bluuebunny/crossref_metadata_2025 huggingface dataset:
Unmet Questions About Frailty in Kidney Transplant Candidates
Authors: Pérez-Sáez María José , Pascual Julio
Published: June 2024

Frailty occurs frequently among patients with advanced chronic kidney disease, especially among women. Assessing frailty in kidney transplant (KT) candidates is crucial for informing them about associated risks. However, there is poor agreement between frailty scales and research on their correlation with transplant outcomes. Being prefrail significantly impacts both graft and patient survival, often beginning with just 1 Fried criterion. Rather than viewing frailty as a categorical state, it should be regarded as a spectrum ranging from 1 to 5 criteria, with the risk of adverse outcomes escalating as frailty worsens. Frailty status fluctuates during the waiting period for KT; hence, a 1-time frailty evaluation is insufficient to determine risks and implement strategies for improving functional status. Further research should investigate the components of frailty that most frequently change during this waiting period and establish strategies to prevent or reverse frailty. Although careful evaluation of frail KT candidates is necessary to prevent early complications and mortality, exclusion based solely on a frailty score is unwarranted. Instead, efforts should focus on timely interventions to enhance their condition before transplantation. Although evidence is limited, exercise programs appear feasible and yield positive results. A pretransplant clinical framework encompassing multimodal prehabilitation—comprising physical therapy, nutritional measures, and psychological support—during the waiting list period may help alleviate the effects of frailty and poor fitness after KT, ultimately improving key outcomes. Despite logistical challenges, there is a pressing need for interventional trials in this area.
Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review
Authors: Yadav Manu , Vaishkiar Ishita , Sharma Ananya , Shukla Akanksha , Mohan Aradhana , Girdhar Madhuri , Kumar Anil , Malik Tabarak , Mohan Anand
Published: June 2024

Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as
ABCB1
,
AKT
,
S100A8/A9
,
TAGLN2
and
NPM
. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.
Correlated evolution of oxidative physiology and MHC-based immunosurveillance in birds
Authors: Minias Piotr , Pap Péter L. , Vincze Orsolya , Vágási Csongor I.
Published: June 2024

Maintenance and activation of the immune system incur costs, not only in terms of substrates and energy but also via collateral oxidative damage to host cells or tissues during immune response. So far, associations between immune function and oxidative damage have been primarily investigated at intra-specific scales. Here, we hypothesized that pathogen-driven selection should favour the evolution of effective immunosurveillance mechanisms (e.g. major histocompatibility complex, MHC) and antioxidant defences to mitigate oxidative damage resulting from immune function. Using phylogenetically informed comparative approaches, we provided evidence for the correlated evolution of host oxidative physiology and MHC-based immunosurveillance in birds. Species selected for more robust MHC-based immunosurveillance (higher gene copy numbers and allele diversity) showed stronger antioxidant defences, although selection for MHC diversity still showed a positive evolutionary association with oxidative damage to lipids. Our results indicate that historical pathogen-driven selection for highly duplicated and diverse MHC could have promoted the evolution of efficient antioxidant mechanisms, but these evolutionary solutions may be insufficient to keep oxidative stress at bounds. Although the precise nature of mechanistic links between the MHC and oxidative stress remains unclear, our study suggests that a general evolutionary investment in immune function may require co-adaptations at the level of host oxidative metabolism.
Limited potexvirus diversity in eastern Gulf of Mexico seagrass meadows
Authors: Lim Shen Jean , Rosario Karyna , Kernbach Meredith E. , Gross Anthony J. , Furman Bradley T. , Breitbart Mya
Published: June 2024

Turtlegrass virus X, which infects the seagrass Thalassia testudinum, is the only potexvirus known to infect marine flowering plants. We investigated potexvirus distribution in seagrasses using a degenerate reverse transcription polymerase chain reaction (RT-PCR) assay originally designed to capture potexvirus diversity in terrestrial plants. The assay, which implements Potex-5 and Potex-2RC primers, successfully amplified a 584 nt RNA-dependent RNA polymerase (RdRp) fragment from TVX-infected seagrasses. Following validation, we screened 74 opportunistically collected, apparently healthy seagrass samples for potexviruses using this RT-PCR assay. The survey examined the host species T. testudinum, Halodule wrightii, Halophila stipulacea, Syringodium filiforme, Ruppia maritima, and Zostera marina. Potexvirus PCR products were successfully generated only from T. testudinum samples and phylogenetic analysis of sequenced PCR products revealed five distinct TVX sequence variants. Although the RT-PCR assay revealed limited potexvirus diversity in seagrasses, the expanded geographic distribution of TVX shown here emphasizes the importance of future studies to investigate T. testudinum populations across its native range and understand how the observed fine-scale genetic diversity affects host-virus interactions.
Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects
Authors:   Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, Lee Jong-Min , McLean Zachariah L. , Correia Kevin , Shin Jun Wan , Lee Sujin , Jang Jae-Hyun , Lee Yukyeong , Kim Kyung-Hee , Choi Doo Eun , Long Jeffrey D. , Lucente Diane , Seong Ihn Sik , Pinto Ricardo Mouro , Giordano James V. , Mysore Jayalakshmi S. , Siciliano Jacqueline , Elezi Emanuela , Ruliera Jayla , Gillis Tammy , Wheeler Vanessa C. , MacDonald Marcy E. , Gusella James F. , Gatseva Anna , Ciosi Marc , Lomeikaite Vilija , Loay Hossameldin , Monckton Darren G. , Wills Christopher , Massey Thomas H. , Jones Lesley , Holmans Peter , Kwak Seung , Sampaio Cristina , Orth Michael , Bernhard Landwehrmeyer G. , Paulsen Jane S. , Ray Dorsey E. , Myers Richard H.
Published: June 2024

