bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erectile Dysfunction in Men with and without Type 2 Diabetes Mellitus at Livingstone University Teaching Hospital, Zambia: A cross-sectional study
Authors: Muchaili Lweendo , Mweene Bislom C. , Hamooya Benson M. , Masenga Sepiso Kenias 
Published: March 2024

AbstractBackgroundErectile dysfunction (ED) is frequently undiagnosed in males with type 2 diabetes mellitus (T2DM), despite its high prevalence. Early detection of ED in T2DM is crucial for effective treatment and prevention of severe complications such as cardiovascular events. This study explores the prevalence of ED and its associated factors in males with and without T2DM at Livingstone University Teaching Hospital (LUTH), Zambia.MethodologyWe conducted a cross-sectional study at LUTH among 42 males aged ≥18 years (22 with and 20 without T2DM). T2DM diagnosis was confirmed through medical records, and erectile dysfunction was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. Logistic regression identified factors associated with ED, with significance set at a p-value less than 0.05ResultsThe overall prevalence of ED was 74% (31/42). Among T2DM participants, the prevalence of ED was 91% (20/22; 95% confidence interval (CI) 70.8-98.9) whereas among the non-diabetic participants, the prevalence was 55% (11/20; 95%CI 31.5-76.9). The majority [40% (8/20)] of the T2DM participants with ED had mild ED, 35% (7/20) had mild to moderate ED, 15% (3/20) had moderate ED and 10% (2/20) had severe ED. 54.5% (6/11)] of the non-T2DM participants with ED had mild ED, 36.4% (4/11) had mild to moderate ED, 9.1% (1/11) had moderate ED, and none had severe ED. In the multivariable analysis, employed individuals had lower odds of erectile dysfunction compared to the unemployed (OR 0.01, 95% CI 0.00 - 0.84, p = 0.041); while elevated plasma creatinine levels were associated with an increased risk of erectile dysfunction (OR 1.22, 95% CI 1.03 - 1.45, p = 0.021).ConclusionThis study underscores a significant prevalence of ED, particularly heightened in T2DM participants; and significantly associated with plasma creatinine levels and employment status. The findings highlight the need for comprehensive assessment and management of ED in T2DM individuals. There is a need for further research with larger sample sizes to validate the findings and for a clearer understanding of associated factors and identification of effective targeted interventions.
HDAC1 controls the generation and maintenance of effector-like CD8+T cells during chronic viral infection
Authors: Rica Ramona , Waldherr Monika , Schülein Marlene , Miyakoda Emi , Sandner Lisa , Stolz Valentina , Waltenberger Darina , Krausgruber Thomas , Bock Christoph , Boucheron Nicole , Ellmeier Wilfried , Sakaguchi Shinya 
Published: March 2024

AbstractCD8+T cell exhaustion is a complex process that involves the differentiation of persistently activated CD8+T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+Tex cells in a CD8+T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex cell subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 knockout altered the chromatin landscape in progenitor Tex cells, abrogated the expression of effector-like signature genes and interfered with cell fate specification toward the CX3CR1+Tex cell subset. We conclude that HDAC1 is functionally required for controlling viral load during chronic infection by ensuring adequate CX3CR1+Tex cell subset differentiation.HighlightsHDAC1 promotes the generation of CX3CR1+effector-like Tex cell subsets in chronic viral infection in a CD8+T cell-intrinsic manner.Deletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia.HDAC1 is required for the maintenance of the CX3CR1+Tex cell pool.HDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells.
Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Distinct Subgroups and Proteins Associated with Time-To-Recurrence
Authors: Werner Tilman , Budau Klara-Luisa , Cosenza-Contreras Miguel , Hause Frank , Kurowski Konrad , Pinter Niko , Schüler Julia , Werner Martin , Sigel Carlie , Tang Laura H. , Bronsert Peter , Schilling Oliver 
Published: March 2024

