bluuebunny/crossref_metadata_2025 huggingface dataset:
Belief, Confidence, and Motivation to Use the Paretic Upper Limb in Daily Life Over the First 24 Weeks After Stroke
Authors: Waddell Kimberly J. , Tabak Rachel G. , Strube Michael J , Haire-Joshu Debra , Lang Catherine E.
Published: August 2019

Background and Purpose:

The recovery patterns of upper limb (UL) impairment after stroke are established. Psychosocial factors such as belief that paretic UL recovery is possible, confidence, and motivation to use the paretic UL in everyday tasks are unexplored early after stroke. The purpose of this exploratory study was to characterize belief, confidence, and motivation to use the paretic UL in daily life, and self-perceived barriers to UL recovery over the first 24 weeks after stroke.

Methods:

This was a longitudinal cohort study (N = 30) with 8 assessment sessions over the first 24 weeks after stroke. Belief, confidence, and motivation to use the paretic UL and self-perceived barriers were quantified via survey and analyzed using descriptive statistics. Change in the number of self-perceived barriers between weeks 2 and 24 was tested using a paired-samples t test. The relationship between UL capacity, depressive symptomatology, cognition, and each psychosocial factor was examined using Spearman rank-order correlation analyses.

Results:

Twenty-two participants completed all study assessments. Belief, confidence, and motivation were high across the 24 weeks, with little variation. There was no difference between the average number of barriers from weeks 2 to 24. There was no relationship between the clinical measures and psychosocial factors at week 2, 12, or 24.

Discussion and Conclusions:

High levels of belief, confidence, and motivation appear consistent over the first 6 months after stroke. The lack of correlations between psychosocial factors and clinical measures suggests belief, confidence, and motivation may not be vulnerable to functional status early after stroke.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A283).
Poststroke Fatigue Is Related to Motor and Cognitive Performance: A Secondary Analysis
Authors: Goh Hui-Ting , Stewart Jill C.
Published: August 2019

Background and Purpose:

Poststroke fatigue (PSF) is a common debilitating and persistent symptom after stroke. The relationship between PSF and motor and cognitive function remains inconclusive partly due to lack of control for effects of depression and use of insensitive measures. We examined the relationship between PSF and motor and cognitive performance using a comprehensive set of behavioral measures and excluding individuals with depression.

Methods:

Fifty-three individuals poststroke (16 female) were included (median age: 63 years, median months poststroke: 20 months). Poststroke fatigue was quantified using the Fatigue Severity Scale (FSS) and cognitive performance was measured with the Montreal Cognitive Assessment, simple and choice reaction time (SRT and CRT) tasks. Lower extremity motor performance included Fugl-Meyer Motor Assessment, 5 times sit-to-stand test (5 × STS), Berg Balance Scale, Functional Ambulation Category, and gait speed. Upper extremity motor performance was indexed with Fugl-Meyer, grip strength, and Box and Block test. Spearman correlation and stepwise linear regression analyses were performed to examine relationships.

Results:

Two motor performance measures, Berg Balance Scale and Functional Ambulation Category, were significantly correlated with FSS (ρ = −0.31 and −0.27, respectively) while all cognitive measures were significantly correlated with FSS (ρ = −0.28 for Montreal Cognitive Assessment, 0.29 for SRT, and 0.29 for CRT). Regression analysis showed that Berg Balance Scale was the only significant determinant for FSS (R2= 0.11).

Discussion and Conclusions:

Functional gait, balance, and cognitive performance are associated with PSF. Fatigue should be considered when planning and delivering interventions for individuals with stroke. Future studies are needed to explore the potential efficacy of balance and cognitive training in PSF management.

Video Abstract availablefor more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A287).
Distance-Induced Changes in Walking Speed After Stroke: Relationship to Community Walking Activity
Authors: Awad Louis , Reisman Darcy , Binder-Macleod Stuart
Published: August 2019

Background and Purpose:

Physical inactivity is a major contributing factor to reduced health and quality of life. The total distance walked during the 6-Minute Walk Test is a strong indicator of real-world walking activity after stroke. The purpose of this study was to determine whether measurement of distance-induced changes in walking speed during the 6-Minute Walk Test improves the test's ability to predict community walking activity.

Methods:

For 40 individuals poststroke, community walking activity (steps/d), the total distance walked during the 6-Minute Walk Test (6MWTtotal), and the difference between the distances walked during the final and first minutes of the test (Δ6MWTmin6–min1) were analyzed using moderated regression. Self-efficacy, assessed using the Activities-specific Balance Confidence scale, was also included in the model.

Results:

Alone, 6MWTtotal explained 41% of the variance in steps/d. The addition of Δ6MWTmin6–min1 increased explanatory power by 29% (ΔR
2 = 0.29, P < 0.001). The final model accounted for 71% of steps/d variance (F
4,32 = 19.52, P < 0.001). Examination of a significant 6MWTtotal × Δ6MWTmin6–min1 interaction revealed a positive relationship between 6MWTtotal and steps/d, with individuals whose distances declined from minute 1 to minute 6 by 0.10 m/s or more presenting with substantially fewer steps/d than those whose distances did not decline.

