bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-6883 downregulates HIF1α in colorectal and breast cancer cells
Authors: Jensen-Velez Nicole , Carlsen Lindsey , El-Deiry Wafik 
Published: September 2023

AbstractColorectal cancer (CRC) and breast cancer (BC) are deadly diseases that rank as the second and fourth leading causes of cancer-related deaths, respectively. We have previously shown that miR-6883 targets CDK4/6 and that palbociclib-mediated CDK4/6 inhibition destabilizes HIF1α. We hypothesize that miR-6883 downregulates HIF1α in CRC and BC cells. miR-6883 was transfected under normoxia or hypoxia and western blot analysis revealed that miR-6883 downregulates CDK4/6 and HIF1α in CRC and BC cells, pointing to miR-6883 as a promising therapeutic to target hypoxic cancers or HIF1α-deregulated tumor cells. Future studies will further investigate miR-6883 as a cancer biomarker, effects on HIF–related proteins and therapeutic usesin vivo.Abstract FigureFigure 1.miR-6883 downregulates CDK4/6 and HIF1α in colorectal and breast cancer cellsA) Colorectal cancer cells were treated with doses of palbociclib ranging from 0-20 µM. Cell viability was measured by imaging the bioluminescent signal after addition of CellTiter-Glo reagent. B) Percent viability of colorectal cancer cells treated with palbociclib was calculated and nonlinear regression analysis was completed using GraphPad Prism software. C-H) CRC cells were transfected with miR-6883 under normoxia or hypoxia (<0.5% O2) and protein levels of CDK4/6, HIF1α, Glut1, and Ran were measured by Western blot.
Quantitative proteomics reveals tissue-specific, infection-induced and species-specific neutrophil protein signatures
Authors: Sollberger Gabriel , Brenes Alejandro J. , Warner Jordan , Arthur J. Simon C. , Howden Andrew J.M. 
Published: September 2023

SummaryNeutrophils are one of the first responders to infection and are a key component of the innate immune system through their ability to phagocytose and kill invading pathogens, secrete antimicrobial molecules and produce extracellular traps. Neutrophils are produced in the bone marrow, circulate within the blood and upon immune challenge migrate to the site of infection. We wanted to understand whether this transition shapes the mouse neutrophil protein landscape, how the mouse neutrophil proteome is impacted by systemic infection and perform a comparative analysis of human and mouse neutrophils. Using quantitative mass spectrometry we reveal tissue-specific, infection-induced and species-specific neutrophil protein signatures. We show a high degree of proteomic conservation between mouse bone marrow, blood and peritoneal neutrophils, but also identify key differences in the molecules that these cells express for sensing and responding to their environment. Systemic infection triggers a change in the bone marrow neutrophil population with considerable impact on the core machinery for protein synthesis and DNA replication along with environmental sensors. We also reveal profound differences in mouse and human blood neutrophils, particularly their granule contents. Our proteomics data provides a valuable resource for understanding neutrophil function and phenotypes across species and model systems.
Genomic, Functional, and Metabolic Enhancements in Multidrug-ResistantEnterobacter bugandensisFacilitating its Persistence and Succession in the International Space Station
Authors: Sengupta Pratyay , Sivabalan Shobhan Karthick Muthamilselvi , Singh Nitin Kumar , Raman Karthik , Venkateswaran Kasthuri 
Published: September 2023

