bluuebunny/crossref_metadata_2025 huggingface dataset:
MIRS: an AI scoring system for predicting the prognosis and therapy of breast cancer
Authors: Huang Chen , Deng Min , Leng Dongliang , Leung Elaine Lai-Han , Sun Baoqing , Zheng Peiyan , Zhang Xiaohua Douglas
Published: December 2021

Current scoring systems for prognosis of breast cancer are available but usually consider only one prognostic feature. We aim to develop a novel prognostic scoring system based on both immune-infiltration and metastatic features to not only assess the patient prognoses more accurately but also guide therapy for patients with breast cancer. Computational immune-infiltration and gene profiling analysis identified a 12-gene panel firstly characterizing immune-infiltrating and metastatic features. Neural network model yielded a precise prognostic scoring system called metastatic and immunogenomic risk score (MIRS). The influence of MIRS on the prognosis and therapy of breast cancer was then comprehensively investigated. MIRS significantly stratifies patients into high risk-group (MIRShigh) and low risk-group (MIRSlow) in both training and test cohorts. The MIRSlow patients exhibit significantly improved survival rate compared with MIRShigh patients. A series of analyses demonstrates that MIRS can well characterize the metastatic and immune landscape of breast cancer. Further analysis on the usage of MIRS in chemotherapy suggests that MIRShigh patients may benefit from three chemotherapeutic drugs (Cisplatin, Tamoxifen and Vincristine). Higher immune infiltration and significantly prolonged survival are observed in MIRSlow patients, indicating a better response in immune checkpoint inhibitor therapy. Our analysis demonstrates that MIRS could effectively improve the accuracy of prognosis for patients with breast cancer. Also, MIRS is a useful webtool, which is deposited at https://lva85.github.io/MIRS/, to help clinicians in designing personalized therapies for patients with breast cancer.
Mendelian randomization analyses clarify the effects of height on cardiovascular diseases
Authors: Hui Daniel , Sanford Eric , Lorenz Kimberly , Damrauer Scott M. , Assimes Themistocles L. , Thom Christopher S. , Voight Benjamin F.
Published: December 2021

An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (∼6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures.
Human blood DNA methylation patterns reflect individual lifestyle
Authors: Klemp Ireen , Hoffmann Anne , Müller Luise , Hagemann Tobias , Horn Kathrin , Rohde-Zimmermann Kerstin , Tönjes Anke , Thiery Joachim , Löffler Markus , Burkhardt Ralph , Böttcher Yvonne , Stumvoll Michael , Blüher Matthias , Krohn Knut , Scholz Markus , Baber Ronny , Franks Paul W , Kovacs Peter , Keller Maria
Published: December 2021

Obesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.
Deficits in hospital care among clinically vulnerable children aged 0 to 4 years during the COVID-19 pandemic
Authors: Etoori David , Harron Katie , Grath-Lone Louise Mc , Verfuerden Maximiliane , Gilbert Ruth , Blackburn Ruth
Published: December 2021

Objective

To quantify deficits in hospital care for clinically vulnerable children during the COVID-19 pandemic.

Design

Birth cohort in Hospital Episode Statistics (HES).

Setting

NHS hospitals in England.

Study population

All children aged <5 years with a birth recorded in hospital administrative data (January 2010 to March 2021).

Main exposure

Clinical vulnerability defined by a chronic health condition, preterm birth (<37 weeks gestation) or low birthweight (<2500g).

Main outcomes

Deficits in care defined by predicted rates for 2020, estimated from 2015- 2019, minus observed rates per 1000 child years during the pandemic (March 2020-2021).

Results

Of 3,813,465 children, 17.7% (1 in 6) were clinically vulnerable (9.5% born preterm or low birthweight, 10.3% had a chronic condition). Deficits in hospital care during the pandemic were much higher for clinically vulnerable children than peers: respectively, outpatient attendances (314 versus 73 per 1000 child years), planned admissions (55 versus 10), and unplanned admissions (105 versus 79). Clinically vulnerable children accounted for 50.1% of the deficit in outpatient attendances, 55.0% in planned admissions, and 32.8% in unplanned hospital admissions. During the pandemic, weekly rates of planned care returned to pre-pandemic levels for infants with chronic conditions but not older children. Deficits in care differed by ethnic group and level of deprivation. Virtual outpatient attendances increased from 3.2% to 24.8% during the pandemic.

