bluuebunny/crossref_metadata_2025 huggingface dataset:
Concentration and purification of viruses
Authors: Minor P D
Published: November 2023

Virus infectivity or its neutralization by antibodies can usually be measured on non-concentrated preparations, but for many other purposes concentration and purification are essential because of the small mass of the infectious agent. For example, 1 × 106 plaque-forming units of poliovirus may have a total mass of about 1 ng, of which 250 pg will be genomic RNA. While this is sufficient for genome amplification where the sequence is known, more concentrated and purified preparations will be required for investigations such as: physical analysis genetic analysis where the genome sequence is not known use as an antigen or immunogen Concentrated virus preparations will contain the virus at a higher concentration than in the starting material but still include substantial amounts of impurities such as components from host cells. These crude preparations can be used successfully in a variety of applications, including immunoprecipitation with specific antibodies, some routine antibody assays such as ELISA for known viruses, or as immunogens to produce neutralising antibodies. Possible adverse effects of non-viral impurities can include false-positive reactions with antibodies, the induction of antibodies to non-viral antigens, or the detection of non-viral nucleic acids, and some purification procedure is usual following concentration.
Application of the baculoviral expression system to signal transduction
Authors: Paterson Andrew
Published: November 2023

The Baculovirus Expression Vector System (BEYS) is an extremely versatile and powerful laboratory tool (1). In simplest terms, the BEYS allows the forced heterologous expression of recombinant protein in susceptible host strains of insect cells. Gene products from the simplest prokaryotes through to the higher eukaryotes have been expressed successfully in this system. Recombinant proteins are recovered in a folded and active form, and posttranslation modifications, such as phosphorylation, lipid acylation, and simple glycosylation are often preserved. Oligomerization is preserved also, as is the ability to form holomeric complexes. This has been demonstrated clearly with expression of the - 40 k Da G proteins in their native al3 ‘) ‘ heterotrimeric complexes (2), and extended to the activation of the kinase, c-Raf, upon coexpression with Ras and Src tyrosine kinase (3). Since the host insect cells maintain the ability to process eukaryotic pre-mRNA, heterologous expression from genomic DNA is possible. However, the most attractive facet of BEYS must be the high level of heterologous protein expression with values of between 0.1 and 30% of total cell protein being reported, and often with gene products that fail to express with activity or reasonable yield in other systems. The rationale of the BEYS is fairly simple. The baculoviral genome is engineered to incorporate the coding sequence of a foreign protein. Incorporation is directed to a position downstream, and under the control, of a strong viral promoter.
Phospholipase D and phosphatidylcholine metabolism
Authors: Meier Kathryn E , Gibbs Terra C
Published: November 2023

Phospholipase D (PLD) catalyses the hydrolysis of phospholipids to phosphatidic acid (PA). The preferred substrate for most PLDs is phosphatidylcholine, although utilization of other substrates (e.g. phosphatidylethanolamine) has been reported. PLDs are expressed in mammals, insects, plants, yeast, and certain bacteria. In mammalian cells, PLD is activated in response to a broad range of agonists (reviewed in refs 1-4). In general, PLD activity is increased by agonists that bind to G protein-coupled receptors (GPCRs) inducing phospholipase C (PLC) activation. Various growth factors, hormones, and cytokines can activate PLD. Phorbol-12-myristate-13-acetate (PMA), a tumour promoter that activates protein kinase C (PKC) isoforms, induces PLD activation in most mammalian cell types. The roles of PLDs in signal transduction remain of great interest, but poorly defined. The recent molecular cloning of PLD isoforms has greatly accelerated work in this research area.
Protein-ligand interactions and their analysis
Authors: Chowdhry Babur Z , Harding Stephen E
Published: November 2023

In each cell of an organism, a myriad of reactions, covalent and non-covalent, occur at any given point in time. These reactions are co-ordinated and regulated, both spatially and temporally. Each reaction has a specific purpose, occurs as a result of finely-tuned inter- and intramolecular recognition mechanisms, and forms part of an intricate network of interdependent multi-component linear/ non-linear reactions in interconnected compartments (organelles etc.) of the cell. Moreover the frontiers of viability of such reactions-and the living organ isms that depend on them-are marked by extreme conditions: 1-12 for pH, -5-110 °C for temperature, 0.1-120 MPa for hydrostatic pressure, and 0.6-1.0 for water activity. Amongst the many molecules that participate in such reactions in the complex-and, as yet hardly understood, milieu of the cell-are proteins.
Quantitative characterization of ligand binding by chromatography
Authors: Winzer Donald J
Published: November 2023

