bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-species proteomic and microRNA comparison of extracellular vesicles in human milk, cow’s milk, and infant formula products: moving towards next generation infant formula products
Authors: Turner Natalie P. , Abeysinghe Pevindu , Sadowski Pawel , Mitchell Murray D. 
Published: February 2023

AbstractMilk and milk products such as infant formula (IF) play a fundamental role in serving the nutritional needs of the developing infant. Extracellular vesicles (EVs) in human (HM) and cow’s milk (CM) contain molecular cargo such as proteins and micro(mi)RNA that serve as functional messengers between cells and may be of importance to infant health. Here, we have developed a pipeline using advanced proteomics and transcriptomics to enable cross-species comparison of milk and IF EVs. EVs from HM, CM and IF were subjected to data-independent acquisition mass spectrometry and RNA-seq. Differentially abundant proteins (143) and miRNAs (514) were identified in HM and CM EVs, and CM EV proteins and miRNAs were preserved in IF EVs (∼20% protein; ∼90% miRNA). We foresee this work to be used in large scale studies to determine biologically relevant species-specific differences in milk EVs that could be leveraged to improve IF products.
Elucidation of Genome-wide Understudied Proteins targeted by PROTAC-induced degradation using Interpretable Machine Learning
Authors: Xie Li , Xie Lei 
Published: February 2023

AbstractProteolysis-targeting chimeras (PROTACs) are hetero-bifunctional molecules. They induce the degradation of a target protein by recruiting an E3 ligase to the target. The PROTAC can inactivate disease-related genes that are considered as understudied, thus has a great potential to be a new type of therapy for the treatment of incurable diseases. However, only hundreds of proteins have been experimentally tested if they are amenable to the PROTACs. It remains elusive what other proteins can be targeted by the PROTAC in the entire human genome. For the first time, we have developed an interpretable machine learning model PrePROTAC, which is based on a transformer-based protein sequence descriptor and random forest classification to predict genome-wide PROTAC-induced targets degradable by CRBN, one of the E3 ligases. In the benchmark studies, PrePROTAC achieved ROC-AUC of 0.81, PR-AUC of 0.84, and over 40% sensitivity at a false positive rate of 0.05, respectively. Furthermore, we developed an embedding SHapley Additive exPlanations (eSHAP) method to identify positions in the protein structure, which play key roles in the PROTAC activity. The key residues identified were consistent with our existing knowledge. We applied PrePROTAC to identify more than 600 novel understudied proteins that are potentially degradable by CRBN, and proposed PROTAC compounds for three novel drug targets associated with Alzheimer’s disease.Author SummaryMany human diseases remain incurable because disease-causing genes cannot by selectively and effectively targeted by small molecules. Proteolysis-targeting chimera (PROTAC), an organic compound that binds to both a target and a degradation-mediating E3 ligase, has emerged as a promising approach to selectively target disease-driving genes that are not druggable by small molecules. Nevertheless, not all of proteins can be accommodated by E3 ligases, and be effectively degraded. Knowledge on the degradability of a protein will be crucial for the design of PROTACs. However, only hundreds of proteins have been experimentally tested if they are amenable to the PROTACs. It remains elusive what other proteins can be targeted by the PROTAC in the entire human genome. In this paper, we propose an intepretable machine learning model PrePROTAC that takes advantage of powerful protein language modeling. PrePROTAC achieves high accuracy when evaluated by an external dataset which comes from different gene families from the proteins in the training data, suggesting the generalizability of PrePROTAC. We apply PrePROTAC to the human genome, and identify more than 600 understudied proteins that are potentially responsive to the PROTAC. Furthermore, we design three PROTAC compounds for novel drug targets associated with Alzheimer’s disease.
SNP discovery and analysis of genetic diversity between commercial crossbred and indigenous chickens from three different agro-ecological zones using DArT-Seq technology
Authors: Adomako Kwaku , Sovi Selorm , Kyei Bismark , Hamidu Jacob Alhassan , Olympio Oscar Simon , Aggrey Samuel E. 
Published: February 2023