Conclusion

1 in 6 clinically vulnerable children accounted for one-third to one half of the deficit in hospital care during the pandemic.
A Machine Learning Ensemble Based on Radiomics to Predict BI-RADS Category and Reduce the Biopsy Rate of Ultrasound-Detected Suspicious Breast Masses
Authors: Interlenghi Matteo , Salvatore Christian , Magni Veronica , Caldara Gabriele , Schiavon Elia , Cozzi Andrea , Schiaffino Simone , Carbonaro Luca Alessandro , Castiglioni Isabella , Sardanelli Francesco
Published: December 2021

We developed a machine learning model based on radiomics to predict the BI-RADS category of ultrasound-detected suspicious breast lesions and support medical decision making towards short-interval follow-up versus tissue sampling. From a retrospective 2015–2019 series of ultrasound-guided core needle biopsies performed by four board-cer-tified breast radiologists using six ultrasound systems from three vendors, we collected 821 images of 834 suspicious breast masses from 819 patients, 404 malignant and 430 benign according to histopathology. A balanced image set of biopsy-proven benign (n = 299) and malignant (n = 299) lesions were used for training and cross-validation of ensembles of ma-chine learning algorithms supervised during learning by histopathological diagnosis as a reference standard. Based on a majority vote (over 80% of the votes to have a valid prediction of benign lesion), an ensemble of support vector machines showed an ability to reduce the biopsy rate of benign lesions by 15% to 18%, always keeping a sensitivity over 94%, when externally tested on 236 images from two image sets: 1) 123 lesions (51 malignant and 72 benign) obtained from the same four ultrasound systems used for training, resulting into a positive predictive value (PPV) of 45.9% (95% confidence inter-val 36.3-55.7%) versus a radiologists’ PPV of 41.5% (p < 0.005), combined with a 98.0% sensitivity (89.6–99.9%); 2) 113 lesions (54 malignant and 59 benign) obtained from two ultrasound systems from vendors different from those used for training, resulting into a 50.5% PPV (40.4–60.6%) versus a radiologists’ PPV of 47.8% (p < 0.005), combined with a 94.4% sensitivity (84.6–98.8%). Errors in BI-RADS 3 category (i.e., assigned by the model as BI-RADS 4) were 0.8% and 2.7% in the Testing set I and II, respectively. The board-certified breast radiologist accepted the BI-RADS classes assigned by the model in 114 masses (92.7%) and modified the BI-RADS classes of 9 breast masses (7.3%). In 6 of 9 cases the model performed better than the radiologist, since it assigned a BI-RADS 3 classification to histopathology-confirmed benign masses that were classified as BI-RADS 4 by the radiologist.
Cash Transfer Programs and HIV-Related Outcomes: an Analysis of 42 Countries from 1996 to 2019
Authors: Richterman Aaron , Thirumurthy Harsha
Published: December 2021

Background

Many low- and middle-income countries have introduced cash transfer programs as part of their poverty reduction and social protection strategies. These programs have the potential to overcome various drivers of HIV risk behaviors and usage of HIV services, but their overall effects on a broad range of HIV-related outcomes remains unknown.

Methods

We used publicly reported data to determine whether low- and middle-income countries with HIV prevalence >1% and baseline annual incidence >1/1000 had conditional or unconditional cash transfer programs that covered >5% of the impoverished population, and the year in which those programs began and ended. We obtained country- and individual-level data on HIV-related outcomes from UNAIDS and population-representative household surveys, focusing on the period between 1996 and 2019. We conducted difference-in-differences analyses with country and year fixed effects to evaluate the effects of cash transfer programs on country- and individual-level HIV-related outcomes.

Findings

Forty-two countries across three continents were included. Among these, 21 were in the intervention group, having implemented cash program(s) with impoverished population coverage greater than 5% during the study period. Cash transfer programs were associated with lower probability of reporting sexually transmitted infection within the last 12 months among females (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.50-0.91) and higher probability of an HIV test within the last 12 months among females (OR 2.61, 95% CI 1.15-5.88) and males (OR 3.19, 95% CI 2.45-4.15). For country-level outcomes, cash transfer programs were associated with a reduction in new HIV infections (incidence rate ratio [IRR] 0.94, 95% CI 0.89-0.99), but not with the proportion of people with HIV receiving antiretroviral therapy (5.0%, 95% CI -0.2-10.1) or AIDS-related deaths (IRR 0.99, 95% CI 0.95-1.03), though temporal analyses showed delayed improvements in both antiretroviral coverage and deaths.

Interpretations

Cash transfer programs, which are being expanded in the context of the COVID-19 pandemic, have the potential to promote ongoing efforts to end HIV as a public health threat. Alongside the already existing focus on expanding biomedical services, these anti-poverty programs can play a greater role in achieving global targets for HIV prevention and treatment.

Funding

None
Predictors of SARS-CoV-2 infection in a multi-ethnic cohort of United Kingdom healthcare workers: a prospective nationwide cohort study (UK-REACH)
Authors: Martin Christopher A. , Pan Daniel , Melbourne Carl , Teece Lucy , Aujayeb Avinash , Baggaley Rebecca F. , Bryant Luke , Carr Sue , Gregary Bindu , Gupta Amit , Guyatt Anna L. , John Catherine , McManus I Chris , Nazareth Joshua , Nellums Laura B. , Reza Rubina , Simpson Sandra , Tobin Martin D. , Woolf Katherine , Zingwe Stephen , Khunti Kamlesh , Abrams Keith R. , Gray Laura J. , Pareek Manish
Published: December 2021

Introduction

Healthcare workers (HCWs), particularly those from ethnic minority groups, have been shown to be at disproportionately higher risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) compared to the general population. However, there is insufficient evidence on how demographic and occupational factors influence infection risk among ethnic minority HCWs.