The power of chromatography as a means of separating molecµles on the basis of charge (ion-exchange chromatography), size (exclusion or gel chromatography), and biospecificity (affinity chromatography) is recognized universally. Less well known is the scope of the technique for the quantitative characterization of ligand binding in terms of the stoichiometry and strength of the equilibrium phenomenon.
Capillary electrophoresis
Authors: Heegaard Niels H H
Published: November 2023

Electrophoresis is the transport of charged molecules in solution by the action of an electrical field (1). Electrophoretic techniques are widely used to separate and characterize biomolecular mixtures and very high resolution may be achieved by the use of denaturing one- or two-dimensional gel methods. The separation efficiency in these techniques is normally achieved at the expense of analyte functions such as enzyme and ligand binding activities that are adversely affected by the denaturing conditions required. With the advent of capillary electro phoresis (CE) (2), however, it has become possible to preserve molecular function whilst still maintaining separation efficiency for the reason that extremely high resolution can be obtained in buffers that do not interfere with the native structure of the analyte. This has expanded the use of affinity electrophoresis methods considerably.
Proteins of the major histocompatibility complex and their interactions with T-cell receptors
Authors: Dafforn Tim R
Published: November 2023

Surgical patients, if not immunosuppressed by drugs, will reject transplanted organsunless the donor is an identical twin-because the transplant is recognized as being foreign. The immunological distinction between ‘self’ and ‘non-self’ resides in the proteins of the Major Histocompatibility Complex (MHC) and their interaction with T-cell receptors. MHC proteins bind intracellularly produced peptides and present them on cell surfaces. The triggering event in alerting the immune system to the presence of a foreign protein is the recognition, by a T-cell receptor, of a complex between an MHC protein and a peptide derived from the foreign protein.
RNA editing in kinetoplastid mitochondria
Authors: Stuart Kenneth D
Published: November 2023

All three major classes of RNA undergo post-transcriptional processing by nucleolytic cleavage and base modification before they become functional (1). A general theme in RNA processing is (cis or trans) RNA–RNA interactions and the association with a macromolecular complex. Ribosomal RNA precursors are processed by a series of endonucleolytic cleavages that are catalyzed by RNA or protein enzymes. The rRNA bases are modified at sites which are guided by base pairing with small nucleolar (sno) RNAs (2). Similarly, tRNAs are cleaved from precursors, and the site of the 5’ cleavage is guided by bases pairing with the RNA component of RNase P. In addition, many bases of tRNA are modified by a variety of enzymes that select the base by RNA–RNA interactions that result from the tRNA structure (3). The mRNA precursors also undergo a variety of processing reactions. These include cleavage, 5’ capping, 3’ polyadenylation and intron excision (splicing). An important aspect of RNA splicing is that it produces informationally correct mature mRNA and, indeed, the appropriate mRNA version in the case of alternative splicing. Splicing is catalyzed by the spliceosome, a ribonucleoprotein complex that is composed of numerous proteins and several small RNAs that base pair with the mRNA and guide the sites of catalysis. Indeed, spliceosome RNAs may catalyze some of the steps of splicing. More recently, it was found that mRNAs undergo other forms of RNA processing that are collectively termed RNA editing since they alter the sequence from that encoded in the structural gene (4). RNA editing falls into two categories: base modification and nucleotide insertion/deletion. The first observed, and perhaps most complex, form of RNA editing is that which occurs in the mitochondrion of kinetoplastid protozoa (trypanosomatids). This type of editing is the subject of this chapter and has been covered in several excellent previous reviews (5, 6). This type of editing inserts and deletes uridylates (Us) to produce mature mRNAs with sequences that are specified by small guide RNAs (gRNAs). The editing in trypanosomes occurs in association with a macromolecular complex. It occurs in all kinetoplastids but is most extensive in African trypanosomes. Editing in this group will be the focus of this review.
RNA editing in plant mitochondria and chloroplasts
Authors: Bock Ralph
Published: November 2023

In plants, genetic information is distributed among three cellular compartments: the nucleus, mitochondria and plastids. Each of these compartments carries its own genome and, consequently, expresses heritable traits. Plastids and mitochondria do not obey Mendelian rules and are often transmitted uniparentally to the next generation, a phenomenon early recognized as being one of the characteristics of extranuclear inheritance (1).
Adenosine-to-inosine RNA editing: substrates and consequences
Authors: Emeson Ronald B
Published: November 2023

The conversion of adenosine to inosine (A→I) by RNA editing is an increasingly recognized RNA processing event by which multiple RNA and protein isoforms can be generated from a single genomic locus. This type of modification was first observed in yeast tRNAs (1, 2), but has since been identified in multiple viral RNA transcripts and cellular mRNA species (3–5). Since inosine preferentially base-pairs with cytidine, an inosine within RNA transcripts is read as guanosine during translation, often resulting in specific change(s) in the amino acid coding potential of the mRNA, which can dramatically alter the functional properties of the encoded protein product. In several instances, A→I editing events have also been described in untranslated RNA species (e.g. tRNAs) (6, 7) and non-coding regions of mRNA transcripts (8–11), suggesting that such modifications may also affect other aspects of RNA function including translation, splicing and stability.
Introduction
Authors: Slater Røbert J
Published: November 2023

