bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the Basic Region of the Mason-Pfizer Monkey Virus Nucleocapsid Protein Affect Reverse Transcription, Genomic RNA Packaging, and the Virus Assembly Site
Authors: Dostálková Alžběta , Kaufman Filip , Křížová Ivana , Kultová Anna , Strohalmová Karolína , Hadravová Romana , Ruml Tomáš , Rumlová Michaela 
Published: March 2018

ABSTRACT

In addition to specific RNA-binding zinc finger domains, the retroviral Gag polyprotein contains clusters of basic amino acid residues that are thought to support Gag-viral genomic RNA (gRNA) interactions. One of these clusters is the basic K
16
NK
18
EK
20
region, located upstream of the first zinc finger of the Mason-Pfizer monkey virus (M-PMV) nucleocapsid (NC) protein. To investigate the role of this basic region in the M-PMV life cycle, we used a combination of
in vivo
and
in vitro
methods to study a series of mutants in which the overall charge of this region was more positive (RNRER), more negative (AEAEA), or neutral (AAAAA). The mutations markedly affected gRNA incorporation and the onset of reverse transcription. The introduction of a more negative charge (AEAEA) significantly reduced the incorporation of M-PMV gRNA into nascent particles. Moreover, the assembly of immature particles of the AEAEA Gag mutant was relocated from the perinuclear region to the plasma membrane. In contrast, an enhancement of the basicity of this region of M-PMV NC (RNRER) caused a substantially more efficient incorporation of gRNA, subsequently resulting in an increase in M-PMV RNRER infectivity. Nevertheless, despite the larger amount of gRNA packaged by the RNRER mutant, the onset of reverse transcription was delayed in comparison to that of the wild type. Our data clearly show the requirement for certain positively charged amino acid residues upstream of the first zinc finger for proper gRNA incorporation, assembly of immature particles, and proceeding of reverse transcription.

IMPORTANCE
We identified a short sequence within the Gag polyprotein that, together with the zinc finger domains and the previously identified RKK motif, contributes to the packaging of genomic RNA (gRNA) of Mason-Pfizer monkey virus (M-PMV). Importantly, in addition to gRNA incorporation, this basic region (KNKEK) at the N terminus of the nucleocapsid protein is crucial for the onset of reverse transcription. Mutations that change the positive charge of the region to a negative one significantly reduced specific gRNA packaging. The assembly of immature particles of this mutant was reoriented from the perinuclear region to the plasma membrane. On the contrary, an enhancement of the basic character of this region increased both the efficiency of gRNA packaging and the infectivity of the virus. However, the onset of reverse transcription was delayed even in this mutant. In summary, the basic region in M-PMV Gag plays a key role in the packaging of genomic RNA and, consequently, in assembly and reverse transcription.
Prevalence of frailty and prefrailty among community-dwelling older adults in low-income and middle-income countries: a systematic review and meta-analysis
Authors: Siriwardhana Dhammika D , Hardoon Sarah , Rait Greta , Weerasinghe Manuj C , Walters Kate R 
Published: March 2018

ObjectiveTo systematically review the research conducted on prevalence of frailty and prefrailty among community-dwelling older adults in low-income and middle-income countries (LMICs) and to estimate the pooled prevalence of frailty and prefrailty in community-dwelling older adults in LMICs.DesignSystematic review and meta-analysis. PROSPERO registration number is CRD42016036083.Data sourcesMEDLINE, EMBASE, AMED, Web of Science, CINAHL and WHO Global Health Library were searched from their inception to 12 September 2017.SettingLow-income and middle-income countries.ParticipantsCommunity-dwelling older adults aged ≥60 years.ResultsWe screened 7057 citations and 56 studies were included. Forty-seven and 42 studies were included in the frailty and prefrailty meta-analysis, respectively. The majority of studies were from upper middle-income countries. One study was available from low-income countries. The prevalence of frailty varied from 3.9% (China) to 51.4% (Cuba) and prevalence of prefrailty ranged from 13.4% (Tanzania) to 71.6% (Brazil). The pooled prevalence of frailty was 17.4% (95% CI 14.4% to 20.7%, I2=99.2%) and prefrailty was 49.3% (95% CI 46.4% to 52.2%, I2=97.5%). The wide variation in prevalence rates across studies was largely explained by differences in frailty assessment method and the geographic region. These findings are for the studies with a minimum recruitment age 60, 65 and 70 years.ConclusionThe prevalence of frailty and prefrailty appears higher in community-dwelling older adults in upper middle-income countries compared with high-income countries, which has important implications for healthcare planning. There is limited evidence on frailty prevalence in lower middle-income and low-income countries.PROSPERO registration numberCRD42016036083.
Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial
Authors: Crockett Seth D , Barry Elizabeth L , Mott Leila A , Ahnen Dennis J , Robertson Douglas J , Anderson Joseph C , Wallace Kristen , Burke Carol A , Bresalier Robert S , Figueiredo Jane C , Snover Dale C , Baron John A 
Published: March 2018

ObjectiveSerrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically.DesignParticipants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models.ResultsSPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively).ConclusionIn a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6–10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation.Trial registration numberNCT00153816; Results.
Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome
Authors: McCarthy John M , McCann-Crosby Bonnie M , Rech Megan E , Yin Jiani , Chen Chun-An , Ali May A , Nguyen HaiThuy N , Miller Jennifer L , Schaaf Christian P 
Published: March 2018

BackgroundNonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS.MethodsIn nine individuals with SYS (5 female/4 male; aged 5–17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density.ResultsLow IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below −2 SDs.ConclusionThis is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS.
Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features
Authors: Kutkowska-Kaźmierczak Anna , Rydzanicz Małgorzata , Chlebowski Aleksander , Kłosowska-Kosicka Kamila , Mika Adriana , Gruchota Jakub , Jurkiewicz Elżbieta , Kowalewski Cezary , Pollak Agnieszka , Stradomska Teresa Joanna , Kmieć Tomasz , Jakubowski Rafał , Gasperowicz Piotr , Walczak Anna , Śladowski Dariusz , Jankowska-Steifer Ewa , Korniszewski Lech , Kosińska Joanna , Obersztyn Ewa , Nowak Wieslaw , Śledziński Tomasz , Dziembowski Andrzej , Płoski Rafał 
Published: March 2018

BackgroundIchthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.ObjectivesTo identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.MethodsWhole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography–mass spectrometry in stably transfected HEK2932 cells and in cultured patient’s fibroblasts.ResultsProbands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10−6 vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10−7, P=1.2×10−5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10−7, P=1.9×10−4, respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient’s fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0–C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased.ConclusionThe ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD.
Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus
Authors: Kheir Joseph M , Guthridge Carla J , Johnston Jonathon R , Adams Lucas J , Rasmussen Astrid , Gross Timothy F , Munroe Melissa E , Bourn Rebecka L , Sivils Kathy L , Guthridge Joel M , Weisman Michael H , Wallace Daniel J , Anaya Juan-Manuel , Rojas Villarraga Adriana , Jarvis James N , Harley John B , James Judith A 
Published: March 2018

