bluuebunny/crossref_metadata_2025 huggingface dataset:
Decadal‐Scale Variability in the Surface Flow of the Gulf of Maine Coastal Current: The Impact of Changing Climate Conditions on Coastal Circulation
Authors: Burkholder Kristin C. , Lee Jane HyoJin , Kime Meredith , Calabro Cassandra , Manning James P.
Published: April 2024

The Gulf of Maine (GOM) is one of the most productive and ecologically important marine environments on the planet. The Gulf of Maine Coastal Current (GMCC), which stretches along the western side of the GOM from the Bay of Fundy to Cape Cod, plays an important role in supporting this productivity by transporting nutrients, larvae and dinoflagellates southwestward along the Canadian and New England coastlines. Climate change has led to alterations in GOM ecosystems in recent years: GOM water temperatures have warmed and distributions of marine species have shifted. However, the impacts of the changing climate on the circulation within the GOM, including the path and velocity of the GMCC, have remained unclear. Here, we examine data collected by satellite tracked surface drifters and velocity data collected by the NERACOOS buoy array in order to investigate inter‐decadal changes to the flow of the GMCC. We find that over inter‐decadal timescales, the alongshore surface flow of the GMCC has slowed, particularly in the region southwest of Penobscot Bay. The slowdown observed in the GMCC surface flow is most likely attributed to a local strengthening of the southwesterly winds over the time period of interest.
Impact of Virtual Reality-Delivered Biofeedback and Yoga on Pediatric Headaches: A Pilot Study
Authors: Stassart Céline , Dupuis Gilles , Bouchard Stéphane
Published: April 2024

Objectives:

This study assessed the feasibility and acceptability of two types of innovative approaches, namely biofeedback-assisted relaxation in virtual reality ([VR]-delivered biofeedback) and yoga in the management of pediatric headaches. The secondary aim was to evaluate the preliminary efficacy of both interventions.

Method:

Children were randomized to three conditions: waiting list, yoga, and VR-delivered biofeedback. Feasibility was assessed by applicability to the pain problem, and acceptability by attendance (missed sessions, dropout rate) and the use of learned strategies in everyday life. Preliminary efficacy was evaluated with questionnaires: frequency of headaches, functional disabilities, pain anxiety, and pain catastrophizing. Mean scale scores postintervention and two months afterward were compared with the baseline with repeated-measures analyses of variance and contrast analyses.

Results:

A total of 46 children were enrolled; 39 completed the questionnaires at the baseline and participated in interventions. Regarding feasibility, the safety of the interventions seems demonstrated by the absence or infrequency of headaches during sessions. Regarding acceptability, compliance with the sessions was excellent for VR-delivered biofeedback condition and satisfactory for yoga. Most of the children reported using the strategies learned in daily life, even after the interventions. Regarding efficacy, participants reported significantly fewer headaches and functional disabilities postintervention and 2 months later. Minimal or no effects were observed on pain anxiety and pain catastrophizing.

Conclusion:

This pilot study indicates that VR-delivered biofeedback and yoga exercises may be feasible and acceptable interventions for the treatment of pediatric headaches.

Implications for Impact Statement

This study evaluates the feasibility and preliminary efficacy of two innovative interventions for pediatric headaches: virtual reality-delivered biofeedback and yoga exercises. The findings indicate that these interventions are feasible and applicable (good attendance, limited or no discomfort, and positive evaluation) and show preliminary efficacy (improvements in frequency of headaches and functional disabilities).
Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases
Authors: Levy Michal , Elron Eyal , Shohat Mordechai , Lifshitz Shira , Kahana Sarit , Shani Hagit , Grossman Anat , Amar Shirly , Narkis Ginat , Sagi-Dain Lena , Basel-Salmon Lina , Maya Idit
Published: April 2024

Background

Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance.

Methods

We identified cases of distal Xq28 duplication (chrX: 154,126,575–154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication.

Results

Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200–300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males.