On the grounds of safety, whenever an experiment is being considered the need for a radioisotope must be questioned: is a radioisotope absolutely essential to the experiment planned? Or put another way, are non-radioactive methods available that will achieve the same end?
Point mutations and chimeric receptors in studies of ligand binding domains and second messenger activation of α1-adrenoceptors
Authors: Perez Dianne M , Zuscik Michael J , Ross Sean A , Waugh David J J
Published: November 2023

The creation of point mutations or the generation of chimeric receptors is a valuable model system for the evaluation of structure-function relationships of G protein-coupled receptors (GPCRs). One can essentially mutate any area in the receptor structure and then determine the functional and/or binding consequences of that mutation; thus, interpreting the importance of the original amino acid in receptor structure. This chapter will outline two basic techniques to generate mutations, how to transfect into mammalian cells, then to analyse the effects of the mutations by either binding or function.
A Systematic Review and Meta-Analysis of Mapping Biopsy for Primary Extramammary Paget’s Disease in Reducing Recurrence Following Surgical Excision
Authors: Murugan Thirrisha , Wong Louis Choon Kit , Ong Xing-Yi Sarah , Tan Sze Huey , Tan Joey Wee-Shan , Liu Ying , Shannon Nicholas B. , Chiang Jianbang , Poon Eileen , Chan Jason Yongsheng , Yang Valerie Shiwen , Somasundaram Nagavalli , Farid Mohamad , Wong Ru Xin , Nei Wen Long , Kwek Jin Wei , Thng Choon Hua , Hennedige Tiffany , Tang Po Yin , Selvarajan Sathiyamoorthy , Tay Kae Jack , Abdul Mohamed Rezal , Wong Jolene Si Min , Seo Chin Jin , Soo Khee Chee , Chia Claramae Shulyn , Ong Chin-Ann Johnny
Published: November 2023

Objective:

To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget’s disease (EMPD).

Background:

Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence.

Methods:

Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported.

Results:

A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32–0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03–1.84). Qualitative assessment of the remaining selected studies revealed equivocal results.

Conclusions:

Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.
A Network Meta-analysis of the Efficacy and Safety of Targeted Drug Combinations in the Treatment of Pulmonary Arterial Hypertension
Authors: Wang Rui , Wei Meng , Wang Jie , Huang Xiang , Yan Qianzhi , Wang Shichao , Wu Yun
Published: November 2023

Objective:

This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension (PAH).

Methods:

Searches were conducted in Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1, 2022. The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. A network meta-analysis was performed using Stata 16.0 software. The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot, funnel plot, and surface under the cumulative ranking.

Results:

A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study. The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy. Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels. Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure, whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance. Bosentan in combination with tadalafil significantly improved the Borg dyspnea score, and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class. In terms of safety, there was no significant reduction in the incidence of adverse events, hospitalizations, or all-cause mortality for combination therapy compared with monotherapy. Bosentan combined with sildenafil significantly reduced the risk of serious adverse events, but the risk of discontinuation due to an adverse event was higher than monotherapy. Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH.

Conclusion:

Compared with monotherapy, targeted drug combinations for PAH significantly improves exercise tolerance, pulmonary hemodynamic parameters, and reduces the risk of serious adverse events and clinical worsening in patients. Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH. Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.
STAT3-CD163 cross-talk exhibits promising biomarkers for a progressive ischemic cardiomyopathy: integrative computational and gene expression profiling based on Gene Expression Omnibus datasets
Authors: Mohareb Mina W. , Kariem Mohammed A. , Tohamy Aly , Gamal Noha M. , Mosaad Rehab M. , Esmaiel Nora N. , Fayez Alaaeldin G.
Published: November 2023

Background and purpose:

Ischemic heart disease frequently leads to heart failure, often resulting in death. In this study, we aimed to identify common hub mRNAs and pathways involved in the pathological progression of ischemic cardiomyopathy (ICM).

Methods:

Validation quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out on peripheral blood and left ventricle specimens from patients in three groups with stable coronary artery disease (CAD), myocardial infarction (MI), and ICM and compared with corresponding controls. qRT-PCR was preceded by computational analysis of eight high-throughput RNA sequencing and microarray datasets from 499 patients and 233 controls, to determine possible common biologically meaningful differentially expressed genes (DEGs). To determine the potential pathological pathways, we performed Gene Ontology functional annotation, pathway enrichment analysis, protein–protein interaction (PPI) analysis, and constructed transcriptional factor/miRNA regulatory networks. Finally, approved drugs were screened.

