Complete Genomes of Symbiotic Cyanobacteria Clarify the Evolution of Vanadium-Nitrogenase.

Plant endosymbiosis with nitrogen-fixing cyanobacteria has independently evolved in diverse plant lineages, offering a unique window to study the evolution and genetics of plant-microbe interaction. However, very few complete genomes exist for plant cyanobionts, and therefore little is known about their genomic and functional diversity. Here, we present four complete genomes of cyanobacteria isolated from bryophytes. Nanopore long-read sequencing allowed us to obtain circular contigs for all the main chromosomes and most of the plasmids. We found that despite having a low 16S rRNA sequence divergence, the four isolates exhibit considerable genome reorganizations and variation in gene content. Furthermore, three of the four isolates possess genes encoding vanadium (V)-nitrogenase (vnf), which is uncommon among diazotrophs and has not been previously reported in plant cyanobionts. In two cases, the vnf genes were found on plasmids, implying possible plasmid-mediated horizontal gene transfers. Comparative genomic analysis of vnf-containing cyanobacteria further identified a conserved gene cluster. Many genes in this cluster have not been functionally characterized and would be promising candidates for future studies to elucidate V-nitrogenase function and regulation

Preferential, enhanced breast cancer cell migration on biomimetic electrospun nanofiber ‘cell highways’

BACKGROUND: Aggressive metastatic breast cancer cells seemingly evade surgical resection and current therapies, leading to colonization in distant organs and tissues and poor patient prognosis. Therefore, high-throughput in vitro tools allowing rapid, accurate, and novel anti-metastatic drug screening are grossly overdue. Conversely, aligned nanofiber constitutes a prominent component of the late-stage breast tumor margin extracellular matrix. This parallel suggests that the use of a synthetic ECM in the form of a nanoscale model could provide a convenient means of testing the migration potentials of cancer cells to achieve a long-term goal of providing clinicians an in vitro platform technology to test the efficacy of novel experimental anti-metastatic compounds. METHODS: Electrospinning produces highly aligned, cell-adhesive nanofiber matrices by applying a strong electric field to a polymer-containing solution. The resulting fibrous microstructure and morphology closely resembles in vivo tumor microenvironments suggesting their use in analysis of migratory potentials of metastatic cancer cells. Additionally, a novel interface with a gel-based delivery system creates CXCL12 chemotactic gradients to enhance CXCR4-expressing cell migration. RESULTS: Cellular dispersions of MCF-10A normal mammary epithelial cells or human breast cancer cells (MCF-7 and MDA-MB-231) seeded on randomly-oriented nanofiber exhibited no significant differences in total or net distance traveled as a result of the underlying topography. Cells traveled ~2-5 fold greater distances on aligned fiber. Highly-sensitive MDA-MB-231 cells displayed an 82% increase in net distance traversed in the presence of a CXCL12 gradient. In contrast, MCF-7 cells exhibited only 31% increase and MCF-10A cells showed no statistical difference versus control or vehicle conditions. MCF-10A cells displayed little sensitivity to CXCL12 gradients, while MCF-7 cells displayed early sensitivity when CXCL12 concentrations were higher. MDA-MB-231 cells displayed low relative expression levels of CXCR4, but high sensitivity resulting in 55-fold increase at late time points due to CXCL12 gradient dissipation. CONCLUSIONS: This model could create clinical impact as an in vitro diagnostic tool for rapid assessment of tumor needle biopsies to confirm metastatic tumors, their invasiveness, and allow high-throughput drug screening providing rapid development of personalized therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-825) contains supplementary material, which is available to authorized users

Determining Ancestry of Unprovenienced Human Remains from the Grenadines, Southern Caribbean: Dental Morphology and Craniometric

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Calcification of the Planktonic Foraminiferaglobigerinabulloidesand Carbonate Ion Concentration Resultsfrom the Santa Barbara Basin

Planktonic foraminiferal calcification intensity, reflected by shell wall thickness, has been hypothesized to covary with the carbonate chemistry of seawater. Here we use both sediment trap and box core samples from the Santa Barbara Basin to evaluate the relationship between the calcification intensity of the planktonic foraminifera species Globigerina bulloides, measured by area density (µg/µm2), and the carbonate ion concentration of seawater ([CO32−]). We also evaluate the influence of both temperature and nutrient concentration ([PO43−]) on foraminiferal calcification and growth. The presence of two G. bulloides morphospecies with systematically different calcification properties and offset stable isotopic compositions was identified within sampling populations using distinguishing morphometric characteristics. The calcification temperature and by extension calcification depth of the more abundant “normal” G. bulloides morphospecies was determined using δ18O temperature estimates. Calcification depths vary seasonally with upwelling and were used to select the appropriate [CO32−], temperature, and [PO43−] depth measurements for comparison with area density. Seasonal upwelling in the study region also results in collinearity between independent variables complicating a straightforward statistical analysis. To address this issue, we use additional statistical diagnostics and a down core record to disentangle the respective roles of each parameter on G. bulloides calcification. Our results indicate that [CO32−] is the primary variable controlling calcification intensity while temperature influences shell size. We report a modern calibration for the normal G. bulloides morphospecies that can be used in down core studies of well‐preserved sediments to estimate past [CO32−]