AbstractIndigenous and commercial chickens have developed unique adaptations to their environments, which may include nutrition, pathogens, and thermal stress. Besides, environmental pressures and artificial selection have generated significant genome-wide divergence in chickens, as those selection pressures contribute a considerable evolutionary force to phenotypic and genotypic differentiation. Herein, we determined genomic diversity of indigenous chickens from semi-deciduous rainforest (SDR), coastal savannah (CC) and Guinea savannah (GS) agro-ecological zones (AEZs) in Ghana and commercial crossbreds reared at the Kwame Nkrumah University of Science and Technology (KNUST). We generated SNP markers from 82 chickens (62 indigenous chicken ecotypes and 26 commercial crossbred ecotype) using DArT-Seq technology. A total of 85,396 SNP markers were generated and after filtering the data, 58,353 markers were used to study genetic diversity and population structure analyses. Polymorphism information content (PIC) values ranged from 0.0 to 0.5, with 21,285 SNP markers (35%) being in the lowest PIC value range (0 to 0.15) while 13,511 (21%) were in the highest PIC value range (0.45 to 0.50). Between the KNUST population and the indigenous ecotypes, pairwise FSTvalues were estimated to be 0.105 between CS, 0.096 between SDF, and 0.133 between GS. Furthermore, PCA analysis showed that the CC, SDF and GS chickens clustered together and are genetically distant from the commercial crossbred. We herein show that chickens from the AEZs studied can be considered as one population. However, due the abundance of agro-byproducts in the SDR compared to the CS and GS, chickens from the SDR AEZ had better growth compared to their counterparts. It is suggested that the genetic diversity within the local ecotypes could form the basis for genetic improvement.
Optimized SMRT-UMI protocol produces highly accurate sequence datasets from diverse populations – application to HIV-1 quasispecies
Authors: Westfall Dylan H. , Deng Wenjie , Pankow Alec , Murrell Hugh , Chen Lennie , Zhao Hong , Williamson Carolyn , Rolland Morgane , Murrell Ben , Mullins James I. 
Published: February 2023

AbstractPathogen diversity resulting in quasispecies can enable persistence and adaptation to host defenses and therapies. However, accurate quasispecies characterization can be impeded by errors introduced during sample handling and sequencing which can require extensive optimizations to overcome. We present complete laboratory and bioinformatics workflows to overcome many of these hurdles. The Pacific Biosciencessinglemoleculereal-time platform was used to sequence PCR amplicons derived from cDNA templates tagged withuniversalmolecular identifiers (SMRT-UMI). Optimized laboratory protocols were developed through extensive testing of different sample preparation conditions to minimize between-template recombination during PCR and the use of UMI allowed accurate template quantitation as well as removal of point mutations introduced during PCR and sequencing to produce a highly accurate consensus sequence from each template. Handling of the large datasets produced from SMRT-UMI sequencing was facilitated by a novel bioinformatic pipeline, Probabilistic Offspring Resolver for Primer IDs (PORPIDpipeline), that automatically filters and parses reads by sample, identifies and discards reads with UMIs likely created from PCR and sequencing errors, generates consensus sequences, checks for contamination within the dataset, and removes any sequence with evidence of PCR recombination or early cycle PCR errors, resulting in highly accurate sequence datasets. The optimized SMRT-UMI sequencing method presented here represents a highly adaptable and established starting point for accurate sequencing of diverse pathogens. These methods are illustrated through characterization of human immunodeficiency virus (HIV) quasispecies.Author SummaryThere is a great need to understand the genetic diversity of pathogens in an accurate and timely manner, but many errors can be introduced during the sample handling and sequencing steps which may prevent accurate analyses. In some cases, the errors introduced during these steps can be indistinguishable from real genetic variation and prevent analyses from identifying true sequence variation present in the pathogen population. There are established methods which can help to prevent these types of errors, but can involve many different steps and variables, all of which must be optimized and tested together to ensure the desired effect. Here we show results from testing different methods on a set of HIV+ blood plasma samples and arrive at a streamlined laboratory protocol and bioinformatic pipeline which prevents or corrects for different types of errors that can arise in sequence datasets. These methods should be an accessible starting point for anyone wanting accurate sequencing without extensive optimizations.
Intraluminal neutrophils limit epithelium damage by reducing pathogen assault on intestinal epithelial cells duringSalmonellagut infection
Authors: Gül Ersin , Fattinger Stefan A. , Nguyen Bidong D. , Hausmann Annika , Furter Markus , Barthel Manja , Sellin Mikael E. , Hardt Wolf-Dietrich 
Published: February 2023

