bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of the Cannabis sativa olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases
Authors: Kearsey Lewis J. , Prandi Nicole , Karuppiah Vijaykumar , Yan Cunyu , Leys David , Toogood Helen , Takano Eriko , Scrutton Nigel S. 
Published: October 2019

In the native pathway to therapeutic cannabinoid biosynthesis in Cannabis sativa, the three‐step production of a key intermediate, olivetolic acid, is catalysed by the enzymes tetraketide synthase (TKS; linear tetraketide intermediate production in two stages) and olivetolic acid cyclase (OAC; final C2 → C7 aldol condensation). In the absence of OAC, a nonenzymatic C2 → C7 decarboxylative aldol condensation of the tetraketide intermediate occurs forming olivetol. TKS is a type III polyketide synthase, and the question arises why it is unable to form olivetolic acid directly, but instead forms this unwanted side product. We determined the TKS, CoA complex structure, and performed structurally guided mutagenesis studies to identify potential residues responsible for cyclization pathway discrimination in type III polyketide synthases. Prior studies suggested an ‘aldol switch’ is necessary to allow linear tetraketide intermediate release prior to cyclization, thereby enabling subsequent olivetolic acid production by OAC. However, our studies do not support the presence of a universal or predictable ‘aldol switch’ consensus sequence. Instead, we propose the mode of ordered active site water activation between type III polyketide synthases catalysing different cyclization mechanisms is subtle and homologue‐specific. Our work indicates that subtle structural variations between homologous enzymes can have a major mechanistic impact on the catalytic outcome. This highlights the importance of embedding high‐resolution structural analysis of multiple enzyme homologues with classical site‐directed mutagenesis studies when investigating highly similar enzymes with different mechanistic pathway outcomes.EnzymesTKS, EC 2.3.1.206; OAC, EC 4.4.1.26; chalcone synthase, EC 2.3.1.74; stilbene synthase, EC 2.3.1.95; 2‐PS, EC 2.3.1.-.Accession numbersThe atomic coordinates and structure factors for the crystal structure of TKS have been deposited in the Protein Data Bank with accession number 6GW3.
Stabilization of backbone‐circularized protein is attained by synergistic gains in enthalpy of folded structure and entropy of unfolded structure
Authors: Shibuya Risa , Miyafusa Takamitsu , Honda Shinya 
Published: October 2019

Backbone circularization is an effective technique for protein stabilization. Here, we investigated the effect of a connector, an engineered segment that connects two protein termini, on the conformational stability of previously designed circularized variants of granulocyte colony‐stimulating factor (G‐CSF). Heat tolerance and chemical denaturation analyses revealed that aggregation resistance and thermodynamic stability of the circularized variants were superior to those of linear G‐CSF. Crystal structure and molecular dynamics (MD) simulation of the most thermodynamically stable variant (C166) revealed a high number of intramolecular hydrogen bonds in both the connector region and Helix D adjacent to the connector region in the folded structure. MD simulations and theoretical calculations involving different force fields indicated a reduction in the main chain entropy of C166 in the unfolded state and increase in the intramolecular hydrogen bond energy of C166 in the folded structure. Although backbone circularization is usually considered to alter chain entropy of the unfolded state, the data indicated that it could also improve the conformational enthalpy of the folded state. Further structural examination of the connector region confirmed that protein design based on a statistical analysis of local structures is an effective approach for predicting an optimum connector length to improve the conformational stability of backbone‐circularized proteins. Protein design using backbone circularization with an optimum connector length will be useful for the development of effective and safe protein therapeutics.DatabaseStructural data are available in Protein Data Bank under the accession number 5ZO6.
Mutations in the Scn8a DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Nav1.6 sodium channels
Authors: Inglis George Andrew S. , Wong Jennifer C. , Butler Kameryn M. , Thelin Jacquelyn T. , Mistretta Olivia C. , Wu Xuewen , Lin Xi , English Arthur W. , Escayg Andrew 
Published: October 2019

