bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating Chemokine-Induced NF-κB Activation in Retinal Cells and Its Contribution to Age-Related Macular Degeneration Pathogenesis: A Systematic Review
Authors: Siddiqui Ifrah , Khan Nabeel Ahmad , Ahmad Fatima , Nawaz Maham , Naeem Almas , Khalid Muhammad Usaid , Mirza Usman Haroon , Danish Hamza Ali , Khalid Syed Saqib 
Published: September 2024

AbstractObjectiveTo investigate the roles of chemokines in activating the NF-κB signaling pathway in retinal pigment epithelium (RPE) and photoreceptor cells, and their contribution to the pathogenesis of age-related macular degeneration (AMD).BackgroundAMD is a leading cause of vision loss in older adults, driven by chronic inflammation and oxidative stress. The NF-κB transcription factor plays a key role in regulating these processes, with various chemokines, such as CCL2 and CX3CL1, influencing NF-κB activation. Despite advances in treatment, a deeper understanding of how chemokines affect NF-κB activation in RPE and photoreceptor cells remains critical for developing effective therapies. This study seeks to address this gap and improve AMD management.MethodsA comprehensive search of databases, including PubMed, MEDLINE, and Google Scholar, was conducted to identify relevant studies on the roles of chemokines in activating NF-κB signaling in RPE and photoreceptor cells. The search covered chemokines such as CCL2 (MCP-1), CX3CL1 (Fractalkine), CCL3 (MIP-1α), CCL5 (RANTES), CXCL8 (IL-8), CXCL10 (IP-10), CXCL1 (GRO-α), CXCL12 (SDF-1), CCL11 (Eotaxin), CXCL16, CXCL9 (MIG), and CXCL11 (I-TAC). Studies were systematically reviewed following PRISMA guidelines to assess the involvement of these chemokines in NF-κB activation.ResultsThe analysis revealed that chemokines, including CCL2, CX3CL1, CCL3, and CCL5, significantly activated NF-κB in RPE and photoreceptor cells, leading to increased inflammation and apoptosis through enhanced cytokine production and reactive oxygen species (ROS) generation. Additionally, CXCL8, CXCL10, CXCL1, and CXCL12 triggered NF-κB activation, contributing to oxidative stress and extracellular matrix (ECM) remodeling, which disrupts retinal structure and function. Other chemokines, such as CCL11, CXCL16, CXCL9, and CXCL11, sustained chronic inflammation and modulated matrix metalloproteinases (MMPs), further implicating them in AMD progression.ConclusionChemokines, including CCL2, CX3CL1, CCL3, CCL5, CXCL8, CXCL10, CXCL1, CXCL12, CCL11, CXCL16, CXCL9, and CXCL11, activate the NF-κB pathway in RPE and photoreceptor cells, driving chronic inflammation, oxidative stress, and ECM remodeling in AMD. These findings highlight potential therapeutic targets to mitigate disease progression.
Discriminatory ability of adiposity phenotypes in identifying cardiometabolic disorders in indigenous and non-indigenous African populations
Authors: Kufe Clement Nyuyki , Mbanya Jean Claude 
Published: September 2024