Huntington’s disease (HD), due to expansion of a CAG repeat inHTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyondtransmodifiers, differential effects are also illustrated atHTTby a 5’-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.
BiomiX, a User-Friendly Bioinformatic Tool for Automatized Multiomics Data Analysis and Integration
Authors: Iperi Cristian , Fernández-Ochoa Álvaro , Barturen Guillermo , Pers Jacques-Olivier , Foulquier Nathan , Bettacchioli Eleonore , Alarcón-Riquelme Marta ,   PRECISESADS Flow Cytometry Study Group,   PRECISESADS Clinical Consortium, Cornec Divi , Bordron Anne , Jamin Christophe
Published: June 2024

BiomiX addresses the data analysis bottleneck in high-throughput omics technologies, enabling the efficient, integrated analysis of multiomics data obtained from two cohorts. BiomiX incorporates diverse omics data. DESeq2/Limma packages analyze transcriptomics data, while statistical tests determine metabolomics peaks. The metabolomics annotation uses the mass-to-charge ratio in the CEU Mass Mediator database and fragmentation spectra in the TidyMass package while Methylomics analysis is performed using the ChAMP R package. Multiomics Factor Analysis (MOFA) integration and interpretation identifies common sources of variations among omics. BiomiX provides comprehensive outputs, including statistics and report figures, also integrating EnrichR and GSEA for biological process exploration. Subgroup analysis based on user gene panels enhances comparisons. BiomiX implements MOFA automatically, selecting the optimal MOFA model to discriminate the two cohorts being compared while providing interpretation tools for the discriminant MOFA factors. The interpretation relies on innovative bibliography research on Pubmed, which provides the articles most related to the discriminant factor contributors. The interpretation is also supported by clinical data correlation with the discriminant MOFA factors and pathways analyses of the top factor contributors. The integration of single and multi-omics analysis in a standalone tool, together with the implementation of MOFA and its interpretability by literature, constitute a step forward in the multi-omics landscape in line with the FAIR data principles. The wide parameter choice grants a personalized analysis at each level based on the user requirements. BiomiX is a user-friendly R-based tool compatible with various operating systems that aims to democratize multiomics analysis for bioinformatics non-experts.

Key points

BiomiX is the first user-friendly multiomics tool to perform single omics analysis for transcriptomics, metabolomics and methylomics and their data integration by MOFA in the same platform.

MOFA algorithm was made accessible to non-bioinformaticians and improved to select the best model automatically, testing the MOFA factor’s performance in groups separation.

Large improvement of MOFA factor’s interpretability by correlation, pathways analysis and innovative bibliography research.

BiomiX is embedded in a network of other online tools as GSEA, metaboanalyst EnrichR etc, to provide a format compatible with further analyses in these tools.

Interface and usage are intuitive and compatible with all the main operating systems, and rich parameters are set to grant personalized analysis based on the user’s needs.
Improving Inverse Folding models at Protein Stability Prediction without additional Training or Data
Authors: Dutton Oliver , Bottaro Sandro , Invernizzi Michele , Redl Istvan , Chung Albert , Hoffmann Falk , Henderson Louie , Ruschetta Stefano , Airoldi Fabio , Owens Benjamin M J , Foerch Patrik , Fisicaro Carlo , Tamiola Kamil
Published: June 2024

Deep learning protein sequence models have shown outstanding performance atde novoprotein design and variant effect prediction. We substantially improve performance without further training or use of additional experimental data by introducing a second term derived from the models themselves which align outputs for the task of stability prediction. On a task to predict variants which increase protein stability the absolute success probabilities of ProteinMPNN and ESMifare improved by 11% and 5% respectively. We term these models ProteinMPNN-ddG and ESMif-ddG.
Enhancing Blood Availability in Latin America: A Study on Public Perceptions and Barriers to Blood Donation in Guatemala during the COVID-19 Pandemic
Authors: Perez-Iglesias Carolina Torres , Monzon Jose C. , Faria Isabella , Kundu Shreenik , Zil-E-Ali Ahsan , Jhunjhunwala Rashi , Raykar Nakul , Asturias Sabrina
Published: June 2024

Objectives

Guatemala faces a significant challenge with one of the lowest voluntary blood donation rates in Latin America, a problem further exacerbated by the COVID-19 pandemic. This study aimed to investigate the population factors influencing blood donation behavior in Guatemala during the COVID-19 pandemic.

