bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal variation may have diverse impacts on range limits
Authors: Holt Robert D. , Barfield Michael , Peniston James H.
Published: February 2022

Environmental fluctuations are pervasive in nature, but the influence of non-directional temporal variation on range limits has received scant attention. We synthesize insights from the literature and use simple models to make conceptual points about the potentially wide range of ecological and evolutionary effects of temporal variation on range limits. Because organisms respond nonlinearly to environmental conditions, temporal variation can directionally alter long-term growth rates, either to shrink or to expand ranges. We illustrate this diversity of outcomes with a model of competition along a mortality gradient. Temporal variation can permit transitions between alternative states, potentially facilitating range expansion. We show this for variation in dispersal, using simple source–sink population models (with strong Allee effects, or with gene flow hampering local adaptation). Temporal variation enhances extinction risk owing to demographic stochasticity, rare events, and loss of genetic variation, all tending to shrink ranges. However, specific adaptations to exploit variation (including dispersal) may permit larger ranges than in similar but constant environments. Grappling with temporal variation is essential both to understand eco-evolutionary dynamics at range limits and to guide conservation and management strategies.

This article is part of the theme issue ‘Species’ ranges in the face of changing environments (Part II)’.
A review on trade-offs at the warm and cold ends of geographical distributions
Authors: Willi Yvonne , Van Buskirk Josh
Published: February 2022

Species’ range limits are ubiquitous. This suggests that the evolution of the ecological niche is constrained in general and at the edges of distributions in particular. While there may be many ecological and genetic reasons for this phenomenon, here we focus on the potential role of trade-offs. We performed a literature search on evidence for trade-offs associated with geographical or elevational range limits. The majority of trade-offs were reported as relevant at either the cold end of species' distribution (n= 19), the warm or dry end (n= 19) or both together (n= 14). One common type of trade-off involved accelerating growth or development (27%), often at the cost of small size. Another common type involved resistance to or tolerance of climatic extremes that occur at certain periods of the year (64%), often at the cost of small size or reduced growth. Trade-offs overlapped with some of the classic trade-offs reported in life-history evolution or thermal adaptation. The results highlight several general insights about species' niches and ranges, and we outline how future research should better integrate the ecological context and test for the presence of microevolutionary trade-offs.

This article is part of the theme issue ‘Species’ ranges in the face of changing environments (Part II)’.
Detailed Clinical and Functional Studies of New MTOR Variants in Smith-Kingsmore Syndrome Reveal Deficits of Circadian and Sleep Homeostasis
Authors: Liu Andrew C. , Shen Yang , Roman Destino , He Hongzhi , Serbinski Carolyn R. , Aschbacher-Smith Lindsey , King Katherine A. , Granadillo Jorge L. , López Isabel , Krueger Darcy A. , Dye Thomas J. , Smith David F. , Hogenesch John B. , Prada Carlos E.
Published: February 2022

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore Syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 new MTOR pathogenic variants, including p.R1480_C1483del or Δ(R1480-C1483). We conducted a detailed natural history study on these patients and found prevalent pathophysiological deficits among SKS individuals, in addition to the common neurodevelopmental symptoms. The new symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, which are indicative of homeostatic imbalance. To better characterize SKS variants, we developed MTOR mutant cellular models and performed biochemical and cellular circadian rhythm assays to study the variants. We showed that these SKS alleles display a range of MTOR activities under nutrient-deficient basal conditions and respond to MTOR inhibitors differently. For example, Δ(R1480-C1483) is more active than the classic SKS variant C1483F and less responsive to MTOR inhibition by rapamycin. Further, we showed that optimal MTOR activity, important for metabolic and protein homeostasis, is required for normal circadian function. These data can help guide treatment strategies. As SKS is caused by gain of function mutations in MTOR, we used rapamycin to treat several patients. While higher doses caused delayed sleep-wake phase disorder, lower doses improved not only sleep but also aggression and repetitive behaviors. Thus, our study expands both the clinical and molecular spectrum of SKS and offers treatment options guided by molecular and sleep/wake data to improve both cognitive and non-cognitive homeostatic functions.
COVID-19 Surveillance in the Biobank at the Colorado Center for Personalized Medicine
Authors: Johnson Randi K. , Marker Katie M. , Mayer David , Shortt Jonathan , Kao David , Barnes Kathleen C. , Lowery Jan T. , Gignoux Christopher R.
Published: February 2022

Background

Characterizing the experience and impact of the COVID-19 pandemic among various populations remains challenging due to the limitations inherent in common data sources such as the electronic health record (EHR) or convenience sample surveys.

Objective

To describe testing behaviors, symptoms, impact, vaccination status and case ascertainment during the COVID-19 pandemic using integrated data sources.

