Miracle-dz/UniFAR-FTUs huggingface dataset:
Neural mechanisms of reinforcement learning under mortality threat

ABSTRACT Reinforcement learning – to adjust behaviors in response to feedback regarding reward and punishment – is pivotal to our survival. The present work investigated whether and how reinforcement learning is affected by thoughts of mortality that endanger one’s survival. We recorded electroencephalographic while adults performed a probabilistic learning task that required a forced-choice between two visual patterns for monetary reward for different beneficiaries (i.e., self, stranger, or no one) followed by reward or no-reward feedback. We found that verbal reminders of mortality (vs. negative emotion) enlarged an early positive component (P1) at the occipital electrodes but decreased a late positive potential (LPP) at the frontocentral electrodes in response to learning stimuli. While no-reward feedback relative to reward feedback stimuli elicited a feedback-related negativity (FRN) and increased non-phase locked theta band (4–8 Hz) activity at the frontocentral electrodes during reward learning for all beneficiaries, verbal reminders of mortality (vs. negative emotion) significantly reduced the FRN amplitude but failed to modulate the theta band activity. These results suggest that mortality salience enhances early attentional processing but dampens late cognitive evaluation of the learning stimuli during reinforcement learning. Moreover, mortality salience decreases the neural sensitivity to feedback signaling the absence of monetary reward.
Development of a Physiologically Relevant Online Chemical Assay to Quantify Aerosol Oxidative Potential.

Large-scale epidemiological studies have shown a close correlation between adverse human health effects and exposure to ambient particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5). The oxidative potential (OP) of ambient PM has been implicated in inducing toxic effects associated with PM exposure. In particular, reactive oxygen species (ROS), either bound to PM or generated by particulate components in vivo, substantially contribute to the OP and therefore toxicity of PM by lowering anti-oxidant concentrations in the lung, which can subsequently lead to oxidative stress, inflammation and disease. Traditional methods for measuring aerosol OP are labor intensive and have poor time resolution, with significant delays between aerosol collection and ROS analysis. These methods may underestimate ROS concentrations in PM because of the potentially short lifetime of some ROS species; therefore, continuous online, highly time-resolved measurement of ROS components in PM is highly advantageous. In this work, we develop a novel online method for measuring aerosol OP based on ascorbic acid chemistry, an anti-oxidant prevalent in the lung, thus combining the advantages of continuous online measurement with a physiologically relevant assay. The method limit of detection is estimated for a range of atmospherically-important chemical components such as Cu(II) 0.22 ± 0.03 µg m-3, Fe(II) 47.8 ± 5.5 µg m-3, Fe(III) 0.63 ± 0.05 µg m-3 and secondary organic aerosol 41.2 ± 6.9 μg m-3, demonstrating that even at this early stage of development, the online method is capable of measuring the OP of PM in polluted urban environments and smog chamber studies.
Electrochemical generation of microbubbles by carbon nanotube interdigital electrodes to increase the permeability and material uptakes of cancer cells

Abstract Artificial cavitation as a prerequisite of sonoporation, plays an important role on the ultrasound (US) assisted drug delivery systems. In this study, we have proposed a new method of microbubble (MB) generation by local electrolysis of the medium. An integrated interdigital array of three-electrode system was designed and patterned on a nickel-coated quartz substrate and then, a short DC electrical pulse was applied that consequently resulted in distributed generation of microbubbles at the periphery of the electrodes. Growth of the carbon nanotube (CNT) nanostructures on the surface of the electrodes approximately increased the number of generated microbubbles up to 7-fold and decreased their average size from ∼20 µm for bare to ∼7 µm for CNT electrodes. After optimizing the three-electrode system, biocompatibility assays of the CNT electrodes stimulated by DC electrical micropulses were conducted. Finally, the effect of the proposed method on the sonoporation efficiency and drug uptake of breast cells were assessed using cell cycle and Annexin V/PI flow cytometry analysis. These results show the potential of electrochemical generation of MBs by CNT electrodes as an easy, available and promising technique for artificial cavitation and ultrasound assisted drug delivery.
Targeting epigenetic modifications as a potential therapeutic option for diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of visual impairment in adults of working age (20–65 years) in developed countries. The metabolic memory phenomena (persistent effect of a glycemic insult even after retrieved) associated with it has increased the risk of developing the complication even after the termination of the glycemic insult. Hence, the need for finding early diagnosis and treatment options has been of great concern. Epigenetic modifications which generally occur during the beginning stages of the disease are responsible for the metabolic memory effect. Therefore, the therapy based on the reversal of the associated epigenetic mechanism can bring new insight in the area of early diagnosis and treatment mechanism. This review discusses the diabetic retinopathy, its pathogenesis, current treatment options, need of finding novel treatment options, and different epigenetic alterations associated with DR. However, the main focus is emphasized on various epigenetic modifications particularly DNA methylation which are responsible for the initiation and progression of diabetic retinopathy and the use of different epigenetic inhibitors as a novel therapeutic option for DR.
Cost-effectiveness of telerehabilitation versus traditional care after total hip replacement: A trial-based economic evaluation