Methods

We conducted a cross-sectional analysis using data from the United Kingdom Research study into Ethnicity And COVID-19 Outcomes in Healthcare workers (UK-REACH) cohort study. We used logistic regression to examine associations of demographic, household and occupational predictor variables with SARS-CoV-2 infection (defined by PCR, serology or suspected COVID-19) in a diverse group of HCWs.

Results

2,496 of the 10,772 HCWs (23.2%) who worked during the first UK national lockdown in March 2020 reported previous SARS-CoV-2 infection. In an adjusted model, demographic and household factors associated with increased odds of infection included younger age, living with other key workers and higher religiosity. Important occupational risk factors associated with increased odds of infection included attending to a higher number of COVID-19 positive patients (aOR 2.49, 95%CI 2.03–3.05 for ≥21 patients per week vs none), working in a nursing or midwifery role (1.35, 1.15– 1.58, compared to doctors), reporting a lack of access to personal protective equipment (1.27, 1.15 – 1.41) and working in an ambulance (1.95, 1.52–2.50) or hospital inpatient setting (1.54, 1.37 – 1.74). Those who worked in Intensive Care Units were less likely to have been infected (0.76, 0.63–0.90) than those who did not. Black HCWs were more likely to have been infected than their White colleagues, an effect which attenuated after adjustment for other known predictors.

Conclusions

We identified key sociodemographic and occupational risk factors associated with SARS-CoV-2 infection amongst UK HCWs, and have determined factors that might contribute to a disproportionate odds of infection in HCWs from Black ethnic groups. These findings demonstrate the importance of social and occupational factors in driving ethnic disparities in COVID-19 outcomes, and should inform policies, including targeted vaccination strategies and risk assessments aimed at protecting HCWs in future waves of the COVID-19 pandemic.

Trial registration

ISRCTN 11811602
Randomized controlled trial of gut decontamination in pediatric patients undergoing allogeneic hematopoietic cell transplantation
Authors: Severyn Christopher J. , Siranosian Benjamin A. , Kong Sandra Tian-Jiao , Moreno Angel , Li Michelle M. , Chen Nan , Duncan Christine N. , Margossian Steven P. , Lehmann Leslie E. , Sun Shan , Andermann Tessa M. , Birbrayer Olga , Silverstein Sophie , Kim Soomin , Banaei Niaz , Ritz Jerome , Fodor Anthony A. , London Wendy B. , Bhatt Ami S. , Whangbo Jennifer S.
Published: December 2021

Background

Gut decontamination (GD) can decrease the incidence and severity of acute graft- versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). Several HCT centers standardly practice GD with different antibiotic regimens. In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.

Methods

We randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).

Results

The two arms did not differ in Shannon diversity of the gut microbiota at two weeks post- HCT (Genus,p=0.8; Species,p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T- cell subsets was similar, but absolute CD19+ B-cell counts were higher in the GD arm at 12 months post-HCT (p=0.02). Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including the genusStaphylococcus.

Conclusions

While GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut microbial pathogens.

Key points:

–

In this phase 2 randomized study of gut decontamination (GD) in 20 pediatric HCT patients, neither two-week post-HCT Shannon diversity of the gut microbiome nor incidence of aGVHD differ between the GD and no-GD arms.

–

All bloodstream infections (BSIs) caused by pathogens traceable to the gut either temporally or via strain-specific analysis (concomitant gut colonization) occurred in patients in the no-GD arm; this suggests that GD with vancomycin-polymyxin B may decrease the incidence of gut-derived BSI in allo-HCT patients.

–

In contrast to prior studies, we find that non-mucosal barrier injury (MBI) pathogens, such asStaphylococcus aureus,can be found in the gut microbiome of HCT patients.
Lower infant mortality and access to contraception reduce fertility in low- and middle-income nations
Authors: Bradshaw Corey J A , Perry Claire , Saraswati Chitra Maharani , Judge Melinda , Heyworth Jane , Le Souëf Peter N
Published: December 2021

Although average contraceptive use has increased globally in recent decades, an estimated 222 million (26%) of women of child-bearing age worldwide face an unmet need for family planning — defined as a discrepancy between fertility preferences and contraception practice, or failing to translate desires to avoid pregnancy into preventative behaviours and practices.