SummaryRecruitment of neutrophils into the gut epithelium is a cardinal feature of intestinal inflammation in response to enteric infections. Previous work using the model pathogenSalmonellaTyphimurium (S. Tm) established that invasion of intestinal epithelial cells byS.Tm leads to recruitment of neutrophils into the gut lumen, where they can reduce pathogen loads transiently. Notably, a fraction of the pathogen population can survive this defense, re-grow to high density, and continue triggering enteropathy. However, the functions of intraluminal neutrophils in the defense against enteric pathogens and their effects on preventing or aggravating epithelial damage are still not fully understood. Here, we address this question via neutrophil depletion in different mouse models ofSalmonellacolitis, which differ in their degree of enteropathy. In an antibiotic pre-treated mouse model, neutrophil depletion by an anti-Ly6G antibody exacerbated epithelial damage. This could be linked to compromised neutrophil-mediated elimination and reduced physical blocking of the gut-luminalS.Tm population such that the pathogen density remained high near the epithelial surface throughout the infection. The removal of luminalS. Tm by gentamicin, an antibiotic restricted to the gut lumen, reversed the effect of neutrophil depletion on epithelial cell loss. Strikingly, when using germ-free mice and anS. TmssaVmutant capable of epithelium invasion, but attenuated for survival and growth within host tissues, neutrophil depletion caused exacerbated immune activation of the gut mucosa and a complete destruction of the epithelial barrier. Together, our data indicate that intraluminal neutrophils are central for maintaining epithelial barrier integrity during acuteSalmonella-induced gut inflammation, by limiting the sustained pathogen assault on the epithelium in a critical window of the infection.Highlights○After the first wave of mucosal invasion (day 1 p.i.),S. Tm maintains the assault from the lumen, triggering the continued expulsion of epithelial cells in antibiotic pre-treated mice.○Neutrophil recruitment into the gut lumen is essential to limit this continuedSalmonellaattack on the epithelium.○In antibiotic pre-treated SPF mice, neutrophil depletion exacerbatesS. Tm invasion, causing excessive epithelial cell loss, which compromises epithelial barrier integrity at later time points (day 2-3 p.i.).○In germ-free mice, neutrophil depletion exacerbates epithelial responses and epithelial barrier destruction even more strongly than in streptomycin pre-treated SPF mice.○Gentamicin treatment andssaVmutant infections indicate that neutrophils prevent epithelial damage by eliminating and physically blocking gut-luminal pathogens.
EXO1-mediated DNA repair by single-strand annealing is essential for BRCA1-deficient cells
Authors: van de Kooij B. , Schreuder A. , Pavani R.S. , Garzero V. , Van Hoeck A. , San Martin Alonso M. , Koerse D. , Wendel T.J. , Callen E. , Boom J. , Mei H. , Cuppen E. , Nussenzweig A. , van Attikum H. , Noordermeer S.M. 
Published: February 2023

SummaryDeficiency for the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) leads to chromosomal instability and diseases such as cancer. Yet, defective HR also results in vulnerabilities that can be exploited for targeted therapy. Here, we identify such a vulnerability and show that BRCA1-deficient cells are dependent on the long-range end-resection factor EXO1 for survival. EXO1 loss results in DNA replication-induced lesions decorated by poly(ADP-ribose)-chains. In cells that lack both BRCA1 and EXO1, this is accompanied by unresolved DSBs due to impaired single-strand annealing (SSA), a DSB repair process that requires the activity of both proteins. In contrast, BRCA2-deficient cells have increased SSA, also in the absence of EXO1, and hence are not dependent on EXO1 for survival. In agreement with our mechanistic data, BRCA1-mutated tumours have elevatedEXO1expression and contain more genomic signatures of SSA compared to BRCA1-proficient tumours. Collectively, our data indicate that EXO1 is a promising novel target for treatment of BRCA1-deficient tumours.
Multiviral Quartet Nanocages Elicit Broad Anti-Coronavirus Responses for Proactive Vaccinology
Authors: Hills Rory A. , Tan Tiong Kit , Cohen Alexander A. , Keeffe Jennifer R. , Keeble Anthony H. , Gnanapragasam Priyanthi N.P. , Storm Kaya N. , Hill Michelle L. , Liu Sai , Gilbert-Jaramillo Javier , Afzal Madeeha , Napier Amy , James William S. , Bjorkman Pamela J. , Townsend Alain R. , Howarth Mark 
Published: February 2023

AbstractDefending against future pandemics may require vaccine platforms that protect across a range of related pathogens. The presentation of multiple receptor-binding domains (RBDs) from evolutionarily-related viruses on a nanoparticle scaffold elicits a strong antibody response to conserved regions. Here we produce quartets of tandemly-linked RBDs from SARS-like betacoronaviruses coupled to the mi3 nanocage through a SpyTag/SpyCatcher spontaneous reaction. These Quartet Nanocages induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented on the vaccine. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increased the strength and breadth of an otherwise narrow immune response. Quartet Nanocages are a strategy with potential to confer heterotypic protection against emergent zoonotic coronavirus pathogens and facilitate proactive pandemic protection.One Sentence SummaryA vaccine candidate with polyprotein antigens displayed on nanocages induces neutralizing antibodies to multiple SARS-like coronaviruses.
FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations
Authors: Godoy-Corchuelo Juan M. , Ali Zeinab , Martins-Bach Aurea B. , Garcia-Toledo Irene , Fernández-Beltrán Luis C. , Nair Remya R. , Spring Shoshana , Nieman Brian J. , Jimenez-Coca Irene , Bains Rasneer S. , Forrest Hamish , Lerch Jason P. , Miller Karla , Fisher Elizabeth M.C. , Cunningham Thomas J. , Corrochano Silvia 
Published: February 2023