Introduction: Physical rehabilitation for total hip replacement patients following hospital discharge is beneficial; however, accessing rehabilitation is often challenging. Telerehabilitation helps negate access issues and is efficacious in total knee and hip replacement patients. This study aims to compare the cost-effectiveness of a telerehabilitation programme delivered remotely into patients’ homes versus traditional care for total hip replacement patients following hospital discharge. Methods: A cost-effectiveness (cost-utility) analysis was conducted from the perspective of a health service alongside a two-arm randomised controlled trial comparing telerehabilitation (n=35) with in-person care (n=35) following hospital discharge after total hip replacement. The primary analysis used an Incremental Cost-Effectiveness Ratio to compare the cost per Quality Adjusted Life Year (QALY) accrued in the telerehabilitation group versus in-person control using costs and effects data from the randomised trial. A secondary analysis was conducted whereby the time accrued by patients attending rehabilitation sessions (including travel time) was considered the “cost” (i.e. a time burden), rather than cost from the health service perspective. Results: Estimated mean differences in healthcare costs and QALYs gained were detected but were not significant. The estimated mean (95%CI) difference in cost of telerehabilitation versus in-person was –$28.90 (–$96.37 to $40.45), favouring the telerehabilitation group. The estimated mean (95%CI) difference in QALYs gained from telerehabilitation versus in-person was –0.0025 (–0.0227 to 0.0217). The estimated mean (95%CI) difference in time burden favoured less time burden for the telerehabilitation group (–4.21 (–4.69 to –3.74) hours). Discussion: Telerehabilitation in the total hip replacement population incurred similar costs and yielded similar effects to traditional in-person care. Telerehabilitation significantly reduced the time burden for patients and carers. These findings are valuable for healthcare providers seeking to implement accessible patient-centred rehabilitation services.
The Application of Statins in the Regeneration of Bone Defects. Systematic Review and Meta-Analysis

This systematic review aims to analyze the effect of the local application of statins in the regeneration of non-periodontal bone defects. A systematic study was conducted with the Pubmed/Medline, Embase, Cochrane Library and Scielo databases for in vivo animal studies published up to and including February 2019. Fifteen articles were included in the analysis. The local application of the drug increased the percentage of new bone formation, bone density, bone healing, bone morphogenetic protein 2, vascular endothelial growth factor, progenitor endothelial cells and osteocalcin. Meta-analyses showed a statistically significant increase in the percentage of new bone formation when animals were treated with local statins, in contrast to the no introduction of filling material or the introduction of polylactic acid, both in an early (4–6 weeks) and in a late period (12 weeks) (mean difference 39.5%, 95% confidence interval: 22.2–56.9, p <0.001; and mean difference 43.3%, 95% confidence interval: 33.6–52.9, p < 0.001, respectively). Basing on the animal model, the local application of statins promotes the healing of critical bone size defects due to its apparent osteogenic and angiogenic effects. However, given the few studies and their heterogenicity, the results should be taken cautiously, and further pilot studies are necessary, with radiological and histological evaluations to translate these results to humans and establish statins’ effect.
Zinc abrogates anticancer drug tamoxifen-induced hepatotoxicity by suppressing redox imbalance, NO/iNOS/NF-ĸB signaling, and caspase-3-dependent apoptosis in female rats

Abstract Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and Drug Administration in 1977. However, TAM therapy is accompanied with hepatotoxicity – a source of worry to clinicians. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM hepatotoxicity. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced hepatotoxicity in female Wistar rats. Rats were subjected to oral pretreatment of Zn (100 mg/kg body weight (b.w.)/day) for 14 days against hepatic toxicity induced by single intraperitoneal administration of TAM (50 mg/kg b.w.) on day 13. TAM markedly elevated serum liver enzymes, whereas total protein and albumin considerably reduced. TAM caused prominent depletion of hepatic-reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity. Also, TAM significantly increased malondialdehyde (MDA) level. Further, it raised liver levels of tumor necrosis factor-α (TNF-α), interleukin-1β, (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by the liver histopathological alterations. The mechanistic inflammatory expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-ĸB), and expression of caspase-3 protein prominently increased. Zinc supplementation significantly modulated serum liver function markers, antioxidant enzymes, and GSH and MDA levels. Zinc downregulated the expression of cytokines, NO, iNOS, NF-ĸB and caspase-3, and ameliorated histopathological changes. Zinc protects against TAM-induced hepatotoxicity; it may serve as an adjuvant supplement for female patients undergoing TAM chemotherapy.
Immunologic Evaluation of Pediatric Chronic and Recurrent Acute Rhinosinusitis

Background Although pediatric rhinosinusitis is a commonly encountered clinical entity, the diagnostic approach and treatment algorithm are constantly evolving. In addition to anatomic and allergic etiologies, immunologic deficiencies have been implicated in the pathogenesis of rhinosinusitis; however, the prevalence of immunologic disease in pediatric rhinosinusitis is poorly defined. Objective To inform the approach to the evaluation of pediatric patients with rhinosinusitis, this retrospective pilot study examined the prevalence of abnormal results detected on immunologic testing in pediatric patients with chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis (RARS). Methods Patients between 2008 and 2018 were identified using International Classification of Diseases 9/10 codes. Imaging, endoscopy findings, and clinical criteria were used to diagnose CRS and RARS (n = 27). We reviewed available results, including quantitative immunoglobulins (Igs), thyroid evaluation, complete blood count, and titers to Streptococcus, Haemophilus influenzae type B (HiB), Diphtheria, and Tetanus. Statistical analyses were performed with the Mann–Whitney U test and Fisher’s exact test. Results Our initial search yielded 140 patients, of which 27 met diagnostic criteria for CRS (17) or RARS (10). Eight patients (29.6%) underwent adenoidectomy and 5 (18.5%) underwent endoscopic sinus surgery. The most common Ig deficiencies were IgM, 13.0%, and IgA, 11.1%. Four (23.5%) of the 17 patients had significantly elevated IgE levels, indicating a possible allergic etiology. Within this cohort, there was an increased incidence of insufficient protective titers to polysaccharide vaccines. HiB titers were not protective in 35% of our cohort. Insufficient pneumococcal protection was more common in patients >10 years, while deficient IgM was more common in those <10 years. Conclusion High-yield testing in pediatric rhinosinusitis should include titers to polysaccharide antigens, specifically Streptococcus pneumoniae and H. influenzae. Low-yield tests that may be deferred during initial testing include thyroid studies and Tetanus and Diphtheria antibodies. Prospective, high-volume studies are required to further elucidate the role of immunologic testing in this population.
Analysis of Hepatitis B Virus Reactivation After Radiotherapy in Patients With Hepatocellular Carcinoma Using the Lyman NTCP Model

Purpose: To analyze the correlation of hepatitis B virus reactivation with patient-related and treatment-related dose–volume factors and to describe the feasibility of hepatitis B virus reactivation analyzed by a normal tissue complication probability model for patients with hepatocellular carcinoma treated with radiotherapy. Materials and Methods: Ninety patients with hepatitis B virus-related hepatocellular carcinoma treated with radiotherapy were enrolled in this retrospective study and were followed from June 2009 to December 2015. Of the 90 patients, 78 had received conventional fractionation radiotherapy to a mean dose of 39.6 to 50.4 Gy and 12 patients were scheduled to receive hypofractionation. The physical doses were converted into 2 Gy equivalents for analysis. The parameters, TD50 (1), n, and m, of the Lyman-Kutcher-Burman normal tissue complication probability model were derived using maximum likelihood estimation. Bootstrap and leave-one-out were employed to against model overfitting and improve the model stability. Results: Radiation-induced liver diseases were 17.8%, hepatitis B virus reactivation was 22.2%, and hepatitis B virus reactivation-induced hepatitis was 21.1%, respectively. In multivariate analysis, the V 5Gy was associated with hepatitis B virus reactivation; TD50 (1), m, and n were 32.3, 0.55, and 0.71 Gy, respectively, for hepatitis B virus reactivation. Bootstrap and leave-one-out results showed that the hepatitis B virus parameter fits were extremely robust. Conclusion: A Lyman-Kutcher-Burman normal tissue complication probability model has been established to predict hepatitis B virus reactivation for patients with hepatocellular carcinoma who received radiotherapy.
Prediction of Disease Comorbidity Using HeteSim Scores based on Multiple Heterogeneous Networks.