Conclusion

Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.
Improving the power of drug toxicity measurements by quantitative nuclei imaging
Authors: Mikheeva Alesya M. , Bogomolov Mikhail A. , Gasca Valentina A. , Sementsov Mikhail V. , Spirin Pavel V. , Prassolov Vladimir S. , Lebedev Timofey D.
Published: April 2024

Imaging-based anticancer drug screens are becoming more prevalent due to development of automated fluorescent microscopes and imaging stations, as well as rapid advancements in image processing software. Automated cell imaging provides many benefits such as their ability to provide high-content data, modularity, dynamics recording and the fact that imaging is the most direct way to access cell viability and cell proliferation. However, currently most publicly available large-scale anticancer drugs screens, such as GDSC, CTRP and NCI-60, provide cell viability data measured by assays based on colorimetric or luminometric measurements of NADH or ATP levels. Although such datasets provide valuable data, it is unclear how well drug toxicity measurements can be integrated with imaging data. Here we explored the relations between drug toxicity data obtained by XTT assay, two quantitative nuclei imaging methods and trypan blue dye exclusion assay using a set of four cancer cell lines with different morphologies and 30 drugs with different mechanisms of action. We show that imaging-based approaches provide high accuracy and the differences between results obtained by different methods highly depend on drug mechanism of action. Selecting AUC metrics over IC50 or comparing data where significantly drugs reduced cell numbers noticeably improves consistency between methods. Using automated cell segmentation protocols we analyzed mitochondria activity in more than 11 thousand drug-treated cells and showed that XTT assay produces unreliable data for CDK4/6, Aurora A, VEGFR and PARP inhibitors due induced cell size growth and increase in individual mitochondria activity. We also explored several benefits of image-based analysis such as ability to monitor cell number dynamics, dissect changes in total and individual mitochondria activity from cell proliferation, and ability to identify chromatin remodeling drugs. Finally, we provide a web tool that allows comparing results obtained by different methods.
Inequality in economic shock exposures across the global firm-level supply network
Authors: Chakraborty Abhijit , Reisch Tobias , Diem Christian , Astudillo-Estévez Pablo , Thurner Stefan
Published: April 2024

For centuries, national economies have been engaging in international trade and production. The resulting international supply networks not only increase wealth for countries, but also allow for economic shocks to propagate across borders. Using global, firm-level supply network data, we estimate a country’s exposure to direct and indirect economic losses caused by the failure of a company in another country. We show the network of international systemic risk-flows. We find that rich countries expose poor countries stronger to systemic risk than vice-versa. The risk is highly concentrated, however, higher risk levels are not compensated with a risk premium in GDP levels, nor higher GDP growth. Our findings put the often praised benefits for developing countries from globalized production in a new light, by relating them to risks involved in the production processes. Exposure risks present a new dimension of global inequality that most affects the poor in supply shock crises.
Impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering
Authors: Isaac Alisa H. , Recalde Phillips Sarea Y. , Ruben Elizabeth , Estes Matthew , Rajavel Varsha , Baig Talia , Paleti Carol , Landsgaard Kirsten , Lee Ryang Hwa , Guda Teja , Criscitiello Michael F. , Gregory Carl , Alge Daniel L.
Published: April 2024

While poly(ethylene glycol) (PEG) hydrogels are generally regarded as biologically inert blank slates, concerns over PEG immunogenicity are growing, and the implications for tissue engineering are unknown. Here, we investigate these implications by immunizing mice against PEG to stimulate anti-PEG antibody production and evaluating bone defect regeneration after treatment with bone morphogenetic protein-2-loaded PEG hydrogels. Quantitative analysis reveals that PEG sensitization increases bone formation compared to naive controls, whereas histological analysis shows that PEG sensitization induces an abnormally porous bone morphology at the defect site, particularly in males. Furthermore, immune cell recruitment is higher in PEG-sensitized mice administered the PEG-based treatment than their naive counterparts. Interestingly, naive controls that were administered a PEG-based treatment also develop anti-PEG antibodies. Sex differences in bone formation and immune cell recruitment are also apparent. Overall, these findings indicate that anti-PEG immune responses can impact tissue engineering efficacy and highlight the need for further investigation.
Rapid evolutionary change in trait correlations of single proteins
Authors: Dasmeh Pouria , Zheng Jia , Erdoğan Ayşe Nisan , Tokuriki Nobuhiko , Wagner Andreas
Published: April 2024

