bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive investigation of pathway enrichment methods for functional interpretation of LC–MS global metabolomics data
Authors: Lu Yao , Pang Zhiqiang , Xia Jianguo
Published: December 2022

Background: Global or untargeted metabolomics is widely used to comprehensively investigate metabolic profiles under various pathophysiological conditions such as inflammations, infections, responses to exposures or interactions with microbial communities. However, biological interpretation of global metabolomics data remains a daunting task. Recent years have seen growing applications of pathway enrichment analysis based on putative annotations of liquid chromatography coupled with mass spectrometry (LC–MS) peaks for functional interpretation of LC–MS-based global metabolomics data. However, due to intricate peak-metabolite and metabolite-pathway relationships, considerable variations are observed among results obtained using different approaches. There is an urgent need to benchmark these approaches to inform the best practices. Results: We have conducted a benchmark study of common peak annotation approaches and pathway enrichment methods in current metabolomics studies. Representative approaches, including three peak annotation methods and four enrichment methods, were selected and benchmarked under different scenarios. Based on the results, we have provided a set of recommendations regarding peak annotation, ranking metrics and feature selection. The overall better performance was obtained for the mummichog approach. We have observed that a ~30% annotation rate is sufficient to achieve high recall (~90% based on mummichog), and using semi-annotated data improves functional interpretation. Based on the current platforms and enrichment methods, we further propose an identifiability index to indicate the possibility of a pathway being reliably identified. Finally, we evaluated all methods using 11 COVID-19 and 8 inflammatory bowel diseases (IBD) global metabolomics datasets.
Personalized immune subtypes based on machine learning predict response to checkpoint blockade in gastric cancer
Authors: Huang Weibin , Zhang Yuhui , Chen Songyao , Yin Haofan , Liu Guangyao , Zhang Huaqi , Xu Jiannan , Yu Jishang , Xia Yujian , He Yulong , Zhang Changhua
Published: December 2022

Immune checkpoint inhibitors (ICI) show high efficiency in a small fraction of advanced gastric cancer (GC). However, personalized immune subtypes have not been developed for the prediction of ICI efficiency in GC. Herein, we identified Pan-Immune Activation Module (PIAM), a curated gene expression profile (GEP) representing the co-infiltration of multiple immune cell types in tumor microenvironment of GC, which was associated with high expression of immunosuppressive molecules such as PD-1 and CTLA-4. We also identified Pan-Immune Dysfunction Genes (PIDG), a conservative PIAM-derivated GEP indicating the dysfunction of immune cell cooperation, which was associated with upregulation of metastatic programs (extracellular matrix receptor interaction, TGF-β signaling, epithelial-mesenchymal transition and calcium signaling) but downregulation of proliferative signalings (MYC targets, E2F targets, mTORC1 signaling, and DNA replication and repair). Moreover, we developed ‘GSClassifier’, an ensemble toolkit based on top scoring pairs and extreme gradient boosting, for population-based modeling and personalized identification of GEP subtypes. With PIAM and PIDG, we developed four Pan-immune Activation and Dysfunction (PAD) subtypes and a GSClassifier model ‘PAD for individual’ with high accuracy in predicting response to pembrolizumab (anti-PD-1) in advance GC (AUC = 0.833). Intriguingly, PAD-II (PIAMhighPIDGlow) displayed the highest objective response rate (60.0%) compared with other subtypes (PAD-I, PIAMhighPIDGhigh, 0%; PAD-III, PIAMlowPIDGhigh, 0%; PAD-IV, PIAMlowPIDGlow, 17.6%; P = 0.003), which was further validated in the metastatic urothelial cancer cohort treated with atezolizumab (anti-PD-L1) (P = 0.018). In all, we provided ‘GSClassifier’ as a refined computational framework for GEP-based stratification and PAD subtypes as a promising strategy for exploring ICI responders in GC. Metastatic pathways could be potential targets for GC patients with high immune infiltration but resistance to ICI therapy.
Learning with uncertainty to accelerate the discovery of histone lysine-specific demethylase 1A (KDM1A/LSD1) inhibitors
Authors: Wang Dong , Wu Zhenxing , Shen Chao , Bao Lingjie , Luo Hao , Wang Zhe , Yao Hucheng , Kong De-Xin , Luo Cheng , Hou Tingjun
Published: December 2022