AbstractBackgroundThe International Space Station (ISS) stands as a testament to human achievement in space exploration. Despite its highly controlled environment, characterised by microgravity, increased CO2levels, and elevated solar radiation, microorganisms occupy a unique niche. These microbial inhabitants play a significant role in influencing the health and well-being of astronauts on board. One microorganism of particular interest in our study isEnterobacter bugandensis, primarily found in clinical specimens including the human gastrointestinal tract, and also reported to possess pathogenic traits, leading to a plethora of infections.ResultsDistinct from their Earth counterparts, ISSE. bugandensisstrains have exhibited resistance mechanisms that categorize them within the ESKAPE pathogen group, a collection of pathogens recognized for their formidable resistance to antimicrobial treatments. During the two-year Microbial Tracking 1 mission, 12 strains of multidrug resistantE. bugandensiswere isolated from various locations within the ISS. We have carried out a comprehensive study to understand the genomic intricacies of ISS-derivedE. bugandensisin comparison to terrestrial strains, with a keen focus on those associated with clinical infections. We unravel the evolutionary trajectories of pivotal genes, especially those contributing to functional adaptations and potential antimicrobial resistance. A hypothesis central to our study was that the singular nature of the stresses of the space environment, distinct from any on Earth, could be driving these genomic adaptations. Extending our investigation, we meticulously mapped the prevalence and distribution ofE. bugandensisacross the ISS over time. This temporal analysis provided insights into the persistence, succession, and potential patterns of colonization ofE. bugandensisin space. Furthermore, by leveraging advanced analytical techniques, including metabolic modelling, we delved into the coexisting microbial communities alongsideE. bugandensisin the ISS across multiple missions and spatial locations. This exploration revealed intricate microbial interactions, offering a window into the microbial ecosystem dynamics within the ISS.ConclusionsOur comprehensive analysis illuminated not only the ways these interactions sculpt microbial diversity but also the factors that might contribute to the potential dominance and succession ofE. bugandensiswithin the ISS environment. The implications of these findings are two-fold. Firstly, they shed light on microbial behavior, adaptation, and evolution in extreme, isolated environments. Secondly, they underscore the need for robust preventive measures, ensuring the health and safety of astronauts by mitigating risks associated with potential pathogenic threats.
TheCandida albicansζ-crystallin homolog Zta1 promotes resistance to oxidative stress
Authors: Gandra Rafael M. , Johnson Chad J. , Nett Jeniel E. , Konopka James B. 
Published: September 2023

ABSTRACTThe fungal pathogenCandida albicansis capable of causing lethal infections in humans. Its pathogenic potential is due in part to the ability to resist various stress conditions in the host, including oxidative stress. Recent studies showed that a family of four flavodoxin-like proteins (Pst1, Pst2, Pst3, Ycp4) that function as quinone reductases promotes resistance to oxidation and is needed for virulence. Therefore, in this study Zta1 was examined because it belongs to a structurally distinct family of quinone reductases that are highly conserved in eukaryotes and have been called the ζ-crystallins. The levels of Zta1 inC. albicansrapidly increased after exposure to oxidants, consistent with a role in resisting oxidative stress. Accumulation of reactive oxygen species was significantly higher in cells lackingZTA1upon exposure to quinones and other oxidants. Furthermore, deletion ofZTA1in a mutant lacking the four flavodoxin-like proteins, resulted in further increased susceptibility to quinones, indicating that these distinct quinone reductases work in combination. These results demonstrate that Zta1 contributes toC. albicanssurvival after exposure to oxidative conditions, which increases the understanding of howC. albicansresists stressful conditions in the host.IMPORTANCECandida albicansis an important human pathogen that can cause lethal systemic infections. The ability ofC. albicansto colonize and establish infections is closely tied to its highly adaptable nature and capacity to resist various types of stress, including oxidative stress. Previous studies showed that fourC. albicansproteins belonging to the flavodoxin-like protein family of quinone reductases are needed for resistance to quinones and for virulence. Therefore, in this study we examined the role of a distinct type of quinone reductase, Zta1, and found that it acts in conjunction with the flavodoxin-like proteins to protect against oxidative stress.
Modelling Microtube Driven Invasion of Glioma
Authors: Hillen Thomas , Loy Nadia , Painter Kevin J. , Thiessen Ryan 
Published: September 2023