AbstractMutations in the voltage‐gated sodium channel gene SCN8A cause a broad range of human diseases, including epilepsy, intellectual disability, and ataxia. Here we describe three mouse lines on the C57BL/6J background with novel, overlapping mutations in the Scn8a DIIS4 voltage sensor: an in‐frame 9 bp deletion (Δ9), an in‐frame 3 bp insertion (∇3) and a 35 bp deletion that results in a frameshift and the generation of a null allele (Δ35). Scn8a
Δ9/+ and Scn8a
∇3/+ heterozygous mutants display subtle motor deficits, reduced acoustic startle response, and are resistant to induced seizures, suggesting that these mutations reduce activity of the Scn8a channel protein, Nav1.6. Heterozygous Scn8a
Δ35/+ mutants show no alterations in motor function or acoustic startle response, but are resistant to induced seizures. Homozygous mutants from each line exhibit premature lethality and severe motor impairments, ranging from uncoordinated gait with tremor (Δ9 and ∇3) to loss of hindlimb control (Δ35). Scn8a
Δ9/Δ9 and Scn8a
∇3/∇3 homozygous mutants also exhibit impaired nerve conduction velocity, while normal nerve conduction was observed in Scn8a
Δ35/Δ35 homozygous mice. Our results suggest that hypomorphic mutations that reduce Nav1.6 activity will likely result in different clinical phenotypes compared to null alleles. These three mouse lines represent a valuable opportunity to examine the phenotypic impacts of hypomorphic and null Scn8a mutations without the confound of strain‐specific differences.
Hypothalamic transcriptome of tame and aggressive silver foxes (Vulpes vulpes) identifies gene expression differences shared across brain regions
Authors: Rosenfeld Cheryl S. , Hekman Jessica P. , Johnson Jennifer L. , Lyu Zhen , Ortega Madison T. , Joshi Trupti , Mao Jiude , Vladimirova Anastasiya V. , Gulevich Rimma G. , Kharlamova Anastasiya V. , Acland Gregory M. , Hecht Erin E. , Wang Xu , Clark Andrew G. , Trut Lyudmila N. , Behura Susanta K. , Kukekova Anna V. 
Published: October 2019

AbstractThe underlying neurological events accompanying dog domestication remain elusive. To reconstruct the domestication process in an experimental setting, silver foxes (Vulpes vulpes) have been deliberately bred for tame vs aggressive behaviors for more than 50 generations at the Institute for Cytology and Genetics in Novosibirsk, Russia. The hypothalamus is an essential part of the hypothalamic‐pituitary‐adrenal axis and regulates the fight‐or‐flight response, and thus, we hypothesized that selective breeding for tameness/aggressiveness has shaped the hypothalamic transcriptomic profile. RNA‐seq analysis identified 70 differentially expressed genes (DEGs). Seven of these genes,DKKL1,FBLN7,NPL,PRIMPOL,PTGRN,SHCBP1LandSKIV2L, showed the same direction expression differences in the hypothalamus, basal forebrain and prefrontal cortex. The genes differentially expressed across the three tissues are involved in cell division, differentiation, adhesion and carbohydrate processing, suggesting an association of these processes with selective breeding. Additionally, 159 transcripts from the hypothalamus demonstrated differences in the abundance of alternative spliced forms between the tame and aggressive foxes. Weighted gene coexpression network analyses also suggested that gene modules in hypothalamus were significantly associated with tame vs aggressive behavior. Pathways associated with these modules include signal transduction, interleukin signaling, cytokine‐cytokine receptor interaction and peptide ligand‐binding receptors (eg, G‐protein coupled receptor [GPCR] ligand binding). Current studies show the selection for tameness vs aggressiveness in foxes is associated with unique hypothalamic gene profiles partly shared with other brain regions and highlight DEGs involved in biological processes such as development, differentiation and immunological responses. The role of these processes in fox and dog domestication remains to be determined.
Variation in Saturated Hydraulic Conductivity at the Outcrop Scale, the Whanganui Basin, New Zealand
Authors: Rees Callum , Palmer Alan , Palmer Julie , Singh Ranvir 
Published: October 2019