Machine learning including modern deep learning models has been extensively used in drug design and screening. However, reliable prediction of molecular properties is still challenging when exploring out-of-domain regimes, even for deep neural networks. Therefore, it is important to understand the uncertainty of model predictions, especially when the predictions are used to guide further experiments. In this study, we explored the utility and effectiveness of evidential uncertainty in compound screening. The evidential Graphormer model was proposed for uncertainty-guided discovery of KDM1A/LSD1 inhibitors. The benchmarking results illustrated that (i) Graphormer exhibited comparative predictive power to state-of-the-art models, and (ii) evidential regression enabled well-ranked uncertainty estimates and calibrated predictions. Subsequently, we leveraged time-splitting on the curated KDM1A/LSD1 dataset to simulate out-of-distribution predictions. The retrospective virtual screening showed that the evidential uncertainties helped reduce false positives among the top-acquired compounds and thus enabled higher experimental validation rates. The trained model was then used to virtually screen an independent in-house compound set. The top 50 compounds ranked by two different ranking strategies were experimentally validated, respectively. In general, our study highlighted the importance to understand the uncertainty in prediction, which can be recognized as an interpretable dimension to model predictions.
Out of the Balkans and Anatolia to the Western Alps? Surprising phylogenetic implications for two endemicAlyssum(Brassicaceae) species:A. cognensesp. nov. andA. rossetii
Authors: Španiel Stanislav , Juillerat Philippe , Kaplan Klaus , Bovio Maurizio , Bäumler Beat , Perret Mathieu , Mártonfiová Lenka , Zozomová-Lihová Judita
Published: December 2022

The European Alps show a high degree of endemism associated mainly with the location of glacial refugia and environmental heterogeneity. Several Alpine endemics have evolved in the genus Alyssum. Here we study perennial Alyssum populations in the Western Alps, mainly distributed in the Aosta Valley region, which hosts high species diversity, although endemics are rare. We addressed the recently described stenoendemic A. rossetii and taxonomically uncertain populations usually attributed to A. montanum s.s. to clarify their phylogenetic position and morphological differentiation. The latter entity has been shown to be distinct from A. montanum s.s. and is described as a new species, Alyssum cognense, phylogenetically placed in the A. montanum–A. repens species complex. Both morphological and genetic patterns revealed that its closest relative occurs in the central Balkans. We present detailed ecological characteristics and morphological differentiation of A. cognense sp. nov. from its relatives and geographically closest species and speculate on its biogeographic origin. Genetic patterns (reduced diversity and nestedness) suggest long-distance dispersal from the central Balkan Peninsula. The second studied species, A. rossetii, is phylogenetically distant and belongs to the mainly Asian Alyssum section Gamosepalum lineage, which includes few representatives in southern and eastern Europe. The phylogenetically closest species of A. rossetii are Anatolian endemics, so this extreme disjunction remains puzzling. The present study illustrates the need for in-depth taxonomic and phylogenetic studies, even in well-explored Alpine regions, and also shows that the processes underlying the evolution of endemics can be complex and poorly understood.
The potential for Treg-enhancing therapies in transplantation
Authors: Steiner Romy , Pilat Nina
Published: December 2022

Since the discovery of regulatory T cells (Tregs) as crucial regulators of immune tolerance against self-antigens, these cells have become a promising tool for the induction of donor-specific tolerance in transplantation medicine. The therapeutic potential of increasing in vivoTreg numbers for a favorable Treg to Teff cell ratio has already been demonstrated in several sophisticated pre-clinical models and clinical pilot trials. In addition to improving cell quantity, enhancing Treg function utilizing engineering techniques led to encouraging results in models of autoimmunity and transplantation. Here we aim to discuss the most promising approaches for Treg-enhancing therapies, starting with adoptive transfer approaches and ex vivoexpansion cultures (polyclonal vs. antigen specific), followed by selective in vivostimulation methods. Furthermore, we address next generation concepts for Treg function enhancement (CARs, TRUCKs, BARs) as well as the advantages and caveats inherit to each approach. Finally, this review will discuss the clinical experience with Treg therapy in ongoing and already published clinical trials; however, data on long-term results and efficacy are still very limited and many questions that might complicate clinical translation remain open. Here, we discuss the hurdles for clinical translation and elaborate on current Treg-based therapeutic options as well as their potencies for improving long-term graft survival in transplantation.
Transcranial magnetic stimulation to the angular gyrus modulates the temporal dynamics of the hippocampus and entorhinal cortex
Authors: Coughlan Gillian , Bouffard Nichole R , Golestani Ali , Thakral Preston P , Schacter Daniel L , Grady Cheryl , Moscovitch Morris
Published: December 2022

Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729–12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) “within” single voxels over time, termed single-voxel autocorrelation and (ii) “between” different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.
Distinct neural activations correlate with maximization of reward magnitude versus frequency
Authors: Balasubramani Pragathi Priyadharsini , Diaz-Delgado Juan , Grennan Gillian , Alim Fahad , Zafar-Khan Mariam , Maric Vojislav , Ramanathan Dhakshin , Mishra Jyoti
Published: December 2022

Choice selection strategies and decision-making are typically investigated using multiple-choice gambling paradigms that require participants to maximize expected value of rewards. However, research shows that performance in such paradigms suffers from individual biases towards the frequency of gains such that users often choose smaller frequent gains over larger rarely occurring gains, also referred to as melioration. To understand the basis of this subjective tradeoff, we used a simple 2-choice reward task paradigm in 186 healthy human adult subjects sampled across the adult lifespan. Cortical source reconstruction of simultaneously recorded electroencephalography suggested distinct neural correlates for maximizing reward magnitude versus frequency. We found that activations in the parahippocampal and entorhinal areas, which are typically linked to memory function, specifically correlated with maximization of reward magnitude. In contrast, maximization of reward frequency was correlated with activations in the lateral orbitofrontal cortices and operculum, typical areas involved in reward processing. These findings reveal distinct neural processes serving reward frequency versus magnitude maximization that can have clinical translational utility to optimize decision-making.
Neuroimaging evidence for the direct role of auditory scene analysis in object perception
Authors: Gurariy Gennadiy , Randall Richard , Greenberg Adam S
Published: December 2022

Auditory Scene Analysis (ASA) refers to the grouping of acoustic signals into auditory objects. Previously, we have shown that perceived musicality of auditory sequences varies with high-level organizational features. Here, we explore the neural mechanisms mediating ASA and auditory object perception. Participants performed musicality judgments on randomly generated pure-tone sequences and manipulated versions of each sequence containing low-level changes (amplitude; timbre). Low-level manipulations affected auditory object perception as evidenced by changes in musicality ratings. fMRI was used to measure neural activation to sequences rated most and least musical, and the altered versions of each sequence. Next, we generated two partially overlapping networks: (i) a music processing network (music localizer) and (ii) an ASA network (base sequences vs. ASA manipulated sequences). Using Representational Similarity Analysis, we correlated the functional profiles of each ROI to a model generated from behavioral musicality ratings as well as models corresponding to low-level feature processing and music perception. Within overlapping regions, areas near primary auditory cortex correlated with low-level ASA models, whereas right IPS was correlated with musicality ratings. Shared neural mechanisms that correlate with behavior and underlie both ASA and music perception suggests that low-level features of auditory stimuli play a role in auditory object perception.
A generalizable connectome-based marker of in-scan sustained attention in neurodiverse youth
Authors: Horien Corey , Greene Abigail S , Shen Xilin , Fortes Diogo , Brennan-Wydra Emma , Banarjee Chitra , Foster Rachel , Donthireddy Veda , Butler Maureen , Powell Kelly , Vernetti Angelina , Mandino Francesca , O’Connor David , Lake Evelyn M R , McPartland James C , Volkmar Fred R , Chun Marvin , Chawarska Katarzyna , Rosenberg Monica D , Scheinost Dustin , Constable R Todd
Published: December 2022

Difficulty with attention is an important symptom in many conditions in psychiatry, including neurodiverse conditions such as autism. There is a need to better understand the neurobiological correlates of attention and leverage these findings in healthcare settings. Nevertheless, it remains unclear if it is possible to build dimensional predictive models of attentional state in a sample that includes participants with neurodiverse conditions. Here, we use 5 datasets to identify and validate functional connectome-based markers of attention. In dataset 1, we use connectome-based predictive modeling and observe successful prediction of performance on an in-scan sustained attention task in a sample of youth, including participants with a neurodiverse condition. The predictions are not driven by confounds, such as head motion. In dataset 2, we find that the attention network model defined in dataset 1 generalizes to predict in-scan attention in a separate sample of neurotypical participants performing the same attention task. In datasets 3–5, we use connectome-based identification and longitudinal scans to probe the stability of the attention network across months to years in individual participants. Our results help elucidate the brain correlates of attentional state in youth and support the further development of predictive dimensional models of other clinically relevant phenotypes.
No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection
Authors: Fang Michelle Z , Jackson Sarah S , Pfeiffer Ruth M , Kim Eun-Young , Chen Sabrina , Hussain Shehnaz K , Jacobson Lisa P , Martinson Jeremy , Prokunina-Olsson Ludmila , Thio Chloe L , Duggal Priya , Wolinsky Steven , O’Brien Thomas R
Published: December 2022

Background

IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers.

