bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOVEL PRPH2/RDS MUTATION IDENTIFIED IN A FAMILY WITH VARYING CLINICAL MANIFESTATIONS: A CASE REPORT
Authors: Tauscher Robert G. , Rahmani Safa , Szymaniak Brittany M. , Jampol Lee M. , Mirza Rukhsana G. 
Published: June 2021

Purpose:
To present the case of a family with a novel PRPH2/RDS mutation.

Methods:
A case report of a 44-year-old woman and her immediate family, including the father and a sister who shared her PRPH2/RDS mutation.

Results:
A 44-year-old woman presented with examination findings consistent with a butterfly-type pattern dystrophy. A sister had a similar butterfly-type dystrophy, whereas their father had a severe cone–rod dystrophy. Genetic testing revealed the same novel PRPH2/RDS mutation in all three affected individuals, suggesting that this single mutation can produce at least two disparate retinal disease phenotypes.

Conclusion:
This case describes a novel p.Y225X nonsense mutation in the PRPH2/RDS gene and demonstrates that it is both pathologic and capable of significant phenotypic variability.
Twelve-Year Incidence of Open-angle Glaucoma: The Thessaloniki Eye Study
Authors: Founti Panayiota , Coleman Anne L. , Wilson M. Roy , Yu Fei , Harris Alon , Pappas Theofanis , Anastasopoulos Eleftherios , Koskosas Archimidis , Salonikiou Angeliki , Keskini Christina , Malamas Angelakis , Kilintzis Vassilis , Raptou Anastasia , Tzoanou Grigoria , Topouzis Fotis 
Published: June 2021

Objective:
The objective of this study was to determine the 12-year incidence of open-angle glaucoma (OAG), with further classification into primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG), in an elderly White population.

Design:
A longitudinal, population-based study in urban Northern Greece.

Participant:
Surviving cohort of the 2554 Thessaloniki Eye Study subjects 60 years and above who had the baseline examination.

Methods:
The surviving cohort was re-examined 12 years after baseline, using the same methodology and the same standard operating procedures as in the baseline examination. The definitions of glaucoma and pseudoexfoliation were consistent throughout the study. The 12-year incidences of OAG, POAG, and PEXG with corresponding 95% confidence intervals (CIs) were calculated for the whole study population, consisting of clinic-visit and home-visit participants. The population at risk was defined as those who did not meet the study criteria for the diagnosis of glaucoma in either eye at baseline.

Main Outcome Measures:
Twelve-year incidence of OAG, with further classification into POAG and PEXG.

Results:
Of 1468 eligible subjects in the surviving cohort, 1092 were examined (participation rate 74%). Mean age at baseline was 68.9±4.6 years. Mean follow-up time was 11.6±1.6 years. The 12-year incidence of OAG was 4.4% (95% CI: 3.3-5.8); 0.37% per year. In the overall population the incidence of POAG and PEXG was 2.1% (95% CI: 1.3-3.2) and 2.3% (95% CI: 1.5-3.4), respectively. The corresponding incidence proportions were 2.9 (95% CI: 1.8-4.3) in those without PEX and 8.9 (95% CI: 5.8-12.9) in those with PEX at baseline and/or incidence. The latter was strongly associated with higher odds for incident glaucoma (odds ratio=3.34, 95% CI: 1.83-6.08, P<0.001). Of all incident OAG cases, 11.1% (95% CI: 4.4-24) had baseline intraocular pressure >21 mm Hg.

Conclusions:
The incidence of OAG was similar or higher compared with other White populations. The incidence of glaucoma in those with PEX was higher compared with the incidence of glaucoma in those without PEX.
Pulmonary hypertension in interstitial lung disease: screening, diagnosis and treatment
Authors: Behr Jürgen , Nathan Steven D. 
Published: June 2021

Purpose of review
Pulmonary vascular disease resulting in pulmonary hypertension in the context of interstitial lung disease (PH-ILD) is a common complication that presents many challenges in clinical practice. Despite recent advances, the pathogenetic interplay between parenchymal and vascular disease in ILD is not fully understood. This review provides an overview of the current knowledge and recent advances in the field.

Recent findings
Clinical trials employing the phosphodiesterase-5-inhibitor sildenafil delivered negative results whereas riociguat showed harmful effects in the PH-ILD population. More recently, inhaled treprostinil showed positive effects on the primary endpoint (six-min walk-distance) in the largest prospective randomized placebo-controlled trial to date in this patient population. Additionally, a pilot trial of ambulatory inhaled nitric oxide suggests beneficial effects based on the novel endpoint of actigraphy.