AbstractGroundwater flow and contaminant transport are strongly influenced by hydrogeological spatial variation. Understanding the textural heterogeneity of aquifer and aquitard units is critical for predicting preferential flow pathways, but is often hindered by sparse hydrogeological data, widely spaced data points, and complex stratigraphy. Here, we demonstrate the application of a relatively new air permeameter technology, providing a cost‐effective, rapid alternative for characterizing hydrostratigraphic units in the field. The aim of this research is to (1) characterize the variation of saturated hydraulic conductivity across shallow‐marine hydrostratigraphic units of the Whanganui Basin, New Zealand, and (2) assess the variation of saturated hydraulic conductivity within individual hydrostratigraphic units and relate these changes to facies and depositional environments. Results suggest heterogeneity within fine‐grained aquitard units is controlled by bioturbation, whereby burrowing, ingestion and defecation results in grain size segregation and differential micrite cementation. Coarse‐grained heterolithic aquifer facies display sharp changes in permeability across planar to cross‐bedded sets, related to current and wave energy fluctuations within shallow‐marine depositional settings. Bedding plane orientation creates high permeability zones that promotes down dip subsurface flow. Down dip gradation of coarse‐grained nearshore facies into fine‐grained shelf facies along the paleo shoreline‐shelf transect is suggested to promote lateral and vertical groundwater flow within the basin fill. Air permeameter techniques have potential for application within groundwater basins around the world, providing datasets that facilitate greater understanding of groundwater systems, informing practices and policies for targeted water quality management.
Pain and Pruritus: a study of their similarities and differences
Authors: Anzelc Madison , Burkhart Craig G. 
Published: October 2019

AbstractPruritus is one of the most common dermatologic complaints and, as the most common dermatologic symptom, is a major contributor to frequent dermatology visits. Chronic pruritus mirrors another major medical condition faced by millions of Americans each year ‐ chronic pain. In older literature, pain and pruritus were thought to have been conveyed by the same C fiber, and the proportion contributing to pruritus was just a small subset of this general fiber. Overall, pain and pruritus share many integral similarities. Although these sensations both initiate the body’s awareness to injury, pain and itch may have evolved for sensing different damages such as a burrowing parasite or a noxious stimulus, respectively. This seems to have been validated through analyses of their pathophysiology, acute and chronic conditions, and treatment modalities. However, their symptoms and intrinsic mechanisms vary considerably. It is important to view pruritus in more of an overall, whole body experience, rather than just the sensory aspect. Future studies should investigate the psychological treatment of chronic pruritus, considering the immense similarities with its chronic pain counterpart.
Fast and fierce versus slow and smooth: Heterogeneity in immune responses to Plasmodium in the controlled human malaria infection model
Authors: Yap Xi Zen , McCall Matthew B. B. , Sauerwein Robert W. 
Published: October 2019

AbstractControlled human malaria infection (CHMI) is an established model in clinical malaria research. Upon exposure to Plasmodium falciparum parasites, malaria‐naive volunteers differ in dynamics and composition of their immune profiles and subsequent capacity to generate protective immunity. CHMI volunteers are either inflammatory responders who have prominent cellular IFN‐γ production primarily driven by adaptive T cells, or tempered responders who skew toward antibody‐mediated humoral immunity. When exposed to consecutive CHMIs under antimalarial chemoprophylaxis, individuals who can control parasitemia after a single immunization (fast responders) are more likely to be protected against a subsequent challenge infection. Fast responders tend to be inflammatory responders who can rapidly induce long‐lived IFN‐γ+ T cell responses. Slow responders or even non‐responders can also be protected, but via a more diverse range of responses that take a longer time to reach full protective efficacy, in part due to their tempered phenotype. The latter group can be identified at baseline before CHMI by higher expression of inhibitory ligands CTLA‐4 and TIM‐3 on CD4+ T cells. Delineating heterogeneity in human immune responses to P. falciparum will facilitate rational design and strategy towards effective malaria vaccines.
Holocene increases in palm abundances in north‐western Amazonia
Authors: Heijink Britte M. , McMichael Crystal N. H. , Piperno Dolores R. , Duivenvoorden Joost F. , Cárdenas Dairon , Duque Álvaro 
Published: October 2019