ABSTRACTFUS (Fused in sarcoma) is a ubiquitously expressed DNA/RNA binding protein. Mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. While most studies have focused on the role of FUS in motor neuron degeneration, little is known about the effect ofFUSmutations in the whole body, and the impact ofFUSmutations in the correct development of the nervous system. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the FUSDelta14 mutation in homozygosity. RNA sequencing was conducting in six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) to identify the genes and pathways altered by the FUSDelta14 mutant protein in the systemic transcriptome. Additionally, brain structural magnetic resonance imaging (MRI) and histological characterisation was conducted in young mice to study the role of FUS mutation in the brain development. FUS mutant protein was upregulated and mislocalised in the cytoplasm in most cells of the tissues analysed. We identified few genes commonly altered in all tissues by this mutation, although most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We demonstrated that the disease aetiology of FUS mutations can include neurodevelopmental and systemic alterations, which should be taken into consideration in the clinic.
A dynamic analysis of a prey–predator population model with a nonlinear harvesting rate
Authors: Mohdeb Nadia 
Published: February 2023

PurposeIn this article, the author discusses dynamical behaviors of a prey-predator population model with nonlinear harvesting rate and offers a mathematical analysis of the model.Design/methodology/approachThe design is by using modelization of populations interaction, qualitative theory of ordinary différential equations, bifurcations analysis, invariant center manifolds theory and Dulac's criterion.FindingsThe author studies the stability of solutions and the existence of periodic solutions in the model, and proves the existence of some invariant sets and the production of a transcritical together with a saddle-node bifurcation.Practical implicationsThe author studies the effects of harvesting on the persistence and extinction properties and its influence in the perspectives of economic views.Originality/valueThe authors considers a predator–prey model with a new nonlinear form of harvesting rate. The author’s intention is to make conceptual adjustments to a well-known predator–prey model in order to incorporate the effects of harvesting.
Does environmental uncertainty drive the use of management control systems and innovation?
Authors: Luiz Thiago Tomaz , Beuren Ilse Maria 
Published: February 2023

PurposeThis paper analyzes the effects of environmental uncertainty on the use of Management Control Systems (MCS) and product and process innovation.Design/methodology/approachThe hypotheses were tested with data from a survey carried out with 140 managers of innovative Brazilian firms using structural equation modeling.FindingsThe analyzes show significant negative effects of environmental uncertainty on MCS use and non-significant ones on product and process innovation, which suggests that when environmental uncertainty increases, the MCS use decreases. In contrast, significant positive effects of MCS use on product and process innovation were found, despite environmental uncertainty permeating innovation. However, no mediating effect of the MCS use on the relationship between environmental uncertainty and innovation was observed.Research limitations/implicationsThis study presents implications to the management literature grounded on the Contingency Theory by pointing out negative effects of environmental uncertainty on MCS use and product and process innovation. This encourages research on other contingency factors that might be predictors of MCS use and innovation.Practical implicationsThe findings provide evidence that the analyzed organizational practices (MCS use and innovation) are conceived and implemented to disregard external stimuli, which may bring dysfunctional consequences that need to be monitored.Originality/valueThe study contributes by revealing that environmental uncertainty inhibits the MCS use and does not favor innovation. It was expected that MCS that produce information about the external environment would be valued and would have effects on the strategic planning in these firms.
Cultivating resilience among Hong Kong's underprivileged ethnic minority groups in the face of a pandemic through a social justice lens
Authors: Arat Gizem , Eryigit-Madzwamuse Suna , Hart Angie 
Published: February 2023

PurposeIn this study, the authors investigated ways to cultivate resilience through a social justice lens among ethnic minorities against COVID-19 in Hong Kong.Design/methodology/approachA qualitative (case study) methodology was adopted to interview 15 social service providers from diverse ethnic backgrounds serving disadvantaged ethnic minority groups (South and Southeast Asian groups from low-income households, foreign domestic workers and asylum seekers/refugees).FindingsTwo major protective factors were identified, contributing to the development of resilience among diverse ethnic groups: (1) individual-based resilience (including being optimistic) and (2) socio-environmental factors (including ongoing support from strong family, peer and religious settings' support, consulates' support, on-going material and nonmaterial donations, support of young volunteers and importance of online connection and communication) using the integration of resilience and social justice frameworks.Originality/valueThis study showed that the protective factors were found to dynamically interact with each other and the environment. The present study recommends additional culturally sensitive service and policy implications for preventing the long-term impact of mass crises among Hong Kong's marginalized minorities.