bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipid pathway dysfunction is prevalent in patients with Parkinson’s disease
Authors: Galper Jasmin , Dean Nicholas J , Pickford Russell , Lewis Simon J G , Halliday Glenda M , Kim Woojin S , Dzamko Nicolas
Published: May 2022

Many genetic risk factors for Parkinson’s disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson’s disease. Moreover, the hallmark Parkinson’s disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson’s disease such as the endosome–lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson’s disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson’s disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson’s disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson’s disease are underexplored.

To better determine the extent of lipid dysregulation in Parkinson’s disease, untargeted high-performance liquid chromatography–tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson’s disease and Parkinson’s disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed.

The main serum lipids that distinguished both Parkinson’s disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson’s disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson’s disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson’s disease cohort (n = 315).

Results from this study demonstrate that dysregulated lipids in Parkinson’s disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson’s disease and therapeutics manipulating these pathways may be beneficial for Parkinson’s disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson’s disease.
Unlocking the Potential of Hybrid Working
Authors: Law Ali , Singh Sathpal
Published: May 2022

Ali Law FBCS and Sathpal Singh CITP FBCS discuss the ways we can all leverage the hybrid working approach to reap its benefits.
How to Prevent the Great Resignation
Authors: Kairinos Nikolas
Published: May 2022

As we emerge into a post-pandemic world, we are re-evaluating our jobs, careers and lives. To keep staff, companies need to adapt, writes Nikolas Kairinos, CEO of Soffos.
Hybrid Working
Authors: Hogan Jacqui
Published: May 2022

COVID changed the way we work forever, writes Jacqui Hogan CITP FCMI FBCS. Because it happened suddenly, we had little time to modify processes, build trust, or understand the resulting fundamental changes in behaviour.
Leadership
Authors: Hall Jon G
Published: May 2022

Jon G Hall CITP FBCS explores how to survive memoryless leadership regeneration.
BCS Impact Report Spring 2022
Authors: Penketh Claire , Aldridge Dan , Nyamande Arnoldis
Published: May 2022

From algrithms to the Ukraine war: the BCS policy team has covered a great deal in the past months. Claire Penketh, Dan Aldridge and Arnoldis Nyamande report.
A Letter from Jamaica
Authors: Runciman Brian
Published: May 2022

A BCS Fellow and a computer society President have provided a great example of partnering in action. Brian Runciman MBCS spoke to Stacey Hines, President of the Jamaica Technology and Digital Alliance (JDTA) and Martin Carpenter FBCS about the IT landscape in Jamaica.
What is a Sustainability and Transformation Plan?
Authors: Sidhu John
Published: May 2022

As organisations work to meet high-level objectives, a sustainability and transformation plan is increasingly relevant. John Sidhu FBCS CITP, Partner at Glue Reply, investigates.
IR35 vs Off-Payroll: 5 Tips for Consultants
Authors: Chaplin Dave
Published: May 2022

What is IR35 and how does off-payroll work? Dave Chaplin, CEO of tax compliance firm IR35 Shield, investigates and explains the key differences between the two schemes.
Blockchain and Emerging Technology to Save the World
Authors: Steedman Robert
Published: May 2022

Technology has always had the power to shape and support good causes. And equally, the power to dismantle them, writes Robert Steedman, Financial Services and UKI Blockchain Practice Lead at IBM.
Give the Planet a Seat at the Table
Authors: Maxted Suzanne
Published: May 2022

Business Architect, Suzanne Maxted MBCS explains how impact transparency is helping to connect everyday projects to the UN Sustainable Development Goals — to reverse climate catastrophe and biodiversity loss, the digital world needs to go back to the future!
Artificial Intelligence
Authors: Smith Adam Leon
Published: May 2022

Adam Leon Smith FBCS explores five ways AI will affect the software testing profession.
Women’s Experience With Screening Mammography During the COVID-19 Pandemic: A Multi-Institutional Prospective Survey Study
Authors: Carnahan Molly B , Sharpe Richard E , Oluyemi Eniola , Parra Laura , Hippe Daniel S , Lorans Roxanne , Perry Hannah , Moey Tammy Hui Lin , Bagadiya Neeti , Lee Janie M
Published: May 2022

Objective

Evaluate women’s anxiety and experience undergoing screening mammography during the COVID-19 pandemic.