Many organismal traits are genetically determined and covary in evolving populations. The resulting trait correlations can either help or hinder evolvability – the ability to bring forth new and adaptive phenotypes. The evolution of evolvability requires that trait correlations themselves must be able to evolve, but we know little about this ability. To learn more about it, we here study two evolvable systems, a yellow fluorescent protein and the antibiotic resistance protein VIM-2 metallo beta-lactamase. We consider two traits in the fluorescent protein, namely the ability to emit yellow and green light, and three traits in our enzyme, namely the resistance against ampicillin, cefotaxime, and meropenem. We show that correlations between these traits can evolve rapidly through both mutation and selection on short evolutionary time scales. In addition, we show that these correlations are driven by a protein’s ability to fold, because single mutations that alter foldability can dramatically change trait correlations. Since foldability is important for most proteins and their traits, mutations affecting protein folding may alter trait correlations mediated by many other proteins. Thus, mutations that affect protein foldability may also help shape the correlations of complex traits that are affected by hundreds of proteins.
Late-stage meta-C–H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step
Authors: Guillemard Lucas , Ackermann Lutz , Johansson Magnus J.
Published: April 2024

Catalysed C–H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)–H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C–H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.
Extrinsic hydrophobicity-controlled silver nanoparticles as efficient and stable catalysts for CO2 electrolysis
Authors: Ko Young-Jin , Lim Chulwan , Jin Junyoung , Kim Min Gyu , Lee Ji Yeong , Seong Tae-Yeon , Lee Kwan-Young , Min Byoung Koun , Choi Jae-Young , Noh Taegeun , Hwang Gyu Weon , Lee Woong Hee , Oh Hyung-Suk
Published: April 2024

To realize economically feasible electrochemical CO2 conversion, achieving a high partial current density for value-added products is particularly vital. However, acceleration of the hydrogen evolution reaction due to cathode flooding in a high-current-density region makes this challenging. Herein, we find that partially ligand-derived Ag nanoparticles (Ag-NPs) could prevent electrolyte flooding while maintaining catalytic activity for CO2 electroreduction. This results in a high Faradaic efficiency for CO (>90%) and high partial current density (298.39 mA cm‒2), even under harsh stability test conditions (3.4 V). The suppressed splitting/detachment of Ag particles, due to the lipid ligand, enhance the uniform hydrophobicity retention of the Ag-NP electrode at high cathodic overpotentials and prevent flooding and current fluctuations. The mass transfer of gaseous CO2 is maintained in the catalytic region of several hundred nanometers, with the smooth formation of a triple phase boundary, which facilitate the occurrence of CO2RR instead of HER. We analyze catalyst degradation and cathode flooding during CO2 electrolysis through identical-location transmission electron microscopy and operando synchrotron-based X-ray computed tomography. This study develops an efficient strategy for designing active and durable electrocatalysts for CO2 electrolysis.
Sustained increase in suspended sediments near global river deltas over the past two decades
Authors: Hou Xuejiao , Xie Danghan , Feng Lian , Shen Fang , Nienhuis Jaap H.
Published: April 2024

River sediments play a critical role in sustaining deltaic wetlands. Therefore, concerns are raised about wetlands’ fate due to the decline of river sediment supply to many deltas. However, the dynamics and drivers of suspended sediment near deltaic coasts are not comprehensively assessed, and its response to river sediment supply changes remains unclear. Here we examine patterns of coastal suspended sediment concentration (SSC) and river sediment plume area (RPA) for 349 deltas worldwide using satellite images from 2000 to 2020. We find a global increase in SSC and RPA, averaging +0.46% and +0.48% yr−1, respectively, with over 59.0% of deltas exhibiting an increase in both SSC and RPA. SSC and RPA increases are prevalent across all continents, except for Asia. The relationship between river sediment supply and coastal SSCs varies between deltas, with as much as 45.2% of the deltas showing opposing trends between river sediments and coastal SSCs. This is likely because of the impacts of tides, waves, salinity, and delta morphology. Our observed increase in SSCs near river delta paints a rare promising picture for wetland resilience against sea-level rise, yet whether this increase will persist remains uncertain.
Modulation of peroxisomal import by the PEX13 SH3 domain and a proximal FxxxF binding motif
Authors: Gaussmann Stefan , Peschel Rebecca , Ott Julia , Zak Krzysztof M. , Sastre Judit , Delhommel Florent , Popowicz Grzegorz M. , Boekhoven Job , Schliebs Wolfgang , Erdmann Ralf , Sattler Michael
Published: April 2024