Summary
In view of these novel developments this review provides an overview of the status quo of screening, diagnosis and management of pulmonary vascular disease and PH in patients with ILD.
Colonic Transit Time and Fecal Impaction in Children and Adolescents With Cystic Fibrosis-associated Constipation
Authors: de Sillos Marcela Duarte , Chiba Sonia Mayumi , Soares Ana Cristina Fontenele , Gomes Clóvis Eduardo Tadeu , de Morais Mauro Batista 
Published: June 2021

ABSTRACT

Background:
Constipation is prevalent in pediatric cystic fibrosis (CF) patients and colonic motility has not been studied in this population. In this study, we aimed to evaluate the total and segmental colonic transit time in children and adolescents with CF based on the presence of constipation and radiological fecal impaction.

Methods:
In this case series, all patients aged 3 to 20 years of a CF reference center were invited to participate. CF-associated constipation was diagnosed based on the European Society for Paediatric Gastroenterology Hepatology and Nutrition criteria. Total and segmental colonic transit time was determined using radiopaque markers. Fecal impaction on plain abdominal radiography was assessed based on the Barr score.

Results:
Of the 43 eligible patients, 34 (79%) agreed to participate. Constipation was found in 44.1% of children and adolescents, predominantly in girls. The total colonic transit time (medians of 42 and 24 hours, respectively, P = 0.028) and the segmental right colon transit time (medians of 8 and 2 hours, respectively, P = 0.012) were significantly longer in CF-associated constipation group than in the group of patients without constipation. The frequency of radiological fecal impaction was similar in patients with (50.0%) and without (64.2%) CF-associated constipation (P = 0.70). There was no relationship between radiological fecal impaction and the total and segmental colonic transit time.

Conclusions:
Children and adolescents with CF-associated constipation had a longer total and segmental right colon transit time. Colonic transit time was similar in patients with and without radiological fecal impaction.
Normative modeling of neuroimaging data using generalized additive models of location scale and shape
Authors: Dinga Richard , Fraza Charlotte J. , Bayer Johanna M.M. , Kia Seyed Mostafa , Beckmann Christian F. , Marquand Andre F. 
Published: June 2021

AbstractNormative modeling aims to quantify the degree to which an individual’s brain deviates from a reference sample with respect to one or more variables, which can be used as a potential biomarker of a healthy brain and as a tool to study heterogeneity of psychiatric disorders. The application of normative models is hindered by methodological challenges and lacks standards for the usage and evaluation of normative models. In this paper, we present generalized additive models for location scale and shape (GAMLSS) for normative modeling of neuroimaging data, a flexible modeling framework that can model heteroskedasticity, non-linear effects of variables, and hierarchical structure of the data. It can model non-Gaussian distributions, and it allows for an automatic model order selection, thus improving the accuracy of normative models while mitigating problems of overfitting. Furthermore, we describe measures and diagnostic tools suitable for evaluating normative models and step-by-step examples of normative modeling, including fitting several candidate models, selecting the best models, and transferring them to new scan sites.
Timing of meristem initiation and maintenance determines the morphology of fern gametophytes
Authors: Wu Xiao , Yan An , McAdam Scott A.M. , Banks Jo Ann , Zhang Shaoling , Zhou Yun 
Published: June 2021

AbstractThe alternation of generations in land plants occurs between the sporophyte phase and the gametophyte phase. The sporophytes of seed plants develop self-maintained, multicellular meristems, and these meristems determine plant architecture. The gametophytes of seed plants lack meristems and are heterotrophic. In contrast, the gametophytes of seed-free vascular plants, including ferns, are autotrophic and free-living, developing meristems to sustain their independent growth and proliferation. Compared to meristems in the sporophytes of seed plants, the cellular mechanisms underlying meristem development in fern gametophytes remain largely unknown. Here, using confocal time-lapse live imaging and computational segmentation and quantification, we determined different patterns of cell divisions associated with the initiation and proliferation of two distinct types of meristems in fern gametophytes. Our results reveal how the simple timing of a switch between two meristems has considerable consequences for the divergent gametophyte morphologies of two closely related ferns from Pteridaceae (Pteris and Ceratopteris). Our result provides evolutionary insight into the function and regulation of gametophyte meristems in seed-free vascular plants.HighlightLive-imaging of cell growth and division in apical initials and lateral meristems reveals that the timing of a switch between the two meristem identities drives morphology variation in fern gametophytes.
A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s Ataxia
Authors: Campos Oscar A. , Attar Narsis , Mallipeddi Nathan V. , Cheng Chen , Vogelauer Maria , Schmollinger Stefan , Merchant Sabeeha S. , Kurdistani Siavash K. 
Published: June 2021

AbstractDisruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich’s Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.TeaserReduction of Cu1+ production by histone H3 restores cellular deficiencies caused by insufficient supply of iron-sulfur clusters.
Value-based decision-making between affective memories
Authors: Pulcu Erdem , Guinea Calum , Clemens Hannah , Harmer Catherine J , Murphy Susannah E 
Published: June 2021

