bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Hidden Structural Variation in a Known IRD Gene: A Cautionary Tale of Two New Disease Candidate Genes
Authors: Scott Hilary A. , Larson Anna , Rong Shi Song , Mehrotra Sudeep , Butcher Rossano , Chao Katherine R. , Wiggs Janey L. , Place Emily M. , Pierce Eric A. , Bujakowska Kinga M. 
Published: October 2021

ABSTRACTRod cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1/3500 people. Over 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with Rod-cone dystrophy (RCD). Family members were given a full ophthalmic exam at the Retinal Service at MEE and consented to genetic testing. Whole exome sequencing (WES) was performed and variants of interest were Sanger validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function.WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187+3A>C and c.1568-8C>A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G>A (p.Glu1290Lys) and c.4603G>A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins), however the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant.Our study demonstrates the importance of thorough functional characterization of new disease candidate genes, and the value of reanalyzing NGS sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.
Onset and stepwise extensions of recombination suppression are common in mating-type chromosomes of Microbotryum anther-smut fungi
Authors: Duhamel Marine , Carpentier Fantin , Begerow Dominik , Hood Michael E. , de la Vega Ricardo C. Rodríguez , Giraud Tatiana 
Published: October 2021

AbstractSex chromosomes and mating-type chromosomes can display large genomic regions without recombination. Recombination suppression often extended stepwise with time away from the sex- or mating-type-determining genes, generating evolutionary strata of differentiation between alternative sex or mating-type chromosomes. In anther-smut fungi of the Microbotryum genus, recombination suppression evolved repeatedly, linking the two mating-type loci and extended multiple times in regions distal to the mating-type genes. Here, we obtained high-quality genome assemblies of alternative mating types for four Microbotryum fungi. We found an additional event of independent chromosomal rearrangements bringing the two mating-type loci on the same chromosome followed by recombination suppression linking them. We also found, in a new clade analysed here, that recombination suppression between the two mating-type loci occurred in several steps, with first an ancestral recombination suppression between one of the mating-type locus and its centromere; later, completion of recombination suppression up to the second mating-type locus occurred independently in three species. The estimated dates of recombination suppression between the mating-type loci ranged from 0.15 to 3.58 million years ago. In total, this makes at least nine independent events of linkage between the mating-type loci across the Microbotryum genus. Several mating-type locus linkage events occurred through the same types of chromosomal rearrangements, where similar chromosome fissions at centromeres represent convergence in the genomic changes leading to the phenotypic convergence. These findings further highlight Microbotryum fungi as excellent models to study the evolution of recombination suppression.
Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
Authors: Einarsson Hjörleifur , Salvatore Marco , Vaagensø Christian , Alcaraz Nicolas , Bornholdt Jette , Rennie Sarah , Andersson Robin 
Published: October 2021

AbstractGenetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter’s DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.
PlasmodiumDDI1 is a potential therapeutic target and important chromatin-associated protein
Authors: Tanneru Nandita , Nivya M Angel , Adhikari Navin , Saxena Kanika , Rizvi Zeba , Sudhakar Renu , Nagwani Amit Kumar , Atul  , Abdul Al-Nihmi Faisal Mohammed , Kota Arun Kumar , Sijwali Puran Singh 
Published: October 2021

AbstractDDI1 proteins are involved in a variety of cellular processes, including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral aspartyl protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins ofPlasmodiumand other Apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain.PlasmodiumDDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasitePlasmodium bergheiand the human malaria parasitePlasmodium falciparumcompromised parasite development. Infection of mice with DDI1 knock-downP. bergheiwas self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating potential of DDI1 knock-down parasites as a whole organism vaccine.P. falciparumDDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors,PlasmodiumDDI1 is a potential therapeutic target for malaria control.
The behavioral variant of Alzheimer’s disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex
Authors: Singleton E.H. , Pijnenburg Y.A.L , Gami-Patel P. , Boon B.D.C. , Bouwman F. , Papma J. , Seelaar H. , Scheltens P. , Grinberg L.T. , Spina S. , Nana A.L. , Rabinovici G.D. , Seeley W.W. , Ossenkoppele R. , Dijkstra A.A. 
Published: October 2021

AbstractBackgroundThe neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo Neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD.MethodsVENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n=9) and compared to typical AD (tAD, n=6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n=18) and controls (n=13) using ANCOVAs adjusted for age and Bonferroni correceted. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss.ResultsThe number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0±15.3, GABRQ-ir pyramidal: 260.44±87.13) and tAD (VENs: 32.0±18.1,p=1.00, GABRQ-ir pyramidal: 349.83±109.64,p=0.38) and controls (VENs: 33.5±20.3,p=1.00, GABRQ-ir pyramidal: 339.38±95.88,p=0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.39±82.58,p=0.01) and no significant differences in number of VENs (bvFTD: 10.9±13.8,p=0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5.DiscussionVENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.
A neural substrate for Bayesian integration in human parietal cortex
Authors: Singletary Nicholas M. , Gottlieb Jacqueline , Horga Guillermo 
Published: October 2021