Discussion and Conclusions:

Coassessment of distance-induced changes in walking speed during the 6-Minute Walk Test and the total distance walked substantially improves the prediction of real-world walking activity after stroke. This study provides new insight into how walking ability after stroke can be characterized to reduce heterogeneity and advance personalized treatments.
Cases Having a Gleason Score 3+4=7 With <5% of Gleason Pattern 4 in Prostate Needle Biopsy Show Similar Failure-free Survival and Adverse Pathology Prevalence to Gleason Score 6 Cases in a Radical Prostatectomy Cohort
Authors: Sato Shun , Kimura Takahiro , Yorozu Takashi , Onuma Hajime , Iwatani Kosuke , Egawa Shin , Ikegami Masahiro , Takahashi Hiroyuki
Published: August 2019

Recent discussions have suggested expanding the inclusion criteria for active prostate cancer surveillance to include cases with a Gleason score (GS) of 3+4=7. In this study, we examined this proposed use of a limited percent Gleason pattern 4 (%GP4) to identify candidates of active surveillance among 315 patients who underwent radical prostatectomy for prostate cancer with a GS of 6 or 3+4=7 via needle biopsy. The latter cases were divided into 4 groups using highest or overall %GP4 cut-off values of 5% and 10% as determined from prostate needle biopsies. The frequency of adverse pathology and risk of biochemical recurrence were compared between the GS 6 and both GS 3+4=7 groups. Adverse pathology was defined as a GS 4+3=7 or higher, pT3b staging or positive lymph node metastasis. Notably, the Gleason pattern 4 <5% and GS 6 groups did not differ significantly in terms of the frequency of adverse pathology and risk of biochemical recurrence by the highest method. However, other highest Gleason pattern 4 categories had significantly higher frequencies and risks. Using the overall method, even the Gleason pattern 4 <5% group had a significantly higher frequency of adverse pathology and risk of biochemical recurrence relative to the GS 6 group. In conclusion, our findings suggest that patients with a GS 3+4=7 on biopsy with a highest %GP4 <5% are similar candidates for active surveillance to men with GS 6 cancers.
Nonaccidental Trauma Is an Independent Risk Factor for Mortality Among Injured Infants
Authors: Delaplain Patrick T. , Grigorian Areg , Won Eugene , Dosch Austin R. , Schubl Sebastian , Covarrubias Jose , Nahmias Jeffry
Published: August 2019

Objectives

The Centers for Disease Control disclosed over 600,000 cases of child abuse or neglect in 2016. Single-institution studies have shown that nonaccidental trauma (NAT) has higher complication rates than accidental trauma (AT). Nonaccidental trauma is disproportionately represented in infants. We hypothesized that NAT would increase the risk of mortality in infants. This study aims to provide a contemporary descriptive analysis for infant trauma patients and determine the association between NAT and mortality.

Methods

Infants (<1 year of age) within the Pediatric Trauma Quality Improvement Program database (2014–2016) were identified. Descriptive statistics (χ2 and t test) were used to compare NAT infants to AT infants. A multivariable logistic regression was used to determine the risk of mortality associated with select variables including NAT.

Results

From 14,965 infant traumas, most presented to a level I pediatric trauma center (53.5%) with a median injury severity score of 9. The most common mechanism was falls (48.6%), followed by NAT (14.5%). Overall mortality was 2.1%. Although most NAT infants were white (60.2%), black infants were overrepresented (23.6% vs 18.3%; P < 0.0001) compared with AT infants. The incidence of mortality was higher in NAT infants (41.6% vs 13.9%; P < 0.0001), and they were more likely to have traumatic brain injury (TBI) (63.1% vs 50.6%; P < 0.001). Nonaccidental trauma [odds ratio (OR), 2.48; P < 0.001], hypotension within 24 hours (OR, 8.93; P < 0.001), injury severity score (OR, 1.12; P < 0.001), and severe abbreviated injury scale-head (OR 1.62, P = 0.014) had the highest association with mortality.

Conclusions

This study confirms the incidence of TBI and NAT in infants. Although providers should be vigilant for NAT, suspicion of NAT should prompt close surveillance, as there is a 2-fold increased risk of mortality independent of injury or TBI.
Dynamic Changes in Prescription Opioids from 2006 to 2017 in Texas
Authors: Ighodaro Ebuwa T , McCall Kenneth L , Chung Daniel Y , Nichols Stephanie D , Piper Brian J
Published: August 2019

Study Objective

The US is experiencing an epidemic of opioid overdoses which may be at least partially due to an over-reliance on opioid analgesics in the treatment of chronic non-cancer pain and subsequent escalation to heroin or illicit fentanyl. As Texas was reported to be among the lowest in the US for opioid use and misuse, further examination of this state is warranted.

Study Design

This study was conducted to quantify prescription opioid use in Texas.

Data Source

Data was obtained from the publically available US Drug Enforcement Administration’s Automation of Reports and Consolidated Orders System (ARCOS) which monitors controlled substances transactions from manufacture to commercial distribution.

