bluuebunny/crossref_metadata_2025_split huggingface dataset:
[225Ac]Ac/[89Zr]Zr-labeled N4MU01 radioimmunoconjugates as theranostics against nectin-4 positive triple negative breast cancer
Authors: Babeker Hanan , Njotu Fabrice Ngoh , Ketchemen Jessica Pougoue , Tikum Anjong Florence , Doroudi Alireza , Nwangele Emmanuel , Uppalapati Maruti , Fonge Humphrey 
Published: March 2024

AbstractPurposeNectin-4 is an overexpressed biomarker in 60-70% of triple-negative breast cancer (TNBC), and an ideal target for radiotherapy and PET imaging. In this study, we have developed theranostic radioimmunoconjugates (RICs) based on a fully-human anti-nectin-4 antibody, N4MU01. We characterized and evaluated the efficacy of these RICs for applications in molecular imaging and radiotherapy of aggressive TNBC models.MethodsAn anti-nectin-4 antibody (N4MU01) was radiolabeled with89Zr and225Ac, for imaging and radiotherapy, respectively, using TNBC xenograft and syngeneic models. Biodistribution & PET imaging of [89Zr]Zr-DFO-N4MU01 RIC was studied in mice bearing nectin-4 positive xenografts. Dosimetry of [225Ac]Ac-Macropa-N4MU01 was studied in healthy mice, and therapeutic efficacy was evaluated in mice bearing human TNBC MDA-MB-468 xenograft and in a syngeneic xenograft model using murine 4T1 breast cancer cells transfected with human nectin-4 (4T1.nectin-4). Mice received 2 doses of 13 kBq or 18.6 kBq 10 days apart.ResultsThe pharmacokinetic profile of [89Zr]Zr-DFO-N4MU01 RIC showed biphasic distribution with a moderate elimination half-life of 63 h. PET imaging and biodistribution of [89Zr]Zr-DFO-N4MU01 in mice bearing MDA-MB-468 xenograft showed high tumor uptake of 13.2 ± 1.12 %IA/g at 120 h. [225Ac]Ac-Macropa-N4MU01 was effectively internalized in MDA-MB-468 and was cytotoxic to the cells with IC50of 1.2 kBq/mL. Mice bearing MDA-MB-468 xenograft treated with [225Ac]Ac-Macropa-N4MU01 (13 kBq or 18.6 kBq) had a remarkable tumor growth inhibition that was dose dependent. For the syngeneic 4T1.nectin-4model, treatment with [225Ac]Ac-Macropa-N4MU01 (13 kBq) led to complete tumor remission in 83.3% (5/6) of mice.ConclusionThe specific tumor uptake and remarkable effectiveness at shrinking aggressive TNBC tumors is very promising towards clinical development of N4MU01 RICs as theranostics against TNBC.
Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine
Authors: Doyle Michelle R. , Beltran Nina M. , Bushnell Mark S. A. , Syed Maaz , Acosta Valeria , Desai Marisa , Rice Kenner C. , Serafine Katherine M. , Gould Georgianna G. , Daws Lynette C. , Collins Gregory T. 
Published: March 2024

AbstractSubstance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long– or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ∼30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long– and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long– and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2or D3receptors, or 5-HT1B, 5-HT2A, or 5-HT2Creceptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.
Proteogenomic analysis reveals adaptive strategies to alleviate the consequences of aneuploidy in cancer
Authors: Boekenkamp Jan-Eric , Keuper Kristina , Redel Stefan , Barthel Karen , Johnson Leah , Wieland Angela , Räschle Markus , Storchova Zuzana 
Published: March 2024

AbstractAneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performedin vitroevolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors required for adaptation to aneuploidyin vitroand in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosome impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.
Synphilin-1 as a modulator of aSyn assembly
Authors: Lázaro Diana F. , Amen Triana , Gerhardt Ellen , Santos Patrícia I. , Milovanovic Dragomir , Höglinger Günter , Outeiro Tiago F. 
Published: March 2024

