bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility
Authors: Zou Jennifer , Gopalakrishnan Shyam , Parker Clarissa C , Nicod Jerome , Mott Richard , Cai Na , Lionikas Arimantas , Davies Robert W , Palmer Abraham A , Flint Jonathan
Published: November 2021

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6, and GM11545 with bone mineral density, and Psmb9 with weight. However, replication at a nominal threshold of 0.05 between the two component studies was low, with less than one-third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations, we integrated information about replication rates, study-specific heterogeneity, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.
A generic hidden Markov model for multiparent populations
Authors: Broman Karl W
Published: November 2021

A common step in the analysis of multiparent populations (MPPs) is genotype reconstruction: identifying the founder origin of haplotypes from dense marker data. This process often makes use of a probability model for the pattern of founder alleles along chromosomes, including the relative frequency of founder alleles and the probability of exchanges among them, which depend on a model for meiotic recombination and on the mating design for the population. While the precise experimental design used to generate the population may be used to derive a precise characterization of the model for exchanges among founder alleles, this can be tedious, particularly given the great variety of experimental designs that have been proposed. We describe an approximate model that can be applied for a variety of MPPs. We have implemented the approach in the R/qtl2 software, and we illustrate its use in applications to publicly available data on Diversity Outbred and Collaborative Cross mice.
Conservation of griseofulvin genes in the gsf gene cluster among fungal genomes
Authors: Aris Parisa , Yan Lihong , Wei Yulong , Chang Ying , Shi Bihong , Xia Xuhua
Published: November 2021

The polyketide griseofulvin is a natural antifungal compound and research in griseofulvin has been key in establishing our current understanding of polyketide biosynthesis. Nevertheless, the griseofulvin gsf biosynthetic gene cluster (BGC) remains poorly understood in most fungal species, including Penicillium griseofulvum where griseofulvin was first isolated. To elucidate essential genes involved in griseofulvin biosynthesis, we performed third-generation sequencing to obtain the genome of P. griseofulvum strain D-756. Furthermore, we gathered publicly available genome of 11 other fungal species in which gsf gene cluster was identified. In a comparative genome analysis, we annotated and compared the gsf BGC of all 12 fungal genomes. Our findings show no gene rearrangements at the gsf BGC. Furthermore, seven gsf genes are conserved by most genomes surveyed whereas the remaining six were poorly conserved. This study provides new insights into differences between gsf BGC and suggests that seven gsf genes are essential in griseofulvin production.
The disease-associated proteins Drosophila Nab2 and Ataxin-2 interact with shared RNAs and coregulate neuronal morphology
Authors: Rounds J Christopher , Corgiat Edwin B , Ye Changtian , Behnke Joseph A , Kelly Seth M , Corbett Anita H , Moberg Kenneth H
Published: November 2021

Nab2 encodes the Drosophila melanogaster member of a conserved family of zinc finger polyadenosine RNA-binding proteins (RBPs) linked to multiple steps in post-transcriptional regulation. Mutation of the Nab2 human ortholog ZC3H14 gives rise to an autosomal recessive intellectual disability but understanding of Nab2/ZC3H14 function in metazoan nervous systems is limited, in part because no comprehensive identification of metazoan Nab2/ZC3H14-associated RNA transcripts has yet been conducted. Moreover, many Nab2/ZC3H14 functional protein partnerships remain unidentified. Here, we present evidence that Nab2 genetically interacts with Ataxin-2 (Atx2), which encodes a neuronal translational regulator, and that these factors coordinately regulate neuronal morphology, circadian behavior, and adult viability. We then present the first high-throughput identifications of Nab2- and Atx2-associated RNAs in Drosophila brain neurons using RNA immunoprecipitation-sequencing (RIP-Seq). Critically, the RNA interactomes of each RBP overlap, and Nab2 exhibits high specificity in its RNA associations in neurons in vivo, associating with a small fraction of all polyadenylated RNAs. The identities of shared associated transcripts (e.g., drk, me31B, stai) and of transcripts specific to Nab2 or Atx2 (e.g., Arpc2 and tea) promise insight into neuronal functions of, and genetic interactions between, each RBP. Consistent with prior biochemical studies, Nab2-associated neuronal RNAs are overrepresented for internal A-rich motifs, suggesting these sequences may partially mediate Nab2 target selection. These data support a model where Nab2 functionally opposes Atx2 in neurons, demonstrate Nab2 shares associated neuronal RNAs with Atx2, and reveal Drosophila Nab2 associates with a more specific subset of polyadenylated mRNAs than its polyadenosine affinity alone may suggest.
Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line
Authors: Arends Danny , Kärst Stefan , Heise Sebastian , Korkuc Paula , Hesse Deike , Brockmann Gudrun A
Published: November 2021