Accumulating experimental studies have indicated that disease comorbidity causes additional pain to patients and leads to the failure of standard treatments compared to patients who have a single disease. Therefore, the accurate prediction of potential comorbidity is essential to design more efficient treatment strategies. However, only a few disease comorbidities have been discovered in the clinic. In this work, we propose PCHS, an effective computational method for predicting comorbidity using HeteSim scores. PCHS utilizes the HeteSim measure to calculate the relatedness score for different disease pairs in the global heterogeneous network, which integrates six networks based on biological information, including disease-disease associations, drug-drug interactions, protein-protein interactions and associations among them. We built the prediction model using the support vector machine (SVM) on HeteSim scores. The results showed that PCHS performed significantly better than previous state-of-the-art approaches and achieved an AUC score of 0.90 in 10-fold cross-validation. Furthermore, some of our predictions have been verified in literatures, indicating the effectiveness of our method.
Patient‐centred care in haemophilia: Patient perspectives on visualization and participation in decision‐making

The British Columbia Adult Haemophilia Team recently adopted a patient‐centred care approach. The team presented visual information on an individual's pharmacokinetic profile and bleed history and encouraged patients to participate in treatment decisions. This qualitative study explored how this approach changed patients’ understanding of haemophilia and how it facilitated them to make treatment decisions.
The C4 Ppc promoters of many C4 grass species share a common regulatory mechanism for gene expression in the mesophyll cell.

C4 photosynthetic plants have evolved from C3 ancestors and are characterized by differential expression of several hundred genes. Strict compartmentalization of key C4 enzymes either to mesophyll (M) or bundle sheath (BS) cells is considered a crucial step towards the evolution of C4 photosynthesis. In this study we demonstrate that the 5´-flanking sequences of the C4 type phosphoenolpyruvate carboxylase (Ppc) gene from three C4 grass species could drive M cell-specific expression of a reporter gene in rice. In addition to that, we identified around 450 bp (upstream of their transcription start site) of the analyzed C4 Ppc promoters contain all the essential regulatory elements for driving M cell-specific expression in rice leaves. Importantly, four motifs of conserved nucleotide sequences (CNS)s were also determined, which are essential for the activity of the promoter. A putative interaction between the CNSs and an unknown upstream element(s) is required for driving M cell-specific expression. This work identifies the evolutionary conservation of C4 Ppc regulatory mechanisms of multiple closely related C4 grass species.
Posterior Hippocampal Spindle Ripples Co-occur with Neocortical Theta Bursts and Downstates-Upstates, and Phase-Lock with Parietal Spindles during NREM Sleep in Humans

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ∼350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ∼5 s on average, whereas ripples on successive SSR peaks are separated by only ∼80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex. SIGNIFICANCE STATEMENT Rodent hippocampal neurons replay waking events during sharpwave ripples (SWRs) in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces SWRs, but spindle ripples predominate in posterior. Whereas SWRs typically occur as cortex emerges from inactivity, spindle ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle ripples can recur within a second, whereas SWRs are separated by ∼5 s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindle ripples may support a related function in humans.
A Theranostic Nanoplatform with Hydrogen Sulfide-Activatable NIR Responsiveness for Imaging-Guided On-Demand Drug Release.

NIR light-responsive nanoplatforms hold great promise for on-demand drug release in precision cancer medicine. However, currently available systems utilize "always-on" photothermal transducers that lack target specificity, thus inaccurately differentiating tumors from normal tissues. Here, we develop a theranostic nanoplatform endowing H2S-mediated in situ production of NIR photothermal agents for imaging-guided and photocontrolled drug release with targeting ability for H2S-rich cancers. This nanoplatform shows H2S-activatable NIR-II emission and NIR light-controllable release of a drug Camptothecin-11. By administrating HCT116 tumor-bearing mice, we find that the tumor is greatly suppressed with minimal side effects, which arises from the cancer-specific and NIR light-activated synergistic therapy. This theranostic nanoplatform thus sheds light on precision medicine with NIR-II imaging guidance.
A new palliative treatment for blastic plasmacytoid dendritic cell neoplasm: a case report and review of the literature

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy that derives from plasmacytoid dendritic cells. The cancer is characterized by aggressive development and dismal prognosis, and due to limited prospective study, there is currently no established standard treatment. In this study, the case of a 77-year old female patient with BPDCN, who presented with a cutaneous lesion on the right of her face, is described. The lesion developed into a serious ulcer due to rapid disease progress, thus, a surgical excision was performed. As the patient refused to receive radiotherapy or haematopoietic stem cell transplantation following surgery, a new palliative combination chemotherapy was administered, comprising gemcitabine, nedaplatin and bleomycin. The therapy gave satisfactory results in terms of short-term treatment response and was well-tolerated. Published literature regarding BPDCN is also reviewed.