AbstractAlpha-synuclein (aSyn) is an intrinsically disordered protein that undergoes phase-separation and is associated with several neurodegenerative conditions. However, the function and the pathological role of aSyn are still elusive. Here, we modeled different types of aSyn assemblies in living cells, and developed a model that reports on gel and solid-like inclusions based on the coexpression of aSyn and synphilin-1 (Sph1). We identified striking morphological differences between aSyn-aSyn and Sph1-aSyn assemblies, characterized by distinct antibody recognition patterns, resistance to Proteinase K treatment, and protein mobilities. Importantly, we showed that the interaction between Sph1-aSyn can be manipulated, altering inclusion size and number. Sph1-aSyn interactions were central for inclusion formation and localization, and that inclusions include lysosomes and AP-1 vesicles, consistent with previous studies in human brain tissue. In total, we provide novel insight into the biology of protein aggregation, shedding light on potential therapeutic strategies that extend beyond conventional targets. Deciphering the role of Sph1 and other aSyn-interacting proteins on aSyn biology and pathobiology will be essential for treating synucleinopathies.
A Novel Humanized Mouse Model for HIV and Tuberculosis Co-infection Studies
Authors: Bohórquez José Alejandro , Adduri Sitaramaraju , Ansari Danish , John Sahana , Florence Jon , Adejare Omoyeni , Singh Gaurav , Konduru Nagarjun , Jagannath Chinnaswamy , Yi Guohua 
Published: March 2024

ABSTRACTTuberculosis (TB), caused byMycobacterium tuberculosis(Mtb), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. Further, co-infections with HIV andMtbhave severe effects in the host, with people infected with HIV being fifteen to twenty-one times more likely to develop active TB. The use of an appropriate animal model for HIV/Mtbco-infection that can recapitulate the diversity of the immune response in humans would be a useful tool for conducting basic and translational research in HIV/Mtbinfections. The present study was focused on developing a humanized mouse model for investigations on HIV-Mtbco-infection. Using NSG-SGM3 mice that can engraft human stem cells, our studies showed that they were able to engraft human CD34+ stem cells which then differentiate into a full-lineage of human immune cell subsets. After co-infection with HIV andMtb, these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally,Mtbcaused infections in both lungs and spleen, and induced the development of granulomatous lesions in the lungs, detected by CT scan and histopathology. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections. Our results suggest that the humanized NSG-SGM3 mice are able to recapitulate the effects of HIV andMtbinfections and co-infection in the human host at pathological, immunological and metabolism levels, providing a dependable small animal model for studying HIV/Mtbco-infection.
Cohort profile: The WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort (WHO-CMRS) to identify predictors of mortality through early childhood
Authors: Schwinger Catherine , Kaldenbach Siri , Berkley James A. , Walson Judd L. , Argaw Alemayehu , Chowdhury Ranadip , Strand Tor A. , Rollins Nigel 
Published: March 2024

ABSTRACTPurposeTo provide details of a pooled dataset that will be used to estimate absolute and relative mortality risks and other outcomes among children less than 59 months of age and the predictive performance of common risk exposures, both individually and in combination.ParticipantsChildren from birth to five years of age recruited at health facilities or community settings into 33 longitudinal observational or intervention studies in 18 low-and middle-income countries.Findings to dateThe dataset includes 75,287 children with a median age of 3 months (IQR 1, 12) at first measurement. In the pooled sample, 2,805 (3.7%) of the study children died. Data on birthweight was recorded in 18 studies, and gestational age in 13 studies. Among these, 14% of the included children were reported with low birthweight and 14% preterm birth. At first measurement, 33% of the children were stunted, 24% were wasted, and 35% underweight. 13% and 7% of caregivers reported that their child had acute diarrhoea or acute lower respiratory tract infection before the study visit, respectively. The proportion of children being breastfed at any study visit decreased from 99% at age <6 months to 77% in the age group 12-23 months. Child characteristics differed considerably between studies in the community and health care settings. The median study period was 15 months (IQR 7.6 to 18.4 months).Future plansThe WHO Child Mortality Risk Stratification Multi-Country Pooled Cohort (WHO-CMRS) provides a large dataset including child, parental, and household characteristics from a diverse range of geographical, community and health system settings; planned analyses will examine knowledge gaps with the aim of informing global guidelines and their derivatives such as clinical management tools and implementation guidance, and to inform future research agendas.STRENGTHS AND LIMITATIONSStrengths– A large dataset that integrates diverse geographical areas in LMICs, with children recruited from community and health system settings.– Prospective data collection and availability of key time-varying exposures, such as nutritional status, common childhood morbidities, and feeding practices and non-time varying exposures, such as birth characteristics and socio-demographics.– Ability to estimate age-specific absolute mortality risks from different exposure domains and combinations thereof.Limitations– Non-systematic selection of included datasets.– Heterogeneity of inclusion criteria, exposures collected and follow-up schedules across studies.
Evaluation of a novel respiratory virus inactivating buffer for parallel RT-qPCR and quick antigen testing
Authors: Deprez Sigrid , Steyaert Sophia , Claeys Mikhail , Verhasselt Ludwig , Vandesompele Jo 
Published: March 2024

