The power of structural information for informing biological mechanisms is clear for stable folded macromolecules, but similar structure–function insight is more difficult to obtain for highly ...dynamic systems such as intrinsically disordered proteins (IDPs) which must be described as structural ensembles. Here, we present IDPConformerGenerator, a flexible, modular open-source software platform for generating large and diverse ensembles of disordered protein states that builds conformers that obey geometric, steric, and other physical restraints on the input sequence. IDPConformerGenerator samples backbone phi (φ), psi (ψ), and omega (ω) torsion angles of relevant sequence fragments from loops and secondary structure elements extracted from folded protein structures in the RCSB Protein Data Bank and builds side chains from robust Monte Carlo algorithms using expanded rotamer libraries. IDPConformerGenerator has many user-defined options enabling variable fractional sampling of secondary structures, supports Bayesian models for assessing the agreement of IDP ensembles for consistency with experimental data, and introduces a machine learning approach to transform between internal and Cartesian coordinates with reduced error. IDPConformerGenerator will facilitate the characterization of disordered proteins to ultimately provide structural insights into these states that have key biological functions.
Abstract
The impacts of climatic changes on forests may appear gradually on time scales of years to centuries due to the long generation times of trees. Consequently, current forest extent may not ...reflect current climatic patterns. In contrast with these lagged responses, abrupt transitions in forests under climate change may occur in environments where alternative vegetation states are influenced by disturbances, such as fire. The Klamath forest landscape (northern California and southwest Oregon, USA) is currently dominated by high biomass, biodiverse temperate coniferous forests, but climate change could disrupt the mechanisms promoting forest stability (e.g. growth, regeneration and fire tolerance). Using a landscape simulation model, we estimate that about one-third of the Klamath forest landscape (500,000 ha) could transition from conifer-dominated forest to shrub/hardwood chaparral, triggered by increased fire activity coupled with lower post-fire conifer establishment. Such shifts were widespread under the warmer climate change scenarios (RCP 8.5) but were surprisingly prevalent under the climate of 1949–2010, reflecting the joint influences of recent warming trends and the legacy of fire suppression that may have enhanced conifer dominance. Our results demonstrate that major forest ecosystem shifts should be expected when climate change disrupts key stabilizing feedbacks that maintain the dominance of long-lived, slowly regenerating trees.
Objective To evaluate the phenotyping performance of three major electronic health record (EHR) components: International Classification of Disease (ICD) diagnosis codes, primary notes, and specific ...medications.
Materials and Methods We conducted the evaluation using de-identified Vanderbilt EHR data. We preselected ten diseases: atrial fibrillation, Alzheimer’s disease, breast cancer, gout, human immunodeficiency virus infection, multiple sclerosis, Parkinson’s disease, rheumatoid arthritis, and types 1 and 2 diabetes mellitus. For each disease, patients were classified into seven categories based on the presence of evidence in diagnosis codes, primary notes, and specific medications. Twenty-five patients per disease category (a total number of 175 patients for each disease, 1750 patients for all ten diseases) were randomly selected for manual chart review. Review results were used to estimate the positive predictive value (PPV), sensitivity, and F-score for each EHR component alone and in combination.
Results The PPVs of single components were inconsistent and inadequate for accurately phenotyping (0.06–0.71). Using two or more ICD codes improved the average PPV to 0.84. We observed a more stable and higher accuracy when using at least two components (mean ± standard deviation: 0.91 ± 0.08). Primary notes offered the best sensitivity (0.77). The sensitivity of ICD codes was 0.67. Again, two or more components provided a reasonably high and stable sensitivity (0.59 ± 0.16). Overall, the best performance (F score: 0.70 ± 0.12) was achieved by using two or more components. Although the overall performance of using ICD codes (0.67 ± 0.14) was only slightly lower than using two or more components, its PPV (0.71 ± 0.13) is substantially worse (0.91 ± 0.08).
Conclusion Multiple EHR components provide a more consistent and higher performance than a single one for the selected phenotypes. We suggest considering multiple EHR components for future phenotyping design in order to obtain an ideal result.
Interrelationships among skeletal maturity status, body size, ventilator thresholds (VT) and peak oxygen uptake (VO2peak) were considered in 47 adolescent male soccer players aged 12.5-15.4 years. ...Body mass, stature, and the triceps and subscapular skinfolds were measured. The latter were used to estimate fat mass and fat-free mass. Skeletal age was assessed with the Fels method. VO2peak and VO2 at the first (VT1) and second (VT2) ventilatory thresholds were determined during an incremental maximal exercise test on a motorized treadmill. Ratio standards and allometric models were used in the analysis. Scaling exponents suggested linearity for all combinations between size descriptors and physiological variables, except between log-transformed values of VT1 and body mass (mL·kg-0.801·min, 95%CI: 0.649 to 0.952). Early maturing players attained greater values than players classified as "on-time" in skeletal maturity for the three ventilatory parameters expressed in absolute terms (d ranged from 0.65 to 0.71). The differences were attenuated after normalizing for mass descriptors using ratio standards and scaled variables (d ranged from 0.00 to 0.31). The results suggested significant variability between maturity groups when moving from VT1 to maximal metabolic conditions expressed by unit of stature (VT1: t = -2.413, p = 0.02, d = 0.60; VT2: t = -2.488, p = 0.02, d = 0.65; VO2peak: t = -2.475, p = 0.02, d = 0.65). Skeletal maturity status and associated variation in overall body size affects VT1, VT2 and VO2peak. The observed scaling of ventilatory outputs for body size may be related to the better running economy and smaller body size of average maturing athletes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human land‐use change is a major threat to natural ecosystems worldwide. Nonetheless, the effects of human land‐uses on the structure of plant and animal assemblages and their functional ...characteristics need to be better understood. Furthermore, the pathways by which human land uses affect ecosystem functions, such as biomass production, still need to be clarified.