Methods

Conducted between August and September 2020, this cross-sectional electronic anonymous survey employed purposive sampling. Participants were questioned about their donation history, knowledge of donation processes, preferences, and barriers and motivators for blood donation. Quantitative and qualitative data were collected and analyzed.

Comparative analyses were conducted based on gender, age, and education level. Regression analysis was used to identify predictors of blood donation behavior. Open-ended responses were studied via thematic content analysis.

Results

Among the 1141 respondents, 53.5% reported a history of blood donation. Most donations occurred via referred donations to family or friends (78.5%). Factors such as male gender, older age, and higher education were associated with previous blood donation.

Familiarity with donation centers and willingness to donate strongly influenced donation behavior. Among never donors, 89% expressed willingness to donate. Constraints in accessing donation centers, limited operation hours, insufficient knowledge about the donation process, and concerns over hygiene and safety were identified as the most prevalent barriers to donation.

Conclusions

Respondents demonstrated a strong willingness to donate blood voluntarily. Understanding demographic and population factors is critical to inform tailored initiatives to facilitate access to voluntary blood donation in Guatemala.
Combining ability analysis ofCucurbita moschataD. in Cote d’Ivoire and classification of promising lines based on their gca effects
Authors: Kouago Badié Arnaud , Seka Dagou , Brou Kouakou Fulgence , Bonny Beket Severin , Koffi Konan Henri Joel , Adjoumani Koffi , Sie Raoul Sylvère
Published: June 2024

Twelve hybrids and their four parental lines were evaluated for their general performances, combining abilities, potency ratio and heterosis effects. Taller plants and smaller fruits characterized the parental lineLong, while theSoubreparent showed favorable fruit and seed traits but with a small number of seeds. The lineZouan-Hexhibited performances that are close toSoubrebut with a smaller number of fruits per plant, higher number of seeds per fruit and the weight of the fruit is one-half that of theSoubreline. TheOvalparent is characterized by a high number of seeds per fruit, smaller fruits and shorter plants. Significant effects of heterosis were observed in different hybrids for different characters. And the computed values of potency ratio indicated that gene(s) expressions were characterized by partial dominance in many cases and super dominance in some other cases. The variance of the effect of the general combining ability of the female parent was highly significant for all the evaluated traits. The variance of the effect of the general combining ability for the male parent was significant for some characters. The variance due to the effect of the specific combining ability was also highly significant for all the traits evaluated. It showed that the effects of additive genes and non-additive genes contributed to the expressions of the characters. However, the general predictive ratio was closer to 1.00 for all the fruit-related traits implying the strong effects of additive genes in the determination of the fruit-related characters. A classification of the parental lines based on the effects of their general combining ability grouped theSoubrelines as promising contributors to fruit yield. The parental linesLongandOvalformed another group likely on the basis of the small size of their fruits, the small pulps, the smaller number of fruits per plant and the high number of seeds per fruit.Longwould be a candidate parent for the development of cultivars with longer vegetative growth. The parental lineZouan-Hformed the third group and it was mostly characterized by its advantageous seed traits.
Elasticity and Thermal Stability are Key Determinants of Hearing Rescue by Mini-Protocadherin-15 Proteins
Authors: De-la-Torre Pedro , Wen Haosheng , Brower Joseph , Martínez-Pérez Karina , Narui Yoshie , Yeh Frank , Hale Evan , Ivanchenko Maryna V. , Corey David P. , Sotomayor Marcos , Indzhykulian Artur A.
Published: June 2024

Protocadherin-15 is a core protein component of inner-ear hair-cell tip links pulling on transduction channels essential for hearing and balance. Protocadherin-15 defects can result in non-syndromic deafness or Usher syndrome type 1F (USH1F) with hearing loss, balance deficits, and progressive blindness. Three rationally engineered shortened versions of protocadherin-15 (mini-PCDH15s) amenable for gene therapy have been used to rescue function in USH1F mouse models. Two can successfully or partially rescue hearing, while another one fails. Here we show that despite varying levels of hearing rescue, all three mini-PCDH15 versions can rescue hair-cell mechanotransduction. Negative-stain electron microscopy shows that all three versions form dimers like the wild-type protein, while crystal structures of some engineered fragments show that these can properly fold and bind calcium ions essential for function. In contrast, simulations predict distinct elasticities and nano differential scanning fluorimetry shows differences in melting temperature measurements. Our data suggest that elasticity and thermal stability are key determinants of sustained hearing rescue by mini-PCDH15s.
Enhancing Phylogenetic Independent Contrasts: Addressing Abrupt Evolutionary Shifts with Outlier- and Distribution-Guided Correlation
Authors: Chen Zheng-Lin , Huang Rui , Guo Hong-Ji , Niu Deng-Ke
Published: June 2024

