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1.
Abrar M. Babateen Oliver M. Shannon Gerard M. OBrien Edward Okello Anmar A. Khan Sofia Rubele Emma Wightman Ellen Smith Nicholas McMahon Dilara Olgacer Christina Koehl William Fostier Inês Mendes David Kennedy John C. Mathers Mario Siervo 《Nutrients》2021,13(3)
Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO3−) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m2) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO3− (HN: 2 × 70 mL BJ/day) (2) medium-NO3− (MN: 70 mL BJ/day), (3) low-NO3− (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO3−-depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO3− intake, and by measuring NO3− and NO2− concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO3− dose and the increase in plasma and urinary NO3− concentration (R2 = 0.71, p < 0.001 and R2 = 0.46 p < 0.001, respectively), but relationships between NO3− dose and changes in salivary NO3− and NO2− were non-linear (R2 = 0.35, p = 0.002 and R2 = 0.23, p = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults. 相似文献
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Joseph Driver Samantha E Hoffman Sherwin Tavakol Eleanor Woodward Eduardo A Maury Varun Bhave Noah F Greenwald Farshad Nassiri Kenneth Aldape Gelareh Zadeh Abrar Choudhury Harish N Vasudevan Stephen T Magill David R Raleigh Malak Abedalthagafi Ayal A Aizer Brian M Alexander Keith L Ligon David A Reardon Patrick Y Wen Ossama Al-Mefty Azra H Ligon Adrian M Dubuc Rameen Beroukhim Elizabeth B Claus Ian F Dunn Sandro Santagata Wenya Linda Bi 《Neuro-oncology》2022,24(5):796
BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients. 相似文献
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Khang D. Nguyen Jiali Han Tricia Li Abrar A. Qureshi 《Archives of dermatological research》2014,306(6):555-560
Little data on cutaneous squamous cell carcinoma (SCC) epidemiology within the United States are currently available. Prior studies have focused on populations outside of the United States or been limited to regions within the US. In this study, prospective data were collected via biennial questionnaires from a total of 261,609 participants, which included women in the Nurses’ Health Study (NHS, 1976–2008) and Nurses’ Health Study II (NHS II, 1989–2009), and men in the Health Professionals Follow-Up Study (HPFS, 1986–2008). History of physician-diagnosed invasive SCC was confirmed by pathology record review. Over the entire follow-up period for each cohort, there were 1,265 invasive SCC cases per 100,000 persons in the NHS cohort, 389 cases per 100,000 persons in NHS II, and 2,154 cases per 100,000 persons in HPFS. An 18-year follow-up of participants in these cohorts revealed increasing invasive SCC incidence rates over time, with rates for men being consistently higher than those for women. In women, a larger proportion of invasive SCC lesions occurred on the lower extremities as compared to men (21 % in NHS vs. 6 % in HPFS, p < 0.0001; 14 % in NHS II vs. 6 % in HPFS, p < 0.0001), while in men, a larger proportion occurred on the head/neck (43 % in NHS vs. 60 % in HPFS, p < 0.0001; 48 % in NHS II vs. 60 % in HPFS, p < 0.0001). In summary, invasive SCC incidence rates among US men have been greater than those for women with distinct sites of common occurrence between men and women. 相似文献
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Ka Man Carmen Chan Ashley L. Arthur Johannes Morstein Meiyan Jin Abrar Bhat Drte Schlesinger Sungmin Son Dont A. Stevens David G. Drubin Daniel A. Fletcher 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(1)
Fusion-associated small transmembrane (FAST) proteins are a diverse family of nonstructural viral proteins. Once expressed on the plasma membrane of infected cells, they drive fusion with neighboring cells, increasing viral spread and pathogenicity. Unlike viral fusogens with tall ectodomains that pull two membranes together through conformational changes, FAST proteins have short fusogenic ectodomains that cannot bridge the intermembrane gap between neighboring cells. One orthoreovirus FAST protein, p14, has been shown to hijack the actin cytoskeleton to drive cell-cell fusion, but the actin adaptor-binding motif identified in p14 is not found in any other FAST protein. Here, we report that an evolutionarily divergent FAST protein, p22 from aquareovirus, also hijacks the actin cytoskeleton but does so through different adaptor proteins, Intersectin-1 and Cdc42, that trigger N-WASP–mediated branched actin assembly. We show that despite using different pathways, the cytoplasmic tail of p22 can replace that of p14 to create a potent chimeric