Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for the formation and compositional regulation of ...biomolecular condensates. Here, we review the key concepts of phase transitions of aqueous solutions of associative biomacromolecules, specifically proteins that include folded domains and intrinsically disordered regions. The phase transitions of these systems come under the rubric of coupled associative and segregative transitions. The concepts underlying these processes are presented, and their relevance to biomolecular condensates is discussed.
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IJS, KILJ, NUK, PNG, UL, UM
Despite the high prevalence of depression and other mental illnesses in autistic adults, screening instruments such as the Patient Health Questionnaire (PHQ-9) have not been specifically validated in ...an autistic sample. Using data from two Autism CRC longitudinal studies (
n
= 581), confirmatory factor analysis supported the two-factor model (somatic and cognitive/affective) in the autistic sample and one-factor model in the community comparison sample. Confirmatory bifactor analysis also supported use of the PHQ-9 total score in autism. Good convergent validity was found with two measures of psychological well-being for PHQ-9 total and subdomain scores. The PHQ-9 is a useful tool for autism research allowing comparison across autistic and non-autistic participants.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
24.
Risk Factors for Severe COVID-19 in Children Graff, Kelly; Smith, Christiana; Silveira, Lori ...
The Pediatric infectious disease journal,
04/2021, Volume:
40, Issue:
4
Journal Article
Peer reviewed
There are limited pediatric data regarding severe COVID-19 disease. Our study aims to describe the epidemiology and identify risk factors for severe COVID-19 disease in children.
This is a ...retrospective cohort study among children with positive SARS-CoV-2 PCR from March to July 2020 at Children's Hospital Colorado. Risk factors for severe disease were analyzed as defined by hospital admission, respiratory support, or critical care. Univariable and multivariable analyses were conducted.
Among 454 patients identified with SARS-CoV-2, 191 (42.1%) were females, median age 11 years. Fifty-five percent of all patients identified as Hispanic compared with 29% among all hospital visits in 2019 (P < 0.0001). In multivariable analyses, age 0-3 months or >20 years adjusted odds ratio (aOR), 7.85; P < 0.0001 and aOR, 5.1; P = 0.03, respectively, preterm birth history (aOR, 3.7; P = 0.03), comorbidities including immunocompromise (aOR, 3.5; P = 0.004), gastrointestinal condition (aOR, 2.7; P = 0.009), diabetes (aOR, 6.6; P = 0.04), asthma (aOR, 2.2; P = 0.04), and specific symptoms at presentation were predictors for admission. Age 0-3 months or >20 years, asthma, gastrointestinal condition, and similar symptoms at presentation were also predictors for respiratory support. Elevated C-reactive protein was associated with the need for critical care with median of 17.7 mg/dL (IQR, 5.3-22.9) versus 1.95 mg/dL (IQR, 0.7-5.5) among patients requiring critical versus no critical care (OR, 1.2; P = 0.02).
Extremes of age, comorbid conditions, and elevated CRP are predictors of severe disease in children. Findings from this study can inform pediatric providers and public health officials to tailor clinical management, pandemic planning, and resource allocation.
Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years. Median survival is between 3 ...and 5 years after diagnosis. IPF is characterized primarily by excessive deposition of extracellular matrix (ECM) proteins by activated lung fibroblasts and myofibroblasts, resulting in reduced gas exchange and impaired pulmonary function. Growing evidence supports the concept of a pro-fibrotic environment orchestrated by underlying factors such as genetic predisposition, chronic injury and aging, oxidative stress, and impaired regenerative responses may account for disease development and persistence. Currently, two FDA approved drugs have limited efficacy in the treatment of IPF. Many of the genes and gene networks associated with lung development are induced or activated in IPF. In this review, we analyze current knowledge in the field, gained from both basic and clinical research, to provide new insights into the disease process, and potential approaches to treatment of pulmonary fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent associative macromolecules. Phase separation coupled to percolation is one example of such ...transitions. Here, we characterize molecular and mesoscale structural descriptions of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform to sticker-and-spacers architectures. Stickers are cohesive motifs that drive associative interactions through reversible crosslinking and spacers affect the cooperativity of crosslinking and overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific phase behaviors of PLCDs. Within simulated condensates, networks of reversible inter-sticker crosslinks organize PLCDs into small-world topologies. The overall dimensions of PLCDs vary with spatial location, being most expanded at and preferring to be oriented perpendicular to the interface. Our results demonstrate that even simple condensates with one type of macromolecule feature inhomogeneous spatial organizations of molecules and interfacial features that likely prime them for biochemical activity.