We compiled a unique dataset of fish, arthropod and macrophyte assemblages from 61 stream ecosystems in two Neotropical biomes: Amazonian rainforest and Uruguayan grasslands. We then tested how the cover of agriculture, pasture, urbanization and afforestation affected the taxonomic richness and functional diversity of those three species assemblages, and the consequences of these effects for animal biomass production. Single trait categories and functional diversity were evaluated, combining recruitment and life‐history, resource and habitat‐use, and body size.
The effects of intensive human land‐uses on taxonomic and functional diversities were as strong as other drivers known to affect biodiversity, such as local climate and environmental factors. In both biomes, the taxonomic richness and functional diversity of animal and macrophyte assemblages decreased with increasing cover of agriculture, pasture, and urbanization. Human land‐uses were associated with functional homogenization of both animal and macrophyte assemblages. Human land‐uses reduced animal biomass through direct and indirect pathways mediated by declines in taxonomic and functional diversities.
Our findings indicate that converting natural ecosystems to supply human demands results in species loss and trait homogenization across multiple biotic assemblages, ultimately reducing animal biomass production in streams.
This paper shows that multiple human land‐uses combined to (i) decrease the diversity and biomass production of streams across different Neotropical biomes; (ii) induce a loss of animal and plant species with unique functional traits, triggering functional homogenization of streams; and (iii) make the animal diversity‐biomass relationship negative.
BACKGROUNDManagement of positive margins after nonmelanoma skin cancer (NMSC) excision is debated in the literature. The purpose of this study is to determine the rate of residual tumor in reexcised ...NMSC specimens after previous excision with positive margins, to determine the rate of recurrence in patients who had positive margins but did not undergo reexcision, and to define the financial burden of negative reexcisions.
METHODSAn Institutional Review Board-approved retrospective review was conducted on all patients with NMSC excision over a 15-year period. Patients who met inclusion criteria and underwent initial NMSC excision with negative frozen section margins, but had positive permanent section margins were divided into 2 groupsthose who underwent reexcision for clearance of tumor (n = 161) or those who did not undergo further reexcision (n = 105). Variables collected include demographics, previous skin cancer, tumor location, cancer subtype, excision measurements, and time between first and second excisions. For those patients who did not undergo reexcision, charts were examined for recurrence.
RESULTSTwo hundred sixty-six patients met inclusion criteria with mean follow-up of 60 months. Eighty-three (52%) of 161 patients with positive margins on initial excision had no evidence of residual cancer upon reexcision. Residual tumor on permanent section was confirmed in 48% of patients. Patients with a previous history of basal cell carcinoma were more likely to have a true-positive margin after reexcision (P = 0.02). Larger reexcisions were more likely to harbor residual cancer (5.9 cm, P = 0.04). Patients with positive margins that did not undergo reexcision, only 7 of 105 patients (6.6%) had recurrence. No mortalities were reported from NMSC recurrence. US $247,672 was spent in reexcision for negative margins in 98 patients for an average cost of US $2984 per case.
CONCLUSIONSForty-eight percent of NMSC patients with positive margins had residual tumor upon reexcision. There were 6.6% of the patients who did not undergo resection after positive margins developed recurrence of disease at 5 years. Patients requiring larger reexcisions or those with a prior history of BCC were more likely to have residual cancer upon reexcision. This study suggests that observation is an appropriate option of care for certain patients with residual NMSC on permanent pathology.
Neural interfaces are well-established as a tool to understand the behaviour of the nervous system
via
recording and stimulation of living neurons, as well as serving as neural prostheses. ...Conventional neural interfaces based on metals and carbon-based materials are generally optimised for high conductivity; however, a mechanical mismatch between the interface and the neural environment can significantly reduce long-term neuromodulation efficacy by causing an inflammatory response. This paper presents a soft composite material made of gelatin methacryloyl (GelMA) containing graphene oxide (GO) conjugated with gold nanorods (AuNRs). The soft hydrogel presents stiffness within the neural environment range of modulus below 5 kPa, while the AuNRs, when exposed to light in the near infrared range, provide a photothermal response that can be used to improve the spatial and temporal precision of neuromodulation. These favourable properties can be maintained at safer optical power levels when combined with electrical stimulation. In this paper we provide mechanical and biological characterization of the optical activity of the GO-AuNR composite hydrogel. The optical functionality of the material has been evaluated
via
photothermal stimulation of explanted rat retinal tissue. The outcomes achieved with this study encourage further investigation into optical and electrical costimulation parameters for a range of biomedical applications.
Neural interfaces are well-established as a tool to understand the behaviour of the nervous system
via
recording and stimulation of living neurons, as well as serving as neural prostheses.
Objective: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often ...iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites.
Materials and Methods: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic.
Results: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar.
Conclusion: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.
Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide ...(LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll‐like receptor 4 (TLR4), which links to activation of nuclear factor‐κB (NF‐κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF‐κB, and promoter activity was inhibited by p65/p50. Nested 0.5‐ and 1.0‐kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF‐κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF‐κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF‐κB to down‐regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.