mineral + barrier membrane; (d) BioCaP + barrier membrane and (e) BMP‐2/BioCaP + barrier membrane (6 quadrants with 18 teeth per group). Eight weeks later, clinical examinations, micro‐CT, and histomorphometric analyses were performed. Results Clinical examinations, including plaque index, bleeding index, and probing depth, were similar for all groups. In contrast, the clinical attachment loss was significantly lower in defects grafted with BMP‐2/BioCaP and barrier membrane. The micro‐CT results showed that the height of mineralized tissue in defects grafted with BMP‐2/BioCaP and barrier membrane was significantly higher. For histometric analysis, the defects grafted with BMP‐2/BioCaP and barrier membrane exhibited significantly more connective tissue height, new cementum height, new bone height and area, as well as less down‐growth of junctional epithelium. Conclusion BMP‐2/BioCaP could be a promising bone substitute for periodontal regeneration.
Peripheral Blood Stem Cell Therapy Does Not Improve Outcomes of Femoral Head Osteonecrosis With Cap‐Shaped Separated Cartilage Defect

A combination treatment with porous tantalum rod implantation and intra‐arterial infusion of peripheral blood stem cells (PBSCs) provides a promise for treating early and intermediate stages of osteonecrosis of the femoral head (ONFH). However, its clinical indications and application restrictions remain unclear. This study aims to determine the clinical, histological, and radiological outcomes of a combination treatment using mechanical support and a targeted intra‐arterial infusion of PBSCs for painful ONFH with a cap‐shaped separation (CSS) cartilage defect. Compared with the standard pain management (control group), this combination treatment did not improve the Harris Hip Score (HHS) at 36 months. Micro‐CT and histologic analyses showed severe focal destruction in all CSS‐ONFH femoral heads in both the combination and control groups. Femoral heads showed a higher percentage of bone lesions in the combination treatment group than in the control group. There was no significant difference in osteoclast number in the subchondral bone areas between the two groups. A high level of expression of inflammatory cytokines, including tumor necrosis factor‐α and interleukin‐1β, was detected in blood vessels around the subchondral bone in both groups. The RANKL/OPG (receptor activator of the nuclear factor‐kB ligand/osteoprotegerin) ratio was also similar between the control and combination treatment groups. Our results indicate that this combination treatment is not an effective method for the treatment of patients with painful CSS‐ONFH. Moreover, this combination treatment did not inhibit inflammatory osteoclastogenesis in patients with more advanced disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:269‐276, 2020
Human cardiac myosin–binding protein C restricts actin structural dynamics in a cooperative and phosphorylation-sensitive manner

Cardiac myosin–binding protein C (cMyBP-C) is a thick filament-associated protein that influences actin-myosin interactions. cMyBP-C alters myofilament structure and contractile properties in a protein kinase A (PKA) phosphorylation-dependent manner. To determine the effects of cMyBP-C and its phosphorylation on the microsecond rotational dynamics of actin filaments, we attached a phosphorescent probe to F-actin at Cys-374 and performed transient phosphorescence anisotropy (TPA) experiments. Binding of cMyBP-C N-terminal domains (C0–C2) to labeled F-actin reduced rotational flexibility by 20–25°, indicated by increased final anisotropy of the TPA decay. The effects of C0–C2 on actin TPA were highly cooperative (n = ∼8), suggesting that the cMyBP-C N terminus impacts the rotational dynamics of actin spanning seven monomers (i.e. the length of tropomyosin). PKA-mediated phosphorylation of C0–C2 eliminated the cooperative effects on actin flexibility and modestly increased actin rotational rates. Effects of Ser to Asp phosphomimetic substitutions in the M-domain of C0–C2 on actin dynamics only partially recapitulated the phosphorylation effects. C0–C1 (lacking M-domain/C2) similarly exhibited reduced cooperativity, but not as reduced as by phosphorylated C0–C2. These results suggest an important regulatory role of the M-domain in cMyBP-C effects on actin structural dynamics. In contrast, phosphomimetic substitution of the glycogen synthase kinase (GSK3β) site in the Pro/Ala-rich linker of C0–C2 did not significantly affect the TPA results. We conclude that cMyBP-C binding and PKA-mediated phosphorylation can modulate actin dynamics. We propose that these N-terminal cMyBP-C–induced changes in actin dynamics help explain the functional effects of cMyBP-C phosphorylation on actin-myosin interactions.