Effectiveness of direct-acting antiviral therapy among Aboriginal and Torres Strait Islander peoples with HCV infection in Australia: A national real-world cohort (REACH-C)

Aboriginal and Torres Strait Islander peoples experience a disproportionate burden of hepatitis C virus (HCV) infection. This study assessed the effectiveness of direct-acting antiviral (DAA) therapy among Aboriginal peoples in the three years following universal access in Australia. REACH-C, a national multicentre prospective cohort study, evaluated HCV treatment outcomes from sequential DAA initiations across 33 health services between March 2016 and June 2019. DAA effectiveness was assessed by sustained virological response (SVR) in the total (full analysis set) and effectiveness (modified analysis set excluding those lost to follow-up) populations. Overall, 915 (10%) Aboriginal and 8095 (90%) non-Indigenous people commenced DAA therapy, of whom 30% and 16% reported current injecting drug use and 73% and 42% were treated in primary care, respectively. SVR in the total and effectiveness populations was 74% and 94% among Aboriginal people and 82% and 94% among non-Indigenous people, with loss to follow-up contributing to lower SVR in the total population analysis (22% Aboriginal, 13% non-Indigenous). Among Aboriginal people, returning for follow-up was positively associated with older age (aOR 1.20; 95% CI 1.04, 1.39) and SVR was negatively associated with cirrhosis (aOR 0.39; 95% CI 0.19, 0.80) and prior DAA treatment (aOR 0.14; 95% CI 0.04, 0.49). Factors reflecting higher vulnerability or inequity were not associated with returning for testing or SVR. DAA therapy was highly effective among Aboriginal peoples with HCV treated through primary and tertiary services. Tailored community-led interventions are necessary to optimize follow-up and engagement. Sustained DAA uptake and equitable access to care, treatment and prevention are required for HCV elimination

Association of Blood Biomarkers With Acute Sport-Related Concussion in Collegiate Athletes: Findings From the NCAA and Department of Defense CARE Consortium

Importance: There is potential scientific and clinical value in validation of objective biomarkers for sport-related concussion (SRC). Objective: To investigate the association of acute-phase blood biomarker levels with SRC in collegiate athletes. Design, Setting, and Participants: This multicenter, prospective, case-control study was conducted by the National Collegiate Athletic Association (NCAA) and the US Department of Defense Concussion Assessment, Research, and Education (CARE) Consortium from February 20, 2015, to May 31, 2018, at 6 CARE Advanced Research Core sites. A total of 504 collegiate athletes with concussion, contact sport control athletes, and non-contact sport control athletes completed clinical testing and blood collection at preseason baseline, the acute postinjury period, 24 to 48 hours after injury, the point of reporting being asymptomatic, and 7 days after return to play. Data analysis was conducted from March 1 to November 30, 2019. Main Outcomes and Measures: Glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain, and tau were quantified using the Quanterix Simoa multiplex assay. Clinical outcome measures included the Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom evaluation, Standardized Assessment of Concussion, Balance Error Scoring System, and Brief Symptom Inventory 18. Results: A total of 264 athletes with concussion (mean [SD] age, 19.08 [1.24] years; 211 [79.9%] male), 138 contact sport controls (mean [SD] age, 19.03 [1.27] years; 107 [77.5%] male), and 102 non-contact sport controls (mean [SD] age, 19.39 [1.25] years; 82 [80.4%] male) were included in the study. Athletes with concussion had significant elevation in GFAP (mean difference, 0.430 pg/mL; 95% CI, 0.339-0.521 pg/mL; P < .001), UCH-L1 (mean difference, 0.449 pg/mL; 95% CI, 0.167-0.732 pg/mL; P < .001), and tau levels (mean difference, 0.221 pg/mL; 95% CI, 0.046-0.396 pg/mL; P = .004) at the acute postinjury time point compared with preseason baseline. Longitudinally, a significant interaction (group × visit) was found for GFAP (F7,1507.36 = 16.18, P < .001), UCH-L1 (F7,1153.09 = 5.71, P < .001), and tau (F7,1480.55 = 6.81, P < .001); the interaction for neurofilament light chain was not significant (F7,1506.90 = 1.33, P = .23). The area under the curve for the combination of GFAP and UCH-L1 in differentiating athletes with concussion from contact sport controls at the acute postinjury period was 0.71 (95% CI, 0.64-0.78; P < .001); the acute postinjury area under the curve for all 4 biomarkers combined was 0.72 (95% CI, 0.65-0.79; P < .001). Beyond SCAT-3 symptom score, GFAP at the acute postinjury time point was associated with the classification of athletes with concussion from contact controls (β = 12.298; 95% CI, 2.776-54.481; P = .001) and non-contact sport controls (β = 5.438; 95% CI, 1.676-17.645; P = .005). Athletes with concussion with loss of consciousness or posttraumatic amnesia had significantly higher levels of GFAP than athletes with concussion with neither loss of consciousness nor posttraumatic amnesia at the acute postinjury time point (mean difference, 0.583 pg/mL; 95% CI, 0.369-0.797 pg/mL; P < .001). Conclusions and Relevance: The results suggest that blood biomarkers can be used as research tools to inform the underlying pathophysiological mechanism of concussion and provide additional support for future studies to optimize and validate biomarkers for potential clinical use in SRC