Import of proteins into peroxisomes depends on PEX5, PEX13 and PEX14. By combining biochemical methods and structural biology, we show that the C-terminal SH3 domain of PEX13 mediates intramolecular interactions with a proximal FxxxF motif. The SH3 domain also binds WxxxF peptide motifs in the import receptor PEX5, demonstrating evolutionary conservation of such interactions from yeast to human. Strikingly, intramolecular interaction of the PEX13 FxxxF motif regulates binding of PEX5 WxxxF/Y motifs to the PEX13 SH3 domain. Crystal structures reveal how FxxxF and WxxxF/Y motifs are recognized by a non-canonical surface on the SH3 domain. The PEX13 FxxxF motif also mediates binding to PEX14. Surprisingly, the potential PxxP binding surface of the SH3 domain does not recognize PEX14 PxxP motifs, distinct from its yeast ortholog. Our data show that the dynamic network of PEX13 interactions with PEX5 and PEX14, mediated by diaromatic peptide motifs, modulates peroxisomal matrix import.
An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Authors: Ding Jiarui , Garber John J. , Uchida Amiko , Lefkovith Ariel , Carter Grace T. , Vimalathas Praveen , Canha Lauren , Dougan Michael , Staller Kyle , Yarze Joseph , Delorey Toni M. , Rozenblatt-Rosen Orit , Ashenberg Orr , Graham Daniel B. , Deguine Jacques , Regev Aviv , Xavier Ramnik J.
Published: April 2024

Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15+ macrophages, PRDM16+ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Ligand–receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4+ TRM cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.
Detecting m6A at single-molecular resolution via direct RNA sequencing and realistic training data
Authors: Chan Adrian , Naarmann-de Vries Isabel S. , Scheitl Carolin P. M. , Höbartner Claudia , Dieterich Christoph
Published: April 2024

Direct RNA sequencing offers the possibility to simultaneously identify canonical bases and epi-transcriptomic modifications in each single RNA molecule. Thus far, the development of computational methods has been hampered by the lack of biologically realistic training data that carries modification labels at molecular resolution. Here, we report on the synthesis of such samples and the development of a bespoke algorithm, mAFiA (m6A Finding Algorithm), that accurately detects single m6A nucleotides in both synthetic RNAs and natural mRNA on single read level. Our approach uncovers distinct modification patterns in single molecules that would appear identical at the ensemble level. Compared to existing methods, mAFiA also demonstrates improved accuracy in measuring site-level m6A stoichiometry in biological samples.
The genetic landscape of a metabolic interaction
Authors: Nguyen Thuy N. , Ingle Christine , Thompson Samuel , Reynolds Kimberly A.
Published: April 2024

While much prior work has explored the constraints on protein sequence and evolution induced by physical protein-protein interactions, the sequence-level constraints emerging from non-binding functional interactions in metabolism remain unclear. To quantify how variation in the activity of one enzyme constrains the biochemical parameters and sequence of another, we focus on dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS), a pair of enzymes catalyzing consecutive reactions in folate metabolism. We use deep mutational scanning to quantify the growth rate effect of 2696 DHFR single mutations in 3 TYMS backgrounds under conditions selected to emphasize biochemical epistasis. Our data are well-described by a relatively simple enzyme velocity to growth rate model that quantifies how metabolic context tunes enzyme mutational tolerance. Together our results reveal the structural distribution of epistasis in a metabolic enzyme and establish a foundation for the design of multi-enzyme systems.
Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs
Authors: Eisenson Daniel , Hisadome Yu , Santillan Michelle , Iwase Hayato , Chen WeiLi , Shimizu Akira , Schulick Alex , Gu Du , Akbar Armaan , Zhou Alice , Koenig Kristy , Kuravi Kasinath , Rahman Farzana , Sorrells Lori , Burdorf Lars , DeSmet Kristina , Warren Daniel , Peterson Leigh , Lorber Marc , Ayares David , Cameron Andrew , Yamada Kazuhiko
Published: April 2024

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.
Towards establishing a fungal economics spectrum in soil saprobic fungi
Authors: Camenzind Tessa , Aguilar-Trigueros Carlos A. , Hempel Stefan , Lehmann Anika , Bielcik Milos , Andrade-Linares Diana R. , Bergmann Joana , dela Cruz Jeane , Gawronski Jessie , Golubeva Polina , Haslwimmer Heike , Lartey Linda , Leifheit Eva , Maaß Stefanie , Marhan Sven , Pinek Liliana , Powell Jeff R. , Roy Julien , Veresoglou Stavros D. , Wang Dongwei , Wulf Anja , Zheng Weishuang , Rillig Matthias C.
Published: April 2024