Methods

In summer 2020 and 2021, we surveyed participants enrolled in the Biobank at the Colorado Center for Personalized Medicine (CCPM, N = 180,599) about their experience with COVID-19. Prevalence of testing, symptoms, and the impacts of COVID-19 on employment, family life, and physical and mental health were calculated overall and by demographic categories. Using the Electronic Health Record (EHR), we compared COVID-19 case ascertainment and characteristics in the EHR versus the survey.

Results

Of the 25,063 survey respondents (13.9%), 42.5% had been tested for COVID-19 and of those, 12.8% tested positive. Nearly half of those tested had symptoms and/or had been exposed to someone who was infected. Young adults (18-29 years) and Hispanics were more likely to have positive tests compared to older adults and persons of other racial/ethnic groups. Mental health (54.6%) and family life (48.8%) were most negatively affected by the pandemic and more so among younger groups and women; negative impacts on employment were more commonly reported among Black respondents. After integration with EHR data up to the time of the survey completion, 4.0% of survey respondents (n=1,006) had discordant COVID-19 case status between the EHR and the survey. Using all longitudinal EHR and survey data, we identified 11,472 COVID-positive cases among Biobank participants (6.4%). In comparison to COVID-19 cases identified through the survey, EHR-identified cases were younger and more likely to be Hispanic.

Conclusions

Integrated data assets such as the Biobank at the CCPM are key resources for population health monitoring in response to public health emergencies, such as the COVID-19 pandemic.
Prevalence and Outcome of Cardio-Embolic Stroke Patients Admitted at Referral Neurology Hospital in Bangladesh
Authors: Been Sayeed S K Jakaria , Haque A K M Mahmudul , Moniruzzaman Md. , Mahmud Reaz , Yusuf Md. Abdullah , Das Subir Chandra , Rashid Mohammad Bazlur , Rahman Sabrina , Nayeem Abu , Kabir A K M Humayon , Haque Chowdhury M S Jahirul , Rahman Md. Mujibur
Published: February 2022

Background

Stroke is the second leading cause of mortality worldwide; where the majority of stroke is ischemic. Among ischemic stroke, cardio-embolic has both higher severity and mortality.

Objective

To find out clinical outcomes and determine predictors of mortality related to cardio-embolic stroke.

Methodology

This prospective cohort study was conducted among patients of acute ischemic stroke of cardiac origin admitted at the National Institute of Neurosciences and Hospital, Bangladesh from 1st October 2020 to 30 September, 2021. Patients were kept under follow-up to 90 days from discharge.

Results

A total of 689 ischemic stroke patients were screened, 156 had confirmed Cardio-embolic stroke. So, the frequency of cardio-embolic stroke was 22.64%. Male to female ratio was 1.3:1, mean age of 63 years. Hypertension 119 (76.3%), atrial fibrillation 107 (68.6%), and IHD 40 (25.6%) were most common comorbidities. Interestingly, we found only 23 (14.7%) patients with chronic rheumatic heart diseases. NIH Stroke scale score (median, IQR) during admission was 13 [7-19]. Overall mortality was 47 (29.9%), among them 30 (19.2%) died within 48 hours of hospital admission while 17 (10.9%) within 90 days of hospital discharge. Modified Rankin score at 90 days was 2 [min 0, max 5] those who survived. Cumulative incidence of recurrent stroke was 9 (7.1%) and incidence of anticoagulant induced hemorrhage were 5 (3.2%) among them. Risk factors associated with mortality (odds ratio, [95% CI], p value) were acute myocardial infarction (1.6 [1.14 – 2.52], 0.04), raised Troponin (1.89 [1.16-2.99], 0.01), reduced ejection fraction (3.38 [2.17-5.27], <0.001), hypotension (3.12 [2.07 – 4.68], < 0.001), chronic kidney disease (1.82 [1.06 - 3.10], 0.04), raised Creatinine (2.41 [1.52 - 3.84], 0.01), raised blood sugar (1.82 [1.14 - 2.89], 0.02), severe stroke (9.45 [3.57 – 25.03], <0.001), large infarct (53.67 [7.59 - 379.47], < 0.001), hemorrhagic transformation (4.43 [2.89 – 6.84], < 0.001) and aspiration pneumonia (1.9 [1.28-2.39], 0.01).

Conclusion

Overall frequency, severity, functional disability, and mortality in cardio-embolic stroke are higher. Acute myocardial infarction, severe stroke, presence of hyperglycemia, hypotension, renal impairment, low ejection fraction, large infarct, hemorrhagic transformations, and aspiration pneumonia are both clinically and statistically significantly associated with mortality in cardio-embolic stroke.
Genetic influences on neurodevelopmental disorders and their overlap with co-occurring conditions in childhood and adolescence: A meta-analysis
Authors: Gidziela Agnieszka , Ahmadzadeh Yasmin I. , Michelini Giorgia , Allegrini Andrea G. , Agnew-Blais Jessica , Lau Lok Yan , Duret Megan , Procopio Francesca , Daly Emily , Ronald Angelica , Rimfeld Kaili , Malanchini Margherita
Published: February 2022