Results:

Fifteen common DEGs with P < 0.01 were identified. STAT3, CEBPD, GLUL, and CD163 were hub-enriched mRNAs with an interaction score ≥ 0.50. Our qRT-PCR analysis showed an increased expression of STAT3 in all three patient groups and CD163, mainly in cardiac samples, in a remarkably ascending manner. Interaction modules showed co-regulators supporting high STAT3-CD163 connectivity, suggesting a potential role for STAT3-CD163 cross-talk-mediated inflammatory responses in ICM progression.

Conclusions:

Our results provided a novel perspective for understanding the underlying mechanisms of ICM progression and exploring new therapeutic agents.

Clinical trial registration:

URL: www.clinicaltrials.gov. Unique identifier: NCT05508269.
Travel for abortion care: implications for clinical practice
Authors: Lerma Klaira , Coplon Leah , Goyal Vinita
Published: November 2023

Purpose of review

Traveling long distances to obtain abortion care due to restrictions and scarce availability is associated with significant obstacles. We review clinical strategies that can facilitate abortion access and outline considerations to ensure person-centered and equitable care.

Recent findings

Establishing a patient's gestational duration prior to travel may be beneficial to ensure they are eligible for their desired abortion method at the preferred facility or to determine if a multiday procedure is required. If a local ultrasound cannot be obtained prior to travel, evidence demonstrates people can generally estimate their gestational duration accurately. If unable to provide care, clinicians should make timely referrals for abortion. Integration of telemedicine into abortion care is safe and well regarded by patients and should be implemented into service delivery where possible to reduce obstacles to care. Routine in-person follow-up care is not necessary. However, for those who want reassurance, formalized pathways to care should be established to ensure people have access to care in their community. To further minimize travel-related burdens, facilities should routinely offer information about funding and practical support, emotional support, and legal resources.

There are many opportunities to optimize clinical practice to support those traveling for abortion care.
Risk stratification of papillary thyroid cancers using multidimensional machine learning
Authors: Li Yuanhui , Wu Fan , Ge Weigang , Zhang Yu , Hu Yifan , Zhao Lingqian , Gou Wanglong , Shi Jingjing , Ni Yeqin , Li Lu , Fu Wenxin , Lin Xiangfeng , Yu Yunxian , Han Zhijiang , Chen Chuanghua , Xu Rujun , Zhang Shirong , Zhou Li , Pan Gang , Peng You , Mao Linlin , Zhou Tianhan , Zheng Jusheng , Zheng Haitao , Sun Yaoting , Guo Tiannan , Luo Dingcun
Published: November 2023

Background:

Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies with different risk levels. However, preoperative risk assessment of PTC is still a challenge in the worldwide. Here, we first report a Preoperative Risk Assessment Classifier for PTC (PRAC-PTC) by multidimensional features including clinical indicators, immune indices, genetic feature, and proteomics.

Materials and methods:

The 558 patients collected from June 2013 to November 2020 were allocated to three groups: discovery set (274 patients, 274 FFPE), retrospective test set (166 patients, 166 FFPE) and prospective test set (118 patients, 118 FNA). Proteomic profiling was conducted by formalin-fixed paraffin-embedded (FFPE) and fine-needle aspiration (FNA) tissues from the patients. Preoperative clinical information and blood immunological indices were collected. The BRAF
V600E mutation were detected by the amplification refractory mutation system (ARMS).

Results:

We developed a machine learning model of 17 variables based on multidimensional features of 274 PTC patients from a retrospective cohort. The PRAC-PTC achieved areas under the curve (AUC) of 0.925 in the discovery set and validated externally by blinded analyses in a retrospective cohort of 166 PTC patients (0.787 AUC) and a prospective cohort of 118 PTC patients (0.799 AUC) from two independent clinical centres. Meanwhile, the preoperative predictive risk effectiveness of clinicians was improved with the assistance of PRAC-PTC, and the accuracies reached at 84.4% (95% CI 82.9-84.4) and 83.5% (95% CI 82.2-84.2) in the retrospective and prospective test sets, respectively.

Conclusion:

This study demonstrated that the PRAC-PTC that integrating clinical data, gene mutation information, immune indices, high-throughput proteomics and machine learning technology in multi-centre retrospective and prospective clinical cohorts can effectively stratify the preoperative risk of PTC and may decrease unnecessary surgery or overtreatment.
Bronchoscopic lung volume reduction in emphysema: a review
Authors: Ravikumar Nakul , Wagh Ajay , Holden Van K. , Hogarth D. Kyle
Published: November 2023

Purpose of review

Chronic obstructive pulmonary disease (COPD) poses a substantial burden on the healthcare system and is currently considered the sixth leading cause of death in the United States. Emphysema, as evidenced by severe air-trapping in patients with COPD, leads to significant dyspnea and morbidity. Lung volume reduction via surgery or minimally invasive endobronchial interventions are currently available, which improve lung function and quality of life.

