bluuebunny/crossref_metadata_2025 huggingface dataset:
Two liverworts from same habitats developed many similar but few distinct seasonal adaptive strategies: Insights from a transcriptomic approach
Authors: Basu Suvajit , Yadav Sandhya , Jha Vishal Kumar , Biswas Subhankar , Srivastava Akanksha , Tripathi Kritika , Mondal Raju , Chaurasia Neha , Singh Sushil Kumar , Mishra Yogesh
Published: July 2024

Liverworts are among the first land plants to experience seasonal changes after terrestrialization Therefore, we conducted a seasonal transcriptome analysis of two representative liverwort species from India, Dumortiera hirsuta and Plagiochasma appendiculatum, during their distinct growing seasons: the pre-monsoon, monsoon, post-monsoon, and fruiting season to understand the seasonal adaptations. Phylogenetic trees and evolutionary timescale analyses showed that D. hirsuta is primitive compared to P. appendiculatum. The RNA-seq analysis showed that D. hirsuta primarily modifies its transcriptome in the post-monsoon season but mainly induces specific genes in the fruiting season, most likely to develop reproductive organs and to adapt strategically by conserving energy in the fruiting season to deal with the harsh environmental conditions of both seasons. Conversely, P. appendiculatum exhibited significant transcriptome variability during both the fruiting and post-monsoon seasons, albeit to a lesser degree than D. hirsuta. This suggests that, to survive in the harsh conditions of both seasons, it strategically modulated its necessary gene expression levels over an extended period of time while taking energy conservation into consideration. This study offers the first comprehensive view of seasonal adaptive strategies employed by two liverworts that coexist in the same habitat but diverged at different stages in their evolutionary history.
ProtParts, an automated web server for clustering and partitioning protein dataset
Authors: Li Yuchen , Barra Carolina
Published: July 2024

Data leakage originating from protein sequence similarity shared among train and test sets can result in model overfitting and overestimation of model performance and utility. However, leakage is often subtle and might be difficult to eliminate. Available clustering tools often do not provide completely independent partitions, and in addition it is difficult to assess the statistical significance of those differences. In this study, we developed a clustering and partitioning tool, ProtParts, utilizing the E-value of BLAST to compute pairwise similarities between each pair of proteins and using a graph algorithm to generate clusters of similar sequences. This exhaustive clustering ensures the most independent partitions, giving a metric of statistical significance and, thereby enhancing the model generalization. A series of comparative analyses indicated that ProtParts clusters have higher silhouette coefficient and adjusted mutual information than other algorithms using k-mers or sequence percentage identity. Re-training three distinct predictive models revealed how sub-optimal data clustering and partitioning leads to overfitting and inflated performance during cross-validation. In contrast, training on ProtParts partitions demonstrated a more robust and improved model performance on predicting independent data. Based on these results, we deployed the user-friendly web server ProtParts (https://services.healthtech.dtu.dk/services/ProtParts-1.0) for protein partitioning prior to machine learning applications.

GRAPHICAL ABSTRACT
Pre-Assembly NGS Correction of ONT Reads Achieves HiFi-Level Assembly Quality
Authors: Mozheiko Evgeniy , Yi Heng , Lu Anzhi , Kong Heitung , Hou Yong , Zhou Yan , Gao Hui
Published: July 2024

Recently developed hybrid assemblies can achieve Telomere-to-Telomere (T2T) completeness of some chromosomes. However, such approaches involve sequencing a large volume of both Pacific Biosciences high-fidelity (HiFi) and Oxford Nanopore Technologies (ONT) sequencing reads. Along with this, third-generation sequencing techniques are rapidly advancing, increasing the available length and accuracy. To reduce the final cost of genome assembly, here we investigated the possibility of assembly from low-coverage samples and with only ONT corrected by Next-Generation Sequencing (NGS) sequencing reads. We demonstrated that ONT-based assembly approaches corrected by NGS can achieve performance metrics comparable to more expensive hybrid approaches based on HiFi sequencing. We investigated the assembly of different chromosomes and the low-coverage performance of state-of-the-art hybrid assembly tools, including Verkko and Hifiasm, as well as ONT-based assemblers such as Shasta and Flye. We rigorously evaluated the performance of MGI, Illumina, and stLFR NGS technologies across various aspects of hybrid genome assembly, including pre-assembly correction, haplotype phasing, and polishing, and found them to be similarly effective. Additionally, we proposed two-round assembly methods that utilize stLFR linked-read data to achieve assembly phasing performance comparable to that obtained with trio data.
Effects of N361 Glycosylation on Epidermal Growth Factor Receptor Biological Function
Authors: Lam Dennis , Arroyo Brandon , Liberchuk Ariel N. , Wolfe Andrew L.
Published: July 2024

Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase that is frequently modified by glycosylation post-translationally. In cancer, EGFR amplifications and hotspot mutations such as L858R that promote proliferation have been detected in a significant fraction of non-small cell lung carcinomas and breast adenocarcinomas. Molecular dynamic simulations suggested that glycosylation at asparagine residue 361 (N361) promotes dimerization and ligand binding. We stably expressed glycosylation-deficient mutant EGFR N361A, with or without the oncogenic mutation L858R. Immunofluorescence and flow cytometry demonstrated that the mutants were each well expressed at the cell membrane. N361A decreased proliferation relative to wild-type EGFR as well as decreased sensitivity to ligands. Proximity ligation assays measuring co-localization of EGFR with its binding partner HER2 in cells revealed that N361A mutations increased co-localization. N361A, located near the binding interface for the EGFR inhibitor necitumumab, desensitized cells expressing the oncogenic EGFR L858R to antibody-based inhibition. These findings underline the critical relevance of post-translational modifications on oncogene function.

SIGNIFICANCE

EGFR transduces signals from growth factors into cell proliferation and is frequently hyperactivated in tumors. Glycosylation of EGFR at N361 regulates EGFR dimerization, growth factor stimulation of proliferative signaling, and susceptibility to targeted inhibition. Insights into EGFR glycosylation may expand therapeutic opportunities to benefit cancer patients.
Cells in the Polyaneuploid Cancer Cell State are Pro-Metastatic
Authors: Mallin Mikaela M. , Rolle Louis T.A. , Schmidt Michael J. , Priyadarsini Nair Shilpa , Zurita Amado J. , Kuhn Peter , Hicks James , Pienta Kenneth J. , Amend Sarah R.
Published: July 2024

There remains a large need for a greater understanding of the metastatic process within the prostate cancer field. Our research aims to understand the adaptive – ergo potentially metastatic – responses of cancer to changing microenvironments. Emerging evidence has implicated a role of the Polyaneuploid Cancer Cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mountingin vitroevidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study of prostate cancer patients revealed that PACC presence in the prostate at the time of radical prostatectomy was predictive of future metastatic progression. To test for a causative relationship between PACC state biology and metastasis, we leveraged a novel method designed for flow-cytometric detection of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in subcutaneous, caudal artery, and intracardiac mouse models of metastasis. This approach provides both quantitative and qualitative information about the number and PACC-status of recovered CTCs and DTCs. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state.In vivocolonization assays proved PACC populations can regain proliferative capacity at metastatic sites following dormancy. Additional direct and indirect mechanisticin vitroanalyses revealed a PACC-specific partial Epithelial-to-Mesenchymal-Transition phenotype and a pro-metastatic secretory profile, together providing preliminary evidence that PACCs are mechanistically linked to metastasis.

Statement of Significance

We provide the first evidence that cells in the polyaneuploid cancer cell state contribute to increased metastatic competencyin vivo.
A SMARTTR workflow for multi-ensemble atlas mapping and brain-wide network analysis
Authors: Jin Michelle , Ogundare Simon O. , Lanio Marcos , Sorid Sophia , Whye Alicia R. , Santos Sofia Leal , Franceschini Alessandra , Denny Christine. A.
Published: July 2024

In the last decade, activity-dependent strategies for labelling multiple immediate early gene (IEG) ensembles in mice have generated unprecedented insight into the mechanisms of memory encoding, storage, and retrieval. However, few strategies exist for brain-wide mapping of multiple ensembles, including their overlapping population, and none incorporate capabilities for downstream network analysis. Here, we introduce a scalable workflow to analyze traditionally coronally-sectioned datasets produced by activity-dependent tagging systems. Intrinsic to this pipeline issimplemulti-ensembleatlasregistration and statisticaltesting inR(SMARTTR), an R package which wraps mapping capabilities with functions for statistical analysis and network visualization, and support for import of external datasets. We demonstrate the versatility of SMARTTR by mapping the ensembles underlying the acquisition and expression of learned helplessness (LH), a robust stress model. Applying network analysis, we find that exposure to inescapable shock (IS), compared to context training (CT), results in decreased centrality of regions engaged in spatial and contextual processing and higher influence of regions involved in somatosensory and affective processing. During LH expression, the substantia nigra emerges as a highly influential region which shows a functional reversal following IS, indicating a possible regulatory function of motor activity during helplessness. We also report that IS results in a robust decrease in reactivation activity across a number of cortical, hippocampal, and amygdalar regions, indicating suppression of ensemble reactivation may be a neurobiological signature of LH. These results highlight the emergent insights uniquely garnered by applying our analysis approach to multiple ensemble datasets and demonstrate the strength of our workflow as a hypothesis-generating toolkit.
The role of β-Nicotyrine in E-Cigarette abuse liability I: Drug Discrimination
Authors: Smethells JR , Wilde S , Muelken P , LeSage MG , Harris AP
Published: July 2024

Background

β-Nicotyrine (β-Nic) is a unique minor alkaloid constituent in electronic nicotine delivery systems (ENDS) that is derived from nicotine (Nic) degradation and can reach 25% of Nic concentrations in ENDS aerosol. β-Nic slows Nic metabolism and prolongs systemic Nic exposure, which may alter the discriminability of Nic. The present study sought to examine β-Nic has interoceptive effects itself, and if it alters the subjective effects ENDS products within a drug-discrimination paradigm.