Measurement and Main Results

Data for 2006-2017 from Texas for ten prescription opioids including eight primarily used to relieve pain (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, morphine, oxycodone, oxymorphone) and two (buprenorphine and methadone) for the treatment of an Opioid Use Disorder (OUD) were examined. The change in Morphine Mg Equivalent (MME) of all opioids (+23.3%) was only slightly greater than the state’s population gains (21.1%). Opioids used to treat an OUD showed pronounced gains (+90.8%) which were four-fold faster than population growth. Analysis of individual agents revealed pronounced elevations in codeine (+387.5%), hydromorphone (+106.7%), and oxycodone (+43.6%) and a reduction in meperidine (−80.3%) in 2017 relative to 2006. Methadone in 2017 accounted for a greater portion (39.5%) of the total MME than hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, and meperidine, combined. There were differences between urban and rural areas in the changes in hydrocodone and buprenorphine.

Conclusions

Collectively, these findings indicate that continued vigilance is needed in Texas to appropriately treat pain and an OUD while minimizing the potential for prescription opioid diversion and misuse. Texas may lead the US in a return to pre opioid crisis prescription levels.
Impact of overfishing on density and test-diameter size of the sea urchinTripneustes gratillaat Wakatobi Archipelago, south-eastern Sulawesi, Indonesia
Authors: Nane La
Published: August 2019

Sea urchinTripneustes gratillais one of an economic important fisheries resources product for localities at Wakatobi archipelago. High demands for sea urchin gonad have intensified high fishing activity. We hypothesize that sea urchins at Wakatobi have overfished. To answer that hypothesizes; we measure the density and its test diameter size at two different sites. They are Pulau Tomia (inhabited area) and Pulau Sawa (uninhabited area and very distant from the localities). The results show that sea urchin density and its test diameter is significantly different. The densities (mean ± SE) Tripneustes gratilla at Pulau Sawa and Pulau Tomia are 10 ± 0.6 (ind./m2) and 2.7 ± 0.9 ind./m2, respectively. Moreover, the test diameter at Pulau Sawa and Pulau Tomia are 69.7 ± 2.1 mm (mean ± SE), and 58.5 ± 1.7 mm (mean ± SE), respectively. These results have indeed shown that overfishing has occurred. Therefore, sea urchin with test diameter 66–75 mm, 76–85 mm, and 86–95 mm have disappeared at Pulau Tomia. Our conclusion reveals that fishing of sea urchin Tripneustes gratilla at Pulau Tomia has overfished.
“Integrative Genomic Analysis for the Bioprospection of Regulators and Accessory Enzymes Associated with Cellulose Degradation in a Filamentous Fungus (Trichoderma harzianum)”
Authors: Filho Jaire A. Ferreira , Horta Maria Augusta C. , dos Santos Clelton A. , Almeida Deborah A. , Murad Natália F. , Mendes Juliano S. , Sforça Danilo A. , Silva Claudio Benício C. , Crucello Aline , de Souza Anete P.
Published: August 2019

Background

Unveiling fungal genome structure and function reveals the potential biotechnological use of fungi.Trichoderma harzianumis a powerful CAZyme-producing fungus. We studied the genomic regions inT. harzianumIOC3844 containing CAZyme genes, transcription factors and transporters.

Results

We used bioinformatics tools to mine theT. harzianumgenome for potential genomics, transcriptomics, and exoproteomics data and coexpression networks. The DNA was sequenced by PacBio SMRT technology for multi-omics data analysis and integration. In total, 1676 genes were annotated in the genomic regions analyzed; 222 were identified as CAZymes inT. harzianumIOC3844. When comparing transcriptome data under cellulose or glucose conditions, 114 genes were differentially expressed in cellulose, with 51 CAZymes. CLR2, a transcription factor physically and phylogenetically conserved inT. harzianumspp., was differentially expressed under cellulose conditions. The genes induced/repressed under cellulose conditions included those important for plant biomass degradation, including CIP2 of the CE15 family and a copper-dependent LPMO of the AA9 family.

Conclusions

Our results provide new insights into the relationship between genomic organization and hydrolytic enzyme expression and regulation inT. harzianumIOC3844. Our results can improve plant biomass degradation, which is fundamental for developing more efficient strains and/or enzymatic cocktails for the production of hydrolytic enzymes.
Deep Learning-Based Point-Scanning Super-Resolution Imaging
Authors: Fang Linjing , Monroe Fred , Novak Sammy Weiser , Kirk Lyndsey , Schiavon Cara Rae , Yu Seungyoon B. , Zhang Tong , Wu Melissa , Kastner Kyle , Kubota Yoshiyuki , Zhang Zhao , Pekkurnaz Gulcin , Mendenhall John , Harris Kristen , Howard Jeremy , Manor Uri
Published: August 2019

Point scanning imaging systems (e.g. scanning electron or laser scanning confocal microscopes) are perhaps the most widely used tools for high resolution cellular and tissue imaging. Like all other imaging modalities, the resolution, speed, sample preservation, and signal-to-noise ratio (SNR) of point scanning systems are difficult to optimize simultaneously. In particular, point scanning systems are uniquely constrained by an inverse relationship between imaging speed and pixel resolution. Here we show these limitations can be mitigated via the use of deep learning-based super-sampling of undersampled images acquired on a point-scanning system, which we termed point-scanning super-resolution (PSSR) imaging. Oversampled, high SNR ground truth images acquired on scanning electron or Airyscan laser scanning confocal microscopes were "crappified" to generate semi-synthetic training data for PSSR models that were then used to restore real-world undersampled images. Remarkably, our EM PSSR model could restore undersampled images acquired with different optics, detectors, samples, or sample preparation methods in other labs. PSSR enabled previously unattainable 2 nm resolution images with our serial block face scanning electron microscope system. For fluorescence, we show that undersampled confocal images combined with a multiframe PSSR model trained on Airyscan timelapses facilitates Airyscan-equivalent spatial resolution and SNR with ~100x lower laser dose and 16x higher frame rates than corresponding high-resolution acquisitions. In conclusion, PSSR facilitates point-scanning image acquisition with otherwise unattainable resolution, speed, and sensitivity.
Bypass of an epigenetic S-phase transcriptional module by convergent nutrient stress signals
Authors: Delaby Marie , Panis Gaël , Fumeaux Coralie , Degeorges Laurence , Viollier Patrick H.
Published: August 2019