Methods

We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984–1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies.

Results

We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76–1.11]), cytomegalovirus infection (0.94 [.71–1.24]), herpes simplex virus infection (1.37 [.68–2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count.

Conclusions

The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.
Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis
Authors: Chen Jie , Zhou Yajing , Sun Yuhao , Yuan Shuai , Kalla Rahul , Sun Jing , Zhao Jianhui , Wang Lijuan , Chen Xuejie , Zhou Xuan , Dai Siqi , Zhang Yu , Ho Gwo-tzer , Xia Dajing , Cao Qian , Liu Zhanju , Larsson Susanna C , Wang Xiaoyan , Ding Kefeng , Halfvarson Jonas , Li Xue , Theodoratou Evropi , Satsangi Jack
Published: December 2022

Background and Aims

Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence.

Methods

We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk.

Results

Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins.

Conclusion

Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.
Revisiting the characteristics and ablation strategy of biatrial tachycardias: a case series and systematic review
Authors: Lai Yiwei , Guo Qi , Sang Caihua , Gao Mingyang , Huang Lihong , Zuo Song , Lu Zhibing , Jiang Chenxi , Li Songnan , Guo Xueyuan , Wang Wei , Liu Nian , Li Changyi , Liu Xiaoxia , Zhao Xin , Tang Ribo , Long Deyong , Du Xin , Dong Jianzeng , Ma Changsheng
Published: December 2022

Aims

To describe the role of left atrial (LA) epicardial conduction and targets of ablation in biatrial tachycardias (BiATs).

Methods and results

Consecutive patients with BiAT diagnosed by high-density mapping and appropriate entrainment were enrolled. A systematic review of case reports or series was then performed. Biatrial tachycardia was identified in 20 patients aged 63.5 ± 11.1 years. Among them, eight had LA epicardial conduction, including four via the ligament of Marshall, two via myocardial fibres between the great cardiac vein (GCV) and LA, one via septopulmonary bundle, and one via myocardial fibres between the posterior wall and coronary sinus. Ablation was targeted at the anatomical isthmus in 14, including 5 undergoing vein of Marshall ethanol infusion and 2 undergoing ablation in the GCV. Another six underwent ablation at interatrial connections, including one with septopulmonary bundle at the fossa ovalis and five at the atrial insertions of Bachmann’s bundle. After a mean follow-up of 8.7 ± 3.8 months, five patients had recurrence of atrial fibrillation/flutter. Systematic review enrolled 87 patients in previous and the present reports, showing a higher risk of impairment in atrial physiology in those targeting interatrial connections (30.4 vs. 5.0%, P < 0.001) but no significant difference in short- and long-term effectiveness.

Conclusion

Left atrial epicardial conduction is common in BiATs and affects the ablation strategy. Atrial physiology is a major concern in selecting the target of intervention.
Public expectations of good primary health care in China: a national qualitative study
Authors: Wang Wenhua , Zhao Ruixue , Zhang Jinnan , Xu Tiange , Lu Jiao , Nicholas Stephen , Wei Xiaolin , Liu Xiaoyun , Yang Huiyun , Matiland Elizabeth
Published: December 2022

Background

China is currently making efforts to transform the current hospital-centric service delivery system to people-centred primary health care (PHC)-based delivery system, with service delivery organized around the health needs and expectations of people. To help direct China’s PHC reform efforts, a profile of high-quality PHC from the public’s perspective is required.

Objectives

To profile high-quality PHC from the perspective of the Chinese public.

Methods

Semistructured interviews were conducted in 6 provinces (Henan, Shandong, Zhejiang, Shaanxi, Shanxi, and Heilongjiang) in China. In total, 58 interviewees completed the recorded interview. For transcription, trained research assistant listened to the recording of the interviews, summarizing each 30-s segment in English. Next, thematic analysis was performed on the narrative summaries to identify thematic families.

Results

Seven themes and 16 subthemes were generated from the analysis of our interview data. In order of their frequency, the interviewees expressed a high expectation for interpersonal communication and technical quality; followed by access, comprehensive care, cost, continuity, and coordination.