While many studies have reported relationships between availability of contraception, infant mortality, and fertility, these relationships have not been evaluated quantitatively across a broad range of low- and middle-income countries. Using publicly available data from 46 low- and middle-income countries, we collated test and control variables in six themes: (i) availability of family planning, (ii) quality of family planning, (iii) maternal education, (iv) religion, (v) mortality, and (vi) socio-economic conditions. We predicted that higher nation-level availability/quality of family-planning services, maternal education, and wealth reduce average fertility, whereas higher infant mortality and religious adherence increase it. Given the sample size, we first constructed general linear models to test for relationships between fertility and the variables from each theme, from which we retained those with the highest explanatory power within a final general linear model set to determine the partial correlation of dominant test variables. We also applied boosted regression trees, generalised least-squares models, and a generalised linear mixed-effects models to account for non-linearity and spatial autocorrelation. On average among all countries, we found an association between all main variables and fertility, with reduced infant mortality having the strongest relationship with reduced fertility. Access to contraception was the next-highest correlate with reduced fertility, with female secondary education, home health visitations, and adherence to Catholicism having weak, if any, explanatory power. Our models suggest that decreasing infant mortality and increasing access to contraception will have the greatest effect on decreasing global fertility. We thus provide new evidence that progressing the United Nation’s Sustainable Development Goals for reducing infant mortality can be accelerated by increasing access to any form of family planning.
Transcription factor lineages in plant-pathogenic fungi, connecting diversity with fungal virulence
Authors: John Evan , Singh Karam B. , Oliver Richard P. , Tan Kar-Chun
Published: December 2021

Plant-pathogenic fungi span diverse taxonomic lineages. Their host-infection strategies are often specialised and require the coordinated regulation of molecular virulence factors. Transcription factors (TFs) are fundamental regulators of gene expression, controlling development and virulence in plant pathogenic fungi. Recent research has established regulatory roles for several taxonomically conserved fungal TFs, but the evolution of specific virulence regulators is not well understood. This study sought to explore the representation of TFs across a taxonomically-diverse range of fungi, with a focus on plant pathogens. A significant trend was observed among the obligate, host-associated pathogens, which possess a reduced overall TF repertoire, alluding to a lack of pressure for maintaining diversity. A novel orthology-based analysis is then presented that refined TF classifications, traditionally based on the nature of the DNA-binding domains. Using this analysis, cases of TF over/underrepresentation across fungal pathogen lineages are systematically highlighted. Specific examples are then explored and discussed that included the TF orthologues of Ste12, Pf2 and EBR1, plus phytotoxic secondary-metabolite cluster regulators, which all presented novel and distinct evolutionary insights. Ultimately, as the examples presented demonstrate, this resource can be interrogated to guide functional studies that seek to characterise virulence-specific regulators and shed light on the factors underpinning plant pathogenicity.
Emergence of compensatory mutations reveal the importance of electrostatic interactions between HIV-1 integrase and genomic RNA
Authors: Mugisha Christian Shema , Dinh Tung , Kumar Abhishek , Tenneti Kasyap , Eschbach Jenna E. , Davis Keanu , Gifford Robert , Kvaratskhelia Mamuka , Kutluay Sebla B.
Published: December 2021

ABSTRACT

HIV-1 integrase (IN) has a non-catalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Allosteric integrase inhibitors (ALLINIs) and class II IN substitutions inhibit IN-gRNA binding and result in non-infectious viruses marked by mislocalization of the gRNA within virions. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA. However, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are involved remain unknown. To address this, we have isolated compensatory substitutions in the background of a class II IN mutant virus bearing R269A/K273A substitutions within the IN-CTD. We found that the nearby D256N and D270N compensatory substitutions restored the ability of IN to bind gRNA and led to the formation of mature infectious virions. Reinstating the local positive charge of the IN-CTD through individual D256R, D256K, D278R and D279R substitutions was sufficient to restore IN-RNA binding and infectivity for the IN R269A/K273A as well as the IN R262A/R263A class II mutants. Structural modeling suggested that compensatory substitutions in the D256 residue created an additional interaction interface for gRNA binding. Finally, HIV-1 IN R269A/K273A, but not IN R262A/R263A, bearing compensatory mutations was more sensitive to ALLINIs providing key genetic evidence that specific IN residues required for RNA binding also influence ALLINI activity. Taken together, our findings highlight the essential role of CTD in gRNA binding and ALLINI sensitivity, and reveal the importance of pliable electrostatic interactions between the IN- CTD and the gRNA.