Methods

An IRB-approved anonymous survey was administered to women receiving screening mammography across six sites in the U.S. and Singapore from October 7, 2020, to March 11, 2021. Using a 1–5 Likert scale, women rated their pre- and post-visit anxiety regarding having their mammogram during the COVID-19 pandemic, importance of observed COVID-19 precautions, and personal risk factors for breast cancer and severe COVID-19 illness. Post-visit change in anxiety was evaluated. Multivariable logistic regression was used to test associations of pre-visit anxiety with breast cancer and COVID-19 risk factors.

Results

In total, 1086 women completed the survey. Of these, 59% (630/1061) had >1 breast cancer risk factor; 27% (282/1060) had >1 COVID-19 risk factors. Forty-two percent (445/1065) experienced pre-visit anxiety. Pre-visit anxiety was independently associated with risk factors for severe COVID-19 (OR for >2 vs 0 risk factors: 2.04, 95% confidence interval [CI]: 1.11–3.76) and breast cancer (OR for >2 vs 0 risk factors: 1.71, 95% CI: 1.17–2.50), after adjusting for age and site. Twenty-six percent (272/1065) of women reported post-visit anxiety, an absolute 16% decrease from pre-visit anxiety (95% CI: 14%–19%, P < 0.001). Provider masking (941/1075, 88%) and physical distancing (861/1085, 79%) were rated as the most important precautions.

Conclusion

Pre-visit anxiety was associated with COVID-19 or breast cancer risk factors and declined significantly after screening mammography. Provider masking and physical distancing were rated the most important precautions implemented by imaging clinics.
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

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

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

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

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

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

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

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 < .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

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

Nostalgia 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 & Aim

Non‐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.

Methods

Genetic 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.

Results

The 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.

Conclusion

We demonstrated that TET1 down‐regulation plays a protective role in NAFLD progression by targeting lipid metabolism.
Anticancer effects of the Xanthophyll Fucoxanthin on Genetically Different Triple‐Negative Breast Cancer Cells
Authors: Ahmed Shade , Mendonca Patricia , Badisa Ramesh , Messeha Samia S. , Soliman Karam F. A.
Published: May 2022

Breast cancer is the second most diagnosed cause of death in women worldwide compared to other cancer types. Triple‐negative breast cancer (TNBC) is the most aggressive subtype, constituting 15% of diagnosed breast cancers and predominantly found in African American and Caucasian Women. The tumor microenvironment is associated with increased angiogenesis, cell growth, invasive metastasis, and tumor growth progression. Many natural products have been reported to inhibit angiogenesis and slow breast cancer progression. The cytotoxic effect of the natural compound fucoxanthin, a xanthophyll found in the chloroplasts of brown macroalgae, is investigated. Fucoxanthin has been shown to induce G1 cell‐cycle arrest and apoptosis in various cancer cell lines. Here we show that fucoxanthin affects proliferation and angiogenesis in MDA‐MB‐231 (Caucasian) and MDA‐MB‐468 (African American) TNBC cell lines, which are genetically different. The results demonstrate that fucoxanthin induces a decrease in cell viability (concentration range: 1.56 ‐ 300 µM) in a dose‐response manner in MDA‐MB‐231 and MDA‐MB‐468 cells, showing a higher potency in MDA‐MB‐468 cells compared to MDA‐MB‐231 cells after 24h. Fucoxanthin also showed anti‐proliferative effects in lower concentrations in MDA‐MB‐468 cells compared to MDA‐MB‐231 cells after 48h and 72h. Moreover, angiogenesis studies showed that fucoxanthin (6.25 µM) downregulates the expression of VEGF‐A and VEGF‐C in TNF‐α‐stimulated (50 ng/ml) MDA‐MB‐231 cells, but not in MDA‐MB‐468 cells. The findings show that fucoxanthin may be a promising candidate for breast cancer therapy by targeting VEGF‐A, VEGF‐C, and reducing cell proliferation. Also, the data obtained provide evidence that genetically different cells may respond differently to fucoxanthin treatment.
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

Background

Patients 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.