A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs), their co-occurrence, and co-occurrence with other conditions during childhood and adolescence remains incomplete. This meta-analysis bridges gaps in our knowledge. First, we meta-analysed the literature on the relative contribution of genetic and environmental factors to NDDs. Second, we considered the literature on the overlap between different NDD categories. Lastly, we synthesized the literature on the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). We performed multilevel, random-effects meta-analyses on 296 independent studies, including over 4 million children and adolescents. We found all NDDs to be substantially heritable (family-based heritability (h2) = 0.66; SNP h2 = 0.19). Meta-analytic genetic correlations between NDDs, and between NDDs and DICCs were moderate to strong. However, given the paucity of available studies covering the co-occurrence of NDDs and DICCs, these could only be estimated for a few disorders. While our work provides direct evidence to inform and potentially guide clinical and educational diagnostic procedures and practice, it also highlights the imbalance in the research effort that has characterized developmental genetics research.
The impact of theta-burst stimulation on cortical GABA and glutamate in treatment-resistant depression: A surface-based MRSI analysis approach
Authors: Spurny-Dworak B , Godbersen GM , Reed MB , Unterholzner J , Vanicek T , Baldinger-Melich P , Hahn A , Kranz GS , Bogner W , Lanzenberger R , Kasper S
Published: February 2022

Background

Theta burst stimulation (TBS) belongs to one of the biological antidepressant treatment options. When applied bilaterally, excitatory intermittent TBS (iTBS) is commonly targeted to the left and inhibitory continuous TBS (cTBS) to the right dorsolateral prefrontal cortex. TBS was shown to influence neurotransmitter systems, while iTBS is thought to interfere with glutamatergic circuits and cTBS to mediate GABAergic neurotransmission.

Objectives

We aimed to expand insights in the therapeutic effects of TBS on the GABAergic and glutamatergic system utilizing 3D-multivxovel magnetic resonance spectroscopy imaging (MRSI) in combination with a novel surface-based MRSI analysis approach to investigate changes of cortical neurotransmitter levels in patients with treatment resistant depression (TRD).

Methods

Twelve TRD patients (5 female, mean age±SD=35±11 years) completed paired MRSI measurements, using a GABA-edited 3D-multivoxel MEGA-LASER sequence, before and after three weeks of bilateral TBS treatment. Changes in cortical distributions of GABA+/tNAA (GABA+macromolecules relative to total N-acetylaspartate) and Glx/tNAA (Glx=mixed signal of glutamate and glutamine), were investigated in a surface-based region-of-interest (ROI) analysis approach.

Results

ANCOVAs revealed a significant increase in Glx/tNAA ratios in the left caudal middle frontal area (pcorr.=0.046, F=13.292), an area targeted by iTBS treatment. Whereas, contralateral treatment with cTBS evoked no alterations in glutamate or GABA concentrations.

Conclusion

This study demonstrates surface-based adaptions in the stimulation area to the glutamate metabolism after excitatory iTBS but not after cTBS, using a novel surface-based analysis of 3D-MRSI data. The reported impact of facilitatory iTBS on glutamatergic neurotransmission provides further insight into the neurobiological effects of TBS in TRD.
Closing the health inequity gap during the pandemic: COVID-19 mortality among racial and ethnic groups in Connecticut, March 2020 to December 2021
Authors: Schultes Olivia , Lind Margaret L. , Brockmeyer Jessica , Sosensky Peri , Cummings Derek A.T. , Ko Albert I.
Published: February 2022

COVID-19 has disproportionally burdened racial and ethnic minority groups within the United States. Leveraging statewide data, we examined the evolution of racial and ethnic disparities in COVID-19 related deaths among Connecticut residents residing in non-congregate settings over three periods of the COVID-19 pandemic. Despite observing large disparities in the age-adjusted mortality rates between Hispanics, non-Hispanic Blacks, and non-Hispanic Whites during the initial pandemic period (March to August 2020), we observed meaningful reductions in the disparities during the subsequent periods (August 2020 to July 2021; July to mid December 2021). Further, during the third period, we failed to find a significant difference in age-adjusted mortality between non-Hispanic Blacks and non-Hispanic Whites. These findings provide evidence that attenuation of racial and ethnic disparities in COVID-19 related outcomes are achievable.
Systematic review and meta-analysis to estimate the burden of fatal and non-fatal overdose among people who inject drugs
Authors: Shealey Jalissa , Hall Eric W. , Pigott Therese D. , Bradley Heather
Published: February 2022

Background

People who inject drugs (PWID) have high overdose risk. To assess the burden of drug overdose among PWID in light of opioid epidemic-associated increases in injection drug use (IDU), we estimated rates of non-fatal and fatal overdose among PWID living in Organization for Economic Cooperation and Development (OECD) countries using data from 2010 or later.