AbstractAimIn Amazonia, 227 of c. 16,000 tree species account for half the individual trees (termed ‘hyperdominant’ species), and a disproportionate number of these species are palms. Our objectives are to show how and whether palm abundance has changed through the Holocene. Here, we reconstruct a detailed fire and vegetation history from north‐western Amazonia, with a focus on changes in palm abundances, and compare our results with regional data.LocationAmacayacu, Colombia.TaxonAmazonian palms.MethodsWe performed charcoal and phytolith analysis on soil cores, and obtained ages of past fires using 14C dating. We measured charcoal abundances and the relative abundances of phytoliths (silica‐based microfossils) for all samples. We used these data to reconstruct changes in fire and vegetation, and compared these data with the species composition of palms in the modern forest.ResultsSeven 14C dates from charcoal in three cores provided fire ages ranging from 1630 to 2450 calibrated years before present. Charcoal was absent from one‐third of the cores. Palm phytoliths from genera such as Iriartea, Socratea, and Astrocaryum have increased through time, while genera such as Euterpe, Hyospathe, and Oenocarpus have remained relatively stable and similar to modern levels. Overall, palm abundances were negatively correlated with charcoal measurements. Decorated sphere phytoliths, produced from unknown arboreal taxa were positively correlated with charcoal presence and abundance.Main conclusionsPalms have increased at Amacayacu and other forest plots through time, but the increases are largest in north‐western Amazonia. The presence of fire, however, dampens the increase in palms through time. When compared with reconstructions from other Amazon regions, our results suggest that increases in palm abundances in the late Holocene occurred both in the presence and absence of direct pre‐Columbian human influence, and that response was strongest in north‐western Amazonia when human influence was minimal.
Improvement of urban flood damage estimation using a high‐resolution digital terrain
Authors: Kim Young Do , Tak Yong Hun , Park Mun Hyun , Kang Boosik 
Published: October 2019

AbstractBecause urban flooding occurs frequently, it is important to calculate the areal extent of flooding based on flood volumes and water levels, and thus, the extent of expected damage can be effectively estimated. In this study, urban inundation from heavy rainfall and the contribution of topographic scales to urban river drainage basins in Seoul, Korea are simulated. A light detection and ranging (LiDAR)‐based 1× 1 m digital elevation model (DEM) and a 1:5,000 digital map‐based 10 × 10 m DEM are used in this study for the storm water management model (SWMM). Using a multi‐dimensional flood damage analysis to estimate economic damage, the asset value of each building type is analyzed in connection with the construction cost of buildings, household ratio, and building area, and then, the building damage is calculated at each flood level based on the percentage of building damage. Based on the analysis, 119.6 and 55.8 M USD in damages are expected to occur according to the 1 and 10 m DEMs, respectively. The results of this study can be used to evaluate alternatives for urban flooding mitigation and an optimal mitigation measure can be suggested among the alternatives because the methods used for predicting floods are examined and the associated damages are accurately estimated using digital terrain data at precise scales.
The Caregiver Burden of Delirium in Older Adults With Alzheimer Disease and Related Disorders
Authors: Fong Tamara G. , Racine Annie M. , Fick Donna M. , Tabloski Patricia , Gou Yun , Schmitt Eva M. , Hshieh Tammy T. , Metzger Eran , Bertrand Sylvie E. , Marcantonio Edward R. , Jones Richard N. , Inouye Sharon K. 
Published: October 2019

OBJECTIVESTo measure the burden of delirium in older adults with or without Alzheimer disease or related disorders (ADRDs).DESIGNProspective, observational cohort.SETTINGInpatient hospital and study participants' homes.PARTICIPANTSA subset (n = 267) of older medical and surgical patients and their caregivers enrolled in the Better Assessment of Illness study.MEASUREMENTSDelirium burden was measured using the DEL‐B instrument (range = 0‐40, with higher scores indicating greater burden) in caregivers (DEL‐B‐C) and patients 1 month after hospitalization. Severity of cognitive impairment (Montreal Cognitive Assessment [MoCA]), delirium presence (Confusion Assessment Method [CAM]), and delirium severity (CAM‐Severity [CAM‐S]) were measured during hospitalization and at 1‐month follow‐up. ADRD diagnosis was determined by a clinical consensus process.RESULTSFor patients with (n = 56) and without (n = 211) ADRD, both DEL‐B instruments had good internal consistency. DEL‐B‐C scores had a median (interquartile range) among caregivers of patients with and without ADRD of 9 (5‐15) and 5 (1‐11), respectively (P < .05). If the patient developed delirium, caregivers experienced greater burden (β[delirium × ADRD] = −.29; P = .42), regardless of ADRD status. Further, caregiver burden was modestly correlated with patient MoCA scores (Spearman correlation coefficient, ρ = −0.18; P = .01). Patients with ADRD who developed delirium self‐reported less burden than those without ADRD (β[delirium × ADRD] = −.67; P = .044). As with caregivers, delirium burden was modestly correlated with patient MoCA score (ρ = −0.18; P = .005) and correlated with the CAM‐S in patients without ADRD (ρ = 0.38; P < .001) but not for patients with ADRD (ρ = −0.07; P = .61).CONCLUSIONSDelirium resulted in the same degree of increased caregiver burden regardless of whether a patient had ADRD, signifying delirium is equally stressful to caregivers, even among those with experience caring for someone with a chronic cognitive disorder. Delirium burden is only modestly associated with degree of cognitive impairment, suggesting that other aspects of delirium contribute to burden. J Am Geriatr Soc 67:2587–2592, 2019
Comparative evaluation of curcumin and antioxidants in the management of oral submucous fibrosis
Authors: Rai Arpita , Kaur Mandeep , Gombra Virender , Hasan Shamimul , Kumar Narender 
Published: October 2019