ABSTRACTSince the COVID-19 pandemic, many hospitals implemented a dual testing procedure for SARS-CoV-2 to assess the infection risk of an admitted patient. To allow for a short turn-around time, rapid antigen (Ag) testing via lateral flow tests (LFT) is combined with nucleic acid amplification testing (NAAT), requiring two nasopharyngeal swab collections. In this study, a novel, universal pathogen inactivation buffer (DNA/RNA Defend Pro (DRDP)) was evaluated for SARS-CoV-2 inactivation and simultaneous Ag and DNA/RNA stabilization.In an emergency department setting of a General Hospital in Ghent (Belgium), patients were tested for SARS-CoV-2, whereby a LFT for Ag detection (Abbott Panbio COVID-19 Ag Rapid Test) was performed in combination with sample collection for NAAT (Abbott Alinity m). Left-over buffers from LFT were diluted in DRDP to evaluate LFT and NAAT results after dilution. Thirty-six patients were included in the data analysis.Twenty-three diagnostic LFT results were available in the laboratory information system of which all corresponded with results after dilution with DRDP. When correlating NAAT results, seven out of eight positive test results were in agreement, compared to twenty-three out of twenty-five negative results. For thirty-four out of thirty-six samples, LFT and NAAT after dilution with DRDP yielded the same conclusion. Additionally, RNA stability in DRDP was demonstrated when stored for three days at room temperature. At the extreme, a sample stored in the DRDP buffer for 53 days at room temperature was still very positive (Cq 21.95).We demonstrated that, for the first time, a novel collection buffer could inactivate a pathogen (SARS-CoV-2) while also preserving antigen (for rapid antigen testing) and RNA (for molecular testing). This novel buffer holds promise for a single specimen to be used for both antigen and molecular testing in a safe working environment.
Power spectra density and similarity analysis of COVID-19 mortality waves across countries
Authors: Manjarrez Elias , Delfin Erick F , Dominguez-Nicolas Saul M , Flores Amira 
Published: March 2024

AbstractJohns Hopkins University CSSE documented waves of oscillatory COVID-19 mortality patterns worldwide during the COVID-19 pandemic. Here, we calculated the power spectrum density (PSD) of these COVID-19 mortality waves in 199 countries from January 22, 2020, to March 9, 2023. We identified two dominant peaks in the grand averaged PSD: one at a frequency of 1.15 waves per year (i.e., one wave every 10.4 months) and another at 2.7 waves per year (i.e., one wave every 4.4 months). Moreover, we performed a cosine similarity analysis of these PSD patterns among all the countries. The results showed a cosine similarity index distribution that was negatively skewed, with a skewness of −0.54 and a global median of cosine similarity index of 0.84, thus revealing a remarkable similarity in the dominant peaks of the COVID-19 mortality waves. These findings could be helpful if a future pandemic of a similar scale occurs so that effective confinement measures or other actions could be planned during these two identified periods, ensuring more assertive public health policies in advance.
Physical and sociocultural factors influencing hand hygiene behavior during COVID-19 pandemic: A cross-sectional study among traders in Lusaka District, Zambia
Authors: Siame Joyce Namukonda , Libonda Liyali , Kanyata Kanyata 
Published: March 2024