While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 [Berlin Fat Mouse Inbred (BFMI)]. A total of 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays. TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data were used to test for overrepresentation of nonsynonymous SNPs (nsSNPs) in TRD regions. Genetic incompatibilities were tested using the Bateson–Dobzhansky–Muller two-locus model. A total of 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more nsSNPs than randomly selected regions (182 vs 125.9 ± 17.0, P < 1 × 10−4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions [P(BF) < 0.05]. Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein–protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6, and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein–protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of nsSNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein–protein interactions, and determinants of complex traits such as obesity.
The Genealogical Divergence Index Across a Speciation Continuum in Hercules Beetles
Authors: Huang Jen-Pan
Published: November 2021

The genealogical divergence index (gdi) was developed to aid in molecular species delimitation under the multispecies coalescent model, which has been shown to delimit genetic structures but not necessarily species. Although previous studies have used meta-analyses to show that gdi could be informative for distinguishing taxonomically good species, the biological and evolutionary implications of divergences showing different gdi values have yet to be studied. I showed that an increase in gdi value was correlated with later stages of divergence further along a speciation continuum in an Amazonian Hercules beetle system. Specifically, a gdi value of 0.7 or higher was associated with diverge between biological species that can coexist in geographic proximity while maintaining their evolutionary independence. Divergences between allopatric species that were conventionally given subspecific status, such as geographic taxa that may or may not be morphologically divergent, had gdi values that fell within the species delimitation ambiguous zone (0.2 < gdi < 0.7). However, the results could be drastically affected by the sampling design, i.e., the choice of different geographic populations and the lumping of distinct genetic groups when running the analyses. Different gdi values may prove to be biologically and evolutionarily informative should additional speciation continua from different empirical systems be investigated, and the results obtained may help with objectively delimiting species in the era of integrative taxonomy.
Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-β1-induced podocyte migration
Authors: Chen Chien-An , Chang Jer-Ming , Chen Hung-Chun , Chang Eddy-Essen
Published: November 2021

Podocyte migration results in proteinuria and glomerulonephropathy. Transforming growth factor-β1 (TGF-β1), endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) can mediate podocyte migration; however, the crosstalk between them is unclear. This study determined the relationships between these factors. ER stress biomarkers (GRP78, p-eIF2α or CHOP), intracellular ROS generation, integrin-β3 and cell adhesion and migration were studied in a treatment of experiment using TGF-β1 with and without the ER stress inhibitors: 4-phenylbutyric acid (4-PBA, a chemical chaperone), salubrinal (an eIF2α dephosphorylation inhibitor) and N-acetylcysteine (NAC, an antioxidant). ER stress biomarkers (p-eIF2α/eIF2α and GRP78), ROS generation and intergrin-β3 expression increased after TGF-β1 treatment. NAC down-regulated the expression of GRP78 after TGF-β1 treatment. 4-PBA attenuated TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation and intergrin-β3 expression. However, salubrinal did not inhibit TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation or integrin-β3 expression. NAC abrogated TGF-β1-induced integrin-β3 expression. At 24 h after treatment with TGF-β1, podocyte adhesion and migration increased. Furthermore, NAC, 4-PBA and an anti-interin-β3 antibody attenuated TGF-β1-induced podocyte adhesion and migration. This study demonstrated that TGF-β1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2α/CHOP pathway. This intracellular ROS then mediates integrin-β3 expression, which regulates podocyte migration.
The Effects of Rapid Rewarming on Tissue Salvage in Severe Frostbite Injury
Authors: Rogers Charlotte , Lacey Alexandra M , Endorf Frederick W , Punjabi Gopal , Whitley Angela , Gayken Jon , Fey Ryan , Schmitz Kyle , Nygaard Rachel M
Published: November 2021

Frostbite is a high morbidity injury caused by soft tissue freezing, which can lead to digit necrosis requiring amputation. Rapid rewarming is a first-line treatment method that involves placing affected digits into a warm water bath. This study aims to assess the clinical practices for frostbite at facilities outside of dedicated burn centers, and any impact these practices have on tissue salvage. Retrospective chart review at a single burn center identified frostbite patients admitted directly or as transfers over a 7-year period. Records were reviewed to identify initial treatment strategies. If given, time to thrombolytics from admit was noted. Tissue salvage rates were calculated from radiologically derived tissue at-risk scores and final amputation scores. One-hundred patients were transferred from outside facilities, and 108 were direct admissions (N = 208). There was no significant difference in group demographics. Rapid rewarming was the initial treatment modality more commonly in direct admit patients (P = .016). The use of rapid rewarming did not correlate with tissue salvage (P = .112). Early use of thrombolytics had a positive impact on tissue salvage (P = .003). Thrombolytics were given 1.2 hours earlier in direct admit patients (P = .029), however there was no difference in tissue salvage rates between the groups (P = .127). Efforts should focus on larger scale study to further assess the effectiveness of rapid rewarming. Although rapid rewarming did not significantly impact tissue salvage in this study, we continue to recommend its use over less studied treatment methods, and continue to view it as an important bridge to burn center transfer and administration of thrombolytic therapy.
Higher Admission Frailty Scores Predict Increased Mortality, Morbidity, and Healthcare Utilization in the Elderly Burn Population
Authors: Iles Kathleen A , Duchesneau Emilie , Strassle Paula D , Chrisco Lori , Howell Thomas Clark , King Booker , Williams Felicia N , Nizamani Rabia
Published: November 2021