AbstractMaking adaptive decisions often requires inferring unobservable states based on unreliable information. Bayesian logic prescribes that individuals form probabilistic beliefs about a state by integrating the likelihood of new evidence with their prior beliefs, but human neuroimaging studies on probability representations have not typically examined this integration process. We developed an inference fMRI task in which participants estimated the posterior probability of a hidden state while we parametrically modulated the prior probability of the state, the likelihood of the supporting evidence, and a monetary penalty for estimation inaccuracy. Consistent with a neural substrate for Bayesian integration, activation in left posterior parietal cortex tracked the estimated posterior probability of the solicited state and its components of prior probability and likelihood, all independently of expected value. This activation further reflected deviations in individual reports from objective probabilities. Thus, this region may provide a neural substrate for humans’ ability to approximate Bayesian inference.
Chimeric chromosome landscapes of human somatic cell cultures show dependence on stress and regulation of genomic repeats by CGGBP1
Authors: Datta Subhamoy , Patel Manthan , Kashyap Sukesh , Patel Divyesh , Singh Umashankar 
Published: October 2021

ABSTRACTGenomes of somatic cells in culture are prone to spontaneous mutations due to errors in replication and DNA repair. Some of these errors, such as chromosomal fusions, are not rectifiable and subject to selection or elimination in growing cultures. Somatic cell cultures are thus expected to generate background levels of potentially stable chromosomal chimeras. A description of the landscape of such spontaneously generated chromosomal chimeras in cultured cells will help us understand the factors affecting somatic mosaicism. Here we show that short homology-associated non-homologous chromosomal chimeras occur in normal human fibroblasts and HEK293T cells at genomic repeats. The occurrence of chromosomal chimeras is enhanced by heat stress and depletion of a repeat regulatory protein CGGBP1. We also present evidence of homologous chromosomal chimeras between allelic copies in repeat-rich DNA obtained by methylcytosine immunoprecipitation. The formation of homologous chromosomal chimeras at Alu and L1 repeats increases upon depletion of CGGBP1. Our data are derived fromde novosequencing from three different cell lines under different experimental conditions and our chromosomal chimera detection pipeline is applicable to long read as well as short read sequencing platforms. These findings present significant information about the generation, sensitivity and regulation of somatic mosaicism in human cell cultures.
Netrins and receptors control Drosophila optic lobe organization and transmedullary neuron axon targeting
Authors: Zhang Yu , Lowe Scott , Li Xin 
Published: October 2021

AbstractDuring development, integration of temporal patterning and spatial patterning of neural progenitors as well as Notch-dependent binary fate choice between sister neurons contribute to generation of neural diversity. How these upstream neural fate specification programs regulate downstream effector genes to control axon targeting and neuropil assembly remains less well-understood. Here we show that Notch-dependent binary fate choice in Drosophila medulla neurons regulates the expression of Netrin, and that Netrin pathway controls axon guidance of transmedullary (Tm) neurons and contributes to the organization of optic lobe neuropils. Netrins are enriched in the lobula where Tm axons target, and the attractive receptor Frazzled is expressed broadly in medulla neurons, while the repulsive receptor Unc-5 is excluded from Tm neurons and this is necessary for their correct targeting to the lobula. Frazzled is required collectively in a group of early-born Tm neurons to establish the inner optic chiasm (IOC) through which Tm axons target lobula. In addition, Frazzled acts in the layer-specific targeting step of Tm3 and Tm4 cell-autonomously, and is also required for the formation of the lobula branch of TmY3. Moreover, we show that the diffusibility of Netrins is necessary for Netrin enrichment in the lobula, the IOC formation and layer-specific targeting of Tm3 and Tm4. Netrin enrichment in the lobula is promoted by Frazzled expressed in Tm neurons, while Unc-5 appears to have an opposite role in Netrin distribution. Furthermore, we show that Netrin B is expressed in the Notch-on hemilineage of medulla neurons including most Tm and TmY neurons that target lobula, and loss of Su(H) abolished NetB expression in the medulla. Without medulla-originated NetB, Tm axons from late-born medulla columns cannot join the IOC. Therefore, the Notch-dependent binary fate choice regulates the assembly of the optic lobe neuropils by controlling the expression of Netrin.
Mllt11 regulates the migration and neurite outgrowth of cortical projection neurons during development
Authors: Stanton-Turcotte Danielle , Hsu Karolynn , Moore Samantha A. , Yamada Makiko , Fawcett James P. , Iulianella Angelo 
Published: October 2021