Recent findings

Newer studies have noted a survival benefit in patients post bronchoscopic lung volume reduction vs. those subjected to standard of care. The presence of collateral ventilation is one of the most common impeding factors to placing endobronchial valves, and if placed, these patients might not achieve lobar atelectasis; however, there are newer modalities that are now available for patients with collateral ventilation which we have described.

Combining standard of care treatment that includes smoking cessation, bronchodilators, preventive care including vaccinations, pulmonary rehabilitation, and endobronchial treatment using various interventions in decreasing hyperinflation improves quality of life and may improve survival and hence significantly reduce the burden of COPD on healthcare.
The HIV-2 proviral landscape is dominated by defective proviruses
Authors: Koofhethile Catherine K. , Gao Ce , Chang Charlotte , Lian Xiaodong , Shapiro Roger , Yu Xu G. , Lichterfeld Mathias , Kanki Phyllis J.
Published: November 2023

Background:

Compared with HIV-1 infection, HIV-2 infection is associated with a slower progression to AIDS. Understanding the persistence of HIV-2 infection might inform the mechanisms responsible for differences in the pathogenicity of HIV-2 versus HIV-1.

Methods:

In this study, we analyzed the genetic composition of the proviral reservoir in archived blood samples collected from 13 untreated HIV-2-infected adults from Senegal. We used single-genome, near-full-length individual proviral sequencing (FLIP-Seq) to assess the relative frequency of intact and defective proviruses.

Results:

Ten out of 13 (77%) study participants demonstrated virologic suppression (<90 HIV RNA copies/ml) while the remaining 3 (23%) had detectable HIV RNA. We obtained 363 proviral sequences from peripheral blood mononuclear cells (PBMCs) from the 13 study participants. Within these sequences, 342 (94%) defective proviruses were detected. Twenty-one (6%) intact proviruses were detected from three study participants, with one study participant displaying a large clone consisting of 16 genome-intact sequences.

Conclusion:

This data suggests that similar to HIV-1 infection, the proviral landscape of HIV-2 is dominated by defective proviruses.
Parasite-mediated predation determines the infection in a complex predator-prey system
Authors: Híjar-Islas Ana C. , Milne Amy , Eizaguirre Christophe , Huang Weini
Published: November 2023

The interplay of host-parasite and predator-prey interactions is critical in ecological dynamics because both predators and parasites play an important role in regulating populations and communities. But what is the prevalence of infected prey and predators when a parasite is transmitted through trophic interactions, particularly when stochastic fluctuations of demographical changes are allowed arising from individual-level dynamics? Here, we analysed the system stability and the frequency of infected and uninfected host subpopulations in a complex predator-prey-parasite system, where infection happens through trophic interactions transmitting parasites from prey to predators. We varied the parasite virulence implemented as reproductive costs imposed on infected hosts and the probabilities of parasites infecting the hosts per encounter, to investigate how those important evolutionary factors will determine the species coexistence and population composition. We further explored the role of stochasticity in our system by comparing our deterministic analysis with stochastic simulations. Our results show that parasites go extinct when the infection probabilities of either host are small. The success in infecting the final host (the predator) is more critical for the survival of the parasite species, as the threshold for infection probability of the predator is higher than that of the prey for three-species coexistence. While our stochastic simulations agree with deterministic predictions well in most parameter regions. However, in the border parameter regions between coexistence and extinction typically with high infection probabilities, while only one possible outcome in deterministic dynamics, both coexistence and extinction can happen in stochastic repeats under the same parameter values. This illustrates the importance of stochasticity and demographic fluctuations in species coexistence. In addition, the proportion of infected individuals increases with the infection probabilities in our deterministic analysis and stochastic simulations as expected. Interestingly, we found that in some parameter space, the relative frequencies of infected and uninfected individuals are different between the intermediate host (prey) and the final host (predator) populations. This counterintuitive observation shows that the interplay of host-parasite and predator-prey interactions lead to more complex dynamics than a simple resource-consumer relationship.
What has changed in 20 years? Structure and function of soft-sediment macrofauna in a subarctic embayment, Newfoundland (Canada)
Authors: Komendić Ivana , de Moura Neves Bárbara , Ramey-Balci Patricia A.
Published: November 2023