Abstract

Phylogenetic comparative methods are indispensable for analyzing cross-species data while accounting for evolutionary relationships. Traditional methods like phylogenetically independent contrasts (PIC) and phylogenetic generalized least squares (PGLS) are well-suited for gradual evolution under Brownian motion (BM) or similar assumptions. However, their effectiveness diminishes under abrupt evolutionary shifts or heterogeneous evolutionary processes. We introduce a hybrid framework, outlier-guided correlation (OGC) for large datasets and outlier- and distribution-guided correlation (ODGC) for small datasets, collectively termed O(D)GC, which integrates Pearson and Spearman correlation analyses to handle outliers and non-normal data dynamically. Using simulations across diverse evolutionary scenarios, we compared PIC-O(D)GC with a comprehensive range of methods, including eight robust regression approaches (PIC-MM, PIC-L1, PIC-S, PIC-M, and their PGLS counterparts); PGLS optimized using five evolutionary models: BM, lambda, Ornstein–Uhlenbeck random (OU-random), OU-fixed, and Early-burst; Corphylo (an OU-based method); PIC-Pearson; and two advanced models, phylogenetic generalized linear mixed models (PGLMM) and multi-response phylogenetic mixed models (MR-PMM). Our results demonstrate that PIC-O(D)GC and PIC-MM consistently exhibit superior performance under conditions with evolutionary shifts, maintaining low false positive rates and high accuracy. In no-shift scenarios, PIC-O(D)GC and PIC-MM perform comparably to other reliable methods, underscoring their adaptability and robustness across varied datasets. Furthermore, PIC-O(D)GC offers computational efficiency and flexibility, making it particularly suitable for large-scale datasets. These findings underscore the value of adaptive, nonparametric frameworks like PIC-O(D)GC in complementing traditional phylogenetic approaches. By bridging computational simplicity with methodological robustness, O(D)GC provides a versatile tool for trait correlation analysis in both stable and dynamic evolutionary contexts.
Adoption of Modern Beekeeping Technologies and Best Management Practices Among Honey Beekeepers in South West, Nigeria
Authors: Adekola P.J , Aderanti A , Oladoja M. A , Bobadoye Bridget O
Published: June 2024

Colony collapse disorder (CCD) is an abnormal phenomenon which has been largely undocumented in Nigeria. However, several factors have been attributed to high cases of hive abandonment, amongst which is low adoption of hive management practices. This study was carried out to determine adoption of modern technologies and hive management practices amongst beekeepers within the south-west region of Nigeria to reduce the incidence of CCD. A multistage sampling procedure was used to select a total of 399 beekeepers in beekeeping zones across Ekiti, Oyo and Osun and Ondo States in South-West, Nigeria. Interview schedules were used to collect information on beekeepers to determine the level of adoption of modern beekeeping technologies among honey beekeepers to mitigate against colony collapse and results showed that honey beekeepers perception, benefits derived and constraints to adoption of modern honey beekeeping technologies determined what best management practices to adopt. In light of these findings, it is clear that beekeeping in Southwest Nigeria holds significant promise as a source of income and livelihood improvement. To harness this potential, policymakers, government agencies, and relevant stakeholders must consider tailored strategies to address the unique challenges faced by beekeepers in different states. Encouraging the adoption of modern beekeeping technologies and providing the necessary support systems can contribute to the sustainable growth of the beekeeping industry in the region.

In conclusion, there is a need for enhanced education and training initiatives to improve beekeepers’ knowledge of good management practices, which can positively impact beekeeping outcomes. Moreover, addressing the issues related to time constraints and the lack of time for bee farm monitoring is essential to ensure the efficient management of beekeeping activities. The losses and consequent economic damages have encouraged researchers to develop new strategies to control honeybee diseases and pest infestations through the adoption of modern technology.
The comparison of single-cell RNA sequencing platforms based droplets
Authors: Wang Linyan , Zhong Yulong
Published: June 2024

Single-cell sequencing enables to reveal cellular heterogeneity and discover new cellular subpopulations. In terms of the strategy of single-cell sequencing, the main methods are based with combinatorial index, microwell and microfluidic. Due to the simplicity, methods based droplets are widely used for single-cell sequencing for multi-omics. Therefore, in order to facilitate researchers to choose a suitable platform to meet their application scenarios, we compared several commercial platforms: the Chromium X platform of 10x Genomics, the MobiNova-100 platform of MobiDrop, the SeekOne platform of SeekGene, and the C4 platform of BGI. Based the comprehensive assessment of the data analysis, the Chromium X platform shows a excellent performance, closely followed by MobiNova-100 platform.

