The differential extension in dsDNA bound to Rad51 filaments may play important roles in homology recognition and strand exchange

RecA and Rad51 proteins play an important role in DNA repair and homologous recombination. For RecA, X-ray structure information and single molecule force experiments have indicated that the differential extension between the complementary strand and its Watson–Crick pairing partners promotes the rapid unbinding of non-homologous dsDNA and drives strand exchange forward for homologous dsDNA. In this work we find that both effects are also present in Rad51 protein. In particular, pulling on the opposite termini (3′ and 5′) of one of the two DNA strands in a dsDNA molecule allows dsDNA to extend along non-homologous Rad51-ssDNA filaments and remain stably bound in the extended state, but pulling on the 3′5′ ends of the complementary strand reduces the strand-exchange rate for homologous filaments. Thus, the results suggest that differential extension is also present in dsDNA bound to Rad51. The differential extension promotes rapid recognition by driving the swift unbinding of dsDNA from non-homologous Rad51-ssDNA filaments, while at the same time, reducing base pair tension due to the transfer of the Watson–Crick pairing of the complementary strand bases from the highly extended outgoing strand to the slightly less extended incoming strand, which drives strand exchange forward

The Search for Low-mass Companions of B Stars in the Carina Nebula Cluster Trumpler 16

We have developed lists of likely B3--A0 stars (called "late B" stars) in the young cluster Trumpler 16. The following criteria were used: location within 3' of Eta Car, an appropriate V and B-V combination, and proper motion (where available). Color and magnitude cuts have been made assuming an E(B-V) =0.55 mag +/- 0.1, which is a good approximation close to the center of Trumpler 16. These lists have been cross-correlated with X-ray sources found in the Chandra Carina Complex Project (CCCP). Previous studies have shown that only very rarely (if at all) do late main sequence B stars produce X-rays. We present evidence that the X-ray detected sources are binaries with low-mass companions, since stars less massive than 1.4 Msun are strong X-ray sources at the age of the cluster. Both the median X-ray energies and X-ray luminosities of these sources are in good agreement with values for typical low-mass coronal X-ray sources. We find that 39% of the late B stars based on a list with proper motions have low-mass companions. Similarly, 32% of a sample without proper motions have low-mass companions. We discuss the X-ray detection completeness. These results on low-mass companions of intermediate mass stars are complementary to spectroscopic and interferometric results, and probe new parameter space of low mass companions at all separations. They do not support a steeply rising distribution of mass ratios to low masses for intermediate-mass (5 Msun) primaries, such as would be found by random pairing from the Initial Mass Function.Comment: Accepted for the ApJS Special Issue on the Chandra Carina Complex Project (CCCP), scheduled for publication in May 2011. All 16 CCCP Special Issue papers are available at http://cochise.astro.psu.edu/Carina_public/special_issue.html through 2011 at leas

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis

Objective: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. Methods: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. Results: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test–Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55–0.68) and a threshold of −1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71–0.83) and threshold of −1.75 for the SDMT z score to predict impaired BVMT-R. Conclusion: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed

The impact of the COVID-19 pandemic on an international rehabilitation study in MS: the CogEx experience

Pandemic restrictions have led to changes in therapy plans and disrupted rehabilitation services for people with multiple sclerosis. CogEx is an international, multicentre MS dual-intervention (cognitive rehabilitation, aerobic exercise) randomized, controlled rehabilitation trial confined to people with progressive disease. The primary outcome is cognition (processing speed).There are 11 treatment sites in six countries with participants required to make 27 site visits over 12 weeks. Collectively, the large, in-person demands of the trial, and the varying international policies for the containment of COVID-19, might disproportionately impact the administration of CogEx. During the first lockdown, all centres closed on average for 82.9 (SD = 24.3) days. One site was required to lockdown on two further occasions. One site remained closed for 16 months. Ten staff (19.2%) were required to quarantine and eight staff (15.4%) tested positive for COVID. 10 of 264 (3.8%) participants acquired COVID-19. All survived. The mean duration of enrollment delay has been [236.7 (SD = 214.5) days]. Restarting participants whose interventions were interrupted by the pandemic meant recalculating the intervention prescriptions for these individuals. While the impact of the pandemic on CogEx has been considerable, all study sites are again open. Participants and staff have shown considerable flexibility and resilience in keeping a complex, international endeavour running. The future in general remains uncertain in the midst of a pandemic, but there is cautious optimism the study will be completed with sufficient sample size to robustly evaluate our hypothesis and provide meaningful results to the MS community on the impact of these interventions on people with progressive MS. Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated

Chandra Observations of Associates of η\eta Car: I. Luminosities

The region around the $\eta$ Car nebula has three OB associations, which contain a Wolf-Rayet star and several massive O3 stars. An early Chandra ACIS-I image was centered on $\eta$ Car and includes Trumpler 16 and part of Trumpler 14. The Chandra image confirms the well-known result that O and very early B stars are X-ray sources with L$_X$ $\simeq$ 10$^{-7} \times$ L$_{bol}$ over an X-ray luminosity range of about 100. Two new anomalously strong X-ray sources have been found among the hot star population, Tr 16-244, a heavily-reddened O3 I star, and Tr 16-22, a heavily-reddened O8.5 V star. Two stars have an unusually large L$_X$/L$_{bol}$: HD 93162, a Wolf-Rayet star (and possible binary), and Tr 16-22, a possible colliding wind binary In addition, a population of sources associated with cool stars is detected. In the color-magnitude diagram, these X-ray sources sit above the sequence of field stars in the Carina arm. The OB stars are on average more X-ray luminous than the cool star X-ray sources. X-ray sources among A stars have similar X-ray luminosities to cooler stars, and may be due to cooler companions. Upper limits are presented for B stars which are not detected in X-rays. These upper limits are also the upper limits for any cool companions which the hot stars may have. Hardness ratios are presented for the most luminous sources in bands 0.5 to 0.9 keV, 0.9 to 1.5 keV, and 1.5 to 2.04 kev. The available information on the binary nature of the hot stars is discussed, but binarity does not correlate with X-ray strength in a simple way.Comment: accepted by Ap

An Introduction to the Chandra Carina Complex Project

The Great Nebula in Carina provides an exceptional view into the violent massive star formation and feedback that typifies giant HII regions and starburst galaxies. We have mapped the Carina star-forming complex in X-rays, using archival Chandra data and a mosaic of 20 new 60ks pointings using the Chandra X-ray Observatory's Advanced CCD Imaging Spectrometer, as a testbed for understanding recent and ongoing star formation and to probe Carina's regions of bright diffuse X-ray emission. This study has yielded a catalog of properties of >14,000 X-ray point sources; >9800 of them have multiwavelength counterparts. Using Chandra's unsurpassed X-ray spatial resolution, we have separated these point sources from the extensive, spatially-complex diffuse emission that pervades the region; X-ray properties of this diffuse emission suggest that it traces feedback from Carina's massive stars. In this introductory paper, we motivate the survey design, describe the Chandra observations, and present some simple results, providing a foundation for the 15 papers that follow in this Special Issue and that present detailed catalogs, methods, and science results.Comment: Accepted for the ApJS Special Issue on the Chandra Carina Complex Project (CCCP), scheduled for publication in May 2011. All 16 CCCP Special Issue papers are available at http://cochise.astro.psu.edu/Carina_public/special_issue.html through 2011 at least. 43 pages; 18 figure

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients

Do Children with Fragile X Syndrome Show Declines or Plateaus in Adaptive Behavior?

This study explores if children with fragile X syndrome (FXS) show advances, declines, or plateaus in adaptive behavior over time and the relationship of nonverbal cognitive abilities and autistic behavior on these trajectories. Parents of 55 children with FXS completed the Vineland Adaptive Behavior Scales between 3 and 6 times from 2 to 10 years of age. Using raw scores, results indicate that about half of the sample showed advances in adaptive behavior, while the other half showed declines, indicating a regression in skills. Children who were more cognitively advanced and had less autistic behaviors had higher trajectories. Understanding the developmental course of adaptive behavior in FXS has implications for educational planning and intervention, especially for those children showing declines

Multimorbidity and comorbidity in the Dutch population - data from general practices

<p>Abstract</p> <p>Background</p> <p>Multimorbidity is increasingly recognized as a major public health challenge of modern societies. However, knowledge about the size of the population suffering from multimorbidity and the type of multimorbidity is scarce. The objective of this study was to present an overview of the prevalence of multimorbidity and comorbidity of chronic diseases in the Dutch population and to explore disease clustering and common comorbidities.</p> <p>Methods</p> <p>We used 7 years data (2002–2008) of a large Dutch representative network of general practices (212,902 patients). Multimorbidity was defined as having two or more out of 29 chronic diseases. The prevalence of multimorbidity was calculated for the total population and by sex and age group. For 10 prevalent diseases among patients of 55 years and older (N = 52,014) logistic regressions analyses were used to study disease clustering and descriptive analyses to explore common comorbid diseases.</p> <p>Results</p> <p>Multimorbidity of chronic diseases was found among 13% of the Dutch population and in 37% of those older than 55 years. Among patients over 55 years with a specific chronic disease more than two-thirds also had one or more other chronic diseases. Most disease pairs occurred more frequently than would be expected if diseases had been independent. Comorbidity was not limited to specific combinations of diseases; about 70% of those with a disease had one or more extra chronic diseases recorded which were not included in the top five of most common diseases.</p> <p>Conclusion</p> <p>Multimorbidity is common at all ages though increasing with age, with over two-thirds of those with chronic diseases and aged 55 years and older being recorded with multimorbidity. Comorbidity encompassed many different combinations of chronic diseases. Given the ageing population, multimorbidity and its consequences should be taken into account in the organization of care in order to avoid fragmented care, in medical research and healthcare policy.</p

Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome:Results from The GALA Study

BACKGROUND: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.METHODS: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.RESULTS: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (&gt;6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and &lt;10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those &lt;5.0 mg/dL. Median TB levels between ≥5.0 and &lt;10.0 mg/dL and &gt;10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to &lt;5.0 mg/dL. Median TB &lt;5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p&lt;0.001).CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB &lt;5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.</p