Miracle-dz/UniFAR-FTUs huggingface dataset:
The effect of low-frequency equalisation on preference and sensorimotor synchronisation in music

Equalisation, a signal processing technique commonly used to shape the sound of music, is defined as the adjustment of the energy in specific frequency components of a signal. In this work, we investigate the effects of equalisation on preference and sensorimotor synchronisation in music. A total of 21 participants engaged in a goal-directed upper body movements in synchrony with stimuli equalised in three low-frequency sub-bands (0–50, 50–100, and 100–200 Hz). To quantify the effect of equalisation, music features including spectral flux, pulse clarity, and beat confidence were extracted from seven differently equalised versions of music tracks—one original and six manipulated versions for each music track. These music tracks were then used in a movement synchronisation task. Bayesian mixed-effects models revealed different synchronisation behaviours in response to the three sub-bands considered. Boosting energy in the 100–200 Hz sub-band reduced synchronisation performance irrespective of the sub-band energy of the original version. An energy boost in the 0–50 Hz band resulted in increased synchronisation performance only when the sub-band energy of the original version was high. An energy boost in the 50–100 Hz band increased synchronisation performance only when the sub-band energy of the original version was low. Boosting the energy in any of the three sub-bands increased preference regardless of the energy of the original version. Our results provide empirical support for the importance of low-frequency information for sensorimotor synchronisation and suggest that the effects of equalisation on preference and synchronisation are largely independent of one another.
Metabolomics of Dietary Acid Load and Incident Chronic Kidney Disease.

OBJECTIVE Blood biomarkers of dietary intake are more objective than self-reported dietary intake. Metabolites associated with dietary acid load were previously identified in 2 chronic kidney disease (CKD) populations. We aimed to extend these findings to a general population, replicating their association with dietary acid load, and investigating whether the individual biomarkers were prospectively associated with incident CKD. METHODS Among 15,792 participants in the Atherosclerosis Risk in Communities cohort followed up from 1987 to 1989 (baseline) to 2019, we evaluated 3,844 black and white men and women with dietary and metabolomic data in cross-sectional and prospective analyses. We hypothesized that a higher dietary acid load (using equations for potential renal acid load and net endogenous acid production) was associated with lower serum levels of 12 previously identified metabolites: indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine, threonate, oxalate, chiro-inositol, methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate. In addition, we hypothesized that lower serum levels of these 12 metabolites were associated with higher risk of incident CKD. RESULTS Eleven out of 12 metabolites were significantly inversely associated with dietary acid load, after adjusting for demographics, socioeconomic status, health behaviors, health status, and estimated glomerular filtration rate: indolepropionylglycine, indolepropionate, N-methylproline, threonate, oxalate, chiro-inositol, catechol sulfate, hippurate, methyl glucopyranoside (α + β), stachydrine, and tartronate. N-methylproline was inversely associated with incident CKD (hazard ratio: 0.95, 95% confidence interval: 0.91, 0.99, P = .01). The metabolomic biomarkers of dietary acid load significantly improved prediction of elevated dietary acid load estimated using dietary data, beyond covariates (difference in C statistics: 0.021-0.077, P ≤ 1.08 × 10-3). CONCLUSION Inverse associations between candidate biomarkers of dietary acid load were replicated in a general population. N-methylproline, representative of citrus fruit consumption, is a promising marker of dietary acid load and could represent an important pathway between dietary acid load and CKD.
Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.
HEDOS—a computational tool to assess radiation dose to circulating blood cells during external beam radiotherapy based on whole-body blood flow simulations