Methods

The pharmacodynamics of β-Nic were examined in vitro, and a nicotine discrimination paradigm was used to determine if β-Nic (0 – 5.0 mg/kg) shares discriminative stimulus properties with Nic (0.2 mg/kg) in male (n = 13) and female (n = 14) rats after 10- & 60-min β-Nic pretreatment delays. A second group of rats was trained to discriminate β-Nic and Nornicotine (Nornic) from saline to determine if β-Nic alone has interoceptive properties and whether they are similar to Nornic.

Results

β-Nic had similar binding affinity and efficacy at the α4β2 nicotinic receptor subtype as Nornic, ∼50% of Nic efficacy. However, β-Nic only weakly substituted for Nic during substitution testing in female rats, but not males, whereas Nornic fully substituted for Nic. Combination testing at the 10 and 60-min pretreatment intervals showed that β-Nic dose-dependently increased the duration of nicotine’s discriminative stimulus effects, especially at the 60-min delay. Drug naïve rats could reliably discriminate Nornic, but not β-Nic, from Sal.

Conclusion

β-Nic increased and prolonged the interoceptive stimulus properties of Nic, suggesting it may alter to the abuse liability of ENDS through its ability to slow Nic metabolism.
Scales of marine endemism in oceanic islands and the Provincial-Island endemism
Authors: Pinheiro Hudson T. , Rocha Luiz A. , Quimbayo Juan P.
Published: July 2024

Oceanic islands are remote environments commonly harboring endemic species, which often are unique lineages originated and maintained by a variety of ecological, biogeographical and evolutionary processes. Endemic species are found mostly in a single oceanic island or archipelago, however, a great number of species can be considered multiple-island endemics, i.e. species found on multiple oceanic islands that still have a restricted distribution. The geographic criteria chosen to classify endemic species has a direct impact on the endemism rate of islands, and many studies have used multiple scales of endemism (single and multiple-island endemics), which has historically influenced wide-scale comparisons. In this perspective, we accessed the importance of single and multiple-island endemic species to the biodiversity of oceanic islands, introducing the concept of Provincial-island endemism as an additional strategy to standardize biogeography studies.
Enhanced sensitivity of TAPscan v4 enables comprehensive analysis of streptophyte transcription factor evolution
Authors: Petroll Romy , Varshney Deepti , Hiltemann Saskia , Finke Hermann , Schreiber Mona , de Vries Jan , Rensing Stefan A.
Published: July 2024

Transcription associated proteins (TAPs) fulfill multiple functions in regulatory and developmental processes and display lineage-specific evolution. TAPscan is a comprehensive and highly reliable tool for genome-wide TAP annotation via domain profiles. Here, we present TAPscan v4, including an updated web interface (https://tapscan.plantcode.cup.uni-freiburg.de/), which enables an in-depth representation of the distribution of 138 TAP families across 678 species from diverse groups of organisms, with a focus on Archaeplastida (plants in the wide sense). With this release, we also make the underlying “Genome Zoo” available, a curated protein data set with scripts and metadata. 18 new TAP (sub)families were added as part of the update. Nine of those were gained in the most recent common ancestor of the Streptophyta (comprising streptophyte algae and land plants), or within the streptophyte algae. More than one-third of all detected TAP family gains were identified during the evolution of streptophyte algae, before the emergence of land plants, and are thus likely to have been significant for plant terrestrialization. The TAP complement of the Zygnematophyceae was identified to be the most similar to that of land plants, consistent with the finding that this lineage is sister to land plants. Overall, our data retrace the evolution of streptophyte TAPs, allowing us to pinpoint the regulatory repertoire of the earliest land plants.
Differential expression of keratin and keratin associated proteins are linked with hair loss condition in spontaneously mutated inbred mice
Authors: Chilukoti Neeraja , Pavuluri Sivapriya , Kumar Satish
Published: July 2024