AbstractBackgroundWhether any of the anthropometric indices are associated with cardiometabolic outcomes in indigenous Fulani African populations is not known. This study evaluates anthropometric indices in Fulani and non-autochthonous populations in predicting cardiometabolic outcomes in indigenous and non-indigenous populations.MethodsA population-based cross-sectional study recruited 1 921 participants of similar median aged 32 (24–45) years from Fulbe (settled Fulani), Mbororo (nomadic pastoral Fulani) and the general population. Body weight (BW), height, waist circumference (WC), and hip circumference (HC) were measured and body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), Conicity Index (Cindex), body adiposity index (BAI), body roundness index (BRI) and body shape index (ABSI) were determined. The associations of anthropometric indices with cardiometabolic disorders were assessed by multivariable adjusted logistic regression and the area under the receiver-operating characteristic (ROC) curve compared the predictive abilities.ResultsWomen had higher prevalence of MetS and the men had higher prevalence of hypertension and IFG/diabetes/hypertension while the prevalence of IFG/diabetes was similar in men and women. In women, the ROC and multivariable logistic regression analyses both showed consistent good performance of BW and BMI in identifying IFG/Diabetes in Fulbe and general population; BW, HC, BMI and BAI in Mbororo and BW, WC, HC, WHtR, and BRI in general population to predict hypertension and IFG/diabetes/hypertension. All the anthropometric indices showed good performance in all the groups to identify MetS. In men, WC, HC and BRI had good performance in all the groups while WC and BRI had good performance in all groups and HC in Fulbe and Mbororo to predict hypertension. The BW, WC, HC, BMI, WHtR, BAI and BRI showed consistent good performance in all the groups to predict MetS.ConclusionAnthropometric indices of adiposity are important risk assessing tools for cardiometabolic disorders in indigenous as well as non-autochthonous populations varying by ethnic group and sex.
Sex-Specific Skeletal Muscle Gene Expression Responses to Exercise Reveal Novel Direct Mediators of Insulin Sensitivity Change
Authors: Ma S , Morris MC , Hubal MJ , Ross LM , Huffman KM , Vann CG , Moore N , Hauser ER , Bareja A , Jiang R , Kummerfeld E , Barberio MD , Houmard JA , Bennett WB , Johnson JL , Timmons JA , Broderick G , Kraus VB , Aliferis CF , Kraus WE 
Published: September 2024

ABSTRACTBACKGROUNDUnderstanding the causal pathways, systems, and mechanisms through which exercise impacts human health is complex. This study explores molecular signaling related to whole-body insulin sensitivity (Si) by examining changes in skeletal muscle gene expression. The analysis considers differences by biological sex, exercise amount, and exercise intensity to identify potential molecular targets for developing pharmacologic agents that replicate the health benefits of exercise.METHODSThe study involved 53 participants from the STRRIDE I and II trials who completed eight months of aerobic training. Skeletal muscle gene expression was measured using Affymetrix and Illumina technologies, while pre- and post-training Si was assessed via an intravenous glucose tolerance test. A novel gene discovery protocol, integrating three literature-derived and data-driven modeling strategies, was employed to identify causal pathways and direct causal factors based on differentially expressed transcripts associated with exercise intensity and amount.RESULTSIn women, the transcription factor targets identified were primarily influenced by exercise amount and were generally inhibitory. In contrast, in men, these targets were driven by exercise intensity and were generally activating. Transcription factors such as ATF1, CEBPA, BACH2, and STAT1 were commonly activating in both sexes. Specific transcriptional targets related to exercise-induced Si improvements included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key signaling pathways mediating aerobic exercise-induced Si improvements were identified: one centered on estrogen signaling and the other on phorbol ester (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets.CONCLUSIONSThe signaling pathways mediating Si improvements from aerobic exercise differed by sex and were further distinguished by exercise intensity and amount. Transcriptional adaptations in skeletal muscle related to Si improvements appear to be causally linked to estrogen and PKC signaling, with EGFR and other identified targets emerging as potential skeletal muscle-specific drug targets to mimic the beneficial effects of exercise on Si.
Sex-Specific Roles of Hypocretin Receptor Signaling in CRF Neurons on Alcohol Drinking, Anxiety, and BNST Neuronal Excitability
Authors: Ma Yihe , Sardar Haniyyah , Benabou Max E. , Yu Angeline C. , Morningstar Allison R. , Fajardo R. Nicolas , Kandil Isaac F. , Rogers Ethan T. , Vassalli Anne , Kauer Julie A. , Giardino William J. 
Published: September 2024