AbstractBackground & AimsIntrahepatic cholangiocarcinoma (ICC) is a poorly understood cancer with dismal survival and high recurrence rates. ICCs are often detected in advanced stages. Surgical resection is the most important first-line treatment but limited to non-advanced cases, whereas chemotherapy provides only a moderate benefit. The proteome biology of ICC has only been scarcely studied and the prognostic value of initial ICC’s proteomic features for the time-to-recurrence (TTR) remains unclear.MethodsWe dissected formalin-fixed, paraffin-embedded samples from 80 tumor– and 77 matching adjacent non-malignant (TANM) tissues. All samples were measured via liquid-chromatography mass-spectrometry (LC-MS/MS) in data independent acquisition mode (DIA).ResultsTumor– and TANM tissue showed strongly different biologies and DNA-repair, translation, and matrisomal processes were upregulated in ICC. In a hierarchical clustering analysis, we determined two proteomic subgroups of ICC, which showed significantly diverging TTRs. Cluster 1, which is associated with a beneficial prognosis, was enriched for matrisomal processes and proteolytic processing, while cluster 2 showed increased RNA and protein turnover. In a second, independent Cox’ proportional hazards model analysis, we identified individual proteins whose expression correlates with TTR distribution. Proteins with a positive hazard ratio were mainly involved in carbon/glucose metabolism and protein turnover. Conversely, proteins associated with a low hazard ratio were mostly linked to the extracellular matrix. Additional proteome profiling of patient-derived xenograft tumor models of ICC successfully distinguished tumor and stromal proteins and provided insights into cell-matrix interactions.ConclusionsWe successfully determine the proteome biology of ICC and present two proteome clusters in ICC patients with significantly different TTR rates and distinct biological motifs. A xenograft model confirmed the importance of tumor-stroma interactions for this cancer.
Three-dimensional modeling of flow through microvascular beds and surrounding interstitial spaces
Authors: Rajeeva Pandian Navaneeth Krishna , Farell Alanna , Davis Emily , Sundaram Subramanian , van Steen Abraham Christoffel Ignatius , Chang Teo Jessica Li , Eyckmans Jeroen , Chen Christopher S 
Published: March 2024

AbstractThe health and function of microvascular beds are dramatically impacted by the mechanical forces that they experience due to fluid flow. These fluid flow-generated forces are challenging to measure directly and are typically calculated from experimental flow data. However, current computational fluid dynamics (CFD) models either employ truncated 2D models or overlook the presence of extraluminal flows within the interstitial space between vessels that result from the permeability of the endothelium lining the vessels, which are crucial components affecting flow dynamics. To address this, we present a bottom-up modeling approach that assesses fluid flow in 3D-engineered vessel networks featuring an endothelial lining and interstitial space. Using image processing algorithms to segment 3D confocal image stacks from engineered capillary networks, we reconstructed a 3D computational model of the networks. We incorporated vascular permeability and matrix porosity values to model the contributions of the endothelial lining and interstitial spaces to the flow dynamics in the networks. Simulations suggest that including the endothelial monolayer and the interstitium significantly affects the predicted flow magnitude in the vessels and flow profiles in the interstitium. To demonstrate the importance of these factors, we showed experimentally and computationally that while cytokine (IL-1β) treatment did not affect the network architecture, it significantly increased vessel permeability and resulted in a dramatic decrease in wall shear stresses and flow velocities intraluminally within the networks. In conclusion, this framework offers a robust methodology for studying flow dynamics in 3D in vitro vessel networks, enhancing our understanding of vascular physiology and pathology.TRANSLATIONAL IMPACT STATEMENTThis study introduces a new approach to modeling and flow assessment in 3D microvascular beds and surrounding interstitial spaces. Modeling interstitial space and endothelial monolayer thickness is essential for capturing fluid leakage from the microvascular network into the interstitial space and vice versa when the endothelial monolayer permeability is significantly affected in pathological conditions. Our approach to modeling 3D vascular networks can be used in vivo and in clinical settings to understand flow in tissue microvasculature and its surroundings under disease and healthy conditions.
Chromosome-scale pearl millet genomes reveal aCARLACTONOIC ACID METHYL TRANSFERASEas key determinant of strigolactone pattern and Striga susceptibility
Authors: Kuijer Hendrik NJ , Wang Jian You , Bougouffa Salim , Abrouk Michael , Jamil Muhammad , Incitti Roberto , Alam Intikhab , Balakrishna Aparna , Alvarez Derry , Votta Cristina , Chen Guan-Ting Erica , Martínez Claudio , Zuccolo Andrea , Berqdar Lamis , Sioud Salim , Fiorilli Valentina , de Lera Angel R , Lanfranco Luisa , Gojobori Takashi , Wing Rod A , Krattinger Simon G , Gao Xin , Al-Babili Salim 
Published: March 2024