Trait-based frameworks are promising tools to understand the functional consequences of community shifts in response to environmental change. The applicability of these tools to soil microbes is limited by a lack of functional trait data and a focus on categorical traits. To address this gap for an important group of soil microorganisms, we identify trade-offs underlying a fungal economics spectrum based on a large trait collection in 28 saprobic fungal isolates, derived from a common grassland soil and grown in culture plates. In this dataset, ecologically relevant trait variation is best captured by a three-dimensional fungal economics space. The primary explanatory axis represents a dense-fast continuum, resembling dominant life-history trade-offs in other taxa. A second significant axis reflects mycelial flexibility, and a third one carbon acquisition traits. All three axes correlate with traits involved in soil carbon cycling. Since stress tolerance and fundamental niche gradients are primarily related to the dense-fast continuum, traits of the 2nd (carbon-use efficiency) and especially the 3rd (decomposition) orthogonal axes are independent of tested environmental stressors. These findings suggest a fungal economics space which can now be tested at broader scales.
Mechanoelectronic stimulation of autologous extracellular vesicle biosynthesis implant for gut microbiota modulation
Authors: Wan Shuangshuang , Wang Kepeng , Huang Peihong , Guo Xian , Liu Wurui , Li Yaocheng , Zhang Jingjing , Li Zhiyang , Song Jiacheng , Yang Wenjing , Zhang Xianzheng , Ding Xianguang , Leong David Tai , Wang Lianhui
Published: April 2024

Pathogenic gut microbiota is responsible for a few debilitating gastrointestinal diseases. While the host immune cells do produce extracellular vesicles to counteract some deleterious effects of the microbiota, the extracellular vesicles are of insufficient doses and at unreliable exposure times. Here we use mechanical stimulation of hydrogel-embedded macrophage in a bioelectronic controller that on demand boost production of up to 20 times of therapeutic extracellular vesicles to ameliorate the microbes’ deleterious effects in vivo. Our miniaturized wireless bioelectronic system termed inducible mechanical activation for in-situ and sustainable generating extracellular vesicles (iMASSAGE), leverages on wireless electronics and responsive hydrogel to impose mechanical forces on macrophages to produce extracellular vesicles that rectify gut microbiome dysbiosis and ameliorate colitis. This in vivo controllable extracellular vesicles-produced system holds promise as platform to treat various other diseases.
LKRSDH-dependent histone modifications of insulin-like peptide sites contribute to age-related circadian rhythm changes
Authors: Lv Pengfei , Yang Xingzhuo , Du Juan
Published: April 2024

To understand aging impact on the circadian rhythm, we screened for factors influencing circadian changes during aging. Our findings reveal thatLKRSDHmutation significantly reduces rhythmicity in aged flies. RNA-seq identifies a significant increase ininsulin-like peptides(dilps) inLKRSDHmutants due to the combined effects of H3R17me2 and H3K27me3 on transcription. Genetic evidence suggests thatLKRSDHregulates age-related circadian rhythm changes throughart4anddilps. ChIP-seq analyzes whole genome changes in H3R17me2 and H3K27me3 histone modifications in young and old flies withLKRSDHmutation and controls. The results reveal a correlation between H3R17me2 and H3K27me3, underscoring the role ofLKRSDHin regulating gene expression and modification levels during aging. Overall, our study demonstrates thatLKRSDH-dependent histone modifications atdilpssites contribute to age-related circadian rhythm changes. This data offers insights and a foundational reference for aging research by unveiling the relationship between LKRSDH and H3R17me2/H3K27me3 histone modifications in aging.
Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade
Authors: Liefaard M. C. , van der Voort A. , van Seijen M. , Thijssen B. , Sanders J. , Vonk S. , Mittempergher L. , Bhaskaran R. , de Munck L. , van Leeuwen-Stok A. E. , Salgado R. , Horlings H. M. , Lips E. H. , Sonke G. S.
Published: April 2024

Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100–100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99–1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50–1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis.
Critical assessment of G0W0 calculations for 2D materials: the example of monolayer MoS2
Authors: Rodrigues Pela Ronaldo , Vona Cecilia , Lubeck Sven , Alex Ben , Gonzalez Oliva Ignacio , Draxl Claudia
Published: April 2024