We have developed a time-dependent computational framework, hematological dose (HEDOS), to estimate dose to circulating blood cells from radiation therapy treatment fields for any treatment site. Two independent dynamic models were implemented in HEDOS: one describing the spatiotemporal distribution of blood particles (BPs) in organs and the second describing the time-dependent radiation field delivery. A whole-body blood flow network based on blood volumes and flow rates from ICRP Publication 89 was simulated to produce the spatiotemporal distribution of BPs in organs across the entire body using a discrete-time Markov process. Constant or time-varying transition probabilities were applied and their impact on transition time was investigated. The impact of treatment time and anatomical site were investigated using imaging data and dose distributions from a liver cancer and a brain cancer patient. The simulations revealed different dose levels to the circulating blood for brain irradiation compared to liver irradiation even for similar field sizes due to the different blood flow properties of the two organs. The volume of blood receiving any dose (V >0 Gy) after a single radiation fraction increases from 1.2% for a 1 s delivery time to 20.9% for 120 s delivery time for the brain cancer treatment, and from 10% (1 s) to 48.7% (120 s) for a liver cancer treatment. Other measures of the low-dose bath to the circulating blood such as the dose to small volumes of blood (D 2%) decreases with longer delivery time. Furthermore, we demonstrate that the blood dose-volume histogram is highly sensitive to changes in the treatment time, indicating that dynamic modeling of blood flow and radiation fields is necessary to evaluate dose to circulating blood cells for the assessment of radiation-induced lymphopenia. HEDOS is publicly available and allows for the estimation of patient-specific dose to circulating blood cells based on organ DVHs, thus enabling the study of the impact of different treatment plans, dose rates, and fractionation schemes.
Direct oral anticoagulants versus warfarin in people living with human immunodeficiency virus

Human immunodeficiency virus (HIV) is associated with increased rates of cardiovascular disease and vascular events, and people living with HIV (PLWH) may often have indications for therapeutic anticoagulation. However, the ideal anticoagulant in PLWH remains unknown. This retrospective cohort evaluated the tolerability and effectiveness of oral anticoagulants in PLWH. The primary outcome was tolerability, defined as a composite of bleeding and/or discontinuation rates. The secondary outcomes included recurrent thromboembolism, bleeding, and discontinuations, independently. There were 92 patients included for analysis, 48 in the direct oral anticoagulant (DOAC) arm and 44 in the warfarin arm. There were 35 (38%) PLWH that did not tolerate oral anticoagulation therapy in the total cohort. Among these, 19 received a DOAC and 16 received warfarin. There were 16 (17%) PLWH that experienced a bleeding event: six in the DOAC arm and 10 in the warfarin arm. There were 15 (16%) PLWH that experienced recurrent thromboembolism, with similar rates between DOAC versus warfarin (10, 21% vs 5, 11%, respectively; p = 0.11). The most commonly prescribed HIV regimens were protease inhibitor and integrase inhibitor-based regimens. Overall, anticoagulation-related outcomes with either a DOAC or warfarin were poor in our cohort of PLWH, with high rates of bleeding, discontinuations, and recurrent thromboembolism. Further studies are necessary to validate and assess reasons for poor tolerability.
Estimating the net value of treating hepatitis C virus using sofosbuvir-velpatasvir in India

Recently developed direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV) have been groundbreaking for their high efficacy across disease genotypes and lack of severe side effects. This study uses a cost-of-illness (COI) approach to estimate the net value conferred by this class of drugs using the cost and efficacy of one of these novel drug combinations, sofosbuvir and velpatasvir (SOF/VEL), recently licensed for generic manufacture in India. This study considers COI of lifetime earnings lost by patients and potential secondarily infected individuals due to disability and premature death from HCV infection. Expected net benefits of treatment are substantial for non-cirrhotic (NC) and compensated cirrhotic (CC) patients (ranging from 5,98,003 INR for NC women to 1,05,25,504 INR for CC men). Increased earnings are not sufficient to fully offset cost of treatment for decompensated cirrhotic individuals but treatment may still be justified on the basis of the intrinsic value of health improvements and other treatment benefits.
MOCVD Growth of InAlAsSb Layer for High-Breakdown Voltage HEMT Applications

This paper studies the decomposition characteristic of group-III sources during InAlAsSb growth on InP substrates by metalorganic chemical vapor deposition (MOCVD) using trimethylindium (TMI), trimethylaluminum (TMA), trimethylantimony (TMSb) and arsine (AsH 3 ). A composition analysis of InAlAsSb layers shows that the group-III compositions in the InAlAsSb layer change remarkably when the flow rate of the group-V source is varied. To clarify the reason for this phenomenon, the growth rates of InAsSb and AlAsSb component are examined. Their changes indicate that TMSb suppresses the decomposition of TMA while AsH 3 enhances it. Moreover, the HEMT structure with InP/InAlAsSb Schottky barrier layer, whose InP layer acts as a recess-etch-stop layer, is fabricated for the first time. The I-V characteristics of a fabricated Schottky barrier diode indicate that the reverse leakage current of InP/InAlAsSb is about one order of magnitude smaller than that of commonly used InP/InAlAs.
RNA‐binding protein ELAVL2 plays post‐transcriptional roles in the regulation of spermatogonia proliferation and apoptosis