Methods

PubMed, Psych Info, and Embase databases were systematically searched to identify peer-reviewed studies reporting prevalence or rates of recent (past 12 months) fatal or non-fatal overdose events among PWID in OECD countries. Data were extracted and meta-analyzed using random effects models to produce pooled non-fatal and fatal overdose rates.

Results

57 of 13,307 identified reports were included in the review, with 33/57 studies contributing unique data and included in the meta-analysis. Other (24/57) studies presented overlapping data to those included in meta-analysis. The rates of non-fatal and fatal overdose among PWID in OECD countries were 24.74 per 100 person years (PY) (95% CI: 19.86 – 30.83; n=28; I2=98.5%) and 0.61 per 100 PY (95% CI: 0.32 – 1.16; n=8; I2=93.4%), respectively. The rate of non-fatal overdose was 27.79 in North American countries, 25.71 in Canada, 28.59 in the U.S., and 21.44 in Australia.

Conclusion

These findings suggest there is a fatal overdose for every 40 non-fatal overdose events among PWID in OECD countries. The magnitude of overdose burden estimated here underscores the need for expansion of overdose prevention and treatment programs and serves as a baseline estimate for monitoring success of such programs.
Brachypodium antifreeze protein gene products inhibit ice recrystallization, attenuate ice nucleation, and reduce immune response
Authors: Juurakko Collin L. , diCenzo George C. , Walker Virginia K.
Published: February 2022

Antifreeze proteins (AFPs) from the model crop, Brachypodium distachyon, allow freeze survival and attenuate pathogen-mediated ice nucleation. Intriguingly, each Brachypodium AFP gene encodes two proteins, an autonomous AFP and a leucine-rich repeat (LRR). We present structural models suggesting that ice-binding motifs on the ~13 kDa AFPs can “spoil” nucleating arrays on the ~120 kDa bacterial ice nucleating proteins that form ice at high sub-zero temperatures, consistent with decreases in ice nucleating activity by lysates from wildtype compared to transgenic Brachypodium lines. Strikingly, the expression of Brachypodium LRRs in transgenic Arabidopsis inhibited an immune response to pathogen flagella peptides (flg22), with structural modelling suggesting this was due to affinity of the LRR domains to flg22. Thus, these genes play distinctive roles in connecting freeze survival and anti-pathogenic systems via their encoded proteins’ ability to adsorb to ice as well as attenuating bacterial ice nucleation and the host immune response.
Using landscape genomics to infer genomic regions involved in environmental adaptation of soybean genebank accessions
Authors: Haupt Max , Schmid Karl
Published: February 2022

Understanding how crops adapt to specific environmental conditions is becoming increasingly important in the face of accelerating climate change, but the genetics of local adaptation remain little understood for many crops. Landscape genomics can reveal patterns of genetic variation that indicate adaptive diversification during crop evolution and dispersal. Here, we examine genetic differentiation and association signatures with environmental gradients in soybean (Glycine max) germplasm groups from China that were inferred from the USDA Soybean Germplasm Collection (N = 17,019 accessions) based on population structure and passport information. We recover genes previously known to be involved in soybean environmental adaptation and report numerous new candidate genes in selection signatures implicated by genomic resources such as the genome annotation and gene expression datasets to function in flowering regulation, photoperiodism and stress reaction cascades. Linkage disequilibrium network analysis suggested functional relationships between genomic regions with selection signatures, consistent with the polygenic nature of environmental adaptation. We tested whether haplotypes associated with environmental adaptation in China were present in 843 North American and 160 European soybean cultivars and found that haplotypes in major genes for early maturity have been selected during breeding, but also that a large number of haplotypes exhibiting putative adaptive variation for cold regions at high latitudes are underrepresented in modern cultivars. Our results demonstrate the value of landscape genomics analysis in genebank germplasm as a starting point for the study of crop environmental adaptation and have the potential to inform future research efforts focused on improved soybean adaptation. Functional validation of candidate genes will support understanding of their adaptive roles and likely enable the transfer of beneficial adaptive variation into modern breeding germplasm.
Evaluating Chinese Handwriting Performance of Primary School Students Using the Smart Handwriting Analysis and Recognition Platform (SHARP)
Authors: Li-Tsang Cecilia W. P. , Li Tim M. H. , Yang C.N. , Leung Howard W. H. , Zhang Eve W. L.
Published: February 2022

Background

Handwriting is one of the fundamental skills for school-aged children, and it is an intricate and interacting process. An innovative computerized handwriting assessment system, the Smart Handwriting Analysis and Recognition Platform (SHARP) was used to provide a comprehensive and quantitative analysis of Chinese handwriting performance and identify children with handwriting difficulties objectively, accurately, and efficiently.