IMPORTANCE

In addition to its catalytic function, HIV-1 integrase (IN) binds to the viral RNA genome (gRNA) through positively charged residues within its C-terminal domain (CTD) and regulates proper virion maturation. Here we show that compensatory mutations in nearby acidic residues (i.e. D256N and D270N) restore the ability to bind gRNA for IN variants bearing substitutions in these positively charged CTD residues. Similarly, charge reversals through individual D-to-R and D-to-K substitutions at these positions enabled the respective IN mutants to bind gRNA and restore virion infectivity. Further, we show that specific residues within the IN-CTD required for RNA binding also influence sensitivity to allosteric integrase inhibitors, a class of novel IN- targeting compounds that target the non-catalytic function of IN. Taken together, our findings reveal the importance of electrostatic interactions in IN-gRNA binding and provide key evidence for a crucial role of the IN-CTD in allosteric integrase inhibitor mechanism of action.
Divergent clonal differentiation trajectories of T cell exhaustion
Authors: Daniel Bence , Yost Kathryn E. , Sandor Katalin , Xia Yu , Qi Yanyan , Hiam-Galvez Kamir J. , Meier Stefanie L. , Belk Julia A. , Giles Josephine R. , Wherry E. John , Chang Howard Y. , Egawa Takeshi , Satpathy Ansuman T.
Published: December 2021

T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (Tex) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. However, whether all antigen-specific T cell clones follow the same molecular and cellular Tex differentiation trajectory remains unclear. Here, we generate a single-cell multi-omic atlas of T cell exhaustion that redefines the phenotypic diversity and molecular regulation of Tex phenotypes. Longitudinal analysis during chronic viral infection identifies an early effector phenotype that is epigenetically primed for Tex differentiation and two late-stage Tex cell states with either a terminal exhaustion or a killer cell lectin-like receptor (KLR)-expressing cytotoxic gene signature. We define clonal trajectories of antigen-specific T cells using paired single-cell RNA and T cell receptor sequencing and reveal distinct differentiation trajectories resulting in terminal Tex-biased, KLR Tex-biased, or divergent clones that differentiate into both phenotypes. Comparison of Tex phenotypes among shared T cell clones that traffic to multiple organs reveals that clonal differentiation trajectories are maintained across tissues. Finally, we show that differences in clonal differentiation trajectory are driven by TCR signal strength, whereby high-affinity T cell clones preferentially adopt a terminal Tex fate, while low-affinity clones adopt an effector-like KLR Tex fate that is detectable long-term but depleted in high antigen settings. These findings reveal clonal heterogeneity in the T cell response to chronic antigen and genomic programs that underlie Tex fates and persistence.

Highlights

A single-cell atlas of T cell exhaustion identifies novel early effector and KLR Tex states.

Clonal T cell analysis defines divergent differentiation trajectories during chronic viral infection leading to terminal and KLR Tex fates.

The heterogeneity of the Tex pool arises from three primary differentiation patterns and are differentially persistent in the setting of high antigen.

Clonal Tex differentiation patterns are conserved across organ sites and driven by TCR signal strength.
The genome sequence of the lesser marbled fritillary, Brenthis ino, and evidence for a segregating neo-Z chromosome
Authors: Mackintosh Alexander , Laetsch Dominik R. , Baril Tobias , Foster Robert , Dincă Vlad , Vila Roger , Hayward Alexander , Lohse Konrad
Published: December 2021

The lesser marbled fritillary, Brenthis ino (Rottemburg, 1775), is a species of Palearctic butterfly. Male B. ino individuals have been reported to have between 12 and 14 pairs of chromosomes, a much reduced chromosome number than is typical in butterflies. Here we present a chromosome-level genome assembly for B. ino, as well as gene and transposable element annotations. The assembly is 411.8 Mb in span with contig and scaffold N50s of 9.6 and 29.5 Mb respectively. We also show evidence that the male individual from which we generated HiC data was heterozygous for a neo-Z chromosome, consistent with inheriting 14 chromosomes from one parent and 13 from the other. This genome assembly will be a valuable resource for studying chromosome evolution in Lepidoptera, as well as for comparative and population genomics more generally.
4D reconstruction of developmental trajectories using spherical harmonics
Authors: Dalmasso Giovanni , Musy Marco , Niksic Martina , Robert-Moreno Alexandre , Badía-Careaga Claudio , Sanz-Ezquerro Juan J. , Sharpe James
Published: December 2021

Although the full embryonic development of species such as Drosophila and zebrafish can be 3D imaged in real time, this is not true for mammalian organs, as normal organogenesis cannot be recapitulated in vitro. Currently available 3D data is therefore ex vivo images which provide only a snap shot of development at discrete moments in time. Here we propose a computer-based approach to recreate the continuous evolution in time and space of developmental stages from 3D volumetric images. Our method uses the mathematical approach of spherical harmonics to re-map discrete shape data into a space in which facilitates a smooth interpolation over time. We tested our approach on mouse limb buds (from E10 to E12.5) and embryonic hearts (from 10 to 29 somites). A key advantage of the method is that the resulting 4D trajectory takes advantage of all the available data (i.e. it is not dominated by the choice of a few “ideal” images), while also being able to interpolate well through time intervals for which there is little or no data. This method not only provides a quantitative basis for validating predictive models, but it also increases our understanding of morphogenetic processes. We believe this is the first data-driven quantitative 4D description of limb morphogenesis.
Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus
Authors: Mondoloni Sarah , Nguyen Claire , Vicq Eléonore , Jehl Joachim , Durand-de Cuttoli Romain , Torquet Nicolas , Tolu Stefania , Pons Stéphanie , Maskos Uwe , Marti Fabio , Faure Philippe , Mourot Alexandre
Published: December 2021