AbstractThe yield of pearl millet, a resilient cereal crop crucial for African food security, is severely impacted by the root parasitic weedStriga hermonthica,which requires host-released strigolactones (SLs) for seed germination. Herein, we identified four SLs present in the Striga-susceptible line SOSAT-C88-P10 (P10), but absent in the resistant 29Aw (Aw). We generated chromosome-scale genome assemblies including four gapless chromosomes for each line. We found the Striga-resistant Aw lacks a 0.7 Mb genome segment containing two putativeCARLACTONOIC ACID METHYL TRANSFERASE1(CLAMT1) genes. Upon transient expression, P10CLAMT1b produced methyl carlactonoate (MeCLA), an intermediate in SL biosynthesis. Feeding Aw with MeCLA resulted in the production of two P10-specific SLs. Screening a diverse pearl millet panel confirmed the pivotal role of theCLAMT1section for SL diversity and Striga susceptibility. Our results reveal a reason for Striga susceptibility in pearl millet and pave the way for generating resistant lines through marker-assisted breeding or direct genetic modification.
Phosphate-binding pocket on cyclin B governs CDK substrate phosphorylation and mitotic timing
Authors: Ng Henry Y. , Adly Armin N. , Whelpley Devon H. , Suhandynata Raymond T. , Zhou Huilin , Morgan David O. 
Published: March 2024

SummaryCell cycle progression is governed by complexes of the cyclin-dependent kinases (CDKs) and their regulatory subunits cyclin and Cks1. CDKs phosphorylate hundreds of substrates, often at multiple sites. Multisite phosphorylation depends on Cks1, which binds initial priming phosphorylation sites to promote secondary phosphorylation at other sites. Here, we describe a similar role for a recently discovered phosphate-binding pocket (PP) on B-type cyclins. Mutation of the PP in Clb2, the major mitotic cyclin of budding yeast, alters bud morphology and delays the onset of anaphase. Using phosphoproteomicsin vivoand kinase reactionsin vitro, we find that mutation of the PP reduces phosphorylation of several CDK substrates, including the Bud6 subunit of the polarisome and the Cdc16 and Cdc27 subunits of the anaphase-promoting complex/cyclosome. We conclude that the cyclin PP, like Cks1, controls the timing of multisite phosphorylation on CDK substrates, thereby helping to establish the robust timing of cell-cycle events.
Insulin signaling regulates R2 retrotransposon expression to orchestrate transgenerational rDNA copy number maintenance
Authors: Nelson Jonathan O , Slicko Alyssa , Raz Amelie A , Yamashita Yukiko M 
Published: March 2024

AbstractPreserving a large number of essential yet highly unstable ribosomal DNA (rDNA) repeats is critical for the germline to perpetuate the genome through generations. Spontaneous rDNA loss must be countered by rDNA copy number (CN) expansion. Germline rDNA CN expansion is best understood inDrosophila melanogaster, which relies on unequal sister chromatid exchange (USCE) initiated by DNA breaks at rDNA. The rDNA-specific retrotransposon R2 responsible for USCE-inducing DNA breaks is typically expressed only when rDNA CN is low to minimize the danger of DNA breaks; however, the underlying mechanism of R2 regulation remains unclear. Here we identify the insulin receptor (InR) as a major repressor of R2 expression, limiting unnecessary R2 activity. Through single-cell RNA sequencing we find that male germline stem cells (GSCs), the major cell type that undergoes rDNA CN expansion, have reduced InR expression when rDNA CN is low. Reduced InR activity in turn leads to R2 expression and CN expansion. We further find that dietary manipulation alters R2 expression and rDNA CN expansion activity. This work reveals that the insulin pathway integrates rDNA CN surveying with environmental sensing, revealing a potential mechanism by which diet exerts heritable changes to genomic content.
Health-related quality of life in children and adolescents born very preterm and its correlates: a cross-sectional study
Authors: Haile Sarah R , Peralta Gabriela P , Adams Mark , Bharadwaj Ajay N , Bassler Dirk , Moeller Alexander , Natalucci Giancarlo , Radtke Thomas , Kriemler Susi 
Published: March 2024