Aims/Objectives

The purpose of this study is to provide quantitative data on children’s Chinese handwriting process and products using SHARP; to investigate the handwriting difficulties in children with neurodevelopmental problems, and to explore the associations between handwriting and sensorimotor performance, including fine motor skills, visual perceptual skills, visual-motor integration, and oculomotor proficiency.

Material and Methods

Typically developing students and students with neurodevelopmental problems were recruited through teachers and therapists from six primary schools in Hong Kong. SHARP and tests of sensorimotor skills were performed.

Results

The quantitative analysis using the SHARP system showed a progressive developmental change in handwriting performance among the typically developing children at their primary education. There were also significant differences between the typically developing students group and those with neurodevelopmental problems, both in handwriting speed and writing errors. Significant associations between the handwriting process parameters and fine motor skills were identified, while handwriting product parameters were closely correlated with visual-perceptual skills of these typical developing students.

Conclusions and Significance

SHARP appears to provide a comprehensive, quantitative and objective evaluation of students’ handwriting performances, thus assisting both teachers and parents in comparing students’ performance objectively, thus identifying students with handwriting difficulties as early as P1 level. It was observed that handwriting performance has strong relationships with young children’s visual perceptual skills and fine motor skills. The findings could help to facilitate early intervention for those students with handwriting problems.
When Vibrios Take Flight: A Meta-analysis of Pathogenic Vibrios Species in Wild and Domestic Birds
Authors: Ayala Andrea J. , Ogbunugafor C. Brandon
Published: February 2022

Of the over 100 species in the genus Vibrio, approximately twelve are associated with clinical disease, such as cholera and vibriosis. Crucially, eleven of those twelve—V. alginolyticus, V. cholerae, V. cincinnatiensis, V. hollinsae, e.g., Grimontia hollinsae, V. furnissii, V. mimicus, V. parahaemolyticus, V. vulnificus, V. harveyi, V. scophthalmi and V. metschnikovi—have also been isolated from birds. Since 1965, pathogenic Vibrio species have been consistently isolated from aquatic and ground-foraging bird species, which has implications for public health, as well as the One Health paradigm defined as an ecology-inspired, integrative framework for the study of health and disease, inclusive of environmental, human, and animal health. In this meta-analysis, we identified 76 studies from the primary literature which report on or examine birds as hosts for pathogenic Vibrio species. We found that the burden of disease in birds was most commonly associated with V. cholerae, followed by V. metschnikovi and V. parahaemolyticus. Meta-analysis wide prevalences of the Vibrio pathogens varied from 19% for V. parahaemolyticus to 1% for V. mimicus. Wild and domestic birds were both affected, which may have implications for conservation, as well as agriculturally associated avian species. As pathogenic Vibrios become more abundant throughout the world as a result of warming estuaries and oceans, susceptible avian species should be continually monitored as potential reservoirs for these pathogens.
scAnnotate: an automated cell type annotation tool for single-cell RNA-sequencing data
Authors: Ji Xiangling , Tsao Danielle , Bai Kailun , Tsao Min , Xing Li , Zhang Xuekui
Published: February 2022

Motivation

Single-cell RNA-sequencing (scRNA-seq) technology enables researchers to investigate a genome at the cellular level with unprecedented resolution. An organism consists of a heterogeneous collection of cell types, each of which plays a distinct role in various biological processes. Hence, the first step of scRNA-seq data analysis is often to distinguish cell types so they can be investigated separately. Researchers have recently developed several automated cell type annotation tools, requiring neither biological knowledge nor subjective human decisions. Dropout is a crucial characteristic of scRNA-seq data widely used in differential expression analysis. However, dropout information is not explicitly used by any current cell annotation method. Fully utilizing dropout information for cell type annotation motivated this work.

Results

We present scAnnotate, a cell annotation tool that fully utilizes dropout information. We model every gene’s marginal distribution using a mixture model, which describes both the dropout proportion and the distribution of the non-dropout expression levels. Then, using an ensemble machine learning approach, we combine the mixture models of all genes into a single model for cell-type annotation. This combining approach can avoid estimating numerous parameters in the high-dimensional joint distribution of all genes. Using fourteen real scRNA-seq datasets, we demonstrate that scAnnotate is competitive against nine existing annotation methods. Furthermore, because of its distinct modelling strategy, scAnnotate’s misclassified cells are very different from competitor methods. This suggests using scAnnotate together with other methods could further improve annotation accuracy.

Availability

We implemented scAnnotate as an R package and made it publicly available from CRAN.