ObjectiveSystemic lupus erythematosus (SLE) is a systemic autoimmune disease with varied morbidity and mortality. We assessed clinical presentations, autoantibody specificities and therapeutic interventions in Native American (NA) patients with SLE.MethodsPatients with SLE meeting 1997 American College of Rheumatology classification criteria (n=3148) were enrolled between 1992 and 2010 in the multiethnic, cross-sectional Lupus Family Registry and Repository. Clinical, demographic and therapeutic information were extracted from medical records using a standardised form and formalised training. Autoantibodies were assessed by indirect immunofluorescence (antinuclear antibodies (ANA) and antidouble-stranded DNA), precipitin (ENA) and ELISA (IgG and IgM anticardiolipins).ResultsNA patients met SLE classification at a younger age (29.89±12.3 years) than European Americans (EA; 32.02±12.87, P=0.0157) and a similar age to African-Americans (AAs) and Hispanics (HIS). More NA patients had concurrent rheumatic diseases or symptoms, such as Raynaud’s phenomenon, interstitial lung disease, Sjӧgren’s syndrome and systemic sclerosis. Compared with EAs, NAs were more likely to have high-titre ANA (≥1:3240; P<0.0001) and had more SLE-associated autoantibodies. Autoantibodies with unknown specificities were more common in NAs (41%) compared with other racial/ethnic groups in this collection (AA: 24%, P=0.0006; EA: 17%, P<0.0001; HIS: 23%, P=0.0050). Fewer NA patients used hydroxychloroquine (68%) compared with others (AA: 74%, P=0.0308; EA: 79%, P=0.0001, HIS: 77%, P=0.0173); this was influenced by lower hydroxychloroquine use in NA patients from Latin America (32%). NA patients had higher rates of methotrexate use (28%) compared with AA (18%, P=0.0006) and HIS patients (14%, P=0.0003), higher azathioprine use (38%) compared with EA patients (30%, P=0.0105) and higher mycophenolate mofetil use (26%) compared with EA (17%, P=0.0012) and HIS patients (11%, P<0.0001).ConclusionsNA patients are diagnosed with SLE earlier in life and present worse concurrent rheumatic disease symptoms than EA patients. NA patients also are more likely to have expanded autoantibody profiles and precipitins of unknown specificities.
Effects of triceps surae muscle strength and tendon stiffness on the reactive dynamic stability and adaptability of older female adults during perturbed walking
Authors: Epro Gaspar , McCrum Christopher , Mierau Andreas , Leyendecker Michael , Brüggemann Gert-Peter , Karamanidis Kiros 
Published: March 2018

This study aimed to examine whether the triceps surae (TS) muscle-tendon unit (MTU) mechanical properties affect gait stability and its reactive adaptation potential to repeated perturbation exposure in older adults. Thirty-four older adults each experienced eight separate unexpected perturbations during treadmill walking, while a motion capture system was used to determine the margin of stability (MoS) and base of support (BoS). Ankle plantar flexor muscle strength and Achilles tendon (AT) stiffness were analyzed using ultrasonography and dynamometry. A median split and separation boundaries classified the subjects into two groups with GroupStrong ( n = 10) showing higher ankle plantar flexor muscle strength (2.26 ± 0.17 vs. 1.47 ± 0.20 N·m/kg, means ± SD; P < 0.001) and AT stiffness (544 ± 75 vs. 429 ± 86 N/mm; P = 0.004) than GroupWeak ( n = 12). The first perturbation caused a negative ΔMoS (MoS in relation to unperturbed baseline walking) at touchdown of perturbed step (PertR), indicating an unstable position. GroupStrong required four recovery steps to return to ΔMoS zero level, whereas GroupWeak was unable to return to baseline within the analyzed steps. However, after repeated perturbations, both groups increased ΔMoS at touchdown of PertR with a similar magnitude. Significant correlations between ΔBoS and ΔMoS at touchdown of the first recovery step and TS MTU capacities (0.41 < r < 0.57; 0.006 < P < 0.048) were found. We conclude that older adults with TS muscle weakness have a diminished ability to control gait stability during unexpected perturbations, increasing their fall risk, but that degeneration in muscle strength and tendon stiffness may not inhibit the ability of the locomotor system to adapt the reactive motor response to repeated perturbations. NEW & NOTEWORTHY Triceps surae muscle weakness and a more compliant Achilles tendon partly limit older adults’ ability to effectively enlarge the base of support and recover dynamic stability after an unexpected perturbation during walking, increasing their fall risk. However, the degeneration in muscle strength and tendon stiffness may not inhibit the ability of the locomotor system to adapt the reactive motor response to repeated perturbations.
An advanced magnetic resonance imaging perspective on the etiology of deep tissue injury
Authors: Nelissen Jules L. , Traa Willeke A. , de Boer Hans H. , de Graaf Larry , Mazzoli Valentina , Savci-Heijink C. Dilara , Nicolay Klaas , Froeling Martijn , Bader Dan L. , Nederveen Aart J. , Oomens Cees W. J. , Strijkers Gustav J. 
Published: March 2018