AbstractThe COVID-19 epidemiology highlights the challenges for containment, mitigation, and control in low-resource settings like Zambia and suggests that the most vulnerable groups, particularly those living in low-income environments and depending on casual livelihoods, demand attention. This study aimed to determine factors that affect hand hygiene behavior during the COVID-19 Pandemic among traders at the New Soweto Market in Lusaka District. A cross-sectional analytical design was used to quantitatively investigate physical and sociocultural factors that affect hand hygiene behaviour during the COVID-19 pandemic among traders at New Soweto Market in Lusaka District, Zambia. The study sample included a total of 125 registered traders at the New Soweto Market, which is the biggest market in the capital city of Zambia. Majority of the participants (98.1%) demonstrated knowledge on hand hygiene. Remarkably, hand hygiene compliance was significantly associated with acquisition of hand hygiene knowledge [X (6, N = 120) = 41.49, p = 0.000] and cultural customs [X (6, N = 120) = 62.09, p = 0.000]. Further, hand hygiene compliance was significantly associated with availability of hand hygiene services or facilities within the market, [X (6, N = 120) = 13.30, p = 0.038]. Despite this, majority of the participants (61.7%) reported that they did not benefit from any hand hygiene services or facilities from the Local Authority or Ministry of Health. For an effective infection prevention and control program regarding COVID-19 pandemic, relevant authorities should consider supporting traders with hand hygiene related services.
A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma
Authors: Sussman Jonathan H. , Oldridge Derek A. , Yu Wenbao , Chen Chia-Hui , Zellmer Abigail M. , Rong Jiazhen , Parvaresh-Rizi Arianne , Thadi Anusha , Xu Jason , Bandyopadhyay Shovik , Sun Yusha , Wu David , Hunter C. Emerson , Brosius Stephanie , Ahn Kyung Jin , Baxter Amy E. , Koptyra Mateusz P. , Vanguri Rami S. , McGrory Stephanie , Resnick Adam C. , Storm Phillip B. , Amankulor Nduka M. , Santi Mariarita , Viaene Angela N. , Zhang Nancy , Raedt Thomas De , Cole Kristina , Tan Kai 
Published: March 2024

SummaryPediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Throughin vitropharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.
PhyloForge: Unifying micro and macro evolution with comprehensive genomic signals
Authors: Wang Ya , Dong Wei , Liang Yufan , Lin Weiwei , Chen Fei 
Published: March 2024

AbstractWith the explosive growth of biological data, the dimensions of phylogenetic research have expanded to encompass various aspects, including the study of large-scale populations at the microevolutionary level and comparisons between different species or taxonomic units at the macroevolutionary level. Traditional phylogenetic tools often struggle to handle the diverse and complex data required for these different evolutionary scales. In response to this challenge, we introduce PhyloForge-a robust tool designed to seamlessly integrate the demands of both micro- and macro-evolution, comprehensively utilizing diverse phylogenomic signals, such as genes, SNPs, structural variations, as well as mitochondrial and chloroplast genomes. PhyloForge’s groundbreaking innovation lies in its capability to seamlessly integrate multiple phylogenomic signals, enabling unified analysis of multidimensional genomic data. This unique feature empowers researchers to gain a more comprehensive understanding of diverse aspects of biological evolution. PhyloForge not only provides highly customizable analysis tools for experienced researchers but also features an intuitively designed interface, facilitating effortless phylogenetic analysis for beginners. Extensive testing across various domains, including animals, plants, and fungi, attests to its broad applicability in the field of phylogenetics. In summary, the developmental background and innovative features of PhyloForge position it with significant potential in the era of large-scale genomics, offering a new perspective and toolset for a deeper understanding of the evolution of life.
Antisense transcription can induce expression memory via stable promoter repression
Authors: Mutzel Verena , Schwämmle Till , Oeverdieck Svearike , Librenjak Lucija , Boesen Benedikt , Bothe Melissa , Gjaltema Rutger AF , Dunkel Ilona , Noviello Gemma , Schulz Edda G 
Published: March 2024

AbstractThe capacity of cells to retain a memory of previous signals enables them to adopt unique cell fates and adjust to their surrounding environment. The underlying gene expression memory can arise from mutual repression of two genes, forming a toggle switch. Such mutual repression may occur at antisense loci, where two convergently oriented genes repress each other incis. Under which conditions antisense transcription can generate expression memory remains poorly understood. To address this question, we combine mathematical modeling, genomics and a synthetic biology approach. Through simulations we show that stable memory can emerge, if both genes in an antisense pair transcribe through the convergent promoter and induce a stable repressive chromatin state. Genome-wide analysis of nascent transcription further supports antisense-mediated promoter repression with promoter-overlapping antisense gene pairs exhibiting mutually exclusive expression. Through constructing a synthetic antisense locus in mouse embryonic stem cells (mESCs) we then show that such a locus architecture can indeed maintain a memory of a transient stimulus. Mutual repression and the capacity for memory formation are elevated, when mESCs differentiate, showing that epigenetic memory is a cell type-specific property. Our finding that stem cells adapt their ability to remember stimuli as they differentiate might help to elucidate how stemness is maintained.