Conclusions

Using qualitative data from 6 provinces in China, knowledge was generated to reveal the public’s views and expectations for high-quality PHC. Our results confirm the urgent need for quality improvement efforts to improve patient experience and technical quality. The government also needs to further improve the delivery system and medical training programme to better meet public expectation in these areas, especially in establishing an innovative integrated primary care model, and strengthening interpersonal and clinical competency training for family doctors.
Telomeres are shorter in wild Saccharomyces cerevisiae isolates than in domesticated ones
Authors: D’Angiolo Melania , Yue Jia-Xing , De Chiara Matteo , Barré Benjamin P , Giraud Panis Marie-Josèphe , Gilson Eric , Liti Gianni
Published: December 2022

Telomeres are ribonucleoproteins that cap chromosome-ends and their DNA length is controlled by counteracting elongation and shortening processes. The budding yeast Saccharomyces cerevisiae has been a leading model to study telomere DNA length control and dynamics. Its telomeric DNA is maintained at a length that slightly varies between laboratory strains, but little is known about its variation at the species level. The recent publication of the genomes of over 1,000 S. cerevisiae strains enabled us to explore telomere DNA length variation at an unprecedented scale. Here, we developed a bioinformatic pipeline (YeaISTY) to estimate telomere DNA length from whole-genome sequences and applied it to the sequenced S. cerevisiae collection. Our results revealed broad natural telomere DNA length variation among the isolates. Notably, telomere DNA length is shorter in those derived from wild rather than domesticated environments. Moreover, telomere DNA length variation is associated with mitochondrial metabolism, and this association is driven by wild strains. Overall, these findings reveal broad variation in budding yeast's telomere DNA length regulation, which might be shaped by its different ecological life-styles.
High-resolution mid-mantle imaging with multiple-taper SS-precursor estimates
Authors: Frazer William D , Park Jeffrey
Published: December 2022

SS-precursor imaging is used to image sharp interfaces within Earth’s mantle. Current SS-precursor techniques require tightly bandpassed signals (e.g. 0.02–0.05 Hz), limiting both vertical and horizontal resolutions. Higher frequency content would allow for the detection of finer structure in and around the mantle transition zone (MTZ). Here, we present a new SS-precursor deconvolution technique based on multiple-taper correlation (MTC). We show that applying MTC to SS-precursor deconvolution can increase the frequency cut-off up to 0.5 Hz, which potentially sharpens vertical resolution to ∼10 km. Furthermore, the high-pass frequency can be lowered (≪ 0.01 Hz), allowing more long-period energy to be included in the calculation, to better constrain the signal and reduce side lobes. Our method is benchmarked on full-waveform synthetic seismograms computed via AxiSEM3D for the PREM 1-D Earth model. We apply our novel MTC-SS-precursor deconvolution to ∼7000 seismograms recorded at broad-band borehole sensors of the Global Seismographic Network with source–receiver bounce points in the North-Central Pacific Ocean. The MTZ in this region appears to be thin, which agrees with previous results. We do not observe the 520-km discontinuity in our SS-precursor estimates. Additionally, we detect a low-velocity zone above the MTZ to the north of the Hawaiian Islands that has previously been inferred from asymmetry in side lobe amplitudes. Our high-frequency analysis demonstrates this feature to be a sharp interface (≤ 10-km thickness), rather than a thick wave speed gradient.
The 2021MW 6.2 Mamuju, West Sulawesi, Indonesia earthquake: partial rupture of the Makassar Strait thrust
Authors: Meilano Irwan , Salman Rino , Susilo Susilo , Shiddiqi Hasbi Ash , Supendi Pepen , Lythgoe Karen , Tay Cheryl , Bradley Kyle , Rahmadani Suchi , Kristyawan Said , Yun Sang-Ho
Published: December 2022

On the 2021 January 15 (local date), an MW 6.2 earthquake struck the Mamuju and Majene regions of West Sulawesi, Indonesia. This event killed more than 100 inhabitants, leaving at least 30 000 people displaced from their homes, and damaged almost 8000 buildings within a radius of ∼30 km from the main shock's epicentre location (as shown on our damage proxy map). This event was generated by an active fault that continues to the Makassar Strait Thrust (MST) offshore West Sulawesi. The hazard potential of this fault remains poorly understood. In this study, we use seismic and Global Positioning System (GPS) data to investigate the source characteristics of the main shock. The results suggest that the main shock partially ruptured one segment of the MST, activated a secondary fault structure, and likely brought the updip unruptured section of the MST segment closure to failure. Our analysis of interseismic GPS velocities indicates that the Mamuju and Majene regions have a higher crustal strain rate than other nearby regions. The results (partial rupture of the MST segment, the updip unruptured section of the MST and high strain rate in the Mamuju and Majene regions) together suggest a significant seismic hazard potential in West Sulawesi, particularly in the Mamuju and Majene areas.
Assessing inclination flattening in the Holocene: insights from sediment data and global models
Authors: Liu Pengfei , Panovska Sanja , Zhang Keke , Hirt Ann M
Published: December 2022