One-Sentence Summary

As droplet-based single-cell sequencing platforms, Chromium X and MobiNova-100 have comparable data performance.
Methemoglobin aggregation is modulated by the anti-sickling drug voxelotor
Authors: Cove Brandon , Munoz Aldo , Singh Arnav , Jann Gavin , Brandon Kristal , Xing Li , Cocco Melanie J.
Published: June 2024

Sickle cell disease is caused by a mutation in the beta subunit of hemoglobin (HbSS) that drives Hb fiber formation when the protein is in the deoxygenated (tense, T) state. The drug voxelotor was recently approved to treat sickle cell disease by preventing HbSS fiber formation. Voxelotor acts as an allosteric inhibitor of polymerization by maintaining the HbSS protein in the relaxed (R) conformation, limiting polymerization of T-state fibers. Normal blood cells contain small amounts of natural Hb fibers and a few percent of the Fe3+ferric form, metHb, incapable of binding oxygen. Although the drug Voxelotor is now in use, the effect of the drug on the oxidized metHb state has not been reported. Here we assessed the influence of voxelotor on normal human metHb. We compared the aggregation of metHb at two pH values (5.5 and 7.1). MetHb is known to form organized fiber structures at or below pH 5.5. We find that voxelotor significantly enhances fiber formation of metHb R-state at pH 5.5, consistent with the mode of action for this drug in maintaining the Hb R conformation. The opposite effect is observed at physiological pH values. Voxelotor significantly decreases the rate of metHb aggregate formation at pH 7.1 but did not affect protein stability. Notably, drug binding drives metHb into novel spherical particles with a morphology never seen before for Hb. The formation of these particles should be considered in patients being treated for sickle cell disease with voxelotor.

WHY IT MATTERS

Voxelotor is an FDA-approved drug for sickle cell anemia, known to prevent hemoglobin fiber formation. Here, we investigate its effect on methemoglobin, the form of hemoglobin in which iron takes on the ferric Fe3+state. Our study examines voxelotor’s impact on methemoglobin aggregation and stability. At pH 7.1, we found voxelotor to have an effect on methemoglobin solubility as evidenced by the formation of novel methemoglobin spherical structures. We observe that voxelotor significantly increases methemoglobin fiber formation at pH 5.5 but, notably, reduces methemoglobin aggregation at physiological pH levels. Minimal impact on methemoglobin thermodynamic stability is noted. These findings suggest voxelotor’s potential therapeutic efficacy for various hemoglobinopathies, including conditions characterized by Heinz body formation.
PharaCon: A new framework for identifying bacteriophages via conditional representation learning
Authors: Bai Zeheng , Zhang Yao-zhong , Pang Yuxuan , Imoto Seiya
Published: June 2024

Motivation

Identifying bacteriophages (phages) within metagenomic sequences is essential for understanding microbial community dynamics. Transformer-based foundation models have been successfully employed to address various biological challenges. However, these models are typically pre-trained with self-supervised tasks that do not consider label variance in the pre-training data. This presents a challenge for phage identification as pre-training on mixed bacterial and phage data may lead to information bias due to the imbalance between bacterial and phage samples.

Results

To overcome this limitation, this study proposed a novel conditional BERT framework that incorporates labels during pre-training. We developed an approach using a conditional BERT model for pre-training labeled data, incorporating label constraints with modified language modeling tasks. This approach allows the model to acquire label-conditional sequence representations. Additionally, we proposed a solution that utilizes conditional BERT in the fine-tuning phase as a classifier. We applied this conditional BERT framework to identify phages using a novel fine-tuning strategy, introducing PharaCon. We evaluated PharaCon against several existing methods on both simulated sequence datasets and real metagenomic contig datasets. The results demonstrate PharaCon's potential as an effective and efficient method for phage identification, highlighting the effectiveness of conditional B ERT as a solution for learning label-specific representations during pre-training on mixed sequence data.

Availability

The codes of PharaCon are now available in:https://github.com/Celestial-Bai/PharaCon.

