bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Curcumin on Idiopathic Parkinson Disease: A Clinical and Skin Biopsy Study
Authors: Donadio Vincenzo , Incensi Alex , Rizzo Giovanni , Fileccia Enrico , Ventruto Francesco , Riva Antonella , Tiso Domenico , Recchia Martino , Vacchiano Veria , Infante Rossella , Petrangolini Giovanna , Allegrini Pietro , Avino Silvia , Pantieri Roberta , Mostacci Barbara , Avoni Patrizia , Liguori Rocco 
Published: May 2022

Abstract
There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients.
Moderate DNA methylation changes associated with nitrogen remobilization and leaf senescence in Arabidopsis
Authors: Vatov Emil , Zentgraf Ulrike , Ludewig Uwe 
Published: May 2022

Abstract
The lifespan of plants is restricted by environmental and genetic components. Following the transition to reproductive growth, leaf senescence ends cellular life in monocarpic plants to remobilize nutrients to storage organs. In Arabidopsis, we initially observed altered leaf to seed ratios, faster senescence progression, altered leaf nitrogen recovery after transient nitrogen removal, and ultimately enhanced nitrogen remobilization from the leaves in two methylation mutants (ros1 and the triple dmr1/2 cmt3 knockout). Analysis of the DNA methylome in wild type Col-0 leaves identified an initial moderate decline of cytosine methylation with progressing leaf senescence, predominantly in the CG context. Late senescence was associated with moderate de novo methylation of cytosines, primarily in the CHH context. Relatively few differentially methylated regions, including one in the ROS1 promoter linked to down-regulation of ROS1, were present, but these were unrelated to known senescence-associated genes. Differential methylation patterns were identified in transcription factor binding sites, such as the W-boxes that are targeted by WRKYs. Methylation in artificial binding sites impaired transcription factor binding in vitro. However, it remains unclear how moderate methylome changes during leaf senescence are linked with up-regulated genes during senescence.
Likely optical counterpart of the cool middle-aged pulsar J1957+5033
Authors: Zyuzin D A , Zharikov S V , Karpova A V , Kirichenko A Yu , Shibanov Yu A , Geier S , Potekhin A Y , Suleimanov V F , Cabrera-Lavers A 
Published: May 2022

ABSTRACT
The 840-kyr-old pulsar PSR J1957+5033, detected so far only in γ- and X-rays, is a nearby and rather cool neutron star with a temperature of 0.2–0.3 MK, a distance of $\lesssim 1$kpc, and a small colour reddening excess E(B − V) ≈ 0.03. These properties make it an ideal candidate to detect in the optical to get additional constraints on its parameters. We thus performed the first deep optical observations of the pulsar with the 10.4 m Gran Telescopio Canarias in the g′ band and found its possible counterpart with g′ = 27.63 ± 0.26. The counterpart candidate position is consistent with the X-ray coordinates of the pulsar within the 0.5 arcsec accuracy. Assuming that this is the real counterpart, we analysed the pulsar X-ray spectrum together with the derived optical flux density. As a result, we found that the thermal emission from the bulk surface of the cooling neutron star can significantly contribute to its optical flux. Our multiwavelength spectral analysis favours the pulsar nature of the detected optical source, since it provides physically adequate parameters of the pulsar emission. We show that the optical data can provide new constraints on the pulsar temperature and distance.
X-ray eclipse mapping constrains the binary inclination and mass ratio of Swift J1858.6−0814
Authors: Knight Amy H , Ingram Adam , Middleton Matthew 
Published: May 2022