fusogen, suggesting they are modular and play similar functional roles. When we directly couple p22 with the parallel filament nucleator formin instead of the branched actin nucleation promoting factor N-WASP, its ability to drive fusion is maintained, suggesting that localized mechanical pressure on the plasma membrane coupled to a membrane-disruptive ectodomain is sufficient to drive cell-cell fusion. This work points to a common biophysical strategy used by FAST proteins to push rather than pull membranes together to drive fusion, one that may be harnessed by other short fusogens responsible for physiological cell-cell fusion.Aquareovirus and orthoreovirus are two genera of the Reoviridae family of segmented double-stranded RNA viruses that form multinucleated syncytia after infection, which can increase viral spread and pathogenicity (1–4). To drive cell-cell fusion, both aquareovirus and orthoreovirus express a nonstructural, fusion-associated small transmembrane (FAST) protein on the plasma membrane of infected cells. The FAST protein is not required for viral entry, and expression of FAST protein alone is sufficient to cause cells to fuse with naïve neighboring cells, forming large multinucleated syncytium (1, 2, 5–12), confirming they are bona fide cell-cell fusogens. Although they have similar function and topology in the membrane, FAST proteins from aquareovirus and orthoreovirus share minimal sequence identity (13). Based on phylogenetic analysis, they are hypothesized to have evolved from a common, likely nonfusogenic, ancestor 510 million years ago (4, 13, 14). Separate gain-of-function events are believed to have produced fusogenic proteins in both aquareovirus and orthoreovirus, with further divergence or acquisition events resulting in the diversity of FAST proteins found in reoviruses today (13).Aquareovirus and orthoreovirus FAST proteins are single-pass membrane proteins of fewer than 200 residues comprised of a mostly disordered cytoplasmic tail, a transmembrane domain, and a small ectodomain of fewer than 40 residues (1, 2). The membrane-disruptive ectodomains of FAST proteins typically have solvent-exposed hydrophobic residues and/or myristoylation motifs that are necessary for cell-cell fusion (5, 15–17). In contrast to other cell-cell fusogens that fuse membranes by pulling them together using conformational changes in their ∼10 nm-tall ectodomains, the ectodomains of FAST proteins have minimal predicted secondary structure, are unlikely to undergo conformational changes to drive membrane fusion (1, 2), and extend only ∼1 nm above the bilayer (5, 18). How such short fusogens can overcome the ∼2 nm repulsive hydration barrier and larger barrier presented by cell surface proteins to reach and fuse with an opposing membrane (5, 18) has been a long-standing question for FAST proteins and other short cell-cell fusogens, such as myomixer and myomaker that are involved in myoblast fusion (19–22).Recently, we found that the FAST protein from reptilian orthoreovirus, p14, hijacks the host cell actin cytoskeleton to drive cell-cell fusion by forming localized branched actin networks (23). This is accomplished through a c-src phosphorylated tyrosine motif, YVNI, in p14’s disordered cytoplasmic tail that binds to a host adaptor protein, Grb2, which then binds to N-WASP and nucleates branched actin assembly. We hypothesize that this directly couples local actin-generated forces to push p14’s short, fusogenic ectodomain into the opposing cell’s plasma membrane (23). While all FAST family proteins have similarly short ectodomains, it is unclear if this is a general strategy used by other FAST proteins to drive cell-cell fusion.Here, we report that a FAST protein from the divergent aquareovirus, p22, also hijacks the host actin cytoskeleton but does so using a molecular strategy distinct from that of the orthoreovirus FAST protein p14. Instead of binding to Grb2, we find that p22 binds to Intersectin-1 through an SH3 binding motif in its cytoplasmic tail, which binds Cdc42 to activate N-WASP–mediated branched actin assembly. We show that despite minimal sequence identity, the p22 cytoplasmic tail can be functionally swapped with that of p14, suggesting that while the cytoplasmic tails of the two FAST proteins evolved independently, they serve a similar function. By directly coupling the ectodomain to a different actin nucleator, we suggest that actin’s functional role is applying mechanical pressure to a fusogenic ectodomain at the plasma membrane. This biophysical role may be shared across other members of the FAST protein family and could be more generally employed by other cell-cell fusogens. 相似文献
6.