Contact

yaozhong@ims.u-tokyo.ac.jpandimoto@hgc.jp
Dynamic changes in neuronal and glial GAL4 driver expression duringDrosophilaageing
Authors: Delandre Caroline , McMullen John P. D. , Marshall Owen J.
Published: June 2024

Understanding how diverse cell types come together to form a functioning brain relies on the ability to specifically target these cells. This is often done using genetic tools such as the GAL4/UAS system inDrosophila melanogaster. Surprisingly, despite its extensive usage during studies of the ageing brain, detailed spatio-temporal characterisation of GAL4 driver lines in adult flies has been lacking. Here we show that three commonly used neuronal drivers (elav[C155]-GAL4,nSyb[R57C10]-GAL4andChAT-GAL4) and the commonly used glial driverrepo-GAL4all show rapid and pronounced decreases in activity over the first 1.5 weeks of adult life, with activity becoming undetectable in some regions after 30 days. In addition to an overall decrease in GAL4 activity over time, we found notable differences in spatial patterns, mostly occurring soon after eclosion. Although all lines showed these changes, thenSyb-GAL4line exhibited the most consistent and stable expression patterns over ageing. Our findings suggest that gene transcription of key loci decreases in the aged brain, a finding broadly similar to previous work in mammalian brains. Our results also raise questions over past work on long-term expression of disease models in the brain, and stress the need to find better genetic tools for ageing studies.
AI-assisted decoding of molecular signatures essential for NON-PHOTOTROPIC HYPOCOTYL3 condensation and function in phototropism
Authors: Manishankar Prabha , Reuter Lea , Rohr Leander , Fernandez Atiara , Yigit Yeliz Idil , Schmidt Tanja , Droste-Borel Irina , Keicher Jutta , Bock Andrea , Oecking Claudia
Published: June 2024

The plasma membrane-associated protein NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) is a key component of plant phototropism. Blue light induces the release of NPH3 into the cytosol, where it dynamically transitions into membrane-less biomolecular condensates. Here, we combine experimental data with the power of AI-based protein structure prediction to uncover a bipartite C-terminal motif that enables self-interaction of NPH3. We further demonstrate its importance for both the association of NPH3 with the plasma membrane and the assembly of condensates in the cytosol, with a different part of the bipartite motif playing the key role in each case. However, the formation of cytosolic condensates additionally requires the co-operative action of an N-terminal NPH3 signature. We propose that NPH3 forms a crosslinked 3D network in the cytosol based on distinct molecular determinants that simultaneously self-associate. NPH3 variants incapable of condensation are non-functional, suggesting a fundamental role of NPH3 phase separation for phototropism. This structural snapshot could have direct implications for future analyses of the plant-specific NPH3/RPT2-Like protein family.
Avoidable false PSMC population size peaks occur across numerous studies
Authors: Hilgers Leon , Liu Shenglin , Jensen Axel , Brown Thomas , Cousins Trevor , Schweiger Regev , Guschanski Katerina , Hiller Michael
Published: June 2024

Inferring historical population sizes is key to identify drivers of ecological and evolutionary change, and crucial to predict the future of species on our rapidly changing planet. The pairwise sequentially Markovian coalescent (PSMC) method provided a revolutionary framework to reconstruct species’ demographic histories over millions of years based on the genome sequence of a single individual1. Here, we detected and solved a common artifact in PSMC and related methods: recent population peaks followed by population collapses. Combining real and simulated genomes, we show that these peaks do not represent true population dynamics. Instead, ill-set default parameters cause false peaks in our own and published data, which can be avoided by adjusted parameter settings. Furthermore, we show that certain population structure changes can cause similar patterns. Newer methods like Beta-PSMC perform better, but do not always avoid this artifact. Our results suggest testing multiple parameters before interpreting recent population peaks followed by collapses, and call for the development of robust methods.
IspE Kinase as an Anti-infective Target: Role of a Hydrophobic Pocket in Inhibitor Binding
Authors: Hamid Rawia , Walsh Danica J. , Diamanti Eleonora , Aguilar Diana , Lacour Antoine , Hamed Mostafa M. , Hirsch Anna K. H.
Published: June 2024

Enzymes of the methylerythritol phosphate (MEP) pathway are potential targets for antimicrobial drug discovery. Here we focus on 4-diphosphocytidyl-2-C-methyl-D-erythritol (IspE) kinase from the MEP pathway. We use biochemical and structural biology methods to investigate homologs from the pathogenic microorganisms;Escherichia coli, Klebsiella pneumoniae, andAcinetobacter baumannii. We determined the X-ray structures of IspE-inhibitor complexes and studied selected inhibitors’ binding modes targeting the substrate pocket. The experimental results indicate the need for distinct inhibitor strategies due to structural differences among IspE homologs, particularly for A. baumannii IspE, which displays unique inhibitory profile due to a tighter hydrophobic subpocket in the substrate binding site. This study enhances our understanding of the MEP enzymes and sets the stage for structure-based drug design of selective inhibitors to combat pathogenic microorganisms.
Path-based reasoning for biomedical knowledge graphs with BioPathNet
Authors: Hu Yue , Oleshko Svitlana , Firmani Samuele , Zhu Zhaocheng , Cheng Hui , Ulmer Maria , Arnold Matthias , Colomé-Tatché Maria , Tang Jian , Xhonneux Sophie , Marsico Annalisa
Published: June 2024

Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. Representation-based learning techniques improve prediction accuracy by mapping nodes to low-dimensional embeddings, yet they often struggle with interpretability and scalability. We present BioPathNet, a novel graph neural network framework based on the Neural Bellman-Ford Network (NBFNet), addressing these limitations through path-based reasoning for LP in biomedical knowledge graphs. Unlike node-embedding frameworks, BioPathNet learns representations between node pairs by considering all relations along paths, enhancing prediction accuracy and interpretability. This allows visualization of influential paths and facilitates biological validation. BioPathNet leverages a background regulatory graph (BRG) for enhanced message passing and uses stringent negative sampling to improve precision. In evaluations across various LP tasks, such as gene function annotation, drug-disease indication, synthetic lethality, and lncRNA-mRNA interaction prediction, BioPathNet consistently outperformed shallow node embedding methods, relational graph neural networks and task-specific state-of-the-art methods, demonstrating robust performance and versatility. Our study predicts novel drug indications for diseases like acute lymphoblastic leukemia (ALL) and Alzheimer’s, validated by medical experts and clinical trials. We also identified new synthetic lethality gene pairs and regulatory interactions involving lncRNAs and target genes, confirmed through literature reviews. BioPathNet’s interpretability will enable researchers to trace prediction paths and gain molecular insights, making it a valuable tool for drug discovery, personalized medicine and biology in general.
Biochemical and structural insights into the auto-inhibited state of Mical1 and its activation by Rab8
Authors: Rai Amrita , Janning Petra , Vetter Ingrid R. , Goody Roger S.
Published: June 2024

Mical1 regulates F-actin dynamics through the reversible oxidation of actin, a process controlled by its interactions with various proteins. Upon binding to Rab8 family members, Mical1 links endosomes to the cytoskeleton, promoting F-actin disassembly. In the absence of Rab, Mical1 exists in an auto-inhibited state, but its biochemical characterization remains incomplete. Our study reveals that the N-terminal MO-CH-LIM domains of Mical1 form an intramolecular complex with its C-terminal bMERB domain. Mutational analysis, guided by the AlphaFold2 model, identifies critical residues at the binding interface. Additionally, we demonstrate that full-length Mical1 binds to Rab8 in a 1:2 stoichiometry, thereby releasing auto-inhibition. Through structure-based mutational studies, we uncover allostery between the N and C-terminal Rab binding sites. Notably, Rab binding at the high-affinity C-terminal site precedes binding at the N-terminal site, suggesting a sequential binding mode. These findings elucidate how Rab8 binding releases the MO-CH-LIM domains from the Mical1 bMERB domain, facilitating interactions with other proteins and the actin cytoskeleton, thereby modulating actin dynamics.
A bottom-up approach identifies the antipsychotic and antineoplastic trifluoperazine and the ribose derivative deoxytubercidin as novel microglial phagocytosis inhibitors
Authors: Rodriguez-Iglesias Noelia , Paris Iñaki , Valero Jorge , Cañas-Zabala Lorena , Carretero Alejandro , Hatje Klas , Zhang Jitao David , Patsch Christoph , Britschgi Markus , Gutbier Simon , Sierra Amanda
Published: June 2024

Phagocytosis is an indispensable function of microglia, the brain professional phagocytes. Microglia are particularly efficient phagocytosing cells that undergo programmed cell death (apoptosis) in physiological conditions. However, mounting evidence suggests microglial phagocytosis dysfunction in multiple brain disorders. These observations prompted us to search for phagocytosis modulators (enhancers or inhibitors) with therapeutic potential. We used a bottom-up strategy that consisted on the identification of phagocytosis modulators using phenotypic high throughput screenings (HTSs) in cell culture and validation in organotypic cultures andin vivo. We performed two complementary HTS campagnes: at Achucarro, we used primary cultures of mouse microglia and compounds of the Prestwick Chemical Library; at Roche, we used human iPSC derived macrophage-like cells and a proprietary chemo-genomic library with 2,200 compounds with known mechanism-of-action. Next, we validated the more robust compounds using hippocampal organotypic cultures and identified two hits: trifluoperazine, a dopaminergic and adrenergic antagonist used as an antipsychotic and antineoplastic; and deoxytubercidin, a ribose derivative. Finally, we tested whether these compounds were able to modulate phagocytosis of apoptotic newborn cells in the adult hippocampal neurogenic nichein vivoby administering them into the mouse hippocampus using osmotic minipumps. We confirmed that both trifluoperazine and deoxytubercidin have anti-phagocytic activityin vivo, and validated our bottom-up strategy to identify novel phagocytosis modulators. These results show that chemical libraries with anotated mechanism of action are an starting point for the pharmacological modulation of microglia in drug discovery projects aiming at the therapeutic manipulation of phagocytosis in brain diseases.