ABSTRACT
X-ray eclipse mapping is a promising modelling technique, capable of constraining the mass and/or radius of neutron stars (NSs) or black holes (BHs) in eclipsing binaries and probing any structure surrounding the companion star. In eclipsing systems, the binary inclination, i, and mass ratio, q relate via the duration of totality, te. The degeneracy between i and q can then be broken through detailed modelling of the eclipse profile. Here, we model the eclipses of the NS low-mass X-ray binary Swift J1858.6−0814 utilizing archival NICER observations taken while the source was in outburst. Analogous to EXO 0748−676, we find evidence for irradiation driven ablation of the companion’s surface by requiring a layer of stellar material to surround the companion star in our modelling. This material layer extends ∼7000–14 000 km from the companion’s surface and is likely the cause of the extended, energy-dependent and asymmetric ingress and egress that we observe. Our fits return an inclination of i ∼ 81○ and a mass ratio q ∼ 0.14. Using Kepler’s law to relate the mass and radius of the companion star via the orbital period (∼21.3 h), we subsequently determine the companion to have a low mass in the range 0.183 M⊙ ≤ Mcs ≤ 0.372 M⊙ and a large radius in the range 1.02 R⊙ ≤ Rcs ≤ 1.29 R⊙. Our results, combined with future radial velocity amplitudes measured from stellar absorption/emission lines, can place precise constraints on the component masses in this system.
Towards an accurate model of small-scale redshift-space distortions in modified gravity
Authors: Ruan Cheng-Zong , Cuesta-Lazaro Carolina , Eggemeier Alexander , Hernández-Aguayo César , Baugh Carlton M , Li Baojiu , Prada Francisco 
Published: May 2022

ABSTRACT
The coming generation of galaxy surveys will provide measurements of galaxy clustering with unprecedented accuracy and data size, which will allow us to test cosmological models at much higher precision than achievable previously. This means that we must have more accurate theoretical predictions to compare with future observational data. As a first step towards more accurate modelling of the redshift space distortions (RSD) of small-scale galaxy clustering in modified gravity (MG) cosmologies, we investigate the validity of the so-called Skew-T (ST) probability distribution function (PDF) of halo pairwise peculiar velocities in these models. We show that, combined with the streaming model of RSD, the ST PDF substantially improves the small-scale predictions by incorporating skewness and kurtosis, for both Λ cold dark matter (ΛCDM) and two leading MG models: f(R) gravity and the DGP braneworld model. The ST model reproduces the velocity PDF and redshift-space halo clustering measured from MG N-body simulations very well down to $\sim 5 \, h^{-1}\, \mathrm{Mpc}$. In particular, we investigate the enhancements of halo pairwise velocity moments with respect to ΛCDM for a larger range of MG variants than previous works, and present simple explanations to the behaviours observed. By performing a simple Fisher analysis, we find a significant increase in constraining power to detect modifications of General Relativity by introducing small-scale information in the RSD analyses.
Validation of Bromodomain and Extraterminal proteins as therapeutic targets in neurofibromatosis type 2
Authors: Doherty Joanne , Mandati Vinay , González Rodriguez Maria A , Troutman Scott , Shepard Alyssa , Harbaugh David , Brody Rachel , Miller Douglas C , Kareta Michael S , Kissil Joseph L 
Published: May 2022

Abstract

Background
Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by development of schwannomas on the VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors. The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study.

Methods
A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation of the BET BRD4, phospho-kinase arrays and immunohistochemistry (IHC) of BRD4 in vestibular schwannomas.

Results
JQ1 inhibited proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased sensitivity of cells to JQ1. Loss of function experiments identified BRD4, and to a lesser extent BRD2, as BET family members mediating the majority of JQ1 effects. IHC demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. Analysis of signaling pathways effected by JQ1 treatment suggests that the effects of JQ1 treatment are mediated, at least in part, via inhibition of PI3K/Akt signaling.

Conclusions
NF2-deficient Schwann and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. Our results suggest BRD4 regulates PI3K signaling and likely impedes NF2 schwannoma growth via this inhibition. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.
Phylogenomic Comparison of Neisseria gonorrhoeae Causing Disseminated Gonococcal Infections and Uncomplicated Gonorrhea in Georgia, United States
Authors: Cartee John C , Joseph Sandeep J , Weston Emily , Pham Cau D , Thomas Jesse C , Schlanger Karen , St Cyr Sancta B , Farley Monica M , Moore Ashley E , Tunali Amy K , Cloud Charletta , Raphael Brian H 
Published: May 2022