Maturation of West Nile virus modulates sensitivity to antibody-mediated neutralization

West Nile virions incorporate 180 envelope (E) proteins that orchestrate the process of virus entry and are the primary target of neutralizing antibodies. The E proteins of newly synthesized West Nile virus (WNV) are organized into trimeric spikes composed of pre-membrane (prM) and E protein heterodimers. During egress, immature virions undergo a protease-mediated cleavage of prM that results in a reorganization of E protein into the pseudo-icosahedral arrangement characteristic of mature virions. While cleavage of prM is a required step in the virus life cycle, complete maturation is not required for infectivity and infectious virions may be heterogeneous with respect to the extent of prM cleavage. In this study, we demonstrate that virion maturation impacts the sensitivity of WNV to antibody-mediated neutralization. Complete maturation results in a significant reduction in sensitivity to neutralization by antibodies specific for poorly accessible epitopes that comprise a major component of the human antibody response following WNV infection or vaccination. This reduction in neutralization sensitivity reflects a decrease in the accessibility of epitopes on virions to levels that fall below a threshold required for neutralization. Thus, in addition to a role in facilitating viral entry, changes in E protein arrangement associated with maturation modulate neutralization sensitivity and introduce an additional layer of complexity into humoral immunity against WNV

Effects of Non-Aerobic Maximal Effort Exercise on Fatigue in Deconditioned Men and Women with Multiple Sclerosis

Multiple Sclerosis (MS) is a neurodegenerative disease of unknown etiology affecting women more frequently than men. Mental and physical fatigue complaints are often the most disabling symptoms for an MS patient. Both are multifactorial, potentially exacerbated by aerobic exercise, may prevent sustained physical functioning, and significantly interfere with activities of daily living1. A multi-center study was designed to investigate the effects of non-aerobic maximal effort exercise (MEE) for deconditioned persons with MS, with the expectation of minimizing fatigue. The IsoPUMP (Neuromuscular Engineering; Nashville, TN), is a specialized exercise and strength-sensing machine, designed to allow individuals to safely perform and record their non-aerobic MEE sessions. The Modified Fatigue Impact Scale (MFIS) and Multiple Sclerosis Functional Composite (MSFC) are common, accepted methods used to measure fatigue and function. The MFIS is a 21-item questionnaire which assesses the subjects’ perception of physical, cognitive, and psychosocial aspects of fatigue over a four-week period2. Each of the 21 items are scored on a scale from 0 (never) to 4 (almost always), and the total MFIS score is calculated by summing the circled number for each item. Total scores can range from 0 to 84; higher scores indicating a greater impact of fatigue on the person. The MFIS has three distinct subscales: (1) physical, (2) cognitive, and (3) psychosocial. These subscales can be scored independently by summing the questions that pertain to each subscale2. The MFIS physical subscale score can range from 0 – 36 and the MFIS cognitive subscale score can range from 0 – 40. The MSFC combines clinical measures used to assess lower limb function (Timed 25-Foot Walk [25-FW]), upper limb function (9-Hole Peg Test [9-HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT-3”])3. The 25-FW is a quantitative measure of lower extremity function. The 9-HPT is a quantitative measure of arm and hand function where a subject inserts and then removes 9 pegs from a board, using one hand at a time. The time is recorded for each hand with the dominant hand trial first and the non-dominant hand trial second. The final score is recorded as the mean time for both hands. The PASAT-3” is a measure of cognitive function, specifically assessing auditory information processing speed, short-term memory, flexibility, and calculation ability. Cognitive dysfunction affects half of all MS patients; slowing ability to reason, concentrate, and recall5. In this test subjects listen to a series of 61 spoken numbers separated by 3 seconds and must add each number to the prior number. Their final PASAT-3” score is the number of correct additions in the series, with 60 reflecting a perfect score. The MSFC is then evaluated by creating Z-scores for each component, which compare each outcome with the average outcome of the study population. The three Z-scores are then averaged to create an overall composite score (the MSFC score) which represents change over time for that population of MS subjects3