AbstractAimThe present study aims to evaluate the efficacy and safety of curcumin in both topical and systemic forms for management of oral submucous fibrosis in comparison with the antioxidants.MethodsIn this randomized parallel‐group single‐center trial, 119 patients were enrolled. Group I received antioxidants, group II received curcumin in systemic form and group III received curcumin in both systemic and topical forms. The primary outcomes assessed were interincisal mouth opening and burning sensation using a visual analog scale. The secondary outcomes were tongue protrusion and adverse reactions. The response to treatment was analyzed using ANOVA and Fisher's exact test.ResultsSignificant improvement in mouth opening, burning sensation and tongue protrusion was observed in all groups at 12 weeks. Mean improvement in burning sensation did not show statistical difference across the groups. A significant difference between groups II and III for improvement in mouth opening and groups I and III for improvement in tongue protrusion was noted.ConclusionWhen administrated in both systemic and topical forms together, curcumin showed better results in the management of oral submucous fibrosis as compared with the systemic form alone or antioxidants. Curcumin has the potential to emerge as an effective alternative to conventionally prescribed medications.
Long‐term incidence and risk of noncardiovascular and all‐cause mortality in apparently healthy cats and cats with preclinical hypertrophic cardiomyopathy
Authors: Fox Philip R. , Keene Bruce W. , Lamb Kenneth , Schober Karsten E. , Chetboul Valérie , Luis Fuentes Virginia , Payne Jessie Rose , Wess Gerhard , Hogan Daniel F. , Abbott Jonathan A. , Häggström Jens , Culshaw Geoffrey , Fine‐Ferreira Deborah , Cote Etienne , Trehiou‐Sechi Emilie , Motsinger‐Reif Alison A. , Nakamura Reid K. , Singh Manreet , Ware Wendy A. , Riesen Sabine C. , Borgarelli Michele , Rush John E. , Vollmar Andrea , Lesser Michael B. , Van Israel Nicole , Lee Pamela Ming‐Show , Bulmer Barret , Santilli Roberto , Bossbaly Maribeth J. , Quick Nadine , Bussadori Claudio , Bright Janice , Estrada Amara H. , Ohad Dan G. , del Palacio Maria Josefa Fernández , Brayley Jennifer Lunney , Schwartz Denise S. , Gordon Sonya G. , Jung SeungWoo , Bove Christina M. , Brambilla Paola G. , Moïse N. Sydney , Stauthammer Christopher , Quintavalla Cecilia , Manczur Ferenc , Stepien Rebecca L. , Mooney Carmel , Hung Yong‐Wei , Lobetti Remo , Tamborini Alice , Oyama Mark A. , Komolov Andrey , Fujii Yoko , Pariaut Romain , Uechi Masami , Yukie Tachika Ohara Victoria 
Published: October 2019

AbstractBackgroundEpidemiologic knowledge regarding noncardiovascular and all‐cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence‐based healthcare guidelines.ObjectivesTo characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all‐cause mortality in AH and pHCM cats.AnimalsA total of 1730 client‐owned cats (722 AH, 1008 pHCM) from 21 countries.MethodsRetrospective, multicenter, longitudinal, cohort study. Long‐term health data were extracted by medical record review and owner/referring veterinarian interviews.ResultsNoncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P= .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight‐loss‐vomiting‐diarrhea‐anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All‐cause death proportions were greater in pHCM than AH (65% versus 40%, respectively;P< .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years;P= .10), but all‐cause survival was significantly shorter in pHCM (P =.0001).Conclusions and Clinical ImportanceAll‐cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.