AbstractAlcohol use disorder (AUD) is characterized by compulsive alcohol consumption and negative emotional states during withdrawal, often perpetuating a cycle of addiction through arousal dysfunction. The hypocretin/orexin (Hcrt) neuropeptide system, a key regulator of arousal, has been implicated in these processes, particularly in its interactions with corticotropin-releasing factor (CRF) neurons within the bed nucleus of the stria terminalis (BNST). We investigated the role of Hcrt receptor signaling in CRF neurons in modulating alcohol intake, anxiety behaviors, and BNST excitability, with a focus on sex-specific differences. Using CRF-specific genetic deletion of HcrtR1 and/or HcrtR2 receptors in mice, we found that deletion of HcrtR1 significantly reduced alcohol intake, with sex-specific effects on BNST excitability. CRF-specific HcrtR2 deletion, while not affecting alcohol consumption, decreased baseline anxiety-like behaviors in males relative to females. Moreover, the double deletion of both Hcrt receptors from CRF neurons led to reduced alcohol drinking in males and dampened anxiety behaviors and BNST excitability in both sexes during protracted withdrawal. These findings suggest that Hcrt signaling in CRF neurons plays a critical role in the persistence of excessive alcohol consumption and the development of negative affective states, with distinct contributions from HcrtR1 and HcrtR2. The observed sex-specific differences underscore the need for tailored therapeutic approaches targeting the Hcrt system in the treatment of AUD.
Swarming rate and timing of unmanaged honeybee colonies (Apis mellifera carnica) in a forest environment
Authors: Rutschmann Benjamin , Kohl Patrick L. , Steffan-Dewenter Ingolf 
Published: September 2024

ABSTRACTInvestigating the life history of social insect colonies and the demography of their populations are important for their conservation, but data collection is challenging. There is a growing interest in understanding the population status of wild-living honeybee colonies across Europe, for which it is critical to collect data on survival and natality rates. Although survival rates can be investigated through regular inspections of wild nests, the accurate quantification of natality rates (i.e., the number of swarms produced per colony per year) remains a significant challenge. Using digital weight scales, we remotely monitored the natural swarming behavior of ten unmanagedApis mellifera carnicacolonies housed in static-volume hives (45L) in a forest region of southern Germany. During the 2019 season, between mid-May and late June, we recorded 17 swarming events, averaging 1.7 swarms per colony. Our observations offer a reference point for the timing, frequency, and size of honeybee swarms that helps us understand the natural reproductive patterns of wild-living honeybees in a temperate forest environment.
Integrating Phenomic Selection Using Single-Kernel Near-Infrared Spectroscopy and Genomic Selection for Corn Breeding Improvement
Authors: Graciano Rafaela P. , Peixoto Marco Antônio , Leach Kristen A. , Suzuki Noriko , Gustin Jeff , Settles A. Mark , Armstrong Paul R. , Resende Márcio F. R. 
Published: September 2024

AbstractPhenomic Selection (PS) is a cost-effective method proposed for predicting complex traits and enhancing genetic gain in breeding programs. The statistical procedures are similar to those utilized in genomic selection (GS) models, but molecular markers data are replaced with phenomic data, such as near-infrared spectroscopy (NIRS). However, the use of NIRS applied to PS typically utilized destructive sampling or collected data after the establishment of selection experiments in the field. Here, we explored the application of PS using non-destructive, single-kernel NIRS in a sweet corn breeding program, focusing on predicting future, unobserved field-based traits of economic importance, including ear and vegetative traits. Three models were employed on a diversity panel: G-BLUP and P-BLUP models, which used relationship matrices based on SNP and NIRS data, and a combined model. The genomic relationship matrices were evaluated with varying numbers of SNPs. Additionally, the P-BLUP model trained on the diversity panel was used to select doubled haploid (DH) lines for germination before planting, with predictions validated using observed data. The findings indicate that PS generated good predictive ability (e.g., 0.46 for plant height) and effectively distinguished between high and low germination rates in untested DH lines. Although GS generally outperformed PS, the model combining both information yielded the highest predictive ability, with considerably higher accuracies than GS when low marker densities were used. This study highlights the potential of NIRS both to achieve genetic gain where GS may not be feasible and to maintain/improve accuracy with SNP-based information while reducing genotyping costs.Key messagePhenomic selection using whole seeds is a promising alternative to improve genetic gain and complement genomic selection in corn breeding. Models that combine genomic and phenomic data maximize the predictive ability.
Pcbp1 constrains Oct4 expression in the context of pluripotency
Authors: Bakhmet E. I. , Zinovyeva A. S. , Kuzmin A. A. , Smirnova D. V. , Gordeev M. N. , Petrenko E. E. , Aksenov N. D. , Tomilin A. N. 
Published: September 2024