Design

After 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.

Results

Frequency 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.

Conclusion

MSI‐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

Introduction

Heart 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.

Methods

We 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.

Results

We 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.

Conclusion

Our 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.
Altered Mucosal Glycosylation Patterns during Giardia spp. Infection are Time‐Dependent and Tissue‐Specific
Authors: Fekete Elena , Allain Thibault , Buret Andre
Published: May 2022

Introduction

Glycosylation of intestinal mucin proteins is critical for intestinal barrier function and host‐microbe interactions. Altered mucosal glycosylation patterns have been associated with numerous intestinal diseases and may contribute to dysbiosis and an increase in intestinal permeability. Disruption of intestinal mucus has been described during infection with the protozoan parasite Giardia duodenalis, and may contribute to intestinal mucosal barrier dysfunction and dysbiosis during acute and chronic infection. Little is currently known about the role of mucin glycan alteration in the pathogenesis of Giardia or other enteric infections. The aim of this study was to determine if mucosal glycosylation patterns are altered during Giardia infection.

Methods

3‐4‐week‐old C57BL/6 mice were infected with Giardia muris for 2 or 7 days, or with Giardia duodenalis isolate GSM for 7 days. Jejunum and colon sections were collected and stained with various fluorescein‐coupled lectins, and quantitative PCR was performed for mucin and mucin‐associated glycosyltransferase gene expression.

Results

During early infection, at day 2 post‐infection (PI), fucose and sialic acid abundance was increased in the jejunums of G. muris infected mice in comparison to uninfected mice. Expression of the fucosyltransferase Fut2 and the sialyltransferase St6GalNAc1 were similar between controls and infected mice. Expression of the sulfotransferase Chst4 was decreased in both the jejunums and colons upon infection.

At day 7 PI, when trophozoite burden was maximal in the small intestine, the abundance of fucose and sialic acid was significantly decreased in the jejunums of both G. muris and G. duodenalis infected mice. The expression of Fut2 and St6GalNAc1 was increased in infected mice compared to controls. Both fucose abundance and Fut2 expression were similar between control and infected mice in the colon, while sialic acid abundance increased and expression of St6GalNAc1 decreased in the colon upon infection. Expression of the sulfotransferase Chst4 was decreased in infected mice in the jejunum, and similar to control levels in the colon.

Conclusions

Glycosylation patterns and the expression of mucin‐associated glycosyltransferase genes are altered in the intestines upon Giardia spp. infection. These alterations are time‐dependent as well as tissue‐specific, occurring in the small intestine, where Giardia colonization occurs, and in the large intestine where no active trophozoites are present during infection. These effects are isolate non‐specific and may contribute to disruption of intestinal barrier function and dysbiosis during Giardia infections, as well as during numerous enteric infections in which mucus disruption is implicated in disease pathogenesis.
Osteopontin is an integral pro‐fibrotic mediator of myocardial fibrosis in HIV infection.
Authors: Robinson Jake , Brown Amanda , Burdo Tricia
Published: May 2022

With introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV) has transitioned to a chronic, progressive inflammatory disease, with increasing evidence of subclinical and early‐onset cardiovascular comorbidities. PWH have a greater risk and prevalence of diastolic dysfunction compared to seronegative individuals. In a clinical cohort of ART‐adherent, virally suppressed women with HIV, we showed women with HIV exhibited increased myocardial extracellular volume and reduced diastolic strain rate compared to matched seronegative women. Taken together, we hypothesize that chronic HIV infection promotes a pro‐fibrotic environment in the heart, perturbing ventricular homeostatic function. First, we utilized the highly translatable simian immunodeficiency virus (SIV)‐infected rhesus macaque model. We used three cohorts in our study: uninfected animals (SIV‐), SIV‐infected untreated animals (SIV+), and SIV‐infected animals receiving a clinically relevant ART regimen (SIV+ART). Assessing fibrosis in the left ventricle, we observed greater interstitial fibrosis in SIV+ animals compared to SIV‐ and SIV+ART animals. We identified osteopontin as a potential fibrotic signal in the heart from its role in macrophage function, as a matricellular protein, and as an immunomodulatory cytokine. We observed significant differences in post‐translational enzymatic processing of osteopontin between the three groups, and SIV+ animals showed a significant increase in full‐length osteopontin compared to SIV‐ and SIV+ART. Lastly, we used an HIV‐infected humanized mouse model to functionally inhibit osteopontin in vivo with an RNA aptamer. HIV‐infected mice exhibited greater fibrotic burden in the left ventricle of the heart compared to uninfected controls. HIV‐infected mice treated with an osteopontin‐inhibiting RNA aptamer had reduced fibrotic content in the left ventricle compared to HIV infected mice, showing similar levels to uninfected mice. Together, these data suggest that osteopontin is an integral fibrotic signal in the heart and a potential adjunctive target in reducing HIV‐associated myocardial fibrosis.
Protocol Compliance Guiding Angiotensin II Use in Post Cardiovascular Surgery Vasoplegia
Authors: ten Lohuis Caitlin C. , Burke Sarah C. , Jannuzzo Cooper J. , Barker Nicholas A. , Chen Edward P. , Busse Laurence W.
Published: May 2022