AbstractMalignant gliomas are notoriously invasive, a major impediment against their successful treatment. This invasive growth has motivated the use of predictive partial differential equation models, formulated at varying levels of detail, and including (i) “proliferation-infiltration” models, (ii) “go-or-grow” models, and (iii) anisotropic diffusion models. Often, these models use macroscopic observations of a diffuse tumour interface to motivate a phenomenological description of invasion, rather than performing a detailed and mechanistic modelling of glioma cell invasion processes. Here we close this gap. Based on experiments that support an important role played by long cellular protrusions, termed tumour microtubes, we formulate a new model for microtube-driven glioma invasion. In particular, we model a population of tumour cells that extend tissue-infiltrating microtubes. Mitosis leads to new nuclei that migrate along the microtubes and settle elsewhere. A combination of steady state analysis and numerical simulation is employed to show that the model can predict an expanding tumour, with travelling wave solutions led by microtube dynamics. A sequence of scaling arguments allows us reduce the detailed model into simpler formulations, including models falling into each of the general classes (i), (ii), and (iii) above. This analysis allows us to clearly identify the assumptions under which these various models can bea posteriorijustified in the context of microtube-driven glioma invasion. Numerical simulations are used to compare the various model classes and we discuss their advantages and disadvantages.
TGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirsin vivo
Authors: Kim Jinhee , Bose Deepanwita , Araínga Mariluz , Haque Muhammad R. , Fennessey Christine M , Caddell Rachel A , Thomas Yanique , Ferrell Douglas E , Ali Syed , Grody Emanuelle , Goyal Yogesh , Cicala Claudia , Arthos James , Keele Brandon F , Vaccari Monica , Lorenzo-Redondo Ramon , Hope Thomas J , Villinger Francois , Martinelli Elena 
Published: September 2023

AbstractHIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties ofin vivoTGF-β blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on ART were treated with four 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption (ATI). 7 out of 8 macaques rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with64Cu-DOTA-F(ab’)2-p7D3-probe. A decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk, and single-cell (sc)RNAseq revealed a shift toward an effector phenotype in T and NK cells characterized by a progressive downregulation in TCF1.In summary, we demonstrated that galunisertib, a clinical stage TGF-β inhibitor, reverses SIV latency and decreases SIV reservoirs by driving T cells toward an effector phenotype, enhancing immune responsesin vivoin absence of toxicity.One-sentence summaryTGF-β blockade drives an effector phenotype in immune cells leading to SIV latency reversal and enhanced immune responses in vivo.
In Vivo Biorthogonal Antibody Click for Dual Targeting and Augmented Efficacy in Cancer Treatment
Authors: Panikar Sandeep Surendra , Berry Na-Keysha , Shmuel Shayla , Keltee Nai , Pereira Patrícia M.R. 
Published: September 2023

ABSTRACTAntibody-drug conjugates (ADCs) have emerged as promising therapeutics for cancer treatment; however, their effectiveness has been limited by single antigen targeting, potentially leading to resistance mechanisms triggered by tumor compensatory pathways or reduced expression of the target protein. Here, we present antibody-ADC click, an approach that harnesses bioorthogonal click chemistry forin vivodual receptor targeting, irrespective of the levels of the tumor’s expression of the ADC-targeting antigen. Antibody-ADC click enables targeting heterogeneity and enhances antibody internalization and drug delivery inside cancer cells, resulting in potent toxicity. We conjugated antibodies and ADCs to the bioorthogonal click moieties tetrazine (Tz) and trans-cyclooctene (TCO). Through sequential antibody administration in living biological systems, we achieved dual receptor targeting byin vivoclicking of antibody-TCO with antibody-Tz. We show that the clicked antibody therapy outperformed conventional ADC monotherapy or antibody combinations in preclinical models mimicking ADC-eligible, ADC-resistant, and ADC-ineligible tumors. Antibody-ADC click enablesin vivodual-antigen targeting without extensive antibody bioengineering, sustains tumor treatment, and enhances antibody-mediated cytotoxicity.
Hydroxychloroquine and Zinc ameliorate interleukin-6 associated hepato-renal toxicity induced byAspergillus fumigatusin experimental models
Authors: Okoye Jude Ogechukwu , Basil Anslem Tochukwu , Okoli Onyedikachi , Achebe Precious Onyemaechi 
Published: September 2023