Abstract
Disseminated gonococcal infection (DGI) is a rare complication caused by the systemic dissemination of Neisseria gonorrhoeae to normally sterile anatomical sites. Little is known about the genetic diversity of DGI gonococcal strains and how they relate to other gonococcal strains causing uncomplicated mucosal infections. We used whole genome sequencing to characterize DGI isolates (n = 30) collected from a surveillance system in Georgia, United States, during 2017–2020 to understand phylogenetic clustering among DGI as well as uncomplicated uro- and extragenital gonococcal infection (UGI) isolates (n = 110) collected in Fulton County, Georgia, during 2017–2019. We also investigated the presence or absence of genetic markers related to antimicrobial resistance (AMR) as well as surveyed the genomes for putative virulence genetic factors associated with normal human-serum (NHS) resistance that might facilitate DGI. We found that DGI strains demonstrated significant genetic variability similar to the population structure of isolates causing UGI, with sporadic incidences of geographically clustered DGI strains. DGI isolates contained various AMR markers and genetic mechanisms associated with NHS resistance. DGI isolates had a higher frequency of the porB1A allele compared with UGI (67% vs 9%, P &lt; .0001); however, no single NHS resistance marker was found in all DGI isolates. Continued DGI surveillance with genome-based characterization of DGI isolates is necessary to better understand specific factors that promote systemic dissemination.
The Arabidopsis Mitochondrial Pseudouridine Synthase Homolog FCS1 Plays Critical Roles in Plant Development
Authors: Niu Yanli , Zheng Yuan , Zhu Huijie , Zhao Hongyun , Nie Kaili , Wang Xiaopei , Sun Lirong , Song Chun-Peng 
Published: May 2022

Abstract
As the most abundant RNA modification, pseudouridylation has been shown to play critical roles in Escherichia coli, yeast and humans. However, its function in plants is still unclear. Here, we characterized leaf curly and small 1 (FCS1), which encodes a pseudouridine synthase in Arabidopsis. fcs1 mutants exhibited severe defects in plant growth, such as delayed development and reduced fertility, and were significantly smaller than the wild type at different developmental stages. FCS1 protein is localized in the mitochondrion. The absence of FCS1 significantly reduces pseudouridylation of mitochondrial 26S ribosomal RNA (rRNA) at the U1692 site, which sits in the peptidyl transferase center. This affection of mitochondrial 26S rRNA may lead to the disruption of mitochondrial translation in the fcs1-1 mutant, causing high accumulation of transcripts but low production of proteins. Dysfunctional mitochondria with abnormal structures were also observed in the fcs1-1 mutant. Overall, our results suggest that FCS1-mediated pseudouridylation of mitochondrial 26S rRNA is required for mitochondrial translation, which is critical for maintaining mitochondrial function and plant development.
Patterns of brain activity associated with nostalgia: a social-cognitive neuroscience perspective
Authors: Yang Ziyan , Wildschut Tim , Izuma Keise , Gu Ruolei , Luo Yu L L , Cai Huajian , Sedikides Constantine 
Published: May 2022

AbstractNostalgia arises from tender and yearnful reflection on meaningful life events or important persons from one’s past. In the last two decades, the literature has documented a variety of ways in which nostalgia benefits psychological well-being. Only a handful of studies, however, have addressed the neural basis of the emotion. In this prospective review, we postulate a neural model of nostalgia. Self-reflection, autobiographical memory, regulatory capacity and reward are core components of the emotion. Thus, nostalgia involves brain activities implicated in self-reflection processing (medial prefrontal cortex, posterior cingulate cortex and precuneus), autobiographical memory processing (hippocampus, medial prefrontal cortex, posterior cingulate cortex and precuneus), emotion regulation processing (anterior cingulate cortex and medial prefrontal cortex) and reward processing (striatum, substantia nigra, ventral tegmental area and ventromedial prefrontal cortex). Nostalgia’s potential to modulate activity in these core neural substrates has both theoretical and applied implications.
Inhibiting TET1 alleviates non‐alcoholic liver disease progression by targeting lipid metabolic pathways.
Authors: Mulla Joud , Nagaoka Katsuya , Cao Kevin , Cheng Zhixiang , Bai Xuewei , Zhang Hongyu , Ji Chengcheng , Lu Shaolei , Huang Chiung‐Kuei 
Published: May 2022