AbstractObjectiveWe aimed to assess health-related quality of life (HRQOL) in a cohort of very preterm born children and adolescents (aged 5-16), and to compare it with their fullterm born siblings and the general population. We also explored correlates of HRQOL among the very preterm born.DesignCross-sectional surveyPatientsChildren born <32 weeks gestation (N = 442) as well as their fullterm born siblings (N = 145)Main outcome measuresPrimary outcome was KINDL total score (0 worst - 100 best), a validated multidimensional measure of HRQOL in children and adolescents.MethodsLinear mixed models accounted for family unit. Secondary analysis compared very preterm born children to another cohort of healthy children from the same time period. A classification tree analysis explored potential correlates of HRQOL.ResultsOn average, preterm children, both <28 and 28-31 weeks gestational age, had similar KINDL total score to fullterm sibling controls (-2.3, 95% CI -3.6 to -0.6), and to population controls (+1.4, 95% CI 0.2 to 2.5). Chronic non-respiratory health conditions (such as attention deficit hyperactivity disorder (ADHD) or heart conditions, but not including cerebral palsy), age, and respiratory symptoms affecting daily life were key correlates of HRQOL among very preterm born children.ConclusionsVery preterm birth in children and adolescents was not associated with a relevant reduction in HRQOL compared to their fullterm born peers. However, lower HRQOL was explained by other factors, such as older age, and the presence of chronic non-respiratory health conditions, but also by possibly modifiable current respiratory symptoms. The influence of respiratory symptom amelioration and its potential influence on HRQOL needs to be investigated further.What is already known on this topicAs infants born very preterm become more likely to survive, the importance of health-related quality of life (HRQOL) increases. Research on HRQOL in very preterm born children and adolescents often focuses on non-modifiable risk factors without potential interventions.What this study addsHRQOL in very preterm born children and adolescents is similar to that of their siblings and to the general population. Age, respiratory symptoms, and chronic health conditions were associated with HRQOL. Better control of respiratory symptoms could improve HRQOL in very preterm born children and adolescents.How this study might affect research, practice or policyA better understanding of the complex picture of pulmonary disease following prematurity throughout life and interventions to treat respiratory symptoms may be leveraged to improve HRQOL as very preterm born children and adolescents grow.
Generalizability of trial criteria on amyloid-lowering therapy against Alzheimer’s disease to individuals with MCI or early AD in the general population
Authors: Claus Jacqueline J. , vom Hofe Ilse , van Ijlzinga Veenstra Annekee , Licher Silvan , Seelaar Harro , de Jong Frank J. , Neitzel Julia , Vernooij Meike W. , Ikram M. Arfan , Wolters Frank J. 
Published: March 2024