GRAPHICAL ABSTRACT
Self-organized spatial targeting of contractile actomyosin rings for synthetic cell division
Authors: Reverte-López María , Kanwa Nishu , Qutbuddin Yusuf , Jasnin Marion , Schwille Petra
Published: June 2024

One of the challenges of bottom-up synthetic biology is the engineering of a minimal module for self-division of synthetic cells. To produce the contractile forces required for the controlled excision of cell-like compartments such as giant unilamellar vesicles (GUVs), reconstituted cytokinetic rings made of actin are considered to be among the most promising structures of a potential synthetic division machinery. Although the targeting of actin rings to GUV membranes and their myosin-induced constriction have been previously demonstrated, large-scale vesicle deformation has been precluded due to the lacking spatial control of these contractile structures. Here, we show the combinedin vitroreconstitution of actomyosin rings and the bacterial MinDE protein system, effective in targetingE.coliZ-rings to mid-cell, within GUVs. Incorporating this spatial positioning tool, which induces active transport of any diffusible molecule on membranes, yields self-organized assembly of actomyosin rings at the equatorial plane of vesicles. Remarkably, the synergistic effect of Min oscillations and the contractile nature of actomyosin bundles induces mid-vesicle membrane deformation and striking bleb-like protrusions, leading to shape remodeling and symmetry breaking. Our system showcases how functional machineries from various organisms may be synergistically combinedin vitro, leading to the emergence of new functionality towards a synthetic division system.
Dizocilpine derivatives with neuroprotective effect lacking the psychomimetic side effects
Authors: Konecny Jan , Misiachna Anna , Chvojkova Marketa , Kleteckova Lenka , Kolcheva Marharyta , Novak Martin , Prchal Lukas , Ladislav Marek , Hemelikova Katarina , Netolicky Jakub , Hrabinova Martina , Kobrlova Tereza , Karasova Jana Zdarova , Pejchal Jaroslav , Jendelova Pavla , Pang Yuan-Ping , Vales Karel , Korabecny Jan , Soukup Ondrej , Horak Martin
Published: June 2024

We aimed to prepare novel dibenzosuberane derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Ourin silicoanalyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds3land6fto penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy,6fshowed high relative inhibition (∼90% for GluN1/GluN2A), while3lshowed moderate inhibition (∼50%). Anin vivotoxicity study determined that compounds3land6fwere safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound3lat a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzosuberane derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.
Bacterial membrane vesicles ofPseudomonas aeruginosaactivate AMPK signaling through inhibition of mitochondrial complex III
Authors: Müller Julia , Kretschmer Marcel , Opitsch Elise , Holland Svea , Borrero-de Acuña José Manuel , Jahn Dieter , Neumann-Schaal Meina , Wegner Andre
Published: June 2024

Bacterial membrane vesicles (BMVs) are secreted by many pathogenic bacteria and known to stimulate various host responses upon infection, thereby contributing to the pathogenicity of bacterial pathogens likePseudomonas aeruginosa. While the effects of BMVs on host immune responses are well studied, little is known about their impact on cell metabolism and mitochondrial respiration. Here, we show thatP. aeruginosaBMVs (1) reprogram cell metabolism of human lung cells, (2) negatively affect mitochondrial respiration by (3) specifically inhibiting complex III of the electron transport chain leading to (4) the activation of AMP-activated protein kinase (AMPK) signaling which in turn results in (5) AMPK-dependent inhibition of global protein synthesis.
Anuran call properties as reliable indicators of environmental suitability for reproduction
Authors: Pekny Julianne E. , Todd Brian D. , Post Eric
Published: June 2024

The annual onset of breeding activity by animals in seasonal environments is often accompanied by auditory signals such as stridulations in insects and vocalizations in birds, mammals, and anurans. In ectotherms, the seasonal timing of such activity by males signals to females the general favorability of environmental conditions for reproduction. Complementary to this, the acoustic characteristics of male auditory signals are presumed to indicate, primarily, the status or quality of males as mates or territorial competitors. Here, using male anurans as a case study, we present the novel hypothesis that characteristics of auditory signals that are modulated by temperature may also serve as bioclimatic indicators of the suitability of proximal abiotic conditions for reproduction by females. According to this hypothesis, thermal constraints on characteristics such as call rate and duration that are insuperable by males may imbue their calls with features that facilitate tracking of environmental conditions by females independently of information intended for communication by males. We integrate findings from empirical studies spanning multiple fields of ecology and evolution to demonstrate how temporal variation in call properties may directly influence female reproductive behavior and physiology. Finally, we outline how this proposed mechanism may enable environmental tracking, provide guidelines for future research to experimentally test this hypothesis, and discuss how findings from this research can translate into actionable conservation management for species of concern.