Understanding how natural and anthropogenic disturbances affect the structure and functioning of marine ecosystems and their associated services is central to predicting future dynamics. Placentia Bay is an Ecologically and Biologically Significant Area (EBSA) in the north Atlantic exposed to multiple stressors. To investigate changes in the community and functional structure of soft-sediment macrofauna as well as environmental drivers of observed variation, we compared contemporary (2019–2020) and historical (1998) samples at eight stations (n=77) collected 21 years apart. Although community and functional structure significantly differed between these two time points, functional traits were maintained (i.e., no loss of 36 trait modalities). Thirty-seven percent of species/taxa where only observed in either the historical or contemporary community, and the contemporary community exhibited a lower density of macrofauna but had similar richness, resulting in higher evenness and diversity. Highly tolerant subsurface deposit feeders having small body sizes (<10mm) and direct development dominated the historical community, whereas the contemporary community had nearly equal proportions of surface and subsurface deposit feeders with small to medium body sizes (<10–50 mm) with pelagic larvae, and the proportion of highly tolerant species/taxa was reduced. These changes likely reflect the large reduction in polychaetes (91 vs. 58%) and increased bivalves (4 vs. 25%) relative to the historical time point. Community variation was driven by changes in the sedimentary habitat. Contemporary versus historical sediments were ∼4.5x coarser and had higher levels of sedimentary organic matter. This work contributes to advancing our understanding of relationships between benthic macrofauna, functional traits, and the sedimentary habitat in coastal environments.
FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma
Authors: Gillis Katherine , Orellana Walter A. , Wilson Emily , Parnell Timothy J. , Fort Gabriela , Dadzie Headtlove Essel , Zhang Xiaoyang , Snyder Eric L.
Published: November 2023

The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric identity. AfterNkx2-1deletion, FoxA1/2 mediate demethylation of gastric-defining genes through recruitment of TET3, an enzyme that induces DNA demethylation. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of regulatory elements and their 3D interactions at gastric loci. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.
Glucose Challenge Uncovers Temporal Fungibility of Metabolic Homeostasis over a day:night cycle
Authors: Malik Dania M. , Rhoades Seth D. , Zhang Shirley L. , Sengupta Arjun , Barber Annika , Haynes Paula , Arnadottir Erna Sif , Pack Allan , Kibbey Richard G. , Kain Pinky , Sehgal Amita , Weljie Aalim M.
Published: November 2023

Rhythmicity is a cornerstone of behavioral and biological processes, especially metabolism, yet the mechanisms behind metabolite cycling remain elusive. This study uncovers a robust oscillation in key metabolite pathways downstream of glucose in humans. A purpose-built13C6-glucose isotope tracing platform was used to sampleDrosophilaevery 4h and probe these pathways, revealing a striking peak in biosynthesis shortly after lights-on in wild-type flies. A hyperactive mutant (fumin) demonstrates increased Krebs cycle labelling and dawn-specific glycolysis labelling. Surprisingly, neither underlying feeding rhythms nor the presence of food availability explain the rhythmicity of glucose processing across genotypes, suggesting a robust internal mechanism for metabolic control of glucose processing. These results align with clinical data highlighting detrimental effects of mistimed energy intake. Our approach offers a unique insight into the dynamic range of daily metabolic processing and provides a mechanistic foundation for exploring circadian metabolic homeostasis in disease contexts.
Altered Metabolism During the Dark Period inDrosophilaShort Sleep Mutants
Authors: Malik Dania M. , Sengupta Arjun , Sehgal Amita , Weljie Aalim M.
Published: November 2023

Sleep is an almost universally required state in biology. Disrupted sleep has been associated with adverse health risks including metabolic perturbations. Sleep is in part regulated via circadian mechanisms, however, metabolic dysfunction at different times of day arising from sleep disruption is unclear. We used targeted liquid chromatography-mass spectrometry to probe metabolic alterations using high-resolution temporal sampling of twoDrosophilashort sleep mutants,fuminandsleepless, across a circadian day. Discriminant analyses revealed overall distinct metabolic profiles for mutants when compared to a wild type dataset. Altered levels of metabolites involved in nicotinate/nicotinamide, alanine, aspartate, and glutamate, glyoxylate and dicarboxylate metabolism, and the TCA cycle were observed in mutants suggesting increased energetic demands. Furthermore, rhythmicity analyses revealed fewer 24 hr rhythmic metabolites in both mutants. Interestingly, mutants displayed two major peaks in phases while wild type displayed phases that were less concerted. In contrast to 24 hr rhythmic metabolites, an increase in the number of 12 hr rhythmic metabolites was observed infuminwhilesleeplessdisplayed a decrease. These results support that decreased sleep alters the overall metabolic profile with short sleep mutants displaying altered metabolite levels associated with a number of pathways in addition to altered neurotransmitter levels.
A foundation model for bioactivity prediction using pairwise meta-learning
Authors: Feng Bin , Liu Zequn , Huang Nanlan , Xiao Zhiping , Zhang Haomiao , Mirzoyan Srbuhi , Xu Hanwen , Hao Jiaran , Xu Yinghui , Zhang Ming , Wang Sheng
Published: November 2023