Gambling Disorder is a prevalent psychiatric condition often linked to dysfunction of cognitive domains regulating impulsive behavior. Despite the centrality of impulsivity to neurobiological models ...of Gambling Disorder, a comprehensive meta-analysis of all impulsive cognitive domains has yet to be conducted. It is also not clear whether cognitive deficits in Gambling Disorder extend to those with problem (at-risk) gambling. A systematic review was undertaken of case-control studies examining the following cognitive domains in Gambling Disorder or in at-risk (problem) gambling: attentional inhibition, motor inhibition, discounting, decision-making, and reflection impulsivity. Case-control differences in cognition were identified using meta-analysis (random-effects modeling). Moderation analysis explored potential influences of age, gender, presence/absence of comorbidities in cases, geographical region, and study quality on cognitive performance. Gambling Disorder was associated with significant impairments in motor (g = 0.39-0.48) and attentional (g = 0.55) inhibition, discounting (g = 0.66), and decision-making (g = 0.63) tasks. For problem gambling, only decision-making had sufficient data for meta-analysis, yielding significant impairment versus controls (g = 0.66); however, study quality was relatively low. Insufficient data were available for meta-analysis of reflection impulsivity. There was evidence for significant publication bias only for the discounting domain, after an outlier study was excluded. Study quality overall was reasonable (mean score 71.9% of maximum), but most studies (~85%) did not screen for comorbid impulse control and related disorders. This meta-analysis indicates heightened impulsivity across a range of cognitive domains in Gambling Disorder. Decision-making impulsivity may extend to problem (at-risk) gambling, but further studies are needed to confirm such candidate cognitive vulnerability markers.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal ...adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that KrasG12D drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.
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▸ Oncogenic KrasG12D is required for PDAC tumor maintenance ▸ KrasG12D reprograms PDAC metabolism by stimulating glucose uptake and glycolysis ▸ KrasG12D drives enhanced glycolytic flux into glycosylation and ribose biogenesis ▸ This metabolic shift is mediated by MEK activation and Myc-dependent transcription
Pancreatic cancers are frequently associated with activated Kras, which is now shown in a genetically engineered mouse model to reprogram tumor metabolism by channeling glucose into several biosynthetic pathways critical for tumor growth and maintenance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ObjectivesLocally led health research in low and middle income countries (LMICs) is critical for overcoming global health challenges. Yet, despite over 25 years of international efforts, health ...research capacity in LMICs remains insufficient and development attempts continue to be fragmented. The aim of this systematic review is to identify and critically examine the main approaches and trends in health research capacity development and consolidate key thinking to identify a more coherent approach.MethodsThis review includes academic and grey literature published between January 2000 and July 2013. Using a predetermined search strategy, we systematically searched PubMed, hand-searched Google Scholar and checked reference lists. This process yielded 1668 papers. 240 papers were selected based on a priori criteria. A modified version of meta-narrative synthesis was used to analyse the papers.Results3 key narratives were identified: the effect of power relations on capacity development; demand for stronger links between research, policy and practice and the importance of a systems approach. Capacity development was delivered through 4 main modalities: vertical research projects, centres of excellence, North–South partnerships and networks; all were controversial, and each had their strengths and weaknesses. A plurality of development strategies was employed to address specific barriers to health research. However, lack of empirical research and monitoring and evaluation meant that their effectiveness was unclear and learning was weak.ConclusionsThere has been steady progress in LMIC health research capacity, but major barriers to research persist and more empirical evidence on development strategies is required. Despite an evolution in development thinking, international actors continue to use outdated development models that are recognised as ineffective. To realise newer development thinking, research capacity outcomes need to be equally valued as research outputs. While some development actors are now adopting this dedicated capacity development approach, they are in the minority.
Abstract Muscles actuate running by developing forces that propel the body forward while supporting the body’s weight. To understand how muscles contribute to propulsion (i.e., forward acceleration ...of the mass center) and support (i.e., upward acceleration of the mass center) during running we developed a three-dimensional muscle-actuated simulation of the running gait cycle. The simulation is driven by 92 musculotendon actuators of the lower extremities and torso and includes the dynamics of arm motion. We analyzed the simulation to determine how each muscle contributed to the acceleration of the body mass center. During the early part of the stance phase, the quadriceps muscle group was the largest contributor to braking (i.e., backward acceleration of the mass center) and support. During the second half of the stance phase, the soleus and gastrocnemius muscles were the greatest contributors to propulsion and support. The arms did not contribute substantially to either propulsion or support, generating less than 1% of the peak mass center acceleration. However, the arms effectively counterbalanced the vertical angular momentum of the lower extremities. Our analysis reveals that the quadriceps and plantarflexors are the major contributors to acceleration of the body mass center during running.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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