Lacustrine and marine sediments are one of the main sources of information in constructing Holocene global geomagnetic field models. The use of sediment records, however, leads to the question whether the compaction of sediments leads to a systematic biasing of inclination. We evaluate 78 sedimentary records worldwide for inclination flattening using the Elongation–Inclination (E/I) method; 20 records indicate flattening. The uncorrected and corrected values for inclination are compared to global geomagnetic field models. The results suggest that the uncorrected values agree better with the predictions from global geomagnetic field models based on sediment and archaeomagnetic data, but also with a model independent of sediment data. The 20 sites are located in mid-latitudes where inclination anomalies are predicted both in the Holocene and throughout the Brunhes epoch. Our results demonstrate that shallow inclination may not only result from compaction but may reflect the structure of the geomagnetic field on short timescales. This suggests that secular variation is not averaged out over a time period that covers the Holocene.
Characterization of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions
Authors: Sollis Elliot , den Hoed Joery , Quevedo Marti , Estruch Sara B , Vino Arianna , Dekkers Dick H W , Demmers Jeroen A A , Poot Raymond , Deriziotis Pelagia , Fisher Simon E
Published: December 2022

TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here, we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein–protein interaction.
Exploring novel functions of BACH2 in the acquisition of antigen-specific antibodies
Authors: Ochiai Kyoko , Igarashi Kazuhiko
Published: December 2022

BACH2 [BTB (broad-complex, tramtrak and bric à brac) and CNC (cap ‘n’ collar) homolog 2] is known as a transcriptional repressor and broadly functions in regulating immune cell differentiation. Here, we focus on BACH2 function in B cells, where BACH2 was first shown to play an important role in the immune system. In B cells, BACH2 orchestrates the gene regulatory network that promotes class switch and affinity maturation of antibodies and simultaneously represses plasma-cell differentiation. In this context, BACH2 regulates gene expression by modulating chromatin organization, cooperatively with other transcription factors and chromatin regulators, such as IRF4 (interferon regulatory factor 4) and PC4 (positive coactivator 4), respectively. In addition, our recent observation raises the possibility that BACH2 has diverse functions, such as those in gene activation. Since dysfunction of BACH2 leads to the onset of human immune deficiencies, revealing new functions of BACH2 may give a cue to solve how BACH2 contributes to preventing these diseases.
COVID-19 and Changes in Intentions to Migrate from The Gambia
Authors: Bah Tijan L , Batista Catia , Gubert Flore , McKenzie David
Published: December 2022

The COVID-19 pandemic has resulted in border closures in many countries and a sharp reduction in overall international mobility. However, this disruption of legal pathways to migration has raised concerns that potential migrants may turn to irregular migration routes as a substitute. We examine how the pandemic has changed intentions to migrate from The Gambia, the country with the highest pre-pandemic per-capita irregular migration rates in Africa. We use a large-scale survey conducted in 2019 and 2020 to ask about changes in intentions to migrate to Europe and to neighbouring Senegal. We find that youth say that the pandemic has reduced the intention to migrate to both destinations, with approximately one-third of young males expressing less intention to migrate. The largest reductions in migration intentions are for individuals who were unsure of their intent pre-pandemic and for poorer individuals who are no longer able to afford the costs of migrating at a time when these costs have increased and their remittance income has fallen. Nevertheless, despite these decreases in intentions, the overall desire to migrate the backway to Europe remains high, highlighting the need for legal migration pathways to support migrants and divert them from the risks of backway migration.
International Regulation of Industrial Subsidy
Authors: Chi Manjiao
Published: December 2022