Compound bioactivity plays an important role in different stages of drug development and discovery. Existing machine learning approaches have poor generalization ability in compound bioactivity prediction due to the small number of compounds in each assay and incompatible measurements among assays. Here, we propose ActFound, a foundation model for bioactivity prediction trained on 2.3 million experimentally-measured bioactivity compounds and 50, 869 assays from ChEMBL and BindingDB. The key idea of ActFound is to employ pairwise learning to learn the relative value differences between two compounds within the same assay to circumvent the incompatibility among assays. ActFound further exploits meta-learning to jointly optimize the model from all assays. On six real-world bioactivity datasets, ActFound demonstrates accurate in-domain prediction and strong generalization across datasets, assay types, and molecular scaffolds. We also demonstrated that ActFound can be used as an accurate alternative to the leading computational chemistry software FEP+(OPLS4) by achieving comparable performance when only using a few data points for fine-tuning. The promising results of ActFound indicate that ActFound can be an effective foundation model for a wide range of tasks in compound bioactivity prediction, paving the path for machine learning-based drug development and discovery.
Improved detection of methylation in ancient DNA
Authors: Sawyer Susanna , Gelabert Pere , Yakir Benjamin , Lizcano Alejandro Llanos , Sperduti Alessandra , Bondioli Luca , Cheronet Olivia , Neugebauer-Maresch Christine , Teschler-Nicola Maria , Novak Mario , Pap Ildikó , Szikossy Ildikó , Hajdu Tamás , Meshorer Eran , Carmel Liran , Pinhasi Ron
Published: November 2023

Reconstructing premortem DNA methylation levels in ancient DNA (aDNA) has led to breakthrough studies such as the prediction of anatomical features of the Denisovan, as well as the castration status of ancient horses. These studies relied on computationally inferring methylation levels from damage signals in naturally deaminated cytosines. Because of statistical constraints, this inference requires high-coverage sequencing, and is thus not only expensive but also restricted to samples with exceptional DNA preservation. Instead, a method to directly measure methylation levels in aDNA, as exists in modern DNA samples, would open the door to a more thorough and cost effective ability to study ancient DNA methylation. We have tested two methods for direct methylation measurement developed for modern DNA based on either bisulfite or enzymatic methylation treatments. We find that both methods preserve sufficient DNA yields to allow for methylation measurement. Bisulfite treatment, combined with a single stranded library preparation, shows the least reduction in DNA yields compared to no methylation treatment, as well as the least biases during methylation conversion. In addition, we show that applying bisulfite treatment to ∼0.4-fold coverage sample provides a methylation signal that is comparable to, or even better, than the computationally inferred one. We thus present a method to directly measure methylation in ancient DNA that is cost effective and can be used on a wide variety of ancient samples.
Encoding of the colorectal cancer metabolic program through MICU2
Authors: Robert Alison , Crottès David , Bourgeais Jérôme , Gueguen Naig , Chevrollier Arnaud , Dumas Jean-François , Servais Stéphane , Domingo Isabelle , Chadet Stéphanie , Sobilo Julien , Hérault Olivier , Lecomte Thierry , Vandier Christophe , Raoul William , Guéguinou Maxime
Published: November 2023

The mitochondrial Ca2+uniporter (MCU) plays crucial role in intramitochondrial Ca2+uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration usingin vitroandin vivomodels of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming.

Highlights

MICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation

MICU2 stabilizes the mitochondrial network and endoplasmic reticulum–mitochondrial calcium flux

MICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer

Graphical Abstract
Network size affects the complexity of activity in human iPSC-derived neuronal populations
Authors: Uzun Yavuz Selim , Santos Renata , Marchetto Maria C. , Padmanabhan Krishnan
Published: November 2023

Multi-electrode recording of neural activity in cultures offer opportunities for understanding how the structure of a network gives rise to function. Although it is hypothesized that network size is critical for determining the dynamics of activity, this relationship in human neural cultures remains largely unexplored. By applying new methods for analyzing neural activity to human iPSC derived cultures at either low-densities or high-densities, we uncovered the significant impacts that neuron number has on the individual neurophysiological properties of cells (such as firing rates), the collective behavior of the networks these cultures formed (as measured by entropy), and the relationship between the two. As a result, simply changing the densities of neurons generated dynamics and network behavior that differed not just in degree, but in kind. Beyond revealing the relationship between network structure and function, our findings provide a novel analytical framework to study diseases where network level activity is affected.
E4F1 and ZNF148 are transcriptional activators of the −57A > C and wild-typeTERTpromoter
Authors: Chua Boon Haow , Zaal Anuar Nurkaiyisah , Ferry Laure , Domrane Cecilia , Wittek Anna , Mukundan Vineeth T. , Jha Sudhakar , Butter Falk , Tenen Daniel G. , Defossez Pierre-Antoine , Kappei Dennis
Published: November 2023