Two-dimensional (2D) materials combine many fascinating properties that make them more interesting than their three-dimensional counterparts for a variety of applications. For example, 2D materials exhibit stronger electron-phonon and electron-hole interactions, and their energy gaps and effective carrier masses can be easily tuned. Surprisingly, published band gaps of several 2D materials obtained with the GW approach, the state-of-the-art in electronic-structure calculations, are quite scattered. The details of these calculations, such as the underlying geometry, the starting point, the inclusion of spin-orbit coupling, and the treatment of the Coulomb potential can critically determine how accurate the results are. Taking monolayer MoS2 as a representative material, we employ the linearized augmented planewave + local orbital method to systematically investigate how all these aspects affect the quality of G0W0 calculations, and also provide a summary of literature data. We conclude that the best overall agreement with experiments and coupled-cluster calculations is found for G0W0 results with HSE06 as a starting point including spin-orbit coupling, a truncated Coulomb potential, and an analytical treatment of the singularity at q = 0.
The first chromosome-level genome of the stag beetle Dorcus hopei Saunders, 1854 (Coleoptera: Lucanidae)
Authors: Li Xiaolu , Mao Chuyang , He Jinwu , Bin Xiaoyan , Liu Guichun , Dong Zhiwei , Zhao Ruoping , Wan Xia , Li Xueyan
Published: April 2024

Stag beetles (Coleoptera: Lucanidae) represent a significant saproxylic assemblage in forest ecosystems and are noted for their enlarged mandibles and male polymorphism. Despite their relevance as ideal models for the study of exaggerated mandibles that aid in attracting mates, the regulatory mechanisms associated with these traits remain understudied, and restricted by the lack of high-quality reference genomes for stag beetles. To address this limitation, we successfully assembled the first chromosome-level genome of a representative species Dorcus hopei. The genome was 496.58 Mb in length, with a scaffold N50 size of 54.61 Mb, BUSCO values of 99.8%, and 96.8% of scaffolds anchored to nine pairs of chromosomes. We identified 285.27 Mb (57.45%) of repeat sequences and annotated 11,231 protein-coding genes. This genome will be a valuable resource for further understanding the evolution and ecology of stag beetles, and provides a basis for studying the mechanisms of exaggerated mandibles through comparative analysis.
Exploring the role of apolipoprotein E gene promoter polymorphisms in susceptibility to normal-tension glaucoma in a Korean population
Authors: Park Young Jun , Shin Hye-Young , Kim Jong-Il
Published: April 2024

Glaucoma, particularly primary open-angle glaucoma (POAG), poses a significant global health concern. Distinguished by intraocular pressure (IOP), POAG encompasses high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Apolipoprotein E (APOE) is a multifaceted protein with roles in lipid metabolism, neurobiology, and neurodegenerative diseases. However, controversies persist regarding the impact of APOE single-nucleotide polymorphisms (SNPs) on open-angle glaucoma and NTG. This study aimed to identify APOE-specific SNPs influencing NTG risk. A cohort of 178 patients with NTG recruited from Uijeongbu St. Mary’s Hospital and 32,858 individuals from the Korean Genome and Epidemiology Study (KoGES) cohort were included in the analysis. Genotype and haplotype analyses were performed on three promoter SNPs (rs449647, rs769446, and rs405509) and two exonic SNPs (rs429358 and rs7412) located on chromosome 19. Among the five SNPs, rs769446 genotypes exhibited significant differences between cases and controls. The minor allele C of rs769446 emerged as a protective factor against NTG. Furthermore, haplotype analysis of the five SNPs revealed that the A-T-G-T-T haplotype was a statistically significant risk factor for NTG. This study indicated an association between APOE promoter SNPs and NTG in the Korean population. Further studies are required to understand how APOE promoter SNPs contribute to NTG pathogenesis.
SARS-CoV-2 booster vaccine dose significantly extends humoral immune response half-life beyond the primary series
Authors: Korosec Chapin S. , Dick David W. , Moyles Iain R. , Watmough James
Published: April 2024