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half stopped consuming. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we identified β4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.
Computational modelling and near-complete kinetochore tracking reveal how chromosome dynamics during cell division are co-ordinated in space and time
Authors: Harrison Jonathan U. , Sen Onur , McAinsh Andrew D. , Burroughs Nigel J.
Published: December 2021

Mitotic chromosome segregation is a self-organising process that achieves high fidelity separation of 46 duplicated chromosomes into two daughter cells. Chromosomes must be captured by the microtubule-based spindle, aligned at the spindle equator where they undergo oscillatory motion (metaphase) and then pulled to opposite spindle poles (anaphase). These large and small-scale chromosome movements are driven by kinetochores, multi-protein machines, that link chromosomes to microtubules and generate directional forces. Through automated near-complete tracking of kinetochores at fine spatio-temporal resolution over long timescales, we produce a detailed atlas of kinetochore dynamics throughout metaphase and anaphase in human cells. We develop a hierarchical biophysical model of kinetochore dynamics and fit this model to 4D lattice light sheet experimental data using Bayesian inference. We demonstrate that location in the metaphase plate is the largest factor in the variation in kinetochore dynamics, exceeding the variation between cells, whilst within the spindle there is local spatio-temporal coordination between neighbouring kinetochores of directional switching events, kinetochore-fibre (K-fibre) polymerization/depolymerization state and the segregation of chromosomes. Thus, metaphase oscillations are robust to variation in the mechanical forces throughout the spindle, whilst the spindle environment couples kinetochore dynamics across the plate. Our methods provide a framework for detailed quantification of chromosome dynamics during mitosis in human cells.
Systematic simulation of the interactions of Pleckstrin homology domains with membranes
Authors: Le Huray Kyle I.P. , Wang He , Sobott Frank , Kalli Antreas C.
Published: December 2021

Pleckstrin homology (PH) domains can recruit proteins to membranes by recognition of phosphatidylinositol phosphates (PIPs). Here we report the systematic simulation of the interactions of 100 mammalian PH domains with PIP containing model membranes. Comparison with crystal structures of PH domains bound to PIP analogues demonstrates that our method correctly identifies interactions at known canonical and non-canonical sites, while revealing additional functionally important sites for interaction not observed in the crystal structure, such as for P-Rex1 and Akt1. At the family level, we find that the β1 and β2 strands and their connecting loop constitute the primary PIP interaction site for the majority of PH domains, but we highlight interesting exceptional cases. Simultaneous interaction with multiple PIPs and clustering of PIPs induced by PH domain binding are also observed. Our findings support a general paradigm for PH domain membrane association involving multivalent interactions with anionic lipids.

Teaser

Simulating the binding of 100 Pleckstrin homology domains to cell membranes reveals patterns in their lipid interactions.
Menopause modulates the circulating metabolome: evidence from a prospective cohort study
Authors: Karppinen Jari E. , Törmäkangas Timo , Kujala Urho M. , Sipilä Sarianna , Laukkanen Jari , Aukee Pauliina , Kovanen Vuokko , Laakkonen Eija K.
Published: December 2021

Aims

We studied the changes in the circulating metabolome and their relation to the menopausal hormonal shift in 17β-oestradiol and follicle-stimulating hormone levels among women transitioning from perimenopause to early postmenopause.

Methods and Results

We analysed longitudinal data from 218 Finnish women, 35 of whom started menopausal hormone therapy during the study. The menopausal transition was monitored with menstrual diaries and serum hormone measurements. The median follow-up was 14 months (interquartile range: 8–20). Serum metabolites were quantified with targeted nuclear magnetic resonance metabolomics. The model results were adjusted for age, follow-up duration, education, lifestyle, and multiple comparisons. Menopause was associated with 84 metabolite measures. The concentration of apoB (0.17 standard deviation [SD], 99.5% confidence interval [CI] 0.03–0.31), VLDL triglycerides (0.25 SD, CI 0.05–0.45) and particles (0.21 SD, CI 0.05–0.36), LDL cholesterol (0.17 SD, CI 0.01–0.34) and particles (0.17 SD, CI 0.03–0.31), HDL triglycerides (0.24 SD, CI 0.02–0.46), glycerol (0.32 SD, CI 0.07–0.58) and leucine increased (0.25 SD, CI 0.02–0.49). Citrate (−0.36 SD, CI -0.57 to - 0.14) and 3-hydroxybutyrate concentrations decreased (−0.46 SD, CI -0.75 to -0.17). Most metabolite changes were associated with the menopausal hormonal shift. This explained 10% and 9% of the LDL cholesterol and particle concentration increase, respectively. Menopausal hormone therapy was associated with increased medium-to-large HDL particle count and decreased small-to-medium LDL particle and glycine concentration.