Hair loss condition is heritable and is influenced by multifactorial inheritance. In the present study, spontaneously mutated mice showed hair loss phenotype with defect in the first cycle of hair follicle formation leading to cyclic alopecia. These mutant mice follow autosomal recessive inheritance pattern. The transcriptomic profile and differential gene expression analysis of skin tissues by RNA-sequencing at different stages of hair cycle formation was performed. The genes with significant differential genes expression levels in each stage of hair cycle formation were identified and most of these genes were shown to be associated with keratinization process and hair follicle formation. Transcriptome profiling followed by QPCR validation revealed that mRNA levels ofKrt16,Alox15,Fetub(upregulated) andMsx2(downregulated) were significantly differentially expressed in mutant skin tissues during late anagen and catagen stages.Krt6bmRNA and protein levels were significantly higher in the mutant mice during all stages of first hair cycle formation. The present study provides basis for understanding the differential gene expression of hair-related genes, including keratinization-associated proteins and its relevance. These mutant mice can serve as a model for studying hair loss condition that can be further used in the identification, evaluation and treatment strategies for alopecia condition.
The discovery of phages in the Substantia Nigra and its implication for Parkinson’s Disease
Authors: Zhao Yun , Xiong Changxian , Wang Bingwei , Li Daotong , Liu Jiarui , Wei Shizhang , Hou Yujia , Zhou Yuan , Zheng Ruimao
Published: July 2024

Background:

A century ago, a mystery between virus and Parkinson’s disease (PD) was described. Owing to the limitation of human brain biopsy and the challenge of electron microscopy in observing virions in human brain tissue, it has been difficult to study the viral etiology of PD. Recent discovery of virobiota reveals that viruses coexist with humans as symbionts. Newly-developed transcriptomic sequencing and novel bioinformatic approaches for mining the encrypted virome in human transcriptome make it possible to study the relationship between symbiotic viruses and PD. Nevertheless, whether viruses exist in the human substantial nigra (SN), and whether symbiotic viruses underlie PD pathogenesis remain unknown.

Methods:

We collected current worldwide human SN transcriptomic datasets from the United States, the United Kingdom, the Netherlands and Switzerland. We used bioinformatic approaches including viruSITE and the Virus-Track to identify the existence of viruses in the SN of patients. The comprehensive RNA sequencing-based virome analysis pipeline was used to characterize the virobiota in the SN. The Pearson’s correlation analysis was used to examine the association between the viral RNA fragment counts (VRFC) and PD-related human gene sequencing reads in the SN. The differentially expressed genes (DEGs) in the SN between PD patients and non-PD individuals were used to examine the molecular signatures of PD and also evaluate the impact of symbiotic viruses on the SN.

Findings:

We observed the existence of viruses in the human SN. A dysbiosis of virobiota was found in the SN of PD patients. A significant correlation between VRFC and PD-related human gene expression was detected in the SN of PD patients. These PD-related human genes correlated to VRFC were named as the virus-correlated PD-related genes (VPGs). We identified three bacteriophages (phages), including the Proteus phage VB_PmiS-Isfahan, the Escherichia phage phiX174 and the Lactobacillus phage Sha1, that might impair the gene expression of neural cells in the SN of PD patients. The Proteus phage VB_PmiS-Isfahan was a common virus in the SN of patients from the UK, the Netherlands, and Switzerland. VPGs and DEGs together highlighted that the phages might dampen dopamine biosynthesis and weaken cGAS-STING function.

Interpretation:

This is the first study to discover the involvement of phages in PD pathogenesis. A life-long low symbiotic viral load in the SN may be a contributor to PD pathogenesis. Our findings unlocked the black box between brain virobiota and PD, providing a novel insight into PD etiology from the perspective of phages-human symbiosis.
Maintenance of long-term transposable element activity through regulation by nonautonomous elements
Authors: Omole Adekanmi Daniel , Czuppon Peter
Published: July 2024

Transposable elements are DNA sequences that can move and replicate within genomes. Broadly, there are two types: autonomous elements, which encode the necessary enzymes for transposition, and nonautonomous elements which rely on the enzymes produced by autonomous elements for their transposition. Nonautonomous elements have been proposed to regulate the numbers of transposable elements, which is a possible explanation for the persistence of transposition activity over long evolutionary times. However, previous modeling studies indicate that interactions between autonomous and nonautonomous elements usually result in the extinction of one type. Here, we study a stochastic model that allows for the stable coexistence of autonomous and nonautonomous retrotransposons. We determine the conditions for this coexistence and derive an analytical expression for the stationary distribution of their copy numbers, showing that nonautonomous elements regulate stochastic fluctuations and the number of autonomous elements in stationarity. We find that the stationary variances of each element can be expressed as a function of the average copy numbers and their covariance, enabling data comparison and model validation. These results suggest that continued transposition activity of transposable elements, regulated by nonautonomous elements, is a possible evolutionary outcome that could for example explain the long co-evolutionary history of autonomousLINE1and nonautonomousAluelement transposition in the human ancestry.
JAK2/STAT3 signaling pathway mediates methylmercury toxicity in mouse astrocyte neuronal C8-D1A cell line
Authors: Ahmed Aafia , Aschner Michael , Ferrer Beatriz
Published: July 2024