The signals feeding into bacterial S-phase transcription are poorly understood. Cellular cycling in the alpha-proteobacteriumCaulobacter crescentusis driven by a complex circuit of at least three transcriptional modules that direct sequential promoter firing during the G1, early and late S cell cycle phases. In alpha-proteobacteria, the transcriptional regulator GcrA and the CcrM methyltransferase epigenetically activate promoters of cell division and polarity genes that fire in S-phase. By evolvingCaulobacter crescentuscells to cycle and differentiate in the absence of the GcrA/CcrM module, we discovered that phosphate deprivation and (p)ppGpp alarmone stress signals converge on S-phase transcriptional activation. The cell cycle oscillations of the CtrA protein, the transcriptional regulator that implements G1 and late S-phase transcription, are essential in our evolved mutants, but not in wild-type cells, showing that the periodicity in CtrA abundance alone can sustain cellular cycling without GcrA/CcrM. While similar nutritional sensing occurs in other alpha-proteobacteria, GcrA and CcrM are not encoded in the reduced genomes of obligate intracellular relatives. We thus propose that the nutritional stress response induced during intracellular growth obviated the need for an S-phase transcriptional regulator.
Preservation of stemness in high-grade serous ovarian cancer organoids requires low Wnt environment
Authors: Hoffmann Karen , Berger Hilmar , Kulbe Hagen , Thillainadarasan Sukanija , Mollenkopf Hans-Joachim , Zemojtel Tomasz , Taube Eliane , Darb-Esfahani Silvia , Mangler Mandy , Sehouli Jalid , Chekerov Radoslav , Braicu Elena , Meyer Thomas F. , Kessler Mirjana
Published: August 2019

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the parental tumor mutational profile and phenotype. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for generation of HGSOC organoids, while healthy FT organoids depend on BMP suppression by Noggin. Interestingly, FT organoids modified by stable shRNA knockdown (KD) of p53, PTEN, and Retinoblastoma (RB), also require a low Wnt environment for long-term growth, while FT organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotype of normal and KD organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation.
The giant pouched rat (Cricetomys ansorgei) olfactory receptor repertoire
Authors: Freeman Angela R. , Ophir Alexander G. , Sheehan Michael J.
Published: August 2019

For rodents, olfaction is essential for locating food, recognizing mates and competitors, avoiding predators, and navigating their environment. It is thought that rodents may have expanded olfactory receptor repertoires in order to specialize in olfactory behavior. Despite being the largest clade of mammals and depending on olfaction relatively little work has documented olfactory repertoires outside of the conventional laboratory mice and rats. Here we report the olfactory receptor repertoire of the African giant pouched rat (Cricetomys ansorgei), a Muroid rodent distantly related to mice and rats. The African giant pouched rat is notable for its large cortex and olfactory bulbs relative to its body size compared to other sympatric rodents, which suggests anatomical elaboration of olfactory capabilities. We hypothesized that in addition to anatomical elaboration for olfaction, these pouched rats might also have an expanded olfactory receptor repertoire to enable their olfactory behavior. We examined the composition of the olfactory receptor repertoire to better understand how their sensory capabilities have evolved. We identified 1145 functional olfactory genes, and 260 additional pseudogenes within 301 subfamilies from the African giant pouched rat genome. This repertoire is similar to mice and rats in terms of size, pseudogene percentage and number of subfamilies. Analyses of olfactory receptor gene trees revealed that the pouched rat has 6 expansions in different subfamilies compared to mice, rats and squirrels. We identified 99 orthologous genes conserved among 4 rodent species and an additional 167 conserved genes within the Muroid rodents. The orthologous genes shared within Muroidea suggests that there may be a conserved Muroid-specific olfactory receptor repertoire. We also note that the description of this repertoire can serve as a complement to other studies of rodent olfaction, as the pouched rat is an outgroup within Muroidea. Thus, our data suggest that African giant pouched rats are capable of both natural and trained olfactory behaviors with a typical Muriod olfactory receptor repertoire.
Immunosuppression, rather than inflammation, is a salient feature of sepsis in an Indian cohort
Authors: Mukhopadhyay Samanwoy , Thatoi Pravat K , Das Bidyut K , Mohapatra Saroj K
Published: August 2019