ABSTRACTThe formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are generally two types of cortical projection neurons: those that project locally and interhemispherically, and those that project to sub-cerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate, particularly during the formation of the upper or superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is a required for neuritogenesis and proper migration of upper layer cortical projection neurons. Loss of Mllt11 in the superficial cortex leads to a severe reduction in fibres crossing the corpus callosum, a progressive loss in the maintenance of upper layer projection neuron gene expression, and dysplasia of dendritic arborisation patterns. Proteomic analysis revealed that Mllt11 associates with cytoskeletal components including stabilized microtubules consistent with a role in neuronal migration and neuritogenesis. Taken together, our findings support a role for Mllt11 in promoting the formation of mature projection neuron morphologies and connectivity in the cerebral cortex.
A policy prioritization framework using causal layered analysis and MCDM: case study of Iran’s environmental policies
Authors: Fouladgar Mohammad Majid , Borumand Kakhki Ahmad , Nasr Esfehani Alireza , Sedighi Mohammadsadegh 
Published: October 2021

Purpose
This paper aims to propose a policy prioritization framework in view of a layered scenario building along with key stakeholder analysis and has been applied in a case study to determine the priority of Iran environmental policies at the horizon of 2030. A creative framework that covers future scenarios and allows for a more accurate and intelligent policy assessment and prioritization.

Design/methodology/approach
The general environmental policies of the Islamic Republic of Iran are evaluated, and observation policies in social area were identified. Causal layered analysis (CLA) is applied for policy prioritization based on layered probable scenarios and key stakeholder role consideration. The Multiple-criteria decision-making (MCDM) is also used for ranking General Environmental Policies by the technique for order of preference by similarity to ideal solution (TOPSIS).

Findings
Four uncertainties were obtained in different layers based on the CLA analysis, resulting in the creation of four main scenario and 16 discrete scenarios. Finally, Iran’s environmental policies were prioritized given the probable scenarios and the centralized policies on the social and political domains. The proposed model will be effective in policy-making in multilateral atmosphere to prioritize policies and alternative macro-strategies.

Originality/value
This paper shows that foresight and especially developed scenarios provide intelligent, efficient and effective planning and policy-making, and in addition to illustrating surrounding changes and probable future imagery, it generates common understanding and inter-subjective knowledge by increasing participation of various officials and stakeholders.
Talking about the likelihood of risks: an agent-based simulation of discussion processes in risk workshops
Authors: Harten Clemens , Meyer Matthias , Bellora-Bienengräber Lucia 
Published: November 2021

PurposeThis paper aims to explore drivers of the effectiveness of risk assessments in risk workshops.Design/methodology/approachThis study uses an agent-based model to simulate risk assessments in risk workshops. Combining the notions of transactive memory and the ideal speech situation, this study establishes a risk assessment benchmark and then investigates real-world deviations from this benchmark. Specifically, this study models limits to information transfer, incomplete discussions and potentially detrimental group characteristics, as well as interaction patterns.FindingsFirst, limits to information transfer among workshop participants can prevent a correct consensus. Second, increasing the required number of stable discussion rounds before an assessment improves the correct assessment of high but not low likelihood risks. Third, while theoretically advantageous group characteristics are associated with the highest assessment correctness for all risks, theoretically detrimental group characteristics are associated with the highest assessment correctness for high likelihood risks. Fourth, prioritizing participants who are particularly concerned about the risk leads to the highest level of correctness.Originality/valueThis study shows that by increasing the duration of simulated risk workshops, the assessments change – as a rule – from underestimating to overestimating risks, unraveling a trade-off for risk workshop facilitators. Methodologically, this approach overcomes limitations of prior research, specifically the lack of an assessment and process benchmark, the inability to disentangle multiple effects and the difficulty of capturing individual cognitive processes.
Hydraulic Properties of the Riffle Crest and Applications for Stream Ecosystem Management
Authors: Rossi Gabriel J. , Mierau Darren W. , Carah Jennifer K. 
Published: October 2021

AbstractRiffle crests are important hydraulic controls in riffle‐pool‐dominated streams, influencing pool hydraulics and water quality that collectively control lotic habitat for many organisms. We define a simple stream depth measurement, the riffle crest thalweg (RCT), describe measurement methods and utility, and suggest that RCT depth is a better independent variable than streamflow (Q) for many instream flow and habitat assessment applications. Using RCT depth as an independent variable, rather than streamflow, reduces the need for gauging or streamflow measurements in many management applications. Unlike streamflow, RCT depth varies directly with fundamental elements of riverine habitat such as channel morphology and bed roughness. We also suggest that relationships between RCT depth and streamflow (RCT‐Q curves) can be used to evaluate the risk of streamflow alteration at ungauged sites. We describe three case studies to demonstrate the utility of RCT depth and RCT‐Q rating curves in stream ecosystem management: (1) evaluating the effect of a top‐down flow prescription on modeled salmonid habitat, (2) estimating the risk from the incremental reduction of RCT depth on habitat and ecological responses, and (3) identifying relationships between RCT depth and dissolved oxygen in ungauged streams. An easy‐to‐measure, inexpensive, and ecologically sensitive metric, RCT depth holds promise as a useful tool in stream ecosystem management.