The Rockwood Clinical Frailty Scale is a validated rapid assessment of frailty phenotype and predictor of mortality in the geriatric population. Using data from a large tertiary care burn center, we assessed the association between admission frailty in an elderly burn population and inpatient outcomes. This was a retrospective analysis of burn patients ≥65 years from 2015 to 2019. Patients were assigned to frailty subgroups based on comprehensive medical, social work, and therapy assessments. Cox proportional hazards regression was used to estimate associations between admission frailty and 30-day inpatient mortality. Our study included 644 patients (low frailty: 262, moderate frailty: 345, and high frailty: 37). Frailty was associated with higher median TBSA and age at admission. The 30-day cumulative incidence of mortality was 2.3%, 7.0%, and 24.3% among the low, moderate, and high frailty strata, respectively. After adjustment for age, TBSA, and inhalation injury, high frailty was associated with increased 30-day mortality, compared to low (hazard ratio 5.73; 95% confidence interval 1.86, 17.62). Moderate frailty also appeared to increase 30-day mortality, although estimates were imprecise (hazard ratio 2.19; 95% confidence interval 0.87–5.50). High frailty was associated with increased morbidity and healthcare utilization, including need for intensive care stay (68% vs 37% and 21%, P < .001) and rehab or care facility at discharge (41% vs 25% and 6%, P < .001), compared to moderate and low frailty subgroups. Our findings emphasize the need to consider preinjury physiological state and the increased risk of death and morbidity in the elderly burn population.
Infections in Patients With Major Burns: A Retrospective Study of a Burn Intensive Care Unit
Authors: Ozlu Ozer , Basaran Abdulkadir
Published: November 2021

Burn-related infections are challenging conditions to manage and can cause several complications entailing a complicated treatment. In this study, infection in burn patients hospitalized in burn intensive care unit (ICU) of a tertiary care hospital is investigated. This retrospective study was conducted between January 1, 2018 and December 31, 2020 in burn ICU of a tertiary care hospital. Patients with an ICU stay less than 48 hours and survival less than 72 hours were not included in the study. The demographic and clinical data as well as referral status, the type of infections and the isolated microorganisms, antibiotics used for prophylaxis, outcomes, and the mortality rate are evaluated retrospectively from patient files and the hospital registries. A total of 311 patients were included in our study cohort with a mean age of 22.11 ± 20.9 years. The burned TBSA was 28.07 ± 17.1 and abbreviated burn severity index was 5.76 ± 2.3. There were 155 patients with 283 infections and the infection rate was 45.8 per 1000 patient days. The most commonly isolated microorganisms were Candida species in bloodstream and urinary tract infections, Pseudomonas aeruginosa in burn wound infections. Most of the deaths (86.7%) occurred in patients with infections. In major burns strict adherence to isolation procedures, avoiding delays in referrals, early excision, and early wound closure are important measures to reduce infections. Each burn center should develop appropriate antibiotic strategies due to their culture results and prophylaxis with broad-spectrum antibiotics should be avoided.
On the relationship between environmental suitability and habitat use for three neotropical mammals
Authors: Contreras-Díaz Rusby G , Falconi Manuel , Osorio-Olvera Luis , Cobos Marlon E , Soberón Jorge , Townsend Peterson A , Lira-Noriega Andrés , Álvarez-Loayza Patricia , Luis Gonçalves André , Hurtado-Astaiza Johanna , Gonzáles Rocío del Pilar Rojas , Zubileta Ingrid Serrano , Spironello Wilson Roberto , Vásquez-Martínez Rodolfo
Published: November 2021

Recent studies have used occupancy models (OM) and ecological niche models (ENM) to provide a better understanding of species’ distributions at different scales. One of the main ideas underlying the theoretical foundations of both OM and ENM is that they are positively related to abundance: higher occupancy implies higher density and more suitable areas are likely to have more abundant populations. Here, we analyze the relationship between habitat use measured in terms of occupancy probabilities from OM and environmental suitability derived from ENM in three different Neotropical mammal species: Leopardus wiedii, Cuniculus paca, and Dasypus novemcinctus. For ENM, we used climatic and vegetation cover variables and implemented a model calibration and selection protocol to select the most competitive models. For OM, we used a single-species, single-season model with site covariates for camera-trap data from six different sites throughout the Neotropical realm. Covariates included vegetation percentage, normalized difference vegetation index, normalized difference water index, and elevation. For each site, we fit OM using all possible combinations of variables and selected the most competitive (ΔAICc < 2) to build an average OM. We explored relationships between estimated suitability and occupancy values using Spearman correlation analysis. Relationships between ENM and OM tended to be positive for the three Neotropical mammals, but the strength varied among sites, which could be explained by local factors such as site characteristics and conservation status of areas. We conjecture that ENM are suitable to understand spatial patterns at coarser geographic scales because the concept of the niche is about the species as a whole, whereas OM are more relevant to explain the distribution locally, likely reflecting transient dynamics of populations resulting from many local factors such as community composition and biotic processes.
Traumatic rupture of a hemorrhagic hepatic cyst: a case presentation and literature review
Authors: Turner Megan Jenkins , Barghuthi Lutfi , Davis Tyler , Ismael Hishaam
Published: November 2021