1

Sepsis remains a lethal ailment with imprecise treatment and ill-understood biology. A clinical transcriptomic analysis of sepsis patients was performed for the first time in India and revealed large-scale change in blood gene expression in patients of severe sepsis and septic shock admitted to ICU. Three biological processes were quantified using scores derived from the corresponding transcriptional modules. Comparison of the module scores revealed that genes associated with immune response were more suppressed compared to the inflammation-associated genes. These findings will have great implication in the treatment and prognosis of severe sepsis/septic shock if it can be translated into a bedside tool.
How structural brain network topologies associate with cognitive abilities in a value-based decision-making task
Authors: Bañuelos Cristina , Verstynen Timothy
Published: August 2019

Value-based decision-making relies on effective communication across disparate brain networks. Given the scale of the networks involved in adaptive decision-making, variability in how they communicate should impact behavior; however, precisely how the topological pattern of structural connectivity of individual brain networks influences individual differences in value-based decision-making remains unclear. Using diffusion MRI, we measured structural connectivity networks in a sample of community dwelling adults (N=124). We used standard graph theoretic measures to characterize the topology of the networks in each individual and correlated individual differences in these topology measures with differences in the Iowa Gambling Task. A principal components regression approach revealed that individual differences in brain network topology associate with differences in optimal decision-making, as well as associate with differences in each participant’s sensitivity to high frequency rewards. These findings show that aspects of structural brain network organization can constrain how information is used in value-based decision-making.

Abbreviations

MRI - Magnetic Resonance Imaging; IGT – Iowa Gambling Task; DWI – Diffusion Weighted Imaging; QSDR – Q-Space Diffeomorphic Reconstruction; PCA – Principal Components Analysis; GLM – Generalized Linear Models
The IRE1α stress signaling axis is a key regulator of neutrophil antimicrobial effector function
Authors: Abuaita B. H. , Sule G. J. , Schultz T. L. , Gao F. , Knight J. S. , O’Riordan M. X.
Published: August 2019

Activation of the endoplasmic reticulum stress sensor, IRE1α, is required for effective immune responses against bacterial infection and is associated with human inflammatory diseases where neutrophils are a key immune component. However, the specific role of IRE1α in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1α activation licenses neutrophil antimicrobial capacity, including IL-1β production, NET formation, and MRSA killing. Inhibition of IRE1α diminished production of mitochondrial reactive oxygen species (mROS) and decreased CASPASE-2 activation, which both contributed to neutrophil antimicrobial activity. Mice deficient in Caspase-2 were highly susceptible to MRSA infection and failed to form NETs in a subcutaneous abscess. IRE1α activation enhanced calcium influx and citrullination of histone H3 (Cit-H3) independently of mROS production, suggesting that IRE1α coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1α-Caspase-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1α in neutrophil antibacterial function.

One Sentence Summary

IRE1α controls neutrophil antimicrobial defenses
Stochastic Models for Revealing the Dynamics of the Growth of Small Tumor Populations
Authors: Johnson Kaitlyn E. , Brock Amy
Published: August 2019

The widely accepted model of tumor growth assumes tumors grow exponentially at a constant rate during early tumorigenesis when populations are small. The possibility that tumors might exhibit altered slower growth dynamics or even net cell death below a critical tumor size has yet to be fully explored. Deterministic growth models are capable of describing larger populations because population variation becomes small compared with the average, but when the population being modeled is small, the inherent stochasticity of the birth and death process produces significant variation. Recent advances in high throughput data collection allow for precise and sufficiently large data sets needed to capture this variation. Therefore, we present a stochastic modeling framework to describe and test the potential for altered growth dynamics at small tumor populations.
Assortative mating by population of origin in a mechanistic model of admixture
Authors: Goldberg Amy , Rastogi Ananya , Rosenberg Noah A
Published: August 2019

Populations whose mating pairs have levels of similarity in phenotypes or genotypes that differ systematically from the level expected under random mating are described as experiencing assortative mating. Excess similarity in mating pairs is termed positive assortative mating, and excess dissimilarity is negative assortative mating. In humans, empirical studies suggest that mating pairs from various admixed populations—whose ancestry derives from two or more source populations—possess correlated ancestry components that indicate the occurrence of positive assortative mating on the basis of ancestry. Generalizing a two-sex mechanistic admixture model, we devise a model of one form of ancestry-assortative mating that occurs through preferential mating based on source population. Under the model, we study the moments of the admixture fraction distribution for different assumptions about mating preferences, including both positive and negative assortative mating by population. We consider the special cases of assortative mating by population that involve a single admixture event and that consider a model of constant contributions to the admixed population over time. We demonstrate that whereas the mean admixture under assortative mating is equivalent to that of a corresponding randomly mating population, the variance of admixture depends on the level and direction of assortative mating. In contrast to standard settings in which positive assortment increases variation within a population, certain assortative mating scenarios allow the variance of admixture to decrease relative to a corresponding randomly mating population: with the three populations we consider, the variance-increasing effect of positive assortative mating within a population might be overwhelmed by a variance-decreasing effect emerging from mating preferences involving other pairs of populations. The effect of assortative mating is smaller on the X chromosome than the autosomes because inheritance of the X in males depends only on the mother’s ancestry, not on the mating pair. Because the variance of admixture is informative about the timing of admixture and possibly about sex-biased admixture contributions, the effects of assortative mating are important to consider in inferring features of population history from distributions of admixture values. Our model provides a framework to quantitatively study assortative mating under flexible scenarios of admixture over time.
Modulating cellular cytotoxicity and phototoxicity of fluorescent organic salts through counterion pairing
Authors: Broadwater Deanna , Bates Matthew , Jayaram Mayank , Young Margaret , He Jianzhou , Raithel Austin L. , Hamann Thomas W. , Zhang Wei , Borhan Babak , Lunt Richard R. , Lunt Sophia Y.
Published: August 2019