OBJECTIVES:

Catecholamines and vasopressin are commonly used in patients with post cardiovascular surgery vasoplegia (PCSV). Multimodal therapy, including methylene blue (MB), hydroxocobalamin, and angiotensin II (Ang II), may improve outcomes in patients who remain hypotensive despite catecholamine and vasopressin therapy. However, a standardized approach has not been established. We created a protocol at Emory Healthcare (Emory Protocol), which provides guidance on norepinephrine equivalent dose (NED) and the use of noncatecholamines in the setting of PCSV and sought to determine the clinical significance of adherence to the protocol.

DESIGN:

Retrospective study.

SETTING:

Multisite study at Emory University Hospital.

PATIENTS:

Patients receiving Ang II for PCSV in any cardiovascular ICU from 2018 to 2020.

INTERVENTIONS:

Patient encounters were scored on Emory Protocol compliance based on NED (1–5), use of vasopressin (1–2), use of MB (1–2), and documentation of high-output shock (1–4). A compliant score was less than 7, moderately compliant 7 to 8, and poorly compliant greater than 8. Demographics, clinical data, and outcomes were abstracted from the medical records.

MEASUREMENTS AND MAIN RESULTS:

Of the 78 consecutive patients receiving Ang II for PCSV, overall ICU mortality was 26.9%, with an average compliance score of 6.2. ICU mortality was 21.1% for compliant cases (n = 38), 29.7% for moderately compliant cases (n = 24), and 37.5% for poorly compliant cases (n = 16). In regression analysis, the cumulative compliance score to the Emory Protocol was predictive of ICU mortality (p = 0.027).

CONCLUSIONS:

Compliance with the Emory Protocol, emphasizing early initiation of the noncatecholamines vasopressin, MB, hydroxocobalamin, and Ang II at lower catecholamine doses in high-output shock, is associated with improved ICU mortality.
Use of Micro Botulinum Toxin for a Face-lifting Effect: A Systematic Review
Authors: Ng Zhi Yang , Lellouch Alexandre G.
Published: May 2022

BACKGROUND

Micro-Botox (Micro-btx) was described in 2000 for the paralysis of superficial muscle fibers to address facial rhytides. Increasingly, there are reports of its off-label use for a face-lifting effect.

OBJECTIVE

To evaluate the literature for such results.

METHODS AND METHODS

A systematic review was performed according to PRISMA; only Level ≥ III evidence from 2000 to 2020 were included. Data extracted include patient demographics, type of botulinum toxin, dilution, dosage, injection sites and spacing, needle size and syringe, follow-up, patient and physician assessment, and complications.

RESULTS

Three hundred seventy-two patients (average 35.2 years) underwent different botulinum toxin injections (average 39 units/hemiface) of varying dilutions with 30- to 32-G needles, typically with 1-mL syringes, by forming 0.2- to 0.5-cm wheals 1 cm apart. Follow-up averaged 10.5 weeks with both subjective and objective assessments. Facial asymmetry and minor bruising were common. Subjective assessment of face-lifting effects between patients and physicians was highly discordant and injection sites reported were highly variable.