Hemorrhagic hepatic cyst with or without rupture is rare cause of acute abdomen with less than 20 cases reported in the literature. A standardardized management algorithm is currently not present, but literature suggests surgical management is ideal for definitive treatment and successful patient outcome. We report a case of a 39-year-old female with a chief complaint of sudden onset abdominal pain, nausea and vomiting. Abdominal computed tomography scan showed a large, 12-cm cyst in the right hepatic lobe with a hemorrhagic component. Successful laparoscopic operative management was conducted without post-operative complications such as recurrent bleeding. When managing patients with an acute abdomen, ruptured hepatic hemorrhagic cysts should be considered in the differential diagnosis and prompt surgical management should be considered as primary management.
Simulating the Consequences of Adaptive Survey Design in Two Household Panel Studies
Authors: Watson Nicole , Cernat Alexandru
Published: November 2021

Adaptive survey design has been proposed as a solution to the decreasing response rates and higher costs associated with surveys. Much of the adaptive survey design research to date focuses on cross-sectional surveys, yet it seems there is greater potential for this approach within longitudinal surveys as data on the respondent and their survey experience builds each wave. We consider the short- to medium-term impacts of modifications to fieldwork processes in the context of two household panels. We use waves 11–16 of the Household, Income and Labour Dynamics in Australia (HILDA) Survey and waves 1–6 of the UK Household Longitudinal Study (also known as Understanding Society) to simulate eight alternative follow-up strategies. Cases are targeted based on their likelihood to improve sample balance (representativeness), as measured by the R-indicator, or to provide a response, or a combination of these components. Both individual- and household-level targeting are considered. We assess the extent to which these adjustments to fieldwork efforts impact the response rates, sample representativity, and cost. We find that if the follow-up fieldwork effort were reduced by 25 percent the least detrimental strategy is where the best households in terms of improving the R-indicator or the response rates are issued to field for follow-up. This approach resulted in the same sample balance as obtained with full follow-up practice, saved between 17 and 25 percent of follow-up calls but dropped the full balanced panel response rate over four years by 8–12 percentage points.
Influenza A imported from Comoros to France in the summer months of 2021
Authors: Assoumani Loutfia , De Maria Lucille Claire , La Scola Bernard , Launay Franck , Colson Philippe , Gautret Philippe
Published: November 2021

Three children <4 years were diagnosed with influenza A/H3N2 on returning from Comoros to Marseille, France in summer 2021. An outbreak of influenza-like illness is currently affecting children in Comoros. Sentinel travellers returning to developed countries allow identifying pathogens circulating in tropical areas where diagnostic tools are lacking.
Development and Implementation of DIGEST: The Digital Interactive Gastroenterology Education Suite for Trainees
Authors: Reeves Patrick T , Min Steve B , Kolasinski Nathan T
Published: November 2021

Introduction

Clinical clerkship curricula should exist to provide rotating learners on subspecialty rotations with consistent exposure to specific topics geared toward the discipline of interest, such as pediatric gastroenterology (GI). We aim to describe our experience developing and implementing DIGEST: the Digital Interactive Gastroenterology Education Suite for Trainees, a novel, online GI curriculum delivered to virtual, rotating learners during the coronavirus (COVID-19) pandemic stay-at-home order.

Materials and Methods

A general needs assessment in 2019 identified a lack of standardized educational experience amongst the rotating learners on pediatric GI service. The COVID-19 pandemic compelled us to transition our curriculum from our institution’s secure share drive to the GOOGLE classroom. A program evaluation was undertaken and included learner responses to content and confidence questionnaires and a health care professions education (HPE) expert’s response to a course quality assessment rubric.

Results

Feasibility—the final DIGEST product was free of charge to create but incurred direct and indirect costs of time and training on behalf of the authors. Acceptance—7 possible learners participated and responded to the questionnaires (100% response rate). Learners reported a superior learning experience and increased confidence with DIGEST. An HPE expert reported that the course design of DIGEST met or exceeded expectations in all categories.

Conclusions

DIGEST is a novel pediatric GI curriculum for rotating learners that could be rapidly deployed, or adapted, for a wide range of clinical disciplines within the Military Health System.
The Prevalence of Sexually Transmitted Infections and Sociosexual Behaviors in the South Korean Military Before and During the COVID-19 Pandemic
Authors: Oh Tae Hoon , Baeck Jong Hyun , Lee Seung Ryeol , Park Dong Soo , Yu Young Dong
Published: November 2021

Introduction

This study evaluated the epidemiological factors of sexually transmitted infections (STIs) among South Korean troops including the prevalence, therapeutic methods, and sexual risk behaviors.