AbstractAffective biases can influence how past events are recalled from memory. However, the mechanisms underlying how discrete affective events shape memory formation and subsequent recall are not well understood. Further understanding this is important given the central role of negative biases in affective memory recall in depression and antidepressant drug action. In order to capture cognitive processes associated with affective memory formation and recall, we studied value-based decision-making between affective memories in two within-subject experiments (n=45 and n=74). Our findings suggest that discrete affective events, created by large magnitude Wheel of Fortune (WoF) outcomes, influence affective memory formation processes during reinforcement-learning (RL). After 24 hours, we show that healthy volunteers display stable preferences during value-based recall of affective memories in a binary decision-making task. Computational modelling of these preferences demonstrated a positive bias during value-based recall, induced by previously winning in the WoF. We further showed that value-based decision-making between affective memories engages the pupil-linked central arousal systems, leading to pupil constriction prior to, and differential pupil dilation after the decision onset depending on the valence of the chosen options. Taken together, we demonstrate that mechanisms underlying human affective memory systems can be described by RL and probability weighting models. This approach could be used as a translational assay to study the effects of novel antidepressants.
Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome
Authors: Birey Fikri , Li Min-Yin , Gordon Aaron , Thete Mayuri V. , Valencia Alfredo M. , Revah Omer , Pașca Anca M. , Geschwind Daniel H. , Pașca Sergiu P. 
Published: June 2021

SUMMARYDefects in interneuron migration during forebrain development can disrupt the assembly of cortical circuits and have been associated with neuropsychiatric disease. The molecular and cellular bases of such deficits have been particularly difficult to study in humans due to limited access to functional forebrain tissue from patients. We previously developed a human forebrain assembloid model of Timothy Syndrome (TS), caused by a gain-of-function mutation in CACNA1C which encodes the L-type calcium channel (LTCC) Cav1.2. By functionally integrating human induced pluripotent stem cell (hiPSC)-derived organoids resembling the dorsal and ventral forebrain from patients and control individuals, we uncovered that migration is disrupted in TS cortical interneurons. Here, we dissect the molecular underpinnings of this phenotype and report that acute pharmacological modulation of Cav1.2 can rescue the saltation length but not the saltation frequency of TS migrating interneurons. Furthermore, we find that the defect in saltation length in TS interneurons is associated with aberrant actomyosin function and is rescued by pharmacological modulation of MLC phosphorylation, whereas the saltation frequency phenotype in TS interneurons is driven by enhanced GABA sensitivity and can be restored by GABA receptor antagonism. Overall, these findings uncover multi-faceted roles of LTCC function in human cortical interneuron migration in the context of disease and suggest new strategies to restore interneuron migration deficits.
Temperature-Inducible Precision Guided Sterile Insect Technique
Authors: Kandul Nikolay P. , Liu Junru , Akbari Omar S. 
Published: June 2021

ABSTRACTReleases of sterile males are the gold standard for many insect population control programs, and precise sex sorting to remove females prior to male releases is essential to the success of these operations. To advance traditional methods for scaling the generation of sterile males, we previously described a CRISPR-mediated precision-guided sterile insect technique (pgSIT), in which Cas9 and gRNA strains are genetically crossed to generate sterile males for release. While effective at generating F1 sterile males, pgSIT requires a genetic cross between the two parental strains which requires maintenance and sexing of two strains in a factory. Therefore, to further advance pgSIT by removing this crossing step, here we describe a next-generation Temperature-Inducible pgSIT (TI-pgSIT) technology and demonstrate its proof-of-concept in Drosophila melanogaster. Importantly, we were able to develop a true-breeding strain for TI-pgSIT that eliminates the requirement for sex sorting, a feature that may help further automate production at scale.
Here be dragons: important spatial uncertainty driven by climate data in forecasted distribution of an endangered insular reptile
Authors: Dubos Nicolas , Augros Stephane , Deso Gregory , Probst Jean-Michel , Notter Jean-Cyrille , Roesch Markus A. 
Published: June 2021