Light-activated theranostics offer promising opportunities for disease diagnosis, image-guided surgery, and site-specific personalized therapy. However, current fluorescent dyes are limited by low brightness, high cytotoxicity, poor tissue penetration, and unwanted side effects. To overcome these limitations, we demonstrate a platform for optoelectronic tuning, which allows independent control of the optical properties from the electronic properties of fluorescent organic salts. This is achieved through cation-anion pairing of organic salts that can modulate the frontier molecular orbital without impacting the bandgap. Optoelectronic tuning enables decoupled control over the cytotoxicity and phototoxicity of fluorescent organic salts through selective generation of mitochondrial reactive oxygen species that control cell viability. We show that through counterion pairing, organic salt nanoparticles can be tuned to be either nontoxic for enhanced imaging, or phototoxic for improved photodynamic therapy.
A novel fully-human potency-matched dual cytokine-antibody fusion protein targets carbonic anhydrase IX in renal cell carcinomas
Authors: De Luca Roberto , Gouyou Baptiste , Ongaro Tiziano , Villa Alessandra , Ziffels Barbara , Sannino Alessandro , Buttinoni Gianluca , Galeazzi Simone , Mazzacuva Mirko , Neri Dario
Published: August 2019

Certain cytokines synergize in activating anti-cancer immunity at the site of disease and it may be desirable to generate biopharmaceutical agents, capable of simultaneous delivery of cytokine pairs to the tumor. In this article, we have described the cloning, expression and characterization of IL2-XE114-TNFmut, a dual-cytokine biopharmaceutical featuring the sequential fusion of interleukin-2 (IL2) with the XE114 antibody in scFv format and a tumor necrosis factor mutant (TNFmut). The fusion protein recognized the cognate antigen (carbonic anhydrase IX, a marker of hypoxia and of renal cell carcinoma) with high affinity and specificity. IL2-XE114-TNFmut formed a stable non-covalent homotrimeric structure, displayed cytokine activity in in vitro tests and preferentially localized to solid tumors in vivo. The product exhibited a partial growth inhibition of murine CT26 tumors transfected for carbonic anhydrase IX. When administered to Cynomolgus monkey as intravenous injection, IL2-XE114-TNFmut showed the expected plasma concentration of ~1500 ng/ml at early time points, indicating the absence of any in vivo trapping events, and a half-life of ~2 hours. IL2-XE114-TNFmut may thus be considered as a promising biopharmaceutical for the treatment of metastatic clear-cell renal cell carcinoma, since these tumors are known to be sensitive to IL2 and to TNF.

Contribution to the field

There is a growing interest in the antibody-based targeted delivery of pro-inflammatory cytokines for tumor therapy, which may be complementary or alternative to immune checkpoint inhibitors for immunotherapeutic applications. In this article, we have described a novel fusion protein, featuring antibody moieties specific to carbonic anhydrase IX, as well as interleukin-2 and tumor necrosis factor as pro-inflammatory cytokines, which combines the ability to recognize a tumor-associated antigen on the surface of renal cell carcinomas with the simultaneous display of two potent therapeutic payloads. The newly developed product (termed IL2-XE114-TNFmut) exhibited favorable biochemical characteristics, the ability to preferentially localize at the tumor site, a cancer growth inhibition activity and a suitable pharmacokinetic profile in Cynomolgus monkey. IL2-XE114-TNFmut may therefore represent an attractive candidate for the immunotherapy of renal cell carcinoma.
LINC complexes are mechanotransducers that discriminate Epithelial-Mesenchymal Transition programs
Authors: Déjardin Théophile , Carollo Pietro Salvatore , Davidson Patricia M. , Seiler Cynthia , Cuvelier Damien , Cadot Bruno , Sykes Cecile , Gomes Edgar R. , Borghi Nicolas
Published: August 2019

LINC complexes are transmembrane protein assemblies that physically connect the nucleo- and cytoskeletons through the nuclear envelope. Dysfunctions of LINC complexes are associated with pathologies such as cancer and muscular disorders. The mechanical roles of LINC complexes in these contexts are poorly understood. To address this, we used genetically encoded FRET biosensors of molecular tension in LINC complex proteins of fibroblastic and epithelial cells in culture. We exposed cells to mechanical, genetic and pharmacological perturbations, mimicking a range of physiological and pathological situations. We show that LINC complex proteins experience tension generated by the cytoskeleton and act as mechanical sensors of cell packing. Moreover, the LINC complex discriminates between inductions of partial and complete epithelial-mesenchymal transitions (EMT). We identify the implicated mechanisms, which associate nesprin tension sensing with α-catenin capture at the nuclear envelope, thereby regulating β-catenin transcription. Our data thus implicate that LINC complexes are mechanotransducers that fine-tune β-catenin signaling in a manner dependent on the Epithelial-Mesenchymal Transition program.
Exploration of fine-scale recombination rate variation in the domestic horse
Authors: Beeson Samantha K. , Mickelson James R. , McCue Molly E.
Published: August 2019