Material and Methods

The medical records of the STIs diagnosed troops at the Armed Forces Capital Hospital (AFCH) for 36 months (between January 2018 and December 2020) were retrospectively reviewed. The data collection for the study began after obtaining research approvals from the institutional ethics committee of AFCH. The patients were classified into two subgroups, pre-coronavirus disease 2019 (COVID-19) and COVID-19 groups. The clinical parameters of the patients including STI-related symptoms and underlying diseases were analyzed. The sociosexual conduct of the two study groups was evaluated and compared by using a survey questionnaire.

Results

Overall, 138 STI patients with mean age of 21.2 years were included (pre-COVID-19: 106 patients/COVID-19: 32 patients). 32.6% of the patients received college education before the military service. Regarding previous history of STIs, 24 patients (17.4%) had previous experience of STIs, which occurred before participation in the current study. Initial urine analysis results showed that 95 (68.8%) and 79 patients (57.2%) showed pyuria and bacteriuria, respectively. Neisseria gonorrhoeae (29.7%) was the most commonly identified pathogen. Each pathogen was treated with the therapies recommended by the current treatment guidelines, and no patient showed any recurrence of the disease during follow-up. Both pre-COVID-19 (91.5%) and COVID-19 (93.8%) groups showed high rates of binge drinking during off-duty. The pre-COVID-19 group had a greater number of patients (21.7%) having multiple sex partners (during the past 12 months) than the COVID-19 group (15.6%). The COVID-19 group had 18.8% of the troops involved in sexual activity even after the onset of STI-related clinical symptoms, whereas the rate was significantly higher than 2.8% of the pre-COVID-19 group (P = .001). The COVID-19 groups showed a significantly higher number of patients (four patients, 12.5%) experiencing suicidal ideation than the pre-COVID-19 group (two patients, 1.9%) (P = .010). Both groups showed <40% of condom use rates at the last sexual intercourse.

Conclusion

The soldiers with STIs showed high rates of binge alcohol consumption, while the rates of engaging in safe sex by using condoms are markedly low. Although the COVID-19 group was under influence of social distancing and military base lockdown, the soldiers’ sociosexual conduct was not significantly different in the pre-COVID-19 group. The importance of education on alcohol misuse and safe sexual relationships should be taken more seriously within the military.
How gas flows shape the stellar–halo mass relation in the eagle simulation
Authors: Mitchell Peter D , Schaye Joop
Published: November 2021

The difference in shape between the observed galaxy stellar mass function and the predicted dark matter halo mass function is generally explained primarily by feedback processes. Feedback can shape the stellar–halo mass (SHM) relation by driving gas out of galaxies, by modulating the first-time infall of gas on to galaxies (i.e. preventative feedback), and by instigating fountain flows of recycled wind material. We present and apply a method to disentangle these effects for hydrodynamical simulations of galaxy formation. We build a model of linear coupled differential equations that by construction reproduces the flows of gas on to and out of galaxies and haloes in the eaglecosmological simulation. By varying individual terms in this model, we isolate the relative effects of star formation, ejection via outflow, first-time inflow, and wind recycling on the SHM relation. We find that for halo masses $M_{200} \lt 10^{12} \, \mathrm{M_\odot }$ the SHM relation is shaped primarily by a combination of ejection from galaxies and haloes, while for larger M200 preventative feedback is also important. The effects of recycling and the efficiency of star formation are small. We show that if, instead of M200, we use the cumulative mass of dark matter that fell in for the first time, the evolution of the SHM relation nearly vanishes. This suggests that the evolution is due to the definition of halo mass rather than to an evolving physical efficiency of galaxy formation. Finally, we demonstrate that the mass in the circumgalactic medium is much more sensitive to gas flows, especially recycling, than is the case for stars and the interstellar medium.
Metallicity-suppressed collapsars cannot be the dominant r-process source in the milky way
Authors: Fraser Jack , Schönrich Ralph
Published: November 2021

We develop a high-performance analytical model of Galactic Chemical Evolution, which accounts for delay time distributions and lock-up of stellar yields in a thermal-phased ISM. The model is capable of searching, for the first time, through the high-dimensional parameter space associated with the r-process enrichment of the Milky Way by its possible sources: Neutron Star Mergers and Collapsar events. Their differing formation mechanisms give these two processes different time dependencies, a property which has frequently been used to argue in favour of collapsars as the dominant r-process source. However, we show that even with large degrees of freedom in the allowed thermal, structural, and chemical properties of the galaxy, large regions of parameter space are in strong tension with the data. In particular, whilst we are able to find models in which neutron star mergers produce the majority of r-process material, the data rule out all models with dominant collapsar yields. With no other identified source, we conclude that Neutron Star Mergers must be the dominant contributors to the modern Milky Way r-process budget.
Japanese version of Patient-Rated Elbow Evaluation is a useful outcome measure that potentially reflects hand function in patients with rheumatoid arthritis who underwent total elbow arthroplasty
Authors: Harada Ryozo , Nishida Keiichiro , Matsuyama Yoshiyuki , Hashizume Kenzo , Wada Takuro , Nasu Yoshihisa , Nakahara Ryuichi , Horita Masahiro , Senda Masuo , Ozaki Toshifumi
Published: November 2021