SARS-CoV-2 lipid nanoparticle mRNA vaccines continue to be administered as the predominant prophylactic measure to reduce COVID-19 disease pathogenesis. Quantifying the kinetics of the secondary immune response from subsequent doses beyond the primary series and understanding how dose-dependent immune waning kinetics vary as a function of age, sex, and various comorbidities remains an important question. We study anti-spike IgG waning kinetics in 152 individuals who received an mRNA-based primary series (first two doses) and a subset of 137 individuals who then received an mRNA-based booster dose. We find the booster dose elicits a 71–84% increase in the median Anti-S half life over that of the primary series. We find the Anti-S half life for both primary series and booster doses decreases with age. However, we stress that although chronological age continues to be a good proxy for vaccine-induced humoral waning, immunosenescence is likely not the mechanism, rather, more likely the mechanism is related to the presence of noncommunicable diseases, which also accumulate with age, that affect immune regulation. We are able to independently reproduce recent observations that those with pre-existing asthma exhibit a stronger primary series humoral response to vaccination than compared to those that do not, and further, we find this result is sustained for the booster dose. Finally, via a single-variate Kruskal-Wallis test we find no difference between male and female humoral decay kinetics, however, a multivariate approach utilizing  Least Absolute Shrinkage and Selection Operator (LASSO) regression for feature selection reveals a statistically significant (p$$<1\times 10^{-3}$$

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), albeit small, bias in favour of longer-lasting humoral immunity amongst males.
Perceptual (but not acoustic) features predict singing voice preferences
Authors: Bruder Camila , Poeppel David , Larrouy-Maestri Pauline
Published: April 2024

Why do we prefer some singers to others? We investigated how much singing voice preferences can be traced back to objective features of the stimuli. To do so, we asked participants to rate short excerpts of singing performances in terms of how much they liked them as well as in terms of 10 perceptual attributes (e.g.: pitch accuracy, tempo, breathiness). We modeled liking ratings based on these perceptual ratings, as well as based on acoustic features and low-level features derived from Music Information Retrieval (MIR). Mean liking ratings for each stimulus were highly correlated between Experiments 1 (online, US-based participants) and 2 (in the lab, German participants), suggesting a role for attributes of the stimuli in grounding average preferences. We show that acoustic and MIR features barely explain any variance in liking ratings; in contrast, perceptual features of the voices achieved around 43% of prediction. Inter-rater agreement in liking and perceptual ratings was low, indicating substantial (and unsurprising) individual differences in participants’ preferences and perception of the stimuli. Our results indicate that singing voice preferences are not grounded in acoustic attributes of the voices per se, but in how these features are perceptually interpreted by listeners.
Hemodynamic study of the ICA aneurysm evolution to attain the cerebral aneurysm rupture risk
Authors: Huo Huaying , Chang Yigang
Published: April 2024

The influence of the aneurysm evolution on the hemodynamic characteristic of the blood flow inside the sac region is comprehensively investigated. By using the computational method, the blood flow through the vessel and aneurysm of the sac region is examined to find the role of aneurysm evolution on the wall shear stress, pressure, and risk of aneurysm rupture. Three different models of ICA aneurysms are chosen for the investigation of the aneurysm evolution at risk of rupture. Obtained data shows that the evolution of the aneurysm decreases the wall shear stress and pressure on the sac surface while an oscillatory index of blood increases on the aneurysm wall.
Analysis of plasma metabolomes from 11 309 subjects in five population-based cohorts
Authors: Ghosh Nilanjana , Lejonberg Carl , Czuba Tomasz , Dekkers Koen , Robinson Richard , Ärnlöv Johan , Melander Olle , Smith Maya Landenhed , Evans Anne M. , Gidlöf Olof , Gerszten Robert E. , Lind Lars , Engström Gunnar , Fall Tove , Smith J. Gustav
Published: April 2024

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50–80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies.
Affinity chromatography reveals direct binding of the GATA4–NKX2-5 interaction inhibitor (3i-1000) with GATA4
Authors: Jumppanen Mikael , Kinnunen Sini M. , Zore Matej , Välimäki Mika J. , Talman Virpi , Gennäs Gustav Boije af , Ruskoaho Heikki J. , Yli-Kauhaluoma Jari
Published: April 2024

Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. Transcription factors are in a central role in various cellular processes, and in the heart, GATA4 and NKX2-5 transcription factors mediate hypertrophic responses and remodeling. We have identified compounds that modulate the synergistic interaction of GATA4 and NKX2-5 and shown that the most promising compound (1, 3i-1000) is cardioprotective in vitro and in vivo. However, direct evidence of its binding site and mechanism of action has not been available. Due to the disordered nature of transcription factors, classical target engagement approaches cannot be utilized. Here, we synthesized a small-molecule ligand-binding pulldown probe of compound 1 to utilize affinity chromatography alongside CETSA, AlphaScreen, and molecular modeling to study ligand binding. These results provide the first evidence of direct physical binding of compound 1 selectively to GATA4. While developing drugs that target transcription factors presents challenges, advances in technologies and knowledge of intrinsically disordered proteins enable the identification of small molecules that can selectively target transcription factors.
Association between social dominance hierarchy and PACAP expression in the extended amygdala, corticosterone, and behavior in C57BL/6 male mice
Authors: Meloni Edward G. , Carlezon William A. , Bolshakov Vadim Y.
Published: April 2024

The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the association between social dominance hierarchy status established within cages of group-housed mice and the expression of the stress peptide PACAP in the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also examined the relationship between social dominance rank and blood corticosterone (CORT) levels, body weight, motor coordination (rotorod) and acoustic startle. Male C57BL/6 mice were ranked as either Dominant, Submissive, or Intermediate based on counts of aggressive/submissive encounters assessed at 12 weeks-old following a change in homecage conditions. PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following events where dominance status is recapitulated. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies.
The Fur-like regulatory protein MAP3773c modulates key metabolic pathways in Mycobacterium avium subsp. paratuberculosis under in-vitro iron starvation
Authors: Thapa Sajani , Rathnaiah Govardhan , Zinniel Denise K. , Barletta Raul G. , Bannantine John P. , Huebner Marianne , Sreevatsan Srinand
Published: April 2024

Johne’s disease (JD) is a chronic enteric infection of dairy cattle worldwide. Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of JD, is fastidious often requiring eight to sixteen weeks to produce colonies in culture—a major hurdle in the diagnosis and therefore in implementation of optimal JD control measures. A significant gap in knowledge is the comprehensive understanding of the metabolic networks deployed by MAP to regulate iron both in-vitro and in-vivo. The genome of MAP carries MAP3773c, a putative metal regulator, which is absent in all other mycobacteria. The role of MAP3773c in intracellular iron regulation is poorly understood. In the current study, a field isolate (K-10) and an in-frame MAP3773c deletion mutant (ΔMAP3773c) derived from K-10, were exposed to iron starvation for 5, 30, 60, and 90 min and RNA-Seq was performed. A comparison of transcriptional profiles between K-10 and ΔMAP3773c showed 425 differentially expressed genes (DEGs) at 30 min time post-iron restriction. Functional analysis of DEGs in ΔMAP3773c revealed that pantothenate (Pan) biosynthesis, polysaccharide biosynthesis and sugar metabolism genes were downregulated at 30 min post-iron starvation whereas ATP-binding cassette (ABC) type metal transporters, putative siderophore biosynthesis, PPE and PE family genes were upregulated. Pathway analysis revealed that the MAP3773c knockout has an impairment in Pan and Coenzyme A (CoA) biosynthesis pathways suggesting that the absence of those pathways likely affect overall metabolic processes and cellular functions, which have consequences on MAP survival and pathogenesis.
A meta-analysis on the potency of foot-and-mouth disease vaccines in different animal models
Authors: Jiao Jiao , Wu Peng
Published: April 2024

Whether mice can be used as a foot-and-mouth disease (FMD) model has been debated for a long time. However, the major histocompatibility complex between pigs and mice is very different. In this study, the protective effects of FMD vaccines in different animal models were analyzed by a meta-analysis. The databases PubMed, China Knowledge Infrastructure, EMBASE, and Baidu Academic were searched. For this purpose, we evaluated evidence from 14 studies that included 869 animals with FMD vaccines. A random effects model was used to combine effects using Review Manager 5.4 software. A forest plot showed that the protective effects in pigs were statistically non-significant from those in mice [MH = 0.56, 90% CI (0.20, 1.53), P = 0.26]. The protective effects in pigs were also statistically non-significant from those in guinea pigs [MH = 0.67, 95% CI (0.37, 1.21), P = 0.18] and suckling mice [MH = 1.70, 95% CI (0.10, 28.08), P = 0.71]. Non-inferiority test could provide a hypothesis that the models (mice, suckling mice and guinea pigs) could replace pigs as FMDV vaccine models to test the protective effect of the vaccine. Strict standard procedures should be established to promote the assumption that mice and guinea pigs should replace pigs in vaccine evaluation.