Conclusions

Menopause is associated with proatherogenic circulating metabolome alterations. Female sex hormones levels are connected to the alterations, highlighting their impact on women’s cardiovascular health.

‘One-sentence Summary’

Female sex hormone alterations induced by menopause altered the levels of circulating metabolites, leading to a higher risk profile for cardiovascular diseases.
Triangulating evidence for the causal impact of single-dose zinc supplement on glycemic control for type-2 diabetes
Authors: Wang Zhiyang , Ronsmans Carine , Woolf Benjamin
Published: December 2021

Background

Although previous studies suggested the protective effect of zinc for type-2 diabetes, the unitary causal effect remains inconclusive.

Objective

We investigated the causal effect of zinc as a single intervention on glycemic control in type-2 diabetes patients, using a systematic review of RCTs and two-sample Mendelian randomization (MR).

Methods

Four outcomes were identified: fasting blood glucose/fasting glucose, hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), and serum insulin/fasting insulin level. In the systematic review, four databases were searched up to June 2021. Results were synthesized through the random-effects meta-analysis. Single nucleotide polymorphisms (SNPs) that are independent and are strongly related to zinc supplements were selected from MR-base to perform the two-sample MR with inverse-variance weighted (IVW) coefficient.

Results

In the systematic review, 14 trials were included. The zinc supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): - 26.52, 95%CI: -35.13, -17.91), HbA1C (MD: -0.52, 95%CI: -0.90, -0.13), and HOMA-IR (MD: -1.65, 95%CI: -2.62, -0.68), compared to the control group. In the two-sample MR, zinc supplement with 2 SNPs associated with lower fasting glucose (IVW coefficient: -2.04, 95%CI: -3.26, -0.83), but not specified type-2 diabetes.

Conclusion

Although the study was limited by the few trials (review) and SNPs (two-sample MR), we demonstrated that the single zinc supplementary improved glycemic control among type-2 diabetes patients with causal evidence to a certain extent.
‘Inflammaging’ in Major Depressive Disorder: Associations between markers of inflammation and brain ageing in depression across two large community-based cohorts
Authors: Green Claire , Squillace Marco , Stevenson Anna J. , Stolicyn Aleks , Harris Mathew A. , Backhouse Ellen V. , Hawkins Emma L. , Taylor Adele M. , Morris Zoe , Wardlaw Joanna M. , Steele J Douglas , Waiter Gordon D. , Sandu Anca-Larisa , Porteous David J. , Cole James H. , Lawrie Stephen M. , Cavanagh Jonathan , Cox Simon R. , McIntosh Andrew M. , Whalley Heather C.
Published: December 2021

Background

Major Depressive Disorder (MDD) is associated with accelerated ageing trajectories including functional markers of ageing, cellular ageing and markers of poor brain health. The biological mechanisms underlying these associations remain poorly understood. Chronic inflammation is also associated with advanced ageing; however, the degree to which long-term inflammation plays a role in ageing in MDD remains unclear, partly due to difficulties differentiating long-term inflammation from acute cross-sectional measures.

Methods

Here, we use a longer-term measure of inflammation: a DNA methylation-based marker of C-reactive protein (DNAm CRP), in a large cohort of individuals deeply phenotyped for MDD (Generation Scotland, GS;N=804). We investigate associations between DNAm CRP and serum CRP using linear modelling with two brain ageing neuroimaging-derived phenotypes: (i) a machine learning based measure of brain-predicted age difference (brain-PAD) and (ii) white matter hyperintensities (WMH). We then examine inflammation by depression interaction effects for these brain ageing phenotypes. We sought to replicate findings in an independent sample of older community-dwelling adults (Lothian Birth Cohort 1936, LBC1936;N=615).

Results

DNAm CRP was significantly associated with increased brain-PAD (β=0.111, p=0.015), which was replicated in the independent sample with a similar significant effect size (β=0.114, p=0.012). There were no associations between the inflammation markers and WMH phenotypes in the GS-imaging sample, however in the LBC1936 sample, DNAm CRP was significantly associated with both Wahlund infratentorial (β=0.15, PFDR= 0.006) and Fazekas deep white matter hyperintensity scores (β= 0.116, PFDR=0.033). There were no interaction effects between inflammation and MDD in either cohort.