Objectives

We examined the relationship between the Japanese version of Patient-Rated Elbow Evaluation (PREE-J) and other established subjective and objective outcome measures in Japanese patients with rheumatoid arthritis (RA) who underwent total elbow arthroplasty (TEA).

Materials and Methods

This study involved 46 elbows of 40 RA patients. We collected clinical data 1 year after surgery, including the PREE-J, the Mayo Elbow Performance Score (MEPS), Disability of the Arm, Shoulder, and Hand (DASH), and Hand20. The correlation and responsiveness to PREE-J were evaluated compared with other outcome measures preoperatively and postoperatively.

Results

Almost all outcome measures were improved significantly after surgery. Preoperative PREE-J was significantly correlated with preoperative DASH, Hand20, and MEPS. Interestingly, postoperative PREE-J did not correlate with postoperative MEPS. Multiple regression analyses revealed that preoperative grip strength [B = −0.09; 95% confidence interval (95% CI) −0.17 to −0.01, p = 0.03] and preoperative Hand20 (B = 0.31, 95% CI 0.03–0.58, p = 0.03) were significant factors that might influence the postoperative PREE-J.

Conclusions

The PREE-J was shown to correlate well with other preoperative outcome measures among the RA patients included in the current study. The postoperative PREE-J after TEA was influenced by the preoperative grip strength and function of the hand.
Dermatomyositis-related intestinal dysmotility
Authors: Loftis Christine , White Rosa , Dulgheru Emilia C
Published: November 2021

Dermatomyositis (DM) is an inflammatory myopathy (IIM) characterized by proximal muscle weakness and pathognomonic skin lesions. A 69-year-old woman with a recent diagnosis of DM 1 month prior, treated with corticosteroids and immunomodulators, presented to our inpatient rehabilitation with worsening dysphagia and constipation. At the time of our evaluation, physical examination was notable for erythematous papules over the metacarpophalangeal joints, proximal interphalangeal joints, elbows, and knees as well as a violaceous rash on the face. Muscle strength was diminished bilaterally with proximal distribution being affected greater than distal. Laboratory studies were notable for the creatine kinase (CK) level of 31 IU/l, antinuclear antibodies (ANA) by immunofluorescence of 1:80, and aldolase 4 u/l. The 11-antibody myositis panel was negative showed partially treated acquired IIM with perifascicular atrophy. During hospitalisation, she was found to have pulmonary embolism. She received enoxaparin 1 mg/kg subcutaneous BID. Soon after, she developed rectal bleeding. Colonoscopy showed a stercoral ulcer caused by chronic constipation. While dysphagia is common, being present in 25–50% of patients with DM, lower gastrointestinal problems involving the small and large intestine are rare and typically present as a late manifestation of the disease. Decreased peristalsis in the large colon can lead to constipation, impaction, and subsequent mucosal ulceration, and pressure necrosis induced by faecaloma formation. Although rare, our case highlights the importance of recognising gastrointestinal complications that DM can cause and the effects that those complications have on morbidity and mortality.
Music Therapy with Children Whose Mothers Are in Residential Treatment for Substance Use Disorders: A Program Evaluation
Authors: Pasiali Varvara , Benner Gretchen , Tisdale Ashley , Jones Gabrielle E , Tart Miriam , Crate Nicole
Published: November 2021

Children who experience multiple stressors may benefit from music therapy programming that addresses the development of social skills, self-expression, and coping mechanisms. Emerging evidence supports the use of improvisation techniques, group songwriting, and drumming activities to support self-regulation and increase social competence. In this article, we aimed to describe the inception and evaluate the implementation of a music therapy program for children at a residential treatment facility for women with substance use disorders (SUDs) at Dove’s Nest, a residential facility for women with SUDs. In this facility, children can reside with their mothers during the length of treatment. We collected pre/post data from children ages 5–11 (N = 20) who attended 8 nonconsecutive music therapy sessions by asking the mothers to complete the Home and Community Social Behavior Scale (HCSBS; Merrell, K. W., & Caldarella, P. (2008). Home & Community Social Behavior Scales user’s guide. Paul H. Brookes Publishing Company). Statistical analyses showed no significant changes on individual HCSBS subscale pre–post comparisons. The total number of scale items on HCSBS flagged as areas of concern was reduced both in social competence (31 pre to 6 post or a decrease of 80.65%) and antisocial behavior (34 pre to 17 post or a decrease of 50%) scales. Evaluation results indicated that even though the children assessed may score within average ranges for social competence and antisocial behaviors, they still exhibit a high number of areas of concern at baseline, particularly in the defiant/disruptive category, which warrants preventive interventions. Clinicians may need to focus on interventions that promote social integration, self-regulation, and assertiveness while addressing behaviors such as blaming and attention seeking.
LncACTdb 3.0: an updated database of experimentally supported ceRNA interactions and personalized networks contributing to precision medicine
Authors: Wang Peng , Guo Qiuyan , Qi Yue , Hao Yangyang , Gao Yue , Zhi Hui , Zhang Yuanfu , Sun Yue , Zhang Yakun , Xin Mengyu , Zhang Yunpeng , Ning Shangwei , Li Xia
Published: November 2021