Methylmercury (MeHg) is an environmental pollutant. Consumption of contaminated fish is the main exposure route in humans, leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes disrupting glutamate and calcium homeostasis and increasing oxidative stress. Despite extensive research, the molecular mechanisms underlying MeHg neurotoxicity remain incompletely understood. The induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role activating antioxidant responses during MeHg-induced oxidative injury have garnered significant attention as a potential therapeutic target against MeHg toxicity. However, recent studies indicate that the Nrf2 signaling pathway alone may not be sufficient to mitigate MeHg-induced damage, suggesting the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) plays a crucial role in cell growth and survival. Several studies have also highlighted its involvement in regulating redox homeostasis, thereby preventing oxidative stress through mechanisms that involve modulation of nuclear genes that encode electron transport complexes (ETC) and antioxidant enzymes. These characteristics suggest that STAT3 could serve as a viable mechanism to mitigate MeHg toxicity, either in conjunction with or as an alternative to Nrf2 signaling. Our previous findings demonstrated that MeHg activates the STAT3 signaling pathway in the GT1-7 hypothalamic neuronal cell line, suggesting its potential role in promoting neuroprotection. Here, to elucidate the role of the STAT3 signaling pathway in MeHg neurotoxicity, we pharmacologically inhibited STAT3 using AG490 in the C8D1A astrocytic cell line exposed to 10 µM MeHg. Our data demonstrated that pharmacological inhibition of STAT3 phosphorylation exacerbates MeHg-induced mortality, antioxidant responses, and ROS production, suggesting that STAT3 may contribute to neuroprotection against MeHg exposure in astrocytes.
Towards a Rosetta Stone to Decipher the Survival Networks of Senescence
Authors: Olascoaga Samael , López-Diazguerrero Norma Edith
Published: July 2024

Cellular senescence, an irreversible state of cell cycle arrest in response to various stressors that can damage cells, is a key player in developing and progressing multiple chronic degenerative diseases associated with aging. Over the years, these senescent cells accumulate in organs and tissues, it is thought that the accumulation of these cells results from their capacity to evade programmed cell death by developing and activating Senescent Cell Anti-apoptotic Pathways (SCAPs); however, numerous aspects of the development and activation of these SCAPs are still unknown. In this study, we analyzed the variations in the expression levels and co-expression patterns of 39 SCAPs genes across 33 tissues from young and elderly individuals. Surprisingly, we did not observe a consistent increase in SCAPs gene expression with age in any tissue. Instead, we found tissue-specific variations in gene expression levels, changes in the strength of gene coordination, and the wiring and rewiring of gene co-expression networks that depend on the tissue. Our results suggest that the development and activation of SCAPs are far more complex than previously understood; merely increasing the expression of specific survival genes would not adequately explain the anti-apoptotic capabilities of senescent cells. We suggest that the formation and triggering of SCAPs entail a complex interplay of factors, encompassing distinct alterations in expression levels alongside shifts in the intensity and configurations of gene interactions, moreover, these modifications are unique to individual tissues. Our results deepen our understanding of how senescent cells evade programmed cell death and are essential for developing targeted pharmacological therapies that can selectively and safely eliminate senescent cells more effectively.
Androgen receptor plays critical role in regulating cervical cancer cell migration
Authors: Bose Sarpita , Das Subhrangshu , Maity Sebabrata , Chakrabarti Oishee , Chakrabarti Saikat
Published: July 2024

Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify candidates for targeted therapy in metastatic disease. This study used a network biology approach to identify key genes in disease progression. Stage-specific cervical cancer protein-protein interaction networks (PPIN) were constructed by overlaying stage-specific, patient-derived transcriptomics data onto a human protein-protein interaction network (HPPIN). Graph-theory-based network analysis identified important interacting proteins (IIPs) with maximum connectivity, high centrality scores, and significant global and local network perturbation scores. Among the identified IIPs, the Androgen receptor (AR) emerged as one of the crucial yet understudied regulator in cervical cancer. Patient samples and in vitro experiments showed significant downregulation in cervical cancer. Ligand-dependent overexpression of AR reduced cancer cell migration while failed to induce apoptosis in CC cell lines. Downregulation of mesenchymal markers and restoration of epithelial markers suggested AR’s potential in reversing invasive properties of cervical cancer cells. AR overexpression upregulated its downstream target PTEN and restored GSK3β activity by interfering with AKT phosphorylation, probably leading to degradation of mesenchymal markers. Further studies showed AR reduced cell motility by hindering focal adhesion formation and Actin filament assembly. An increased G-Actin ratio suggested AR disrupted cytoskeletal dynamics through the RhoA/ROCK1/LIMK1/CFL1 pathway, impeding cervical cancer cell spread.
Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models
Authors: Struth Eric , Labaf Maryam , Karimnia Vida , Liu Yiran , Cramer Gwendolyn , Dahl Joanna B. , Slack Frank J. , Zarringhalam Kourosh , Celli Jonathan P.
Published: July 2024