Subsidies are frequently used by states as an instrument of industrial policy for promoting economic growth, and are a major reason for international trade frictions. Existing industrial subsidy rules, especially the Agreement on Subsidies and Countervailing Measures (SCM Agreement), appear insufficient for effective international subsidy regulation. Subsidy rules reform has been initiated in and outside the World Trade Organization (WTO). Though subsidies are not a China-specific issue, China is an implied target and a major stakeholder of the reform, given the profound impact of its state-led economy. The reform faces a difficult situation: states are tempted to use subsidies to meet various challenges, whereas multilateral efforts in the WTO seem unpromising due to the different positions of world leading economies, and plurilateral efforts led by the trilateral group also face an unclear prospect of multilateralization. Improving international subsidy regulation calls for both rule-making efforts and political consensus and international cooperation, especially from world leading economies.
HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1
Authors: Brasó-Maristany Fara , Griguolo Gaia , Chic Nuria , Pascual Tomás , Paré Laia , Maues Julia , Galván Patricia , Dieci Maria Vittoria , Miglietta Federica , Giarratano Tommaso , Martínez-Sáez Olga , Marín-Aguilera Mercedes , Schettini Francesco , Conte Benedetta , Angelats Laura , Vidal Maria , Adamo Barbara , Muñoz Montserrat , Sanfeliu Esther , González Blanca , Vivancos Ana , Villagrasa Patricia , Parker Joel S , Perou Charles M , Conte PierFranco , Prat Aleix , Guarneri Valentina
Published: December 2022

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.
Cognitive change in breast cancer patients up to 2 years after diagnosis
Authors: Lange Marie , Lefevre Arbogast Sophie , Hardy-Léger Isabelle , Rigal Olivier , Le Fel Johan , Pistilli Barbara , Petrucci Jean , Lévy Christelle , Capel Aurélie , Coutant Charles , Médeau Laure , Lerebours Florence , Vanlemmens Laurence , Brion Marine , Bourbouloux Emmanuelle , Blain Maxime , Binarelli Giulia , Vaz-Luis Ines , Giffard Bénédicte , Querel Ophélie , Everhard Sibille , André Fabrice , Charles Cécile , Dauchy Sarah , Joly Florence
Published: December 2022

Background

Using the large nationwide French, national, multicenter, prospective cancer and toxicities (CANTO) cohort, we assessed cognitive functioning change after cancer treatments in a subgroup of breast cancer (BC) patients.

Methods

We included patients with newly diagnosed invasive stage I-III BC enrolled in the CANTO substudy focused on cognitive evaluation and healthy control women matched for age and education. Episodic and working memory, executive functions, processing speed, attention, self-report cognitive difficulties (SRCD), fatigue, anxiety and depression were assessed with neuropsychological tests and self-report questionnaires before treatment (baseline) and approximately 1 (year 1) and 2 years (year 2) after diagnosis. We used linear mixed models to study changes in cognition and tested the effect of adjuvant chemotherapy.

Results

We studied 276 localized BC patients (62% chemotherapy) compared with 135 healthy controls (HC). After adjustment, patients had lower baseline working memory, processing speed, and attention scores than HC (P ≤ .001), and the difference remained statistically significant over follow-up for working memory and processing speed. Executive function scores were similar between groups at baseline but decreased at year 1 among patients compared with HC (Pchange = .006). This decrease in chemotherapy patients was statistically significant compared with HC scores (Pchange < .001). After adjustment, SRCD were similar between BC patients and HC at baseline but increased in patients after treatment at year 1 (Pchange = .002).

Conclusions

Cognitive difficulties are an important concern in BC patients, starting at diagnosis. Cancer treatments induce executive function decline and SRCD, which decrease over follow-up.
Coin Diving, Tourism, and Colonialism in the Caribbean, 1890–1940
Authors: Fonseca Stanley
Published: December 2022

Between the late nineteenth and mid-twentieth century, the ongoing crises of the late-colonial Caribbean mingled with an emerging trend: white American and European tourists who flocked in growing numbers to the tropics in search of pleasure, leisure, and adventure. As these travelers arrived in port in the era before commercial flight, they encountered a ubiquitous scene: boys and young men in small rowboats, who would surround the incoming steamship and, nude or nearly nude, dive in the tropical surf for coins tossed overboard. Images and accounts of these coin divers circulated widely in travel media, and were instrumental in constructing a tourist-friendly vision of the Caribbean seaside as exotic, picturesque, erotic, and accessible. In colonial Caribbean sources, however, coin divers were viewed not as an alluring spectacle but as a criminal threat, somewhere between beggar, truant, and sex worker. The divers themselves were working-class youth inhabiting a harbor-world on the periphery of a stratified and shifting society. They experienced firsthand the transition from Caribbean colonialism to mass tourism, and used the harbor to enact a limited autonomy and demand recognition within a system that provided few meaningful alternatives. Analyzing the tensions between these contrasting modes of power—one that commodified and one that criminalized—we can better understand the complex dynamics in the transition from plantation colonialism to tourist neocolonialism in the Caribbean.
Genome-wide association study revealsWRKY42as a novel plant transcription factor that influences oviposition preference ofPierisbutterflies
Authors: Coolen Silvia , Van Dijen Marcel , Van Pelt Johan A , Van Loon Joop J A , Pieterse Corné M J , Van Wees Saskia C M
Published: December 2022