Total genetic map length and local recombination landscapes typically vary within and across populations. As a first step to understanding the recombination landscape in the domestic horse, we calculated population recombination rates and identified likely recombination hotspots using approximately 1.8 million SNP genotypes for 485 horses from 32 distinct breeds. The resulting breed-averaged recombination map spans 2.36 Gb and accounts for 2939.07 cM. Recombination hotspots occur once per 23.8 Mb on average and account for ∼9% of the physical map length. Regions with elevated recombination rates in the entire cohort were enriched for genes in pathways involving interaction with the environment: immune system processes (specifically, MHC class I and class II genes), responses to stimuli, and serotonin receptor pathways. We found significant correlations between differences in local recombination rates and population differentiation quantified by FST. Analysis of breed-specific maps revealed thousands of hotspot regions unique to particular breeds, as well as unique “coldspots,” regions where a particular breed showed below-average recombination, whereas all other breeds had evidence of a hotspot. Finally, we identified relative enrichment (P = 5.88 × 10−27) for the in silico–predicted recognition motif for equine PR/SET domain 9 (PRDM9) in recombination hotspots. These results indicate that selective pressures and PRDM9 function contribute to variation in recombination rates across the domestic horse genome.
RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing
Authors: Dvinge Heidi , Guenthoer Jamie , Porter Peggy L. , Bradley Robert K.
Published: August 2019

Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here show that the RNA components of the spliceosome likewise influence alternative splicing decisions. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and across cancer samples. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially misspliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many cancers, we propose that a full understanding of such dysregulated pre-mRNA processing requires study of snRNAs, as well as protein splicing factors. Together, our data show that the RNA components of the spliceosome are not merely basal factors, as has long been assumed. Instead, these noncoding RNAs constitute a previously uncharacterized layer of regulation of alternative splicing, and contribute to the establishment of global splicing programs in both healthy and malignant cells.
Microsecond time-resolved X-ray diffraction for the investigation of fatigue behavior during ultrasonic fatigue loading
Authors: Ors T. , Ranc N. , Pelerin M. , Michel V. , Favier V. , Castelnau O. , Mocuta C. , Thiaudière D.
Published: August 2019

A new method based on time-resolved X-ray diffraction is proposed in order to measure the elastic strain and stress during ultrasonic fatigue loading experiments. Pure Cu was chosen as an example material for the experiments using a 20 kHz ultrasonic fatigue machine mounted on the six-circle diffractometer available at the DiffAbs beamline on the SOLEIL synchrotron facility in France. A two-dimensional hybrid pixel X-ray detector (XPAD3.2) was triggered by the strain gage signal in a synchronous data acquisition scheme (pump–probe-like). The method enables studying loading cycles with a period of 50 µs, achieving a temporal resolution of 1 µs. This allows a precise reconstruction of the diffraction patterns during the loading cycles. From the diffraction patterns, the position of the peaks, their shifts and their respective broadening can be deduced. The diffraction peak shift allows the elastic lattice strain to be estimated with a resolution of ∼10−5. Stress is calculated by the self-consistent scale-transition model through which the elastic response of the material is estimated. The amplitudes of the cyclic stresses range from 40 to 120 MPa and vary linearly with respect to the displacement applied by the ultrasonic machine. Moreover, the experimental results highlight an increase of the diffraction peak broadening with the number of applied cycles.
Investigation of the local structure of molten ThF4–LiF and ThF4–LiF–BeF2 mixtures by high-temperature X-ray absorption spectroscopy and molecular-dynamics simulation
Authors: Sun Jian , Guo Xiaojing , Zhou Jing , Dai Jianxing , Song Sanzhao , Bao Hongliang , Lin Jian , Yu Haisheng , He Shangming , Jiang Feng , Long Dewu , Zhang Linjuan , Wang Jian-Qiang
Published: August 2019

The microscopic structures of ThF4–LiF and ThF4–LiF–BeF2 molten salts have been systematically investigated by in situ high-temperature X-ray absorption fine-structure (XAFS) spectroscopy combined with molecular-dynamics (MD) simulations. The results reveal that the local structure of thorium ions was much more disordered in the molten state of the ThF4–LiF–BeF2 salt than that in ThF4–LiF, implying that the Th and F ions were exchanged more frequently in the presence of Be ions. The structures of medium-range-ordered coordination shells (such as Th–F2nd and Th–Th) have been emphasized by experimental and theoretical XAFS analysis, and they play a significant role in transport properties. Using MD simulations, the bonding properties in the molten ThF4–LiF and ThF4–LiF–BeF2 mixtures were evaluated, confirming the above conclusion. This research is, to the best of our knowledge, the first systematic study on the ThF4–LiF–BeF2 molten salt via quantitative in situ XAFS analysis and MD simulations.
Focal shift induced by source displacements and optical figure errors
Authors: Manfredda Michele , Raimondi Lorenzo , Mahne Nicola , Zangrando Marco
Published: August 2019