Interactions between tumor and stromal cells are well known to play a prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs. Though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use 3D co-culture geometries to recapitulate juxtacrine interactions between epithelial and stromal cells. In particular, extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1), result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility which leads to highly condensed macroscopic multicellular aggregates as detected using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. To investigate how drug resistance impacts these juxtacrine interactions we contrast cultures in which PANC1 are substituted with a drug resistant subline (PANC1-OR) previously established in our lab. We find that heterotypic cell-cell interactions are highly suppressed in drug-resistant cells relative to the parental PANC1 cells. To investigate further we conduct RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also consistent with loss of hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.
Towards Reliable Diabetes Prediction: Innovations in Data Engineering and Machine Learning Applications
Authors: Talukder Md. Alamin , Islam Md. Manowarul , Uddin Md Ashraf , Kazi Mohsin , Khalid Majdi , Akhter Arnisha , Moni Mohammad Ali
Published: July 2024

Objective

Diabetes is a metabolic disorder that causes the risk of stroke, heart disease, kidney failure, and other long-term complications because diabetes generates excess sugar in the blood. Machine learning (ML) models can aid in diagnosing diabetes at the primary stage. So, we need an efficient machine learning model to diagnose diabetes accurately.

Methods

In this paper, an effective data preprocessing pipeline has been implemented to process the data and random oversampling to balance the data, handling the imbalance distributions of the observational data more sophisticatedly. We used four different diabetes datasets to conduct our experiments. Several ML algorithms were used to determine the best models to predict diabetes faultlessly.

Results

The performance analysis demonstrates that among all ML algorithms, RF surpasses the current works with an accuracy rate of 86% and 98.48% for dataset-1 and dataset-2; XGB and DT surpass with an accuracy rate of 99.27% and 100% for dataset-3 and dataset-4 respectively. Our proposal can increase accuracy by 12.15% compared to the model without preprocessing.

Conclusions

This excellent research finding indicates that the proposed models might be employed to produce more accurate diabetes predictions to supplement current preventative interventions to reduce the incidence of diabetes and its associated costs.
eDNA metabarcoding shows highly diverse but distinct shallow, mid-water, and deep-water eukaryotic communities within a marine biodiversity hotspot
Authors: Cerrillo-Espinosa Patricia , Calderón-Aguilera Luis E. , Medina-Rosas Pedro , Gómez-Gutiérrez Jaime , Reyes-Bonilla Héctor , Cupul-Magaña Amílcar , Gonzalez-Cuellar Ollin T. , Munguia-Vega Adrian
Published: July 2024

As the impact of human activities continues to move beyond shallow coastal waters into deeper ocean layers, it is fundamental to describe how diverse and distinct the eukaryotic assemblages from the deep layers are compared to shallow ecosystems. Environmental DNA (eDNA) metabarcoding has emerged as a molecular tool that can overcome many logistical barriers in exploring remote deep ocean areas. We analyzed thirty-two paired seawater samples collected via SCUBA and Niskin samplers from shallow (< 30 m) and deep ecosystems (40-500 m) within a recognized hotspot of marine biodiversity (Gulf of California, Mexico). We sequenced an eDNA metabarcoding library targeting the COI gene of eukaryotes. We demonstrated that the diversity of operational taxonomic units (OTUs) did not peak at shallow coastal regions and that the deep samples had similar levels of biodiversity to shallow sites but detected a significant vertical zonation between shallow and deeper habitats. Our results suggest that the deep refugia hypothesis applies to about a third of the 5495 OTUs identified that were shared between shallow and deep layer samples. At the same time, most taxa were exclusive from either shallow or deep zones. The observation that deep communities were as rich but quite distinct as shallow communities supports extending spatial management and conservation tools to deeper habitats to include a significant fraction of phylogenetic and functional diversity exclusive of mid and deep-water ecosystems.
OPTIMIZATION OFRECOVERABLE CLEAR PLASTIC POT(rCPP) METHOD AND VALIDATION OF MOLECULAR MARKS FOR THE SCREENING OF DEEP ROOTING OF RICE (Oryza sativaL.)
Authors: Pratama Mukhlis Syahril , Basunanda Panjisakti , Wulandari Rani Agustina , Widyawan Muhammad Habib
Published: July 2024