CONCLUSION

Much heterogeneity in dosage, injection sites, definition of “face-lifting,” and assessment methods remain, all of which preclude accurate and objective evaluation of the current evidence for micro-btx. Future studies should address these variables, given the growing interest in such nonsurgical options for a face-lifting effect.
The Regulatory Mechanism and Effect of Receptor-Interacting Protein Kinase 3 on Phenylephrine-Induced Cardiomyocyte Hypertrophy
Authors: Wang Xue , Zhang Jingjing , Qian Jianan , Cao Ji , Zhang Wei , Jiang Yan
Published: May 2022

As a critical regulatory molecule, receptor-interacting protein kinase 3 (RIPK3) can mediate the signaling pathway of programmed necrosis. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been proved as a new substrate for RIPK3-induced necroptosis. In this study, we aimed to investigate the regulatory mechanism of RIPK3 on phenylephrine (PE)-induced cardiomyocyte hypertrophy. Cardiomyocyte hypertrophy was induced by exposure to PE (100 μM) for 48 hours. Primary cardiomyocytes were pretreated with RIPK3 inhibitor GSK′872 (10 μM), and RIPK3 siRNA was used to deplete the intracellular expression of RIPK3. The indexes related to myocardial hypertrophy, cell injury, necroptosis, CaMKII activation, gene expression, oxidative stress, and mitochondrial membrane potential were measured. We found that after cardiomyocytes were stimulated by PE, the expressions of hypertrophy markers, atrial and brain natriuretic peptides (ANP and BNP), were increased, the release of lactate dehydrogenase was increased, the level of adenosine triphosphate (ATP) was decreased, the oxidation and phosphorylation levels of CaMKII were increased, and CaMKIIδ alternative splicing was disturbed. However, both GSK′872 and depletion of RIPK3 could reduce myocardial dysfunction, inhibit CaMKII activation and necroptosis, and finally alleviate myocardial hypertrophy. In addition, the pretreatment of RIPK3 could also lessen the accumulation of reactive oxygen species (ROS) induced by PE and stabilize the membrane potential of mitochondria. These results indicated that targeted inhibition of RIPK3 could suppress the activation of CaMKII and reduce necroptosis and oxidative stress, leading to alleviated myocardial hypertrophy. Collectively, our findings provided valuable insights into the clinical treatment of hypertrophic cardiomyopathy.
Candida albicans Flexor Tenosynovitis after Trigger Finger Release: A Case Report
Authors: Tanabe Katsuhisa
Published: May 2022

Tenosynovitis caused by fungi, especially Candida species, is rare. We report a case of an immunocompetent patient with finger flexor tenosynovitis caused by Candida albicans after trigger finger release (TFR). Intratendon sheath triamcinolone injection and subsequent TFR surgery might contribute to the occurrence of Candida tenosynovitis. We performed a tenosynovectomy twice because the pathology was unclear after the first tenosynovectomy. The culture of synovial tissue from the first tenosynovectomy was negative. However, the culture from the second tenosynovectomy tested positive for Candida albicans. We must consider the possibility of infection with low virulent pathogens such as fungi even if cultures are negative. When hand tenosynovitis is observed in immunocompromised or immunocompetent patients with invasive procedures, such as local injection or surgery, Candida infection should be considered a potential root cause even in the absence of positive results for the presence of fungi in the specimens being tested.
Computer-aided Planning and Execution in Facial Gender Surgery: Approaches, Concepts, and Implementation
Authors: Louis Matthew , Qiu Cecil S. , Travieso Rob , Marano Drew , Coon Devin
Published: May 2022

Facial gender surgery (FGS) involves major surgical modification of the craniofacial soft tissues and skeleton. Computer-aided surgery (CAS) has improved precision and accuracy of osteotomies and decreased operative time in complex reconstructive craniofacial surgery. FGS is a natural application for CAS because the procedures are not only technically challenging but also demand a high standard of aesthetic results. Planning FGS cases virtually enables better and more reproducible results through simulated surgical planning and precise execution of osteotomies in surgical fields with limited exposure. We describe our experience with CAS in FGS for each of the facial thirds to introduce new concepts for conceptual planning of osteotomy design and patient-specific implants.