AbstractIn Nigeria, immunocompromised persons, particularly those living with HIV, are at an increased risk of developing invasive pulmonary aspergillosis caused byAspergillus fumigatus. Interestingly, this condition produces symptoms that can be easily mistaken for those of COVID-19. To better understand the pathophysiology of Aspergillosis and determine the therapeutic and toxic effects of Zinc and HCQ, this study examined liver and renal functions in experimental models. This experimental study included 28 Albino rats, assigned into 7 Groups (n= 4 each); designated A to G. Group A received the standardized rat chow and distilled water only. Group B received a moderate dose of HCQ only. Group C receivedA. fumigatussuspension (AFS) without any treatments. Group D simultaneously received AFS and a low dose of HCQ. Group E simultaneously received AFS and a moderate dose of HCQ. Group F simultaneously received AFS and a high dose of HCQ. Group G simultaneously received AFS and a moderate dose of HCQ and Zinc. Serum levels of interleukins (IL)-6 and 10, liver enzymes, and renal parameters were measured accordingly. The lungs, liver, and kidneys were excited and weighed. Significance was set at p< 0.05. Higher levels of serum alanine transaminase, creatinine, and urea and lower relative lung weight were observed in group C compared with other groups (p< 0.001). Higher IL-6 levels and IL-6/IL-10 ratio were also observed in group C compared with other groups (p> 0.05). In conclusion, this study revealed that HCQ and Zinc ameliorate oxidative stress and damage induced byA. fumigatus.
Macroevolutionary inference of complex modes of chromosomal speciation in a cosmopolitan plant lineage
Authors: Tribble Carrie M. , Márquez-Corro José Ignacio , May Michael R. , Hipp Andrew L. , Escudero Marcial , Zenil-Ferguson Rosana 
Published: September 2023

SummaryThe effects of single chromosome number change—dysploidy—mediating diversification remain poorly understood. Dysploidy modifies recombination rates, linkage, or reproductive isolation, especially for one-fifth of all eukaryote lineages with holocentric chromosomes. Dysploidy effects on diversification have not been estimated because modeling chromosome numbers linked to diversification with heterogeneity along phylogenies is quantitatively challenging.We propose a new state-dependent diversification model of chromosome evolution that links diversification rates to dysploidy rates considering heterogeneity and differentiates between anagenetic and cladogenetic changes. We apply this model toCarex(Cyperaceae), a cosmopolitan flowering plant clade with holocentric chromosomes.We recover two distinct modes of chromosomal evolution and speciation inCarex. In one diversification mode, dysploidy occurs frequently and drives faster diversification rates. In the other mode, dysploidy is rare and diversification is driven by hidden, unmeasured factors. When we use a model that excludes hidden states, we mistakenly infer a strong, uniform positive effect of dysploidy on diversification, showing that standard models may lead to confident but incorrect conclusions about diversification.This study demonstrates that dysploidy can have a significant role in large plant clade speciation despite the presence of other unmeasured factors that simultaneously affect diversification.
A potential space making role for a lytic transglycosylase in cell wall biogenesis revealed by a beta-lactamase induction phenotype inPseudomonas aeruginosa
Authors: Fumeaux Coralie , Bernhardt Thomas G. 
Published: September 2023