Insect herbivores are amongst the most destructive plant pests, damaging both naturally occurring and domesticated plants. As sessile organisms, plants make use of structural and chemical barriers to counteract herbivores. However, over 75% of herbivorous insect species are well adapted to their host’s defenses and these specialists are generally difficult to ward off. By actively antagonizing the number of insect eggs deposited on plants, future damage by the herbivore’s offspring can be limited. Therefore, it is important to understand which plant traits influence attractiveness for oviposition, especially for specialist insects that are well adapted to their host plants. In this study, we investigated the oviposition preference of Pieris butterflies (Lepidoptera: Pieridae) by offering them the choice between 350 different naturally occurring Arabidopsis accessions. Using a genome-wide association study of the oviposition data and subsequent fine mapping with full genome sequences of 164 accessions, we identified WRKY42 and AOC1 as candidate genes that are associated with the oviposition preference observed for Pieris butterflies. Host plant choice assays with Arabidopsis genotypes impaired in WRKY42 or AOC1 function confirmed a clear role for WRKY42 in oviposition preference of female Pieris butterflies, while for AOC1 the effect was mild. In contrast, WRKY42-impaired plants, which were preferred for oviposition by butterflies, negatively impacted offspring performance. These findings exemplify that plant genotype can have opposite effects on oviposition preference and caterpillar performance. This knowledge can be used for breeding trap crops or crops that are unattractive for oviposition by pest insects.
Medicinal terpenoid UDP-glycosyltransferases in plants: recent advances and research strategies
Authors: Lu Xu , Huang Lijin , Scheller Henrik V , Keasling Jay D
Published: December 2022

Terpenoid glycosides have significant curative effects on many kinds of diseases. Most of these compounds are derived from medicinal plants. Glycosylation is a key step in the biosynthesis of medicinal terpenoids. In plants, UDP-dependent glycosyltransferases comprise a large family of enzymes that catalyze the transfer of sugars from donor to acceptor to form various bioactive glycosides. In recent years, numerous terpenoid UDP-glycosyltransferases (UGTs) have been cloned and characterized in medicinal plants. We review the typical characteristics and evolution of terpenoid-related UGTs in plants and summarize the advances and research strategies of terpenoid UGTs in medicinal plants over the past 20 years. We provide a reference for the study of glycosylation of terpenoid skeletons and the biosynthetic pathways for medicinal terpenoids in plants.
Overexpression of maizeZmLOX6inArabidopsis thalianaenhances damage-induced pentyl leaf volatile emissions that affect plant growth and interaction with aphids
Authors: Tolley Jordan P , Gorman Zachary , Lei Jiaxin , Yeo In-Cheol , Nagashima Yukihiro , Joshi Vijay , Zhu-Salzman Keyan , Kolomiets Michael V , Koiwa Hisashi
Published: December 2022

Pentyl leafy volatiles (PLV) are C5 volatiles produced from polyunsaturated fatty acids by plant 13-lipoxygenases (13-LOX) in concert with other lipid metabolizing enzymes. Unlike related C6 volatiles (GLV, green leafy volatiles), little is known about the biosynthesis and physiological function of PLV in plants. Zea mays LOX6 (ZmLOX6) is an unusual plant LOX that lacks lipid oxygenation activity but acts as a hydroperoxide lyase hypothesized to be specifically involved in PLV synthesis. We overexpressed ZmLOX6 in Arabidopsis thaliana and established that it indeed produces PLVs. Overexpression of ZmLOX6 caused a mild chlorotic phenotype, and induced a similar phenotype in untransformed Col-0 plants grown in close proximity, suggesting that airborne signals, such as PLVs, are responsible for the phenotype. PLV production, dependency on the substrate from endogenous 13-LOX(s), and likely competition with endogenous 13-oxylipin pathway were consistent with the model that ZmLOX6 functions as a hydroperoxide lyase. The abundance of individual PLVs was differentially affected by ZmLOX6 overexpression, and the new profile indicated that ZmLOX6 had reaction products distinct from endogenous PLV-producing activities in the Arabidopsis host plants. ZmLOX6 overexpression also induced a new hormonal status, which is likely responsible for increased attraction and propagation of aphids, nonetheless improving host plant tolerance to aphid infestation.