AbstractOct4 is a commonly known marker of pluripotent stem cells as well as one of the key factors required for pluripotency induction. Its gene (Pou5f1) is subject to complicated regulation through distal and proximal enhancers. Noteworthy, this protein also plays an important role in primitive endoderm (PrE) specification, though the mechanisms driving its expression during this process are still unknown. Here we show that KH-domain protein Pcbp1 occupies poly(C)-sites of thePou5f1enhancers, butPcbp1knockout does not affect the Oct4 expression level in ESCs. On the contrary, Pcbp1 is essential for timely Oct4 downregulation upon differentiation signals. Residual Oct4 expression in turn leads to PrE specification, and this phenotype is reminiscent of that in ESCs constitutively expressing Oct4. Overall, our results point to Pcbp1 is a transcriptional regulator ofPou5f1,purported to synchronize Oct4 expression decline with the pluripotency network shutdown during differentiation. Oct4 being outside of this network loss its functions as factor of pluripotency and acts as PrE specifier.
Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability
Authors: McCrimmon Colin M. , Toker Daniel , Pahos Marie , Lozano Kevin , Lin Jack J. , Parent Jack , Tidball Andrew , Zheng Jie , Molnár László , Mody Istvan , Novitch Bennett G. , Samarasinghe Ranmal A. 
Published: September 2024

AbstractNeurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in theSCN8Agene. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.
Spillover of managed bumble bees from Mediterranean orchards during mass flowering causes minor short-term ecological impacts
Authors: Catalan Nitsan Nachtom , Keasar Tamar , Keasar Chen , Nagari Moshe 
Published: September 2024

ABSTRACTCommercial bumble bee colonies are routinely used for crop pollination in greenhouses, and are increasingly introduced into orchards as well. Bumble bee spillover to natural habitats neighboring the orchards may interfere with local wild bees and impact the pollination of non-crop plants. Concurrently, foraging in natural habitats may diversify the bumble bees’ diets and improve colony development. To evaluate these potential effects, we placed commercialBombus terrestriscolonies in blooming Rosaceae orchards, 25-125 m away from the margins. We recorded the colonies’ mass gain, population sizes, composition of stored pollen, and temperature regulation. We monitored bee activity, and seed sets of the non-crop plantEruca sativa, along transects in a semi-natural shrubland up to 100 m away from the orchards, with managed bumble bees either present or absent. Rosaceae pollen comprised ∼1/3 of the colonies’ pollen stores at all distances from the orchard margins. Colonies placed closest to the margins showed prolonged development, produced fewer reproductive individuals, and had poorer thermoregulation than colonies closer to the orchards’ center. Possibly, abiotic stressors inhibited the bumble bees’ development near orchard borders. Wild bees were as active during the colonies’ deployment as after their removal.E. sativa’s seed sets decreased after bumble bee removal, but similar declines also occurred near a control orchard without managed bumble bees. Altogether, we found no short-term spillover effects of managed bumble bees on nearby plant-bee communities during the orchards’ two-week flowering. The colonies’ prompt removal after blooming can reduce longer-term ecological risks associated with managed bumble bees.
C7-substituted Quinolines as Potent Inhibitors of AdeG Efflux Pumps inAcinetobacter baumannii
Authors: Zhu Yiling , Hind Charlotte K , Al-Adhami Taha , Wand Matthew E. , Clifford Melanie , Sutton J. Mark , Rahman Khondaker Miraz 
Published: September 2024