LncACTdb 3.0 is a comprehensive database of experimentally supported interactions among competing endogenous RNA (ceRNA) and the corresponding personalized networks contributing to precision medicine. LncACTdb 3.0 is freely available at http://bio-bigdata.hrbmu.edu.cn/LncACTdb or http://www.bio-bigdata.net/LncACTdb. We have updated the LncACTdb 3.0 database with several new features, including (i) 5669 experimentally validated ceRNA interactions across 25 species and 537 diseases/phenotypes through manual curation of published literature, (ii) personalized ceRNA interactions and networks for 16 228 patients from 62 datasets in TCGA and GEO, (iii) sub-cellular and extracellular vesicle locations of ceRNA manually curated from literature and data sources, (iv) more than 10 000 experimentally supported long noncoding RNA (lncRNA) biomarkers associated with tumor diagnosis and therapy, and (v) lncRNA/mRNA/miRNA expression profiles with clinical and pathological information of thousands of cancer patients. A panel of improved tools has been developed to explore the effects of ceRNA on individuals with specific pathological backgrounds. For example, a network tool provides a comprehensive view of lncRNA-related, patient-specific, and custom-designed ceRNA networks. LncACTdb 3.0 will provide novel insights for further studies of complex diseases at the individual level and will facilitate the development of precision medicine to treat such diseases.
TRF2 promotes dynamic and stepwise looping of POT1 bound telomeric overhang
Authors: Paul Tapas , Liou Wilson , Cai Xinyi , Opresko Patricia L , Myong Sua
Published: November 2021

Human telomeres are protected by shelterin proteins, but how telomeres maintain a dynamic structure remains elusive. Here, we report an unexpected activity of POT1 in imparting conformational dynamics of the telomere overhang, even at a monomer level. Strikingly, such POT1-induced overhang dynamics is greatly enhanced when TRF2 engages with the telomere duplex. Interestingly, TRF2, but not TRF2ΔB, recruits POT1-bound overhangs to the telomere ds/ss junction and induces a discrete stepwise movement up and down the axis of telomere duplex. The same steps are observed regardless of the length of the POT1-bound overhang, suggesting a tightly regulated conformational dynamic coordinated by TRF2 and POT1. TPP1 and TIN2 which physically connect POT1 and TRF2 act to generate a smooth movement along the axis of the telomere duplex. Our results suggest a plausible mechanism wherein telomeres maintain a dynamic structure orchestrated by shelterin.
TissueNexus: a database of human tissue functional gene networks built with a large compendium of curated RNA-seq data
Authors: Lin Cui-Xiang , Li Hong-Dong , Deng Chao , Guan Yuanfang , Wang Jianxin
Published: November 2021

Mapping gene interactions within tissues/cell types plays a crucial role in understanding the genetic basis of human physiology and disease. Tissue functional gene networks (FGNs) are essential models for mapping complex gene interactions. We present TissueNexus, a database of 49 human tissue/cell line FGNs constructed by integrating heterogeneous genomic data. We adopted an advanced machine learning approach for data integration because Bayesian classifiers, which is the main approach used for constructing existing tissue gene networks, cannot capture the interaction and nonlinearity of genomic features well. A total of 1,341 RNA-seq datasets containing 52,087 samples were integrated for all of these networks. Because the tissue label for RNA-seq data may be annotated with different names or be missing, we performed intensive hand-curation to improve quality. We further developed a user-friendly database for network search, visualization, and functional analysis. We illustrate the application of TissueNexus in prioritizing disease genes. The database is publicly available at https://www.diseaselinks.com/TissueNexus/.
mmCSM-NA: accurately predicting effects of single and multiple mutations on protein–nucleic acid binding affinity
Authors: Nguyen Thanh Binh , Myung Yoochan , de Sá Alex G C , Pires Douglas E V , Ascher David B
Published: November 2021