AbstractBackgroundTreatment with monoclonal antibodies against amyloid-β slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, stringent trial eligibility criteria may affect generalizability of these findings to clinical practice.MethodsWe extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI or early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain MRI, cognitive testing, and cardiovascular assessment. We had continuous linkage with medical records and pharmacy dispensary data. We determined amyloid status using an established and validated prediction model based on age andAPOEgenotype. We assessed progression to dementia within 5 years among participants with MCI, stratified for eligibility.ResultsOf 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 early clinical AD dementia. Across the three drug trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% (95% CI; 73.3-79.3) of participants for aducanumab, 75.8% (73.0-78.7) for lecanemab, and 59.8% (56.4–63.3) for donanemab. Criteria that most often led to exclusion were a history of cardiovascular disease (35.2%), use of anticoagulant (31.2%), use of psychotropic or immunological medications (20.4%), history of anxiety or depression (15.9%), or lack of social support (15.6%). One-third of participants were ineligible based on brain MRI findings alone, which was similar across trials and due predominantly to various manifestations of cerebral small-vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 9% (7.0-11.1) for aducanumab, 8% (6.2-9.9) lecanemab to 15% (12.4-17.5) for donanemab. Risk of progression to dementia tended to be higher for ineligible than for eligible participants for lecanemab (hazard ratio [95%CI]: 1.64 [0.92-2.91]), aducanumab (HR: 1.17 [0.65-2.12]), and only marginally for donanemab (HR: 1.03 [0.67-1.59]).ConclusionsFindings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-β are applicable to less than 15% of community-dwelling individuals with MCI or early AD. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with MCI/AD in routine clinical practice.
Assessing methylation detection for primary human tissue using Nanopore sequencing
Authors: Genner Rylee , Akeson Stuart , Meredith Melissa , Jerez Pilar Alvarez , Malik Laksh , Baker Breeana , Miano-Burkhardt Abigail ,   CARD-long-read Team, Paten Benedict , Billingsley Kimberley J , Blauwendraat Cornelis , Jain Miten 
Published: March 2024

AbstractDNA methylation most commonly occurs as 5-methylcytosine (5-mC) in the human genome and has been associated with human diseases. Recent developments in single-molecule sequencing technologies (Oxford Nanopore Technologies (ONT) and Pacific Biosciences) have enabled readouts of long, native DNA molecules, including cytosine methylation. ONT recently upgraded their Nanopore sequencing chemistry and kits from R9 to the R10 version, which yielded increased accuracy and sequencing throughput. However the effects on methylation detection have not yet been documented.Here we performed a series of computational analyses to characterize differences in Nanopore-based 5mC detection between the ONT R9 and R10 chemistries. We compared 5mC calls in R9 and R10 for three human genome datasets: a cell line, a frontal cortex brain sample, and a blood sample. We performed an in-depth analysis on CpG islands and homopolymer regions, and documented high concordance for methylation detection among sequencing technologies. The strongest correlation was observed between Nanopore R10 and Illumina bisulfite technologies for cell line-derived datasets. Subtle differences in methylation datasets between technologies can impact analysis tools such as differential methylation calling software. Our findings show that comparisons can be drawn between methylation data from different Nanopore chemistries using guided hypotheses. This work will facilitate comparison among Nanopore data cohorts derived using different chemistries from large scale sequencing efforts, such as the NIH CARD Long Read Initiative.
A novel LysinB from an F2 sub-cluster mycobacteriophageRitSun
Authors: Arora Ritu , Nadar Kanika , Bajpai Urmi 
Published: March 2024

ABSTRACTWith the growing antibiotic resistance in mycobacterial species posing a significant threat globally, there is an urgent need to find alternative solutions. Bacteriophage-derived endolysins aid in releasing phage progeny from the host bacteria by attacking the cell wall at the end of their life cycle. Endolysins are attractive antibacterial candidates due to their rapid lytic action, specificity and low risk of resistance development. In mycobacteria, owing to the complex, hydrophobic cell wall, mycobacteriophages usually synthesize two endolysins: LysinA, which hydrolyzes peptidoglycan; LysinB, which delinks mycolylarabinogalactan from peptidoglycan and releases mycolic acid. In this study, we conducted domain analysis and functional characterization of a recombinant LysinB fromRitSun, an F2 sub-cluster mycobacteriophage. Several properties ofRitSunLysinB are important as an antimycobacterial agent: its ability to lyseMycobacterium smegmatis‘from without’, a specific activity of 1.36 U/mg, higher than the reported ones and its inhibitory effect on biofilm formation. Given the impervious nature of the mycobacterial cell envelope, native endolysins’ ability to damage cells on exogenous applications warrants further investigation. A molecular dissection ofRitSunLysinB to identify its cell wall destabilizing sequence could be utilized to engineer other native lysins as fusion proteins and expand their activity profile.