AbstractEfflux, mediated by a series of multidrug efflux pumps, is a major contributor to antibiotic resistance in Gram-negative bacteria. Efflux pump inhibitors (EPIs), which can block efflux, have the potential to be used as adjuvant therapies to re-sensitize bacteria to existing antibiotics. In this study, 36 quinoline-based compounds were synthesized as potential EPIs targeting Resistance Nodulation Division (RND) family pumps in the multidrug-resistant pathogenAcinetobacter baumannii. InA. baumanniistrains with overexpressed AdeFGH (chloramphenicol-adapted) and AdeABC (AYE, Ab5075-UW), these compounds enhanced Hoechst dye accumulation, indicating general efflux inhibition, and potentiated chloramphenicol which is an AdeG substrate. The research focused on two generations of quinoline compounds, with modifications at the C-7 position of first-generation compounds to improve hydrophobic interactions with the Phe loop in the AdeG efflux pump, to generate second-generation compounds. The modified quinolines showed strong pump inhibition and significant chloramphenicol potentiation, with MIC reductions of 4- to 64-fold. Notably, compounds1.8and3.8exhibited the highest inhibitory activity, while compounds1.3and3.3showed up to 64-fold potentiation, highlighting the importance of specific structural features at the C-7 position for efflux pump inhibition. The study also revealed selective inhibition of AdeFGH over AdeABC, with no potentiation observed for gentamicin, showing the specificity of these quinoline- based inhibitors. Importantly, the compounds showed no toxicity in a Galleria mellonella model at a 50 mg/kg dose level, highlighting their suitability as potential antibiotic adjuvants for combating bacterial resistance.
Molecular glues that inhibit deubiquitylase activity and inflammatory signalling
Authors: Chandler Francesca , Reddy Poli Adi Narayana , Bhutda Smita , Ross Rebecca L. , Datta Arindam , Walden Miriam , Walker Kieran , Di Donato Stefano , Cassel Joel A. , Prakesch Michael A. , Aman Ahmed , Datti Alessandro , Campbell Lisa J. , Foglizzo Martina , Bell Lillie , Stein Daniel N. , Ault James R. , Al-awar Rima S. , Calabrese Antonio N. , Sicheri Frank , Del Galdo Francesco , Salvino Joseph M. , Greenberg Roger A. , Zeqiraj Elton 
Published: September 2024

AbstractDeubiquitylases (DUBs) are crucial in cell signalling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). As a Zn2+-dependent JAMM/MPN DUB, BRCC36 is challenging to target with selective inhibitors. We discovered first-in-class inhibitors, termedBRISC molecular glues(BLUEs), which stabilise a 16-subunit BRISC dimer in an autoinhibited conformation, blocking active sites and interactions with the targeting subunit SHMT2. This unique mode of action results in selective inhibition of BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. BLUE treatment reduced interferon-stimulated gene expression in cells containing wild type BRISC, and this effect was absent when using structure-guided, inhibitor-resistant BRISC mutants. Additionally, BLUEs increase IFNAR1 ubiquitylation and decrease IFNAR1 surface levels, offering a potential new strategy to mitigate Type I interferon-mediated diseases. Our approach also provides a template for designing selective inhibitors of large protein complexes by promoting, rather than blocking, protein-protein interactions.
Rational selection of TbpB variants elucidates a bivalent vaccine formulation with broad spectrum coverage againstNeisseria gonorrhoeae
Authors: Fegan Jamie E. , Islam Epshita A. , Curran David M. , Ng Dixon , Au Natalie , Currie Elissa G. , Zeppa Joseph , Lam Jessica , Schryvers Anthony B. , Moraes Trevor F. , Gray-Owen Scott D. 
Published: September 2024

AbstractNeisseria gonorrhoeaeis the causative agent of gonorrhea, an on-going public health problem due in part to the lack of success with efforts to develop an efficacious vaccine to prevent this sexually transmitted infection. An attractive candidate vaccine antigen because of its essential function and surface exposure, the gonococcal transferrin binding protein B (TbpB) exhibits high levels of antigenic variability which poses a significant obstacle in evoking a broadly protective vaccine composition. Here, we utilize phylogenetic information to rationally select TbpB variants for inclusion into a potential gonococcal vaccine and identify two TbpB variants that when formulated together elicit a highly cross-reactive antibody response in both rabbits and mice against a diverse panel of TbpB variants and clinically relevant gonococcal strains. Further, this formulation performed well in experimental proxies of real-world usage, including eliciting bactericidal activity against 8 diverse gonococcal strains and decreasing the median duration of colonization after vaginal infection in female mice by two heterologous strains ofN. gonorrhoeae. Together, these data support the use of a combination of TbpB variants for a broadly protective gonococcal vaccine.