RNA‐binding proteins (RBPs) play essential post‐transcriptional roles in regulating spermatogonial stem cells (SSCs) maintenance and differentiation. We identified a conserved and SSCs‐enriched RBP ELAVL2 from our single‐cell sequencing data, but its function and mechanism in SSCs were unclear.
A scoping review of current non-pharmacological treatment modalities for phantom limb pain in limb amputees

Abstract Purpose Phantom limb pain (PLP) is a chronic neuropathic pain condition of a missing limb following amputation. Pain management is multi-modal, including various non-pharmacological therapies. The purpose of this scoping review was to investigate the evidence surrounding current non-pharmacological treatment modalities for PLP and provide insight into their clinical feasibility. Method A systematic search was conducted using four databases (Medline, Embase, PsychInfo, and CINAHL) following the PRISMA-ScR method. Results from papers meeting the inclusion criteria were charted to summarize findings, demographics, and use of neuroimaging. Results A total of 3387 papers were identified, and full texts of 142 eligible papers were assessed. Eleven treatment modalities for PLP were identified with varying levels of evidence. Overall, there were 25 RCTs, 58 case reports, and 59 a combination of pilot, quasi-experimental, observational, and other study designs. Conclusions Currently, the evidence surrounding most treatment modalities is limited and only a fraction of studies are supported by strong evidence. The findings of this review demonstrated a clear need to conduct more rigorous research with diverse study designs to better understand which modalities provide the most benefit and to incorporate neuroimaging to better determine the neural correlates of PLP and mechanisms of various treatments. Implications for Rehabilitation Phantom limb pain (PLP) is a prevalent and debilitating condition following amputation and health care professionals should incorporate an evidence-based pain management protocol into their rehabilitation program. There exist a number of different non-pharmacological therapies to address PLP, however the scientific rigor and levels of evidence vary across modalities. Prescription of interventions for PLP should consider individual patient differences, accessibility to the patient, and quite possibly, a multi-modal approach, particularly for those who also experience residual limb pain. Imagery-based therapies provide the highest level of current evidence based on robust and large randomized control trials, are readily accessible, and are thus most recommended for relief of PLP.
Yes-activated protein promotes primary resistance of BRAF V600E mutant metastatic colorectal cancer cells to mitogen-activated protein kinase pathway inhibitors.

Background Most colorectal cancer (CRC) patients with the BRAF V600E mutation display resistance to chemotherapy and targeted medicinal treatments. Thus, exploring new drugs and drug resistance mechanisms for the BRAF V600E mutation has become an urgent clinical priority. Methods MTS experiment, cell cloning experiment, cell scratching experiment, Transwell experiment, chromatin immunoprecipitation (ChIP), quantitative polymerase chain reaction (qPCR) and flow cytometry are used. Detect the transcription and protein expression of YAP in colorectal cancer cell lines, establish a transient cell line with YAP gene overexpression and knockdown, and detect the effect of YAP gene expression on the biological functions of colorectal cancer cells RKO and HT-29. And further study the mechanism of YAP regulating the response of RAF and MEK targeted therapy. Results In this study, for the first time, we verified that the expression of transcription factor yes-associated protein (YAP) was upregulated in BRAF V600E mutant CRC cells. After knocking down YAP, we observed a reduction in the growth rate, proliferation, and invasion ability of colon cancer cells. We further verified that YAP knockdown increased sensitivity of BRAF V600E mutant CRC cells to mitogen-activated protein kinase (MAPK) pathway inhibitors. In addition, we clarified the mechanism underlying YAP regulation of RAF and MAPK/extracellular signal-regulated kinase (MEK)-targeted therapy response: YAP cooperates with RAF→MEK pathway inhibitors to regulate the cell cycle, increase cell G1/S phase arrest, and increase apoptosis. Conclusions These results suggest that YAP expression may be related to the primary resistance of MAPK inhibitors in metastatic CRC with the BRAF V600E mutation. Therefore, the combination of YAP and MAPK pathway inhibitors in BRAF V600E mutant metastatic CRC may present a promising treatment method.
Importance of tyrosine phosphorylation for transmembrane signaling in plants