AbstractThe effect of future climate change is poorly documented in the tropics, especially in mountainous areas. Yet, species living in these environments are predicted to be strongly affected. Newly available high-resolution environmental data and statistical methods enable the development of forecasting models. Nevertheless, the uncertainty related to climate models can be strong, which can lead to ineffective conservation actions. Predicted studies aimed at providing conservation guidelines often account for a range of future climate predictions (climate scenarios and global circulation models). However, very few studies considered potential differences related to baseline climate data and/or did not account for spatial information (overlap) in uncertainty assessments. We modelled the environmental suitability forPhelsuma borbonica, an endangered reptile native to Reunion Island. Using two metrics of species range change (difference in overall suitability and spatial overlap), we quantified the uncertainty related to the modelling technique (n = 10), sample bias correction, climate change scenario, global circulation models (GCM) and baseline climate (CHELSAversusWorldclim). Uncertainty was mainly driven by GCMs when considering overall suitability, while for spatial overlap the uncertainty related to baseline climate became more important than that of GCMs. The uncertainty driven by sample bias correction and variable selection was much higher when assessed based on spatial overlap. The modelling technique was a strong driver of uncertainty in both cases. We eventually provide a consensus ensemble prediction map of the environmental suitability ofP. borbonicato identify the areas predicted to be the most suitable in the future with the highest certainty. Predictive studies aimed at identifying priority areas for conservation in the face of climate change need to account for a wide panel of modelling techniques, GCMs and baseline climate data. We recommend the use of multiple approaches, including spatial overlap, when assessing uncertainty in species distribution models.
A Versatile Linker for Probes Targeting Hydrolases via In Situ labeling
Authors: Liu Jun , Chen Zixin , Cui Chao , Sigler Ashton L. , Cui Lina 
Published: June 2021

AbstractHydrolases are important molecules that are involved in a wide range of biological functions and their activities are tightly regulated in healthy or diseased states. Detecting or imaging the activities of hydrolases, therefore, can reveal underlying molecular mechanisms in the context of cells to organisms, and their correlation with different physiological conditions can therefore be used in diagnosis. Due to the nature of hydrolases, substrate-based probes can be activated in their catalytic cycles, and cleavage of covalent bonds frees reporter moieties. For test-tube type bulk detection, spatial resolution is not a measure of importance, but for cell- or organism-based detection or imaging, spatial resolution is a key factor for probe sensitivity that influences signal-to-background ratio. One strategy to improve spatial resolution of the probes is to form a covalent linkage between the reporter moiety and intracellular proteins upon probe activation by the enzyme. In this work, we developed a generalizable linker chemistry that would allow in situ labeling of various imaging moieties via quinone methide species. To do so, we synthesized probes containing a monofluoromethyl or a difluoromethyl groups for β-galactosidase activation, while using fluorescein as a fluorescent reporter. The labeling efficacy of these two probes was evaluated in vitro. The probe bearing a monofluormethyl group exhibited superior labeling efficiency in imaging β-galactosidase activity in living cells. This study provides a versatile linker for applying quinone methide chemistry in the development of hydrolase-targeting probes involving in situ labeling.
Asynchronous rates of lineage, phenotype, and niche diversification in a continental-scale adaptive radiation
Authors: Stone Benjamin W. , Wolfe Andrea D. 
Published: June 2021

AbstractRapidly diversifying clades are central to the study of diversification dynamics. This central importance is perhaps most apparent when rapid evolution occurs across several axes of diversification (e.g., lineage, phenotype, and niche); such clades facilitate investigations into the interplay between adaptive and non-adaptive diversification mechanisms. Yet, empirical evidence from rapidly evolving clades remains unclear about the relationships, if any, across diversification axes. This is especially apparent regarding the timing of diversification rate shifts. We address this knowledge gap through comparisons of the rate and timing of lineage, phenotypic, and niche diversification inPenstemon, a rapidly-evolving angiosperm genus. We find that diversification rate shifts inPenstemonare asynchronous; while we identify a burst and subsequent slowdown in lineage diversification rate ∼2.0-2.5 MYA, shifts in phenotypic and niche diversification rates either lagged behind temporally or did not occur at all. We posit that this asynchronicity in diversification rate shifts is the result of initial niche-neutral diversification followed by adaptive, density-dependent processes. Our findings contribute to a growing body of evidence that asynchronous shifts in diversification rates may be common and question the applicability of expectations for diversification dynamics across disparate empirical systems.
Localization and phosphorylation in the Snf1 network is controlled by two independent pathways
Authors: Österberg Linnea , Welkenhuysen Niek , Persson Sebastian , Hohmann Stefan , Cvijovic Marija 
Published: June 2021

AbstractAMPK/SNF1 is the master regulator of energy homeostasis in eukaryotic cells and has a key role in glucose de-repression. If glucose becomes depleted, Snf1 is phosphorylated and activated. Activation of Snf1 is required but is not sufficient for mediating glucose de-repression indicating a second glucose-regulated step that adjusts the Snf1 pathway. To elucidate this regulation, we further explore the spatial dynamics of Snf1 and Mig1 and how they are controlled by concentrations of hexose sugars. We utilize fluorescence recovery after photobleaching (FRAP) to study the movement of Snf1 and how it responds to external glucose concentrations. We show that the Snf1 pathway reacts to the presence of glucose. Furthermore, we identify a negative feedback loop regulating Snf1 activity. Our data offer insight into the true complexity of regulation of this central signaling pathway by one signal (glucose depletion) interpreted by the cell in different ways.