While protein–nucleic acid interactions are pivotal for many crucial biological processes, limited experimental data has made the development of computational approaches to characterise these interactions a challenge. Consequently, most approaches to understand the effects of missense mutations on protein-nucleic acid affinity have focused on single-point mutations and have presented a limited performance on independent data sets. To overcome this, we have curated the largest dataset of experimentally measured effects of mutations on nucleic acid binding affinity to date, encompassing 856 single-point mutations and 141 multiple-point mutations across 155 experimentally solved complexes. This was used in combination with an optimized version of our graph-based signatures to develop mmCSM-NA (http://biosig.unimelb.edu.au/mmcsm_na), the first scalable method capable of quantitatively and accurately predicting the effects of multiple-point mutations on nucleic acid binding affinities. mmCSM-NA obtained a Pearson's correlation of up to 0.67 (RMSE of 1.06 Kcal/mol) on single-point mutations under cross-validation, and up to 0.65 on independent non-redundant datasets of multiple-point mutations (RMSE of 1.12 kcal/mol), outperforming similar tools. mmCSM-NA is freely available as an easy-to-use web-server and API. We believe it will be an invaluable tool to shed light on the role of mutations affecting protein–nucleic acid interactions in diseases.
What it is like to be a bit: an integrated information decomposition account of emergent mental phenomena
Authors: Luppi Andrea I , Mediano Pedro A M , Rosas Fernando E , Harrison David J , Carhart-Harris Robin L , Bor Daniel , Stamatakis Emmanuel A
Published: November 2021

A central question in neuroscience concerns the relationship between consciousness and its physical substrate. Here, we argue that a richer characterization of consciousness can be obtained by viewing it as constituted of distinct information-theoretic elements. In other words, we propose a shift from quantification of consciousness—viewed as integrated information—to its decomposition. Through this approach, termed Integrated Information Decomposition (ΦID), we lay out a formal argument that whether the consciousness of a given system is an emergent phenomenon depends on its information-theoretic composition—providing a principled answer to the long-standing dispute on the relationship between consciousness and emergence. Furthermore, we show that two organisms may attain the same amount of integrated information, yet differ in their information-theoretic composition. Building on ΦID’s revised understanding of integrated information, termed ΦR, we also introduce the notion of ΦR-ing ratio to quantify how efficiently an entity uses information for conscious processing. A combination of ΦR and ΦR-ing ratio may provide an important way to compare the neural basis of different aspects of consciousness. Decomposition of consciousness enables us to identify qualitatively different ‘modes of consciousness’, establishing a common space for mapping the phenomenology of different conscious states. We outline both theoretical and empirical avenues to carry out such mapping between phenomenology and information-theoretic modes, starting from a central feature of everyday consciousness: selfhood. Overall, ΦID yields rich new ways to explore the relationship between information, consciousness, and its emergence from neural dynamics.
EPCO-14. MULTIFACETED TRANSCRIPTOMIC AND PROTEOMIC ANALYSES IDENTIFIED PUTATIVE ALTERNATIVE SPLICING-DERIVED CELL SURFACE ANTIGENS IN GLIOMA
Authors: Nejo Takahide , Kwok Darwin , Leung Kevin , Wang Lin , Wang Albert , Watchmaker Payal , Diebold David , Driks Hannah , Wells Jim , Diaz Aaron , Costello Joseph , Okada Hideho
Published: November 2021

BACKGROUND

To develop effective immunotherapy for gliomas, it is crucial to expand the repertoire of targetable antigens. Recent studies have suggested that alternative splicing (AS), or its deriving tumor-specific junctions (“neojunctions”), could generate cryptic amino acid sequences that can be a source of neoantigens. In this study, we investigated neojunctions based on multifaceted transcriptomic and proteomic analyses, seeking the potential cell surface antigens that may be targeted by CAR.

METHODS

For screening, we analyzed bulk RNA-sequencing data of TCGA-GBM/LGG with high tumor purity (n = 429) and GTEx normal tissues (n = 9,166). Cohorts of spatially mapped intratumoral samples and longitudinally collected tumors were used to determine clonality and stability of the candidate neojunctions. Nanopore long-read amplicon sequencing was deployed to confirm the full-length transcript sequence. Their protein-level expression was explored by analyzing the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-GBM proteomics dataset.

RESULTS

In the screening analysis comparing TCGA and GTEx datasets, we identified 218 neojunctions with adequate expression, prevalence, and tumor-specificity. Of these, 12 were predicted to be cell-surface antigens. Eight of the 12, such as BCAN, DLL3, and PTPRZ1, were also observed in multiple cases of another validation dataset. In the analysis of tumors with spatially mapped intratumoral samples, 7 of the 12 were recurrently detected in no less than 50% of the samples in multiple cases. In addition, 5 of the 12 were found to be conserved in primary and recurrent pairs of tumors in multiple cases. Full-length transcript sequencing corroborated our predictions based on short reads, and also demonstrated more complex AS patterns. Finally, CPTAC-GBM proteomics analysis identified one cryptic peptide that substantiated the corresponding transcriptome-based prediction. CONCLUSION: We identified neojunctions with the potential to generate cell-surface antigens. These multifaceted transcriptomic and proteomic analyses provide the rationale to pursue the development of immunotherapy targeting neojunction-derived antigens.