Contact

Xuekui Zhang: xuekui@uvic.ca and Li Xing: li.xing@math.usask.ca
Statistical Mechanical theory for spatio-temporal evolution of Intra-tumor heterogeneity in cancers: Analysis of Multiregion sequencing data
Authors: Sinha Sumit , Li Xin , Thirumalai D.
Published: February 2022

Variations in characteristics from one region (sub-population) to another is commonly observed in complex systems, such as glasses and a collection of cells. Such variations are manifestations of heterogeneity, whose spatial and temporal behavior is hard to describe theoretically. In the context of cancer, intra-tumor heterogeneity (ITH), characterized by cells with genetic and phenotypic variability that co-exist within a single tumor, is often the cause of ineffective therapy and recurrence of cancer. Next-generation sequencing, obtained by sampling multiple regions of a single tumor (multi-region sequencing, M-Seq), has vividly demonstrated the pervasive nature of ITH, raising the need for a theory that accounts for evolution of tumor heterogeneity. Here, we develop a statistical mechanical theory to quantify ITH, using the Hamming distance, between genetic mutations in distinct regions within a single tumor. An analytic expression for ITH, expressed in terms of cell division probability (α) and mutation probability (p), is validated using cellular-automaton type simulations. Application of the theory successfully captures ITH extracted from M-seq data in patients with exogenous cancers (melanoma and lung). The theory, based on punctuated evolution at the early stages of the tumor followed by neutral evolution, is accurate provided the spatial variation in the tumor mutation burden is not large. We show that there are substantial variations in ITH in distinct regions of a single solid tumor, which supports the notion that distinct subclones could co-exist. The simulations show that there are substantial variations in the sub-populations, with the ITH increasing as the distance between the regions increases. The analytical and simulation framework developed here could be used in the quantitative analyses of the experimental (M-Seq) data. More broadly, our theory is likely to be useful in analyzing dynamic heterogeneity in complex systems such as super-cooled liquids.
Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures
Authors: Rausch Tobias , Snajder Rene , Leger Adrien , Simovic Milena , Stegle Oliver , Birney Ewan , Bonder Marc Jan , Ernst Aurelie , Korbel Jan O.
Published: February 2022

Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which are likely to escape discovery in short reads. We employed Oxford Nanopore Technologies (ONT) sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a complex SV pattern termed ‘templated insertion thread’, characterized by short (mostly <1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. Templated insertion threads occur in 3% of cancers, with a prevalence ranging to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in seven cancer-driver genes. Our study shows the potential of long-read sequencing in cancer.

Graphical abstract

I) We investigate a single patient with chromothriptic sonic hedgehog medulloblastoma (Li-Fraumeni syndrome), with tissue samples taken from blood, the primary tumor at diagnosis, and a post-treatment (relapse) tumor. II) Data on the three samples has been collected from four sources, 1) Illumina whole-genome, 2) Illumina transcriptome sequencing, 3) Illumina Infinium HumanMethylation450k, as well as 4) long-read whole-genome sequencing using Oxford Nanopore Technologies (ONT) sequencing. III) An integrative analysis combines genomic, epigenomic as well as transcriptomic data to provide a comprehensive analysis of this heavily rearranged tumor sample. Long and short read sequencing data is used to inform the analysis of complex structural genomic variants and methylation called from haplotyped ONT reads and validated through the methylation array data allows for a haplotype-resolved study of genomic and epigenomic variation, which can then be examined for transcriptional effect. IV) This integrative analysis allows us to identify a large number of inter- and intra-chromosomal genomic rearrangements (A) including a complex rearrangement pattern we term templated insertion threads (B), as well as sample-specific and haplotype specific methylation patterns of known cancer genes (C).
Keratinocyte-Associated Protein 3 is a novel gene for adiposity with differential effects in males and females
Authors: Szalanczy Alexandria M , Goff Emily , Seshie Osborne , Deal Aaron , Grzybowski Michael , Klotz Jason , Key Chia-Chi C , Geurts Aron M , Solberg Woods Leah C
Published: February 2022

Objective

Despite the obesity crisis in the United States, the underlying genetics are poorly understood. Our lab previously identified Keratinocyte-associated protein 3, Krtcap3, as a candidate gene for adiposity where increased expression of Krtcap3 correlated with decreased fat mass. Here we seek to confirm that Krtcap3 expression affects adiposity traits.

Methods

We developed an in vivo whole-body Krtcap3 knock-out (KO) rat model. Wild-type (WT) and KO rats were placed onto a high-fat or low-fat diet at six weeks of age and were maintained on diet for 13 weeks, followed by assessments of metabolic health. We hypothesized that Krtcap3-KO rats will have increased adiposity and a worsened metabolic phenotype relative to WT.

Results

We found that KO male and female rats have significantly increased body weight versus WT. KO females ate more, had more fat mass, but were also more insulin sensitive than WT. Alternatively, KO males weighed more and were more insulin resistant than WT, with no differences in eating or fat mass.

Conclusions

This study validates Krtcap3 in body weight regulation and demonstrates sex-specific effects on food intake, adiposity, and insulin sensitivity. Future studies will investigate how Krtcap3 is acting and seek to better understand these sex differences.

Study Importance Questions

What is already known about this subject?

Over 900 low-risk, common genetic variants for BMI have been identified, but these still only explain a fraction of the heritability and many of the underlying causal genes remain unknown

Krtcap3 has been identified as a candidate gene for obesity in both rats and humans, but no verification or functional studies have been done

What are the new findings in your manuscript?