Point mutations within theTERTpromoter are the most recurrent somatic noncoding mutations identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma, and bladder cancer. They are most abundant at −146C > T and −124C > T, and rarer at −57A > C, with the latter originally described as a familial case, but subsequently shown also to occur somatically. All three mutations create de novo E26-specific (ETS) binding sites and result in activation of theTERTgene, allowing cancer cells to achieve replicative immortality. Here, we used a systematic proteomics screen to identify transcription factors preferentially binding to the −146C > T, −124C > T, and −57A > C mutations. Although we confirmed binding of multiple ETS factors to the mutant −146C > T and −124C > T sequences, we identified E4F1 as a −57A > C–specific binder and ZNF148 as aTERTwild-type (WT) promoter binder that showed reduced interaction with the −124C > T allele. Both proteins are activating transcription factors that bind specifically to the −57A > C and WT (at position 124)TERTpromoter sequence in corresponding cell lines, and up-regulateTERTtranscription and telomerase activity. Our work describes new regulators ofTERTgene expression with possible roles in cancer.
How product hedonism affects the Country-of-Origin effect on product perceived quality and price in the China market
Authors: Chow Clement S.F. , Chow Wing Chi , Leong Weng I. , Zheng Shizhe
Published: November 2023

Purpose

Western manufacturers have often benefited from the Country-of-Origin (COO) effect when a product is launched into emerging markets. The authors examine if this still holds true in the China market. The authors believe that the degree of perceived hedonism associated with the product does matter and, therefore, conducted an experiment to test how this influences the effect of COO on perceived quality and price of the product. This paper aims to discuss the aforementioned objective.

Design/methodology/approach

A lab experiment with a 2 (COO: Western vs. Local) x 2 (Hedonism: High vs. Low) factorial design was conducted with Chinese consumers as subjects. The dependent variables were perceived quality and price of the products.

Findings

It was found that Western COO has a positive effect on the product perceived quality and price in the China market, but the effect was significantly moderated by the degree of perceived hedonism of the products.

Originality/value

The study used an experiment to investigate the different prominence of the COO effect on perceived quality and price in terms of hedonic vs. utilitarian products which has not been done previously. The findings provide implications concerning allocation of marketing resources to product positioning in the presence of different degrees of perceived hedonism and suggest additional areas for future examination.
The moderating effect of environmental performance on the relationship between sustainability assurance quality and firm value: a simultaneous equations approach
Authors: Kheireddine Hanene , Lacombe Isabelle , Jarboui Anis
Published: November 2023

Purpose

This study elucidates the interactive relationship of sustainability assurance (SA) quality with corporate environmental sustainability performance (CESP) and firm value and explores the moderating impact of CESP on the SA quality–firm value relationship.

Design/methodology/approach

The sample comprises 320 firm-year observations of 40 companies listed on the Cotation Assistée en Continu (CAC 40) from 2010 to 2019. The authors use the simultaneous equations model to capture the CESP and SA quality–firm value relationship and apply the three-stage regression and generalised method of moments approaches to address possible endogeneity.

Findings

The results show that CESP, as assessed by International Organisation for Standardisation (ISO) 14001 certification, has a significant positive effect on firm value, the relevance of which implies that in the case of good environmental performance, society's perception of a firm is much more favourable; consequently, the firm is likely to be rewarded with a premium value in capital markets. In addition, environmental performance has a stronger interaction with SA quality, acting as a moderator variable; thus, greater SA quality signals credibility owing to increased eco-efficiency. The authors interpret their findings within a multi-theoretical framework that draws insights from legitimacy, stakeholders and signalling theoretical perspectives.

Originality/value

This study contributes to the literature by re-examining the relationship between SA quality and firm value. It also provides new evidence of the moderating effect of CESP on the SA quality–firm value nexus. Specifically, this study explores the joint effects of credibility and eco-efficiency on market confidence in sustainability information. The authors use a simultaneous equation model to capture the reciprocal association between SA quality and firm value, whereas prior studies on SA quality and market performance have frequently used single-equation regression. The authors also find that CESP positively moderates the relationship between SA quality and firm value. Including CESP and exploring the moderating impact of eco-efficiency on the SA quality–firm value relationship is a novel approach.