ABSTRACTPseudomonas aeruginosaencodes the beta-lactamase AmpC, which promotes resistance to beta-lactam antibiotics. Expression ofampCis induced by fragments of the peptidoglycan (PG) cell wall released upon beta-lactam treatment. These drugs target transpeptidase enzymes that form cell wall crosslinks. However, they do not block the activity of the transglycosylases that polymerize the glycan chains. Thus, drug-treated cells produce uncrosslinked PG polymers that have been shown to be rapidly degraded in the related gram-negative bacteriumEscherichia coli. This degradation is performed by enzymes called lytic transglycosylases (LTs), which generate the anhydro-muropeptide (AMP) products sensed by the AmpR regulator that activatesampCexpression. To identify factors required for proper PG biogenesis inP. aeruginosa, we used a reporter gene fusion to theampCpromoter to screen for mutants induced forampCexpression in the absence of drug. To our surprise, we found that inactivation of SltB1, an LT enzyme expected to produce the AMP products required forampCinduction, counterintuitively led to elevatedampCexpression. This induction required another LT enzyme called MltG, suggesting that inactivation of SltB1 reduces the efficiency of PG crosslinking, causing the degradation of a subset of nascent PG strands by MltG to generate the inducing signal. Our results therefore support a model in which SltB1 uses its LT activity to open space in the PG matrix for the efficient insertion of new material, a function commonly thought to be restricted to endopeptidases that cut cell wall crosslinks.IMPORTANCEInducible beta-lactamases like theampCsystem ofPseudomonas aeruginosaare a common determinant of beta-lactam resistance among gram-negative bacteria. The regulation ofampCis elegantly tuned to detect defects in cell wall synthesis caused by beta-lactam drugs. Studies of mutations causingampCinduction in the absence of drug therefore promise to reveal new insights into the process of cell wall biogenesis in addition to aiding our understanding of how resistance to beta-lactam antibiotics arises in the clinic. In this study, anampCinduction phenotype for a mutant lacking an enzyme that cleaves cell wall glycans was used to uncover a potential role for glycan cleavage in making space in the wall matrix for the insertion of new material during cell growth.
Loss of Wdr23 drives neuronal mitochondrial biogenesis
Authors: Irwin Ronald , Liu Jiahui , Duangjan Chatrawee , Curran Sean P. 
Published: September 2023

ABSTRACTMitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of nuclear coded mitochondrial resident proteins in the brain.Wdr23KOalso increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which mediate mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.HIGHLIGHTSLoss of Wdr23 increases nuclear-coded mitochondrial resident proteins.Promoters of transcripts dysregulated in the hippocampus ofWdr23KOmice are enriched for NRF1 regulatory sequences.Insulin degrading enzyme (IDE) expression, which can localize to the mitochondria, is increased in the brain tissues lacking WDR23.Wdr23KOanimals have increased expression of relaxin-3 (RLN3) peptide, but not RLFP3 receptor.
DETERMINATION OF THE ROUTINE SELF-CARE PRACTICES AMONG PATIENTS WITH DMTII IN KITUI COUNTY
Authors: Musembi Mary , Mwenda Catherine Syombua , Ramani M Ramaligham 
Published: September 2023

AbstractWorldwide, an estimated increase of 642 million patients will have been diagnosed with diabetes mellitus by the year 2035, out of this figure more than 90% will have type 2 diabetes mellitus. In Kenya the burden for the disease is equally on rise, consequently there is huge gap in knowledge deficient among the sick individuals and their families on diabetes management making most patients to present with poor self-care practices especially in rural settings where Resources are scarce. The study aims at developing a family-based intervention model to improve family participation in the management of patients with diabetes mellitus type II at Kitui County. A sample of 68 participants was required to participate in the study. Creating informative resources that highlight the importance of family involvement and provide guidance on DMTII self-care practices. A significant proportion of DMTII patients Out of the total sample size, 28 participants (representing 49.1% of the sample) reported that they monitor their blood sugars on a daily basis. On the other hand, 29 participants (50.9% of the sample) indicated that they do not engage in this practice. These monitoring overall health, reviewing medication plans, adjusting treatment as necessary, and receiving education on diabetes management. These findings emphasize the importance of targeted interventions and education to improve self-care practices among individuals with DMTII and address areas where adherence is lacking. While many individuals exhibit positive self-care behaviors, there are areas that require attention and improvement. Healthcare providers can utilize these findings to develop targeted interventions, patient education programs, and support systems to enhance self-care practices among DMTII patients. By promoting and facilitating optimal self-care activities, healthcare providers can help improve health outcomes and reduce the risk of complications for individuals living with DMTII.