Identified Krtcap3 as a novel gene that impacts feeding behavior and adiposity in female rats

Determined that Krtcap3 impacts insulin sensitivity differentially in male and female rats

How might your results change the direction of research or the focus of clinical practice?

This work may lead to identification of new pathways that contribute to obesity without metabolic complications, which will advance understanding of the biology of obesity and potentially identify novel drug targets

This work highlights the need to investigate sex differences in the genetics of obesity
A neonicotinoid pesticide alters how nectar chemistry affects bees
Authors: Richman Sarah K. , Maalouf Isabelle M. , Smilanich Angela M. , Marquez Sanchez Denyse , Miller Sharron Z. , Leonard Anne S.
Published: February 2022

Neonicotinoid pesticides in the nectar and pollen of managed crops and wildflowers contribute to the global declines of bees. These chemicals can have detrimental effects on bees' physiology, behaviour and reproduction. Floral nectar also contains secondary chemistry with its own effects on bee health. How nectar secondary chemistry may act additively or synergistically with neonicotinoids is unknown.

Here, we asked how an acute exposure to a common neonicotinoid, imidacloprid (IMD) affected the longevity, immune function and behaviour of bumble bee Bombus impatiens workers maintained on diets enriched with one of three nectar secondary metabolites (NSMs; the alkaloid caffeine, the terpenoid thymol or the cardiac glycoside digoxin). A factorial design allowed us to assess the potential for additive and interactive effects of each NSM and IMD combination on multiple health outcomes.

Without IMD exposure, different dietary NSMs each had positive effects on life span (caffeine), immune function (digoxin) and activity levels (caffeine, thymol), although these came with trade‐offs. A single sublethal IMD exposure overshadowed these NSM effects, and in two cases, an NSM‐enriched diet magnified the negative effects of pesticide exposure.

In summary, we show that even a single acute exposure to a pesticide has the potential to reshape interactions between pollinators and plants mediated by nectar secondary chemistry.

Read the free Plain Language Summary for this article on the Journal blog.
Small Actions Can Make a Big Difference: Voluntary Employee Green Behaviour at Work and Affective Commitment to the Organization
Authors: Ren Shuang , Tang Guiyao , Zhang Shujie
Published: February 2022

In the workplace, discretionary pro‐environmental actions made by employees are referred to as voluntary employee green behaviour (VEGB). This is increasingly recognised as a contribution to both the environmental and the financial sustainability of the organisation. However, the implications of VEGB beyond its original environmental domain largely remain underspecified, thus constraining the theoretical development of the field and advocacy for organisations in practice. This study thus investigates how VEGB associates with the employee outcome of affective commitment, which especially impacts the psychological relationships that employees develop with their organisations. Drawing on two studies, we found that VEGB was positively associated with affective commitment, as enabled by three mediating mechanisms that enhanced the sense of warm glow and moral credit for employees while protecting them against emotional exhaustion. Moreover, we found that perceived organisational support for the environment served as a boundary condition for VEGB and its mediation by moral credit and emotional exhaustion. Implications for theory and practice are discussed in the paper.
The Degenerative Tendencies of Long‐Serving Governments…1963…1996…2009…the Conservatives in 2022?
Authors: Roe‐Crines Andrew S.
Published: February 2022

Is Boris Johnson's government suffering from the degenerative tendencies of long‐serving government as identified by Timothy Heppell? For his 2008 study, Heppell identified five symptoms of governing degeneration, namely: governing competence; leadership credibility; ideological division; abuses of power; and a renewed opposition/sense that it is time for a change. This approach was tested by Heppell on the longstanding Conservative administrations of 1951–64 and 1979–97, and the Labour administration between 1997 and (at the time of original publication) 2008. Thus, my hypothesis asks whether the similarly long‐serving Conservative government from 2010 to‐date might be exhibiting signs of similar governing degeneration on each of Heppell's criteria. I ask whether the Conservatives under Boris Johnson appear to lack the clear direction of travel and purpose that characterised the final period of the Macmillan/Home, Major, and Brown premierships. Whilst it is by no means the aim of this article to produce an electoral prediction, there is evidence to suggest the current Conservative administration has met the level of governing degeneration that affected the last years of the longstanding administrations evaluated by Heppell.
Arachnoiditis ossificans associated with syringomyelia in a patient with mixed connective tissue disease
Authors: Chung Pui‐man , Chan Allan Ngo‐lun , Po Yin‐chung
Published: February 2022

We report a rare case of arachnoiditis ossificans with syringomyelia in a 58‐year‐old man with mixed connective tissue disease and history of tuberculous meningitis in childhood, presenting with progressive spastic paraplegia and double incontinence.
Octopaminergic neurons function in appetitive but not aversive olfactory learning and memory in Bactrocera dorsalis
Authors: Yu Jin‐Xin , Xiang Qian , Qu Jia‐Bao , Hui Yan‐Min , Lin Tao , Zeng Xin‐Nian , Liu Jia‐Li
Published: February 2022