Folayan Morenike Oluwatoyin Ibigbami Olanrewaju Brown Brandon El Tantawi Maha Uzochukwu Benjamin Ezechi Oliver C. Aly Nourhan M. Abeldaño Giuliana Florencia Ara Eshrat Ayanore Martin Amogre Ayoola Oluwagbemiga O. Osamika Bamidele Emmanuel Ellakany Passent Gaffar Balgis Idigbe Ifeoma Ishabiyi Anthonia Omotola Jafer Mohammed Khan Abeedha Tu-Allah Khalid Zumama Lawal Folake Barakat Lusher Joanne Nzimande Ntombifuthi P. Popoola Bamidele Olubukola Quadri Mir Faeq Ali Rashwan Maher Roque Mark Shamala Anas Al-Tammemi Ala’a B. Yousaf Muhammad Abrar Abeldaño Zuñiga Roberto Ariel Okeibunor Joseph Chukwudi Nguyen Annie Lu 《AIDS and behavior》2022,26(3):739-751
AIDS and Behavior - The aim of the study was to assess if there were significant differences in the adoption of COVID-19 risk preventive behaviors and experience of food insecurity by people living... 相似文献
7.
BACKGROUND: Antibiotics can potentiate warfarin anticoagulation. While preemptive warfarin dose reduction (DR) upon initiation of antibiotics has been advocated by experts, there are no published data regarding the efficacy of this strategy vs. the conventional strategy of not changing warfarin dose and carefully following international normalized ratio (INR) results. METHODS AND RESULTS: We compared the efficacy of preemptive 10-20% DR vs. no change in warfarin dosing in 40 chronically anticoagulated patients initiating trimethoprim-sulfamethoxazole (TMP-SMX) or levofloxacin. Eighteen patients received preemptive warfarin DR and 22 control patients underwent no change in warfarin dosing. There was no difference between the DR and control groups in the mean INR before beginning antibiotic therapy (2.53 +/- 0.12 vs. 2.52 +/- 0.11; P > 0.9). Mean interval between initiation of antibiotic and next INR was 5.1 +/- 0.4 vs. 4.7 +/- 0.5 days for DR vs. control patients, respectively (P > 0.5). For both TMP-SMX and levofloxacin, patients managed with a preemptive warfarin DR strategy did not exhibit a statistically significant change in the INR after initiating antibiotic therapy. In contrast, for each antibiotic, control group patients exhibited a significant increase in mean post-antibiotic INR compared to mean pre-antibiotic INR, though the effect was more pronounced in patients treated with TMP-SMX than with levofloxacin. Of DR group patients who were treated with TMP-SMX, none (0/8) developed a subtherapeutic INR, while 40% (4/10) of levofloxacin-treated patients developed a sub-therapeutic INR. Supra-therapeutic INR results led to transient interruption of warfarin dosing in 2 patients (11%) in the DR group vs. 12 patients (55%) in the control group (P = 0.007). CONCLUSIONS: Prophylactic warfarin DR of 10-20% is effective in maintaining therapeutic anticoagulation in patients initiating TMP-SMX. An expectant strategy consisting of no change in warfarin dosing with short-term INR follow-up appears reasonable in patients treated with levofloxacin. 相似文献
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