In this work the longitudinal shifts of the focal plane of an ellipsoidal mirror induced by longitudinal shifts of the source and by the optical figure error of the mirror itself are investigated. The case of an ideal mirror illuminated by a Gaussian beam is considered first, deriving an analytical formula predicting the source-to-focus shift. Then the realistic case of a mirror affected by surface shape defects is examined, by taking into account metrological data and numerically solving the Huygens–Fresnel integral. The analytical and numerical solutions in the ideal and real cases are compared. Finally, it is shown that an additional dependence of the focal shift is introduced on the wavelength and the pointing angle of the source. Both effects are investigated by numerical computations. We limit the treatment in the XUV spectral range, choosing as a test bench the Kirkpatrick–Baez mirror system of the DiProI and LDM end-stations and at the FERMI seeded free-electron laser (FEL). The work is primarily aimed at disentangling the different causes of focal shift at FEL light sources, where source position, wavelength and pointing angle are either tunable or rapidly fluctuating. The method can be easily extended to parabolic reflectors and refractors (lenses) with other kinds of illuminating sources and wavelengths.
The first crystal structure of the pyrrolo[1,2-c]oxazole ring system
Authors: Zreigh Mohamed M. , Adams Harry , Jackson Richard F. W. , Robertson Craig C.
Published: August 2019

The title compound, C7H4F3NO2, 3-trifluoromethyl-1H-pyrrolo[1,2-c]oxazol-1-one, is the first crystal structure of the pyrrolo[1,2-c]oxazole ring system: the fused ring system is almost planar (r.m.s. deviation = 0.006 Å). In the crystal, weak C—H...O and C—H...F hydrogen bonds link the molecules into [001] chains and π–π stacking interactions consolidate the structure.
Crystal structure of a binuclear mixed-valence ytterbium complex containing a 2-anthracene-substituted phenoxide ligand
Authors: Berg David J. , Twamley Brendan
Published: August 2019

Reaction of 2-(anthracen-9-yl)phenol (HOPhAn, 1) with divalent Yb[N(SiMe3)2]2·2THF in THF–toluene mixtures affords the mixed-valence YbII–YbIII dimer {[2-(anthracen-9-yl)phenolato-κO]bis(tetrahydrofuran)ytterbium(III)}-tris[μ-2-(anthracen-9-yl)phenolato]-κ4
O:O;κO:1,2-η,κO-{[2-(anthracen-9-yl)phenolato-κO]ytterbium(II)} toluene trisolvate, [Yb2(C20H13O)5(C4H8O)2]·3C7H7 or [YbIII(THF)2(OPhAn)](μ-OPhAn)3[YbII(OPhAn)]·3C7H7 (2), as the major product. It crystallized as a toluene trisolvate. The Yb—O bond lengths in the crystal structure of this dimer clearly identify the YbII and YbIII centres. Interestingly, the formally four-coordinate YbII centre shows a close contact with one anthracene C—C bond of a bridging OPhAn ligand, bringing the formal coordination number to five.
Structural comparison of protiated, H/D-exchanged and deuterated human carbonic anhydrase IX
Authors: Koruza K. , Lafumat B. , Nyblom M. , Mahon B. P. , Knecht W. , McKenna R. , Fisher S. Z.
Published: August 2019

Human carbonic anhydrase IX (CA IX) expression is upregulated in hypoxic solid tumours, promoting cell survival and metastasis. This observation has made CA IX a target for the development of CA isoform-selective inhibitors. To enable structural studies of CA IX–inhibitor complexes using X-ray and neutron crystallography, a CA IX surface variant (CA IXSV; the catalytic domain with six surface amino-acid substitutions) has been developed that can be routinely crystallized. Here, the preparation of protiated (H/H), H/D-exchanged (H/D) and deuterated (D/D) CA IXSVfor crystallographic studies and their structural comparison are described. Four CA IXSVX-ray crystal structures are compared: two H/H crystal forms, an H/D crystal form and a D/D crystal form. The overall active-site organization in each version is essentially the same, with only minor positional changes in active-site solvent, which may be owing to deuteration and/or resolution differences. Analysis of the crystal contacts and packing reveals different arrangements of CA IXSVcompared with previous reports. To our knowledge, this is the first report comparing three different deuterium-labelled crystal structures of the same protein, marking an important step in validating the active-site structure of CA IXSVfor neutron protein crystallography.
Effects of map design characteristics on users’ search performance and cognitive load
Authors: Al-Samarraie Hosam , Eldenfria Atef , Price Melissa Lee , Zaqout Fahed , Fauzy Wan Mohamad
Published: August 2019

Purpose

This paper aims to investigate the influence of map design characteristics on users’ cognitive load and search performance. Two design conditions (symbolic vs non-symbolic) were used to evaluate users’ ability to locate a place of interest.

Design/methodology/approach

A total of 19 students (10 male and 9 female, 20-23 years old) participated in this study. The time required for subjects to find a place in the two conditions was used to estimate their searching performance. An electroencephalogram (EEG) device was used to examine students’ cognitive load using event-related desynchronization percentages of alpha, beta and theta brain wave rhythms.

Findings

The results showed that subjects needed more time to find a place in the non-symbolic condition than the symbolic condition. The EEG data, however, revealed that users experienced higher cognitive load when searching for a place in the symbolic condition. The authors found that the design characteristics of the map significantly influenced users’ brain activity, thus impacting their search performance.

Originality/value

Outcomes from this study can be used by cartographic designers and scholars to understand how certain design characteristics can trigger cognitive activity to improve users' searching experience and efficiency.