The generally of Rice plants have shallow roots and require large amounts of water for cultivation. However, water resources are becoming increasingly limited due to climate change. Therefore, efforts are needed to improve rice genetics in order to produce stable crop production in drought-prone areas. One strategy to avoid drought stress is to change the architecture of deeper rooting. The identification can be done by screening the root morphology. Most of the screening methods for deep rooting ability in rice are stilldestructive, so the proposed activity in this study is the optimization of theRecoverable Clear Plastic Pot(rCPP) method that can detect deep rooting ability in rice early andnon-destructively. The method was further validated using InDel and SSR-based molecular markers designed based on theDRO1gene. TheDRO1gene plays a role in increasing the root growth angle, so that the roots grow in a deeper vertical direction. The results showed thatRecoverable Clear Plastic Pot(rCPP) optimization was able to show good screening ability for plant root charactersnon-destructively. Mayangan is the best drought-tolerant genotype based on deep rooting characters that have root distribution centered on theinner circle. The relationship between deep rooting screening using the DRO1 marker provides results that are in line with deep rooting screening through theRecoverable Clear Plastic Pot(rCPP) method.

Highlight

This research is part of an effort to improve rice genetics in order to produce stable crop production in drought-prone areas.

The research activities used the optimizationRecoverable Clear Plastic Pot(rCPP) method.

The rCPP method was validated using InDel and SSR-based molecular markers designed based on theDRO1gene.

Optimization of rCPP shows good screening ability for plant rooting characters in anon-destructive manner.
Two mechanisms of photoenergy regulation revealed by kinetic behaviors of chlorophyll fluorescence during light adaptation
Authors: Chen Junqing , Fu Lijiang , Guo Ya , Tan Jinglu
Published: July 2024

Photochemical reactions were analyzed and modeled to observe photoenergy regulation mechanisms in PSII from measured chlorophyll fluorescence (ChlF) kinetics. Two pH-driven mechanisms were revealed: One is the PsbS-mediated non-photochemical quenching (NPQ) of activated antennae (A*), as commonly understood, and the other is a disruption of energy transfer from A* to P680. Representing the latter with a conformational change from complex formation of zeaxanthin and lutein with antennae closely described measured ChlF from initially dark-adapted state to light-adapted state and measured NPQ variations. Analysis based on the model indicates that zeaxanthin and lutein lead to slow protracted reductions in P680* and ChlF via the second mechanism without strong influence by pH or PsbS. Protonation of PsbS plays a major role via the first mechanism in responding to fast changes in illumination. The research provides insights into the mechanisms for photoenergy regulation in PSII and a kinetic model with broadened applicability.
Loss ofMEF2Cfunction by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice
Authors: Yousefian-Jazi Ali , Kim Suhyun , Choi Seung-Hye , Chu Jiyeon , Nguyen Phuong Thi-Thanh , Park Uiyeol , Lim Kayeong , Hwang Hongik , Lee Kyungeun , Kim Yeyun , Hyeon Seung Jae , Rhim Hyewhon , Ryu Hannah L. , Lim Grewo , Stein Thor D. , Ryu Hoon , Lee Junghee
Published: July 2024

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region ofMEF2C(rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation ofMEF2Creduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of theMEF2Cenhancer decreases expression of mitochondria-encoded genes. Moreover,MEF2Cmutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress.MEF2Cdeficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together,MEF2Cdysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.
Understanding the physical determinants of pressure denaturation: Exploring the unfolding pathways of Yfh1 at different temperatures with High-Pressure NMR
Authors: Roumestand Christian , Dudas Erika , Puglisi Rita , Calió Antonino , Barthe Philippe , Temussi Piero Andrea , Pastore Annalisa
Published: July 2024

Proteins unfold under different environmental insults, among which are heat, cold, high pressure and chaotropic agents. Understanding the mechanisms that determine unfolding under each of these conditions is an important problem that directly relates to the physical forces that determine the three-dimensional structure of a protein. Here, we studied a residue-specific description of the unfolding transitions of the marginally stable yeast protein Yfh1 using high-pressure nuclear magnetic resonance. We compared the cold, heat and pressure unfolded states and demonstrated what has up to now been only a hypothesis: the pressure-unfolded spectrum shares features in common with that at low but not at high temperature and room pressure, suggesting a tighter similarity of the mechanisms and a similar role of hydration in these two processes. By exploring the phase diagram of the protein and mapping unfolding onto the three-dimensional structure of the protein, we also show that the pressure-induced unfolding pathways at low and high temperatures differ, suggesting a synergic mechanism between pressure- and temperature-induced denaturation. Our observations help us to reconstruct the structural events determining unfolding and distinguish the mechanisms that rule the different processes of unfolding.
Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer’s Disease and Frontotemporal Dementia
Authors: Pashova-Dimova Shina , Petrov Peter , Karachanak-Yankova Sena , Belezhanska Diana , Zhelev Yavor , Mehrabian Shima , Traykov Lachezar , Pashov Anastas
Published: July 2024