The biogenic amine octopamine (OA, invertebrate counterpart of noradrenaline) plays critical roles in the regulation of olfactory behavior. Historically, OA has been thought to mediate appetitive but not aversive learning in honeybees, fruit flies (Drosophila), and crickets. However, this viewpoint has recently been challenged because OA activity through a β‐adrenergic‐like receptor drives both appetitive and aversive learning. Here, we explored the roles of OA neurons in olfactory learning and memory retrieval in Bactrocera dorsalis. We trained flies to associate an orange odor with a sucrose reward or to associate methyl eugenol, a male lure, with N,N‐diethyl‐3‐methyl benzoyl amide (DEET) punishment. We then treated flies with OA receptor antagonists before appetitive or aversive conditioning and a memory retention test. Injection of OA receptor antagonist mianserin or epinastine into the abdomen of flies led to impaired of appetitive learning and memory retention with a sucrose reward, while aversive learning and memory retention with DEET punishment remained intact. Our results suggest that the OA signaling participates in appetitive but not aversive learning and memory retrieval in B. dorsalis through OA receptors.
Morphological, histological and ultra‐structural studies on the ultimobranchial body of goat (Capra hircus)
Authors: Beheiry Rasha R. , Goda Nehal I. A. , Ali Sozan A. , El sayed Shafika A.
Published: February 2022

Ultimobranchial body (UBB) remnant was considered as an enigma till the last few years, then it was recognized as a necessary organ where it is the origin of the parafollicular cells. The samples were fixed and processed for the histological and electron microscopic examination. Macroscopically, the UBB remnant appeared as a white mass at the end of the cranial one‐third of the thyroid lobe. It was composed of solid cell nest, cluster of cells and small thyroid follicles. Transmission electron microscope showed some round cells containing euchromatic nuclei, numerous parafollicular cells with darkly stained granules and paler ones. It also showed some mast cells with heterochromatic nuclei and large darkly stained granules. The parafollicular cells were distributed throughout the thyroid gland but concentrated within the UBB remnant. To our knowledge, our findings represent very unique histological manifestations specially the ultra‐structural ones which revealed an original finding about the new clear type of cells suggested to be a UBB remnant and ensure those of the light microscope.
Clinicopathological characteristics of new primary melanomas in patients receiving immune checkpoint inhibitor therapy for metastatic melanoma
Authors: Pennington Thomas E , Zhao Cathy Yunjia , Colebatch Andrew J , Fernandez‐Peñas Pablo , Guitera Pascale , Burke Hazel , Scolyer Richard A , Menzies Alexander M , Carlino Matteo S , Lo Serigne , Long Georgina V , Saw Robyn PM
Published: February 2022

Background

Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors.

Aim

To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma.

Methods

A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared.

Results

Between 2013–2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in‐situ stage (6/14 vs 0/13, P = 0.0016).

Conclusion

NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long‐term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.
Delayed gastric emptying as an independent predictor of mortality in gastroparesis
Authors: Gourcerol Guillaume , Melchior Chloé , Wuestenberghs Fabien , Desprez Charlotte , Prevost Gaëtan , Grosjean Julien , Leroi Anne Marie , Tavolacci Marie Pierre
Published: February 2022

Background

Whether gastroparesis is associated with a shortened life expectancy remains uncertain as no systematic study has evaluated the impact of gastroparesis on mortality, based on gastric emptying (GE) tests.

Aim

This study aimed to assess whether delayed GE was predictive of mortality.

Methods

GE was measured using a 13C‐octanoic acid breath test in 1563 consecutive patients. Delayed GE at baseline defined the gastroparesis group. Patients were followed up for a mean of 8.9 years, yielding 13 466 patients per year. Mortality was assessed using the French CepiDc database with data from local civil registries. The cause of death was determined from medical records. Mortality rates were assessed using the Kaplan‐Meier method and hazard ratio (HR) was calculated using the Cox regression model.

Results

Age and symptoms severity were not different among patients with normal GE (n = 1179) and with delayed GE (n = 384) while diabetes mellitus was more frequent in the gastroparesis group. Kaplan‐Meier analysis showed increased mortality in the gastroparesis group compared to patients with normal GE. Cox regression model identified delayed GE as independently associated with increased mortality (HR = 1.63[1.09‐2.42]; P = 0.02). Other independent factors associated with increased mortality included age, male sex, and diabetes. No difference was observed between groups for the cause of death, with cancer and cardiovascular disease being the leading causes.

Conclusion

This study has shown that gastroparesis, diagnosed on GE tests, was associated with increased mortality, independently of age, sex, BMI or diabetes status (NCT04918329).