Reversible protein phosphorylation is a widespread post-translational modification fundamental for signaling across all domains of life. Tyrosine (Tyr) phosphorylation has recently emerged as being important for plant receptor kinase (RK)-mediated signaling, particularly during plant immunity. How Tyr phosphorylation regulates RK function is however largely unknown. Notably, the expansion of protein Tyr phosphatase and SH2 domain-containing protein families, which are the core of regulatory phospho-Tyr (pTyr) networks in choanozoans, did not occur in plants. Here, we summarize the current understanding of plant RK Tyr phosphorylation focusing on the critical role of a pTyr site (‘VIa-Tyr’) conserved in several plant RKs. Furthermore, we discuss the possibility of metazoan-like pTyr signaling modules in plants based on atypical components with convergent biochemical functions.
Recent advances and perspectives in the synthesis of bioactive coumarins

The impressive pharmacological properties shown by a number of coumarins have led to extraordinarily large emphasis being placed on the design of more efficient and greener synthetic procedures to produce them. The increasing use of enabling technologies, such as microwaves, ultrasound, new heterogeneous catalysts and greener solvents in recent years has made access to coumarin derivatives much simpler. This review will highlight the most recent synthetic advances that make use of non-conventional methods and energy sources and some perspectives for the future, in particular the synthesis of new hybrid molecules bearing a coumarin moiety with a dual mode of biological action.
Hydropenia may accelerates the progression of orthotopic bladder cancer induced by N-methyl-N-nitrosourea by increasing the expression levels of AQP1, AQP3, and AQP4

Background Increasing evidence has demonstrated aquaporins (AQPs) to be critical players in carcinogenesis. Here, we aimed to explore the role of hydropenia in the progression of bladder cancer (BCa), as well as to assess the expression of AQP1, AQP3, and AQP4 in bladder tissues from hydropenic and N-methyl-N-nitrosourea (MNU)-treated rats. Methods An orthotopic BCa model was induced by administering Sprague Dawley rats with MNU. A hydropenic rat model was established by administrating rats with 2/3 of the amount of water given to the control group. At week 8, the rats were sacrificed and their bladder tissues were collected. Then, pathological alterations in the rat bladders were assessed by hematoxylin and eosin staining. The RNA and protein expression levels of AQP1, AQP3, and AQP4 were determined by using qRT-PCR and western blot assays. Results All of the rats (100%) administrated with MNU developed tumors, of which 5 were large (diameter, 0.5–1.0 cm), 10 were medium (diameter, 0.2–0.5 cm), and 5 were small (diameter, <0.2 cm) in size. The tumors were nodular and cauliflower shaped, with multiple satellite focus, and were accompanied by bleeding, ulcers, stones, and residual urine. Hematoxylin and eosin staining revealed that the bladder mucosa was incomplete, with a large amount of necrotic tissue and obvious leukocytic infiltration. The tumor volume in the MNU + hydropenia group was significantly larger than that in the MNU group. Noticeably, hydropenia exacerbated pathological changes induced by MNU administration. QRT-PCR and western blot analysis revealed that the MNU group, hydropenia group, and MNU + hydropenia group had significantly increased levels of AQP1, AQP3, and AQP4 compared to the control group, with the most dramatic increase seen in the MNU + hydropenia group. Conclusions Hydropenia exacerbates pathological alterations induced by MNU in rats with orthotopic BCa by increasing the expression levels of AQP1, AQP3, and AQP4. This study reveals a possible mechanism of the occurrence of BCa.
Multiscale model of hepatitis C virus dynamics in plasma and liver following combination therapy

This work explores the application of a physiologically structured population (PSP) framework in modeling hepatitis C virus (HCV) kinetics. To do so, a model was developed for the viral RNA load in plasma and liver as observed in 15 patients treated with a combination therapy of pegylated interferon, ribavirin, and telaprevir. By including both intracellular and extracellular processes of the HCV lifecycle, the model provided a description of the treatment effect on the intracellular HCV lifecycle. Combining PSP models with a nonlinear mixed effects approach in a single model permits a natural inclusion of the direct‐acting antiviral effect on intracellular processes, which can then be integrated with the viral kinetics within the host while accounting for the interindividual variability between patients. This should allow an exploration of the treatment effect within the entire chronic HCV‐infected population.
Effects of canagliflozin on human myocardial redox signalling: clinical implications

Abstract Aims Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Methods and results Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2. − production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. Conclusions We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.