Background & AimNon‐alcoholic fatty liver disease (NAFLD) affects more than one‐quarter of adults worldwide, with 60% in diabetic patients and 90% in obese people. Epigenetic modifications are highly associated with NAFLD development. It has been reported that the 5‐hydroxymethylcytosine (5hmC) epigenetic modification and its catalyzing enzymes, the Ten‐eleven translocation (TET) family dioxygenases, are involved in NAFLD progression. However, it remains unclear how the TET family enzymes participate in NAFLD development. The current study was aimed to clarify the involvement of TET family proteins in NAFLD.MethodsGenetic TET1 knockout mice were generated and challenged with a high fat diet (HFD) for 16 weeks. Liver and serum lipid contents were analyzed by biochemical assays. To determine liver injuries, histological staining and liver functional assays were used. Immunoblotting and RNA sequencing were adopted for the study of molecular mechanisms associated with TET‐mediated NAFLD.ResultsThe HFD challenge led to significant down‐regulation of TET1 and TET3 in male mice, but a greater extent in TET1. Thus, TET1 knockout (KO) male mice were generated to evaluate how TET1 KO impacts NAFLD development. TET1 KO decreased mouse body weight without affecting the ratio of liver weight over body weight and fat weight over body weight, suggesting that TET1 KO may not significantly impact the development of liver and adipose tissue. Unexpectedly, TET1 KO substantially suppressed HFD‐induced steatosis and liver injuries.Mechanism studies revealed that the TET1‐mediated fatty liver development is not related to food/water consumption and fed glucose levels. Although the crucial metabolic regulators, including Akt and AMPK/LKB1 signaling pathways, are highly disrupted by the HFD feeding, no differences between TET1 wild‐type and KO mice were found. Interestingly, serum cholesterol, hepatic triglyceride, and cholesterol were substantially decreased in TET1 KO mice. The RNA sequencing results illustrated significant down‐regulation of those genes involved in lipid, fatty acid, and cellular lipid metabolic processes in TET1 KO mice. With further bioinformatics analysis, it was found that substantial down‐regulation of PPARγ, CD36, and ABCG1 in TET1 KO mice may contribute to the alleviation of NAFLD progression. The functions of PPARγ, CD36, and ABCG1 are highly associated with fatty acid synthesis, uptake, and cholesterol synthesis and efflux, respectively, thus supporting the role of TET1 in NAFLD development through targeting lipid metabolic pathways.ConclusionWe demonstrated that TET1 down‐regulation plays a protective role in NAFLD progression by targeting lipid metabolism.
Microsatellite Instability Testing for Lynch Syndrome in Colorectal Adenomas
Authors: Anderson Blaire , Javanbahkt Ayda , Green Donald , Godwin Kelly , Tsongalis Gregory , Tafe Laura , Ren Bing 
Published: May 2022