Conclusions

This study found robust associations between a longer-term marker of inflammation and brain ageing as measured by brain-PAD, consistent across two large independent samples. However, we found no evidence for interaction effects between inflammation and MDD on any brain ageing phenotype in these community-based cohorts. These findings provide evidence that chronic inflammation is associated with increased brain ageing, which is not specific to MDD. Future work should investigate these relationships in clinical samples including with other inflammatory biomarkers and should furthermore aim to determine causal directionality.
Microbial growth and attachment of Salmonella and enterohemorrhagic and enteroaggregative Escherichia coli strains on cress microgreens grown in peat soil system
Authors: Namli Sahin , Samut Hilal , Soyer Yesim
Published: December 2021

Purpose

This study aimed to investigate how enteric pathogens and their biofilm populations on fresh produce survive according to time that contamination has occurred on leaves and contamination route: seed irrigation water.

Design/methodology/approach

Cress was contaminated in two different ways: contamination of seeds and irrigation water with 8-log MPN/mL bacterial load, Salmonella Newport, Escherichia coli O157:H7, O104:H4 or O78:H2. While contaminated seeds were cultivated for seed contamination, contaminated irrigation was applied at the end of each week to separate groups of samples obtained from cultivated surface-sterile seeds to understand how long these pathogens could survive until harvest.

Findings

The results indicated these pathogens survived until harvest, and formed biofilms on cress leaves grown using both contaminated seeds and irrigation water. No significant difference was observed among populations of Salmonella and E. coli groups in terms of survival (∼4.5–6.0 log MPN/g) and biofilm formation (∼4.4–5.7 log MPN/g) for contamination by seed. Also, SEM images revealed biofilm-like structures, the proofs of the attachment of these pathogens on leaf surfaces.

Originality/value

From our knowledge this is the first study focusing on the survival and biofilm formation of one Salmonella serotype (Newport) and three E. coli serotypes (O157:H7, O104:H4, and O78:H2), representing enterohemorrhagic and enteroaggregative E. coli pathogenic subgroups, under the same irrigation and growth schemes. Furthermore, this study mimics the contamination of seeds and irrigation water with sewage or wastewater and may shed light on contamination of fresh produce grown using poor wastewater treatment.
Potential disruptive innovation: online learning of public speaking courses in higher education
Authors: Yee Bee Choo , Mohd Nawi Abdullah , Abdullah Tina
Published: December 2021

Purpose

The sudden pandemic of COVID-19 has caused disruptive innovation in all areas of business including education. Despite the educators’ and students’ acceptance and readiness in the new normal, the traditional face-to-face (FTF) public speaking has been shifted to online courses to suit the current needs. This study aims to examine whether there were differences between online and FTF pubic speaking in the students’ anxiety level, speech performance, as well as their perceptions of the challenges in the implementation of online public speaking courses as a potential to disruptive innovation.

Design/methodology/approach

This pilot study was a mixed method research that involved a purposive sampling of two groups of 39 students in higher education. The instruments used were questionnaires of self-report anxiety, speech performance test and observation.

Findings

The findings show that the students preferred the traditional FTF rather than the online mode for public speaking courses. The challenges of internet connection and the lack of a live audience were their main concerns in online public speaking. It also provides a potential for disruptive innovation that could take into consideration of a live audience in university online courses.

Originality/value

This study provides the potential of public speaking course as a disruptive innovation. This brings implications for the innovators, marketers and educators to think of the online courses/programmes that can be best implemented while embracing the changes and the new normal of COVID-19 brings for student learning.
Efficiency and its determinants in the Algerian banks: network data envelopment analysis and partial least squares regression
Authors: Achi Adel
Published: December 2021

Purpose

The purpose of this paper is to evaluate the efficiency of Algerian banks and examine the effects of explanatory factors on their performance.

Design/methodology/approach

In this paper, a methodology of two-stage network data envelopment analysis (DEA) is used to explore the efficiency of a sample of 13 Algerian banks during the 2013–2017 period. In the first stage, the network DEA is used to assess the overall and stages efficiencies. In the second stage, the partial least squares (PLS) regression is conducted to determine the potential effects of explanatory factors on stages efficiency.

Findings

The main empirical results indicate that Algerian banks need an efficiency improvement in both stages. The overall efficiency of the Algerian banking system improves over the study period. The deposit producing efficiency is positively affected by bank size and bank age. The revenue earning efficiency is negatively associated with bank size and bank age. The domestic banks are more efficient than foreign banks in the deposit producing stage and the foreign banks are more efficient than domestic banks in the revenue earning stage.

Practical implications

The results might be used as guidelines for both managers and policymakers in order to improve banks and banking system performance.

Originality/value

To the best of our knowledge, this study is the first that uses the DEA in investigating the efficiency of Algerian banks by dividing the overall efficiency into deposit producing and revenue earning efficiencies. Unlike most studies that have usually used OLS regression, Tobit regression and bootstrapped truncated regression, this study is the first in the bank efficiency literature that uses PLS regression to investigate the potential effect of explanatory variables on deposit producing and revenue earning efficiencies.