Early diagnosis of deep tissue injury remains problematic due to the complicated and multifactorial nature of damage induction and the many processes involved in damage development and recovery. In this paper, we present a comprehensive assessment of deep tissue injury development and remodeling in a rat model by multiparametric magnetic resonance imaging (MRI) and histopathology. The tibialis anterior muscle of rats was subjected to mechanical deformation for 2 h. Multiparametric in vivo MRI, consisting of T2, T2*, mean diffusivity (MD), and angiography measurements, was applied before, during, and directly after indentation as well as at several time points during a 14-day follow-up. MRI readouts were linked to histological analyses of the damaged tissue. The results showed dynamic change in various MRI parameters, reflecting the histopathological status of the tissue during damage induction and repair. Increased T2 corresponded with edema, muscle cell damage, and inflammation. T2* was related to tissue perfusion, hemorrhage, and inflammation. MD increase and decrease was reported on the tissue’s microstructural integrity and reflected muscle degeneration and edema as well as fibrosis. Angiography provided information on blockage of blood flow during deformation. Our results indicate that the effects of a single damage-causing event of only 2 h of deformation were present up to 14 days. The initial tissue response to deformation, as observed by MRI, starts at the edge of the indentation. The quantitative MRI readouts provided distinct and complementary information on the extent, temporal evolution, and microstructural basis of deep tissue injury-related muscle damage. NEW & NOTEWORTHY We have applied a multiparametric MRI approach linked to histopathology to characterize damage development and remodeling in a rat model of deep tissue injury. Our approach provided several relevant insights in deep tissue injury. Response to damage, as observed by MRI, started at some distance from the deformation. Damage after a single indentation period persisted up to 14 days. The MRI parameters provided distinct and complementary information on the microstructural basis of the damage.
Respiratory pump maintains cardiac stroke volume during hypovolemia in young, healthy volunteers
Authors: Skytioti Maria , Søvik Signe , Elstad Maja 
Published: March 2018

Spontaneous breathing has beneficial effects on the circulation, since negative intrathoracic pressure enhances venous return and increases cardiac stroke volume. We quantified the contribution of the respiratory pump to preserve stroke volume during hypovolemia in awake, young, healthy subjects. Noninvasive stroke volume, cardiac output, heart rate, and mean arterial pressure (Finometer) were recorded in 31 volunteers (19 women), 19–30 yr old, during normovolemia and hypovolemia (approximating 450- to 500-ml reduction in central blood volume) induced by lower-body negative pressure. Control-mode noninvasive positive-pressure ventilation was employed to reduce the effect of the respiratory pump. The ventilator settings were matched to each subject’s spontaneous respiratory pattern. Stroke volume estimates during positive-pressure ventilation and spontaneous breathing were compared with Wilcoxon matched-pairs signed-rank test. Values are overall medians. During normovolemia, positive-pressure ventilation did not affect stroke volume or cardiac output. Hypovolemia resulted in an 18% decrease in stroke volume and a 9% decrease in cardiac output ( P < 0.001). Employing positive-pressure ventilation during hypovolemia decreased stroke volume further by 8% ( P < 0.001). Overall, hypovolemia and positive-pressure ventilation resulted in a reduction of 26% in stroke volume ( P < 0.001) and 13% in cardiac output ( P < 0.001) compared with baseline. Compared with the situation with control-mode positive-pressure ventilation, spontaneous breathing attenuated the reduction in stroke volume induced by moderate hypovolemia by 30% (i.e., −26 vs. −18%). In the patient who is critically ill with hypovolemia or uncontrolled hemorrhage, spontaneous breathing may contribute to hemodynamic stability, whereas controlled positive-pressure ventilation may result in circulatory decompensation. NEW & NOTEWORTHY Maintaining spontaneous respiration has beneficial effects on hemodynamic compensation, which is clinically relevant for patients in intensive care. We have quantified the contribution of the respiratory pump to cardiac stroke volume and cardiac output in healthy volunteers during normovolemia and central hypovolemia. The positive hemodynamic effect of the respiratory pump was abolished by noninvasive, low-level positive-pressure ventilation. Compared with control-mode positive-pressure ventilation, spontaneous negative-pressure ventilation attenuated the fall in stroke volume by 30%.