BackgroundPatients with Lynch Syndrome (LS), a hereditary condition linked to increased risk of colorectal cancer (CRC) and a variety of other cancers, carry at least one germline variant in a DNA mismatch repair protein (MMR) gene, which results in microsatellite instability (MSI). Screening for MMR/MSI status in CRCs helps identify patients with LS, which is imperative for treatment and surveillance. MSI high instability (MSI‐H) status has been detected in some colorectal adenomatous polyps (CRAs). If MSI‐H can be detected in CRAs from LS patients, this could aid in the prevention of cancer development and facilitate early surveillance. Currently, MMR/MSI testing in CRAs is not used to identify cases of LS. Here we analyze a set of CRAs to assess the utility of using MSI testing to identify patients with LS.DesignAfter completing a retrospective review of our pathology database, we selected 54 CRAs (including tubular, villous, and tubulovillous CRAs) from 32 patients with a history of LS, 21 CRAs from 14 patients with history of sporadic CRC with BRAF mutation or MLH1 promotor methylation, and 38 CRAs from 34 patients who underwent screening colonoscopy. Results from previous molecular testing confirmed germline mutations in the LS group and BRAF mutations or MLH1 promotor methylation in the sporadic CRC group. FFPE tissue was analyzed for MSI status using the Idylla MSI assay (Biocartis, Belgium). Patient demographics and clinical characteristics, pathologic features CRAs, and MSI results were analyzed.ResultsFrequency of MSI‐H CRA was significantly higher in the LS group (18.5%, [10/54]) than in the sporadic CRC (4.8%, [1/21]) and screening colonoscopy (0/38) groups. CRAs analyzed included 106 tubular CRAs, 2 villous CRAs and 5 tubulovillous CRAs. The MSI‐H CRAs in the LS group included 9 tubular CRAs and one villous CRA. One MSI‐H tubular CRA was identified in the sporadic CRC group. All CRAs from the screening colonoscopy group were MSI stable. Mean ages in years for patients in each study group were 56.9 in the LS group, 79.2 in the sporadic CRC group, and 60.6 in the screening colonoscopy group.ConclusionMSI‐H status is detectable in CRAs from patients with LS. MSI‐H CRAs are more frequently detected in patients with LS than non‐LS patients. These findings demonstrate the utility of MSI testing in CRAs. This can help to identify LS at a pre‐malignant stage, which prevents cancer development and facilitates early surveillance.
Proinflammatory T Cells with Downregulated Unfolded Protein Response Genes Contribute to Experimental Heart Failure with Preserved Ejection Fraction (HFpEF)
Authors: Smolgovsky Sasha , Carrillo‐Salinas Francisco , Bayer Abraham , Anastasiou Marina , Kaur Kuljeet , Aronovitz Mark , Sanders Erin , Blanton Robert , Alcaide Pilar 
Published: May 2022

IntroductionHeart Failure with Preserved Ejection Fraction (HFpEF) is an uncurable widespread syndrome characterized by impaired cardiac relaxation (diastolic function), preserved cardiac contractility (systolic function), and the concordance of several comorbidities, such as obesity and hypertension. While T cell inflammation is known to contribute to HF with reduced cardiac contractility (HF with reduced EF), whether T cell inflammation occurs in HFpEF remains elusive. Recently, downregulation of the unfolded protein response (UPR) in cardiomyocytes was identified as a cardiometabolic HFpEF‐unique molecular signature. Interestingly, downregulation of the UPR has been reported to improve T cell anti‐tumor inflammatory responses. We hypothesized T cells contribute to diastolic dysfunction in HFpEF following T cell UPR downregulation in response to metabolic and nitrosative stress.MethodsWe modeled cardiometabolic HFpEF in male C57/Bl6 (WT), Nur77‐GFP mice, reporter mice for T cell antigen engagement, and T cell receptor‐a (Tcra−/−) mice using high‐fat diet (HFD) and L‐NAME‐supplemented drinking water to mimic obesity and hypertension, respectively. Mice fed standard chow (STD) were used as controls. Invasive hemodynamic analyses were used to measure cardiac function. Immune populations in the heart, mediastinal lymph nodes (MdLN), and spleen were characterized using flow cytometry. CD4+ T cells from MdLN and spleen were isolated using magnetic‐assisted cell sorting, and UPR gene expression was assessed using qPCR.ResultsWe observed significant increases in cardiac CD4+ T cells in WT mice fed HFD/L‐NAME, concordant with diastolic dysfunction and preserved EF, compared to STD mice. We found increased effector CD4+CD62LloCD44hiIFNγ+ T cells in spleens and MdLN isolated from WT HFD/L‐NAME mice compared to STD controls. Nur77‐GFP mice revealed no antigen recognition by CD4+ T cells in the heart following HFD/L‐NAME. Tcra−/−mice fed HFD/L‐NAME did not develop diastolic dysfunction or cardiomyocyte hypertrophy. Strikingly, qPCR analysis of splenic T cells of WT HFD/L‐NAME mice revealed significantly decreased expression of spliced X box‐binding protein 1 (XBP1s), compared to controls, with no significant changes in unspliced XBP1 or activating transcription factor 4 (ATF4). ATF6 and C/EBP homologous protein (CHOP) gene expression was also reduced compared to T cells from control mice.ConclusionOur data demonstrate that diastolic dysfunction and cardiomyocyte hypertrophy are T cell dependent in preclinical cardiometabolic HFpEF and reveal downregulation of two branches of the T cell UPR as a potential novel mechanism that contributes to T cell inflammation in HFpEF.