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers and reliance on invasive procedures. Immune biomarkers, particularly those reflecting the interaction between the central nervous system (CNS) and the peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates the reactivity of serum IgM and IgG from AD and FTD patients against a library of mimotopes representing public IgM reactivities in healthy donors. Serum samples from AD, FTD, and other neurodegenerative dementias (ND), and controls were tested on peptide microarrays. The samples were pooled to mitigate individual variability. The reactivity data were analyzed using graphs to represent the cross-reactivity networks. The analysis revealed distinct reactivity patterns for the studied groups. Public IgM reactivities showed significant correlations with neurodegenerative conditions, with AD and FTD exhibiting loss or gain of specific IgM reactivities. Graph analysis highlighted significant differences in graph density, clustering, and assortativity parameters between disease and control groups. Idiotypic reactivities, particularly in IgM, were more connected in healthy controls compared to those with neurodegenerative diseases. Furthermore, clusters of reactivities showed significant distinctions between AD and FTD, with IgG reactivities providing additional differentiation. A number of self proteins related to neurodegeneration proved to have sequences homologous to disease associated mimotopes. Thus, the public IgM repertoire, characterized by its broad reactivity and inherent autoreactivity, offers valuable insights into the immunological alterations in neurodegenerative diseases. The study supports the potential of IgM and IgG reactivity profiles as another compartment of non-invasive biomarkers for early diagnosis and differentiation of AD and FTD.
Sex-Specific causal dynamic between Insulin resistance and MDD, a bidirectional Mendelian randomization study
Authors: Xia Qizhou , Silveira Patricia P.
Published: July 2024

Aims/hypothesis

Observational studies have shown a bidirectional association between major depressive disorder (MDD), Insulin resistance (IR), and related diseases, which varies between sexes and ancestries. We conducted a sex-specific two-sample bidirectional Mendelian randomization (MR) study to assess the causal associations of MDD with Insulin resistance measured through the TG: HDL-C ratio and vice versa using Caucasian and East Asian data.

Methods

We extracted summary-level data for MDD and insulin resistance from corresponding published large genome-wide association studies of individuals of European descent and partially replicated the analyses using available summary data from studies of individuals of East Asian descent. The random-effects inverse-variance weighted method and MRlap method were used for the main analyses for non-overlapping and overlapping samples, respectively.

Results

Genetic liability to MDD was significantly associated with insulin resistance both generally and sex-specifically, while the causal effect of Insulin resistance on MDD is only consistently significant in females. We did not find any significant causal association between IR and MDD using East Asian data, though the beta estimates suggest potentially ancestry-related differences in the direction of effect.

Conclusions/interpretation

The present study strengthened the evidence that MDD is a potential risk factor for insulin resistance and that insulin resistance plays a sex—and ancestry-specific role in MDD pathology. Together, these findings could contribute to further our understanding of the comorbidity between MDD and IR-related diseases, allowing for more individualized treatment and diagnosis.
Exploring the potential of Claude 2 for risk of bias assessment: Using a large language model to assess randomized controlled trials with RoB 2
Authors: Eisele-Metzger Angelika , Lieberum Judith-Lisa , Toews Markus , Siemens Waldemar , Heilmeyer Felix , Haverkamp Christian , Boehringer Daniel , Meerpohl Joerg J
Published: July 2024

Systematic reviews are essential for evidence based healthcare, but conducting them is time and resource consuming. To date, efforts have been made to accelerate and (semi-) automate various steps of systematic reviews through the use of artificial intelligence and the emergence of large language models (LLMs) promises further opportunities. One crucial but complex task within systematic review conduct is assessing the risk of bias of included studies. Therefore, the aim of this study was to test the LLM Claude 2 for risk of bias assessment of 100 randomized controlled trials using the revised Cochrane risk of bias tool (“RoB 2”; involving judgements for five specific domains and an overall judgement). We assessed the agreement of risk of bias judgements by Claude with human judgements published in Cochrane Reviews. The observed agreement between Claude and Cochrane authors ranged from 41% for the overall judgement to 71% for domain 4 (“outcome measurement”). Cohen’s κ was lowest for domain 5 (“selective reporting”; 0.10 (95% confidence interval (CI): −0.10-0.31)) and highest for domain 3 (“missing data”; 0.31 (95% CI: 0.10-0.52)), indicating slight to fair agreement. Fair agreement was found for the overall judgement (Cohen’s κ: 0.22 (95% CI: 0.06-0.38)). Sensitivity analyses using alternative prompting techniques or the more recent version Claude 3 did not result in substantial changes. Currently, Claude’s RoB 2 judgements cannot replace human risk of bias assessment. However, the potential of LLMs to support risk of bias assessment should be further explored.