bluuebunny/crossref_metadata_2025_split huggingface dataset:
Musicianship modulates cortical (but not brainstem) effects of attention on processing musical triads
Authors: MacLean Jessica , Drobny Elizabeth , Rizzi Rose , Bidelman Gavin M. 
Published: September 2024

AbstractBackgroundMany studies have demonstrated benefits of long-term music training (i.e., musicianship) on the neural processing of sound, including simple tones and speech. However, the effects of musicianship on the encoding of simultaneously presented pitches, in the form of complex musical chords, is less well-established. Presumably, musicians’ stronger familiarity and active experience with tonal music might enhance harmonic pitch representations, perhaps in an attention-dependent manner. Additionally, attention might influence chordal encoding differently across the auditory system. To this end, we explored the effects of long-term music training and attention on processing of musical chords at brainstem and cortical levels.MethodYoung adult participants were separated into musician and nonmusician groups based on extent of formal music training. While recording EEG, listeners heard isolated musical triads that differed only in the chordal third: major, minor, and detuned (4% sharper third from major). Participants were asked to correctly identify chords via key press during active stimulus blocks and watched a silent movie during passive blocks. We logged behavioral identification accuracy and reaction times and calculated information transfer based on the behavioral chord confusion patterns. EEG data were analyzed separately to distinguish between cortical (event-related potential, ERP) and subcortical (frequency-following response, FFR) evoked responses.ResultsWe found musicians were (expectedly) more accurate, though not faster, than nonmusicians in chordal identification. For subcortical FFRs, responses showed stimulus chord effects but no group differences. However, for cortical ERPs, whereas musicians displayed P2 (∼150 ms) responses that were invariant to attention, nonmusicians displayed earlier and reduced P2 during passive listening. Listeners’ degree of behavioral information transfer (i.e., success in distinguishing chords) was also better in musicians and correlated with their neural differentiation of chords, assessed via pairwise differences in the ERPs.ConclusionsOur data suggest long-term music training strengthens even the passive cortical processing of musical sounds, supporting more automated brain processing of musical chords with less reliance on attention. Our results also suggest the degree to which listeners can behaviorally distinguish chordal triads is directly related to their neural specificity to musical sounds primarily at cortical rather than subcortical levels.
The urinary microbiome in association with diabetes and diabetic kidney disease: A systematic review
Authors: Graells Tiscar , Lin Yi-Ting , Ahmad Shafqat , Fall Tove , Ärnlöv Johan 
Published: September 2024

AbstractBackgroundThe urinary microbiome, or urobiome, is a novel area of research that has been gaining attention recently, as urine was thought to be sterile for years. There is limited information about the composition of the urobiome in health and disease. The urobiome may be affected by several factors and diseases such as diabetes, a disease that often leads to kidney damage. Thus, we need to understand the role of the urobiome to assess and monitor kidney disease related to diabetes over time.MethodsWe conducted a systematic review to summarize knowledge about the urobiome in association with diabetes mellitus and diabetic kidney disease. The search was conducted in several electronic databases until November 2024.ResultsEighteen studies were selected including cross-sectional case-control studies, cross-sectional surveys and one prospective longitudinal study. In total, the urobiome of 1,571 people was sequenced, of which 662 people had diabetes, and of these 36 had confirmed diabetic kidney disease; 609 were healthy individuals, 179 had prediabetes or were at risk of type 2 diabetes mellitus and 121 did not have diabetes but had other comorbidities. Eight studies analysed data from females, one was focused on male data, and the other nine had mixed female-male data. Most of the studies had a small sample size, used voided midstream urine, and used 16S rRNA sequencing.ConclusionThis systematic review summarizes trends seen throughout published data available to have a first baseline knowledge of the urinary microbiome, and its microbiota, in association with diabetes including the decreased richness and α-diversity in urinary microbiota in individuals with diabetes compared to healthy controls and the decreased α-diversity with the evolution of kidney disease independently of the cause.
Closing the gaps: testing the efficacy of carbapenem and cephalosporins in treating late-stage anthrax
Authors: Sittner Assa , Bar-David Elad , Glinert Itai , Ben-Shmuel Amir , Schlomovitz Josef , Levy Haim , Weiss Shay 
Published: September 2024

AbstractAnthrax is a fatal zoonotic disease caused by exposure toBacillus anthracisspores. Treatment of systemic anthrax is usually efficient when using the right antibiotics as close as possible to exposure, preferably prior to symptoms’ onset as post exposure prophylaxis (PEP). The efficacy decreases as treatment is initiated later in disease progression. The CDC in its guidelines divides anthrax treatment to three different indications according to the progression of the disease: PEP, systemic and systemic with indications of CNS infection. While the prognosis of PEP or early treatment of systemic anthrax is very good, ingress of the bacteria into the CNS significantly decreases treatment efficacy, creating a substantial clinical challenge. Since anthrax in humans is rare, the CDC recommendations are mainly based on animal model experiments and data obtained from patients infected with other pathogens. Here we use rabbits to test the efficacy of the combined treatment of Meropenem and Doxycycline which is the first choice in the CDC recommendations for treating systemic patients with indication of CNS infection. In addition, we test the efficacy of the first-generation cephalosporin, cefazolin, in treating the different stages of the disease. We found that the combination of Doxycycline and Meropenem is highly effective in treating rabbits in our inhalation and CNS infection models. Cefazoline was efficient only as PEP or systemic stage treatment but not CNS infected animals. Our findings support the CDC recommendation of using a combination of Doxycycline and Meropenem for systemic patients with or without indications for CNS infection. We found that Cefazoline is a decent choice for PEP or early sage systemic disease but recommend considering using this antibiotic only if all other options are not available.
Molecular and Proteomic Profiles of Radioiodine Refractory Papillary Thyroid Cancer
Authors: Liu Hanqing , Wang Jiaxi , Zhou Yan , Hu Pingping , Li Lu , Yang Dan , Kong Deguang , Xu Zhiliang , Sun Yaoting , Chen Chuang 
Published: September 2024

AbstractBackgroundDespite the generally favorable prognosis of papillary thyroid cancers (PTCs) following surgery with/without radioactive iodine (RAI) therapy, approximately one-third of patients experiencing recurrence and metastasis eventually develop resistance to RAI, leading to poor outcomes. However, the mechanisms underlying RAI-refractoriness remain elusive. This study aimed to assess the molecular and proteomic characteristics of RAI-refractory PTC (RR-PTC) for deeper insights.MethodsThe medical records were reviewed for the selection and grouping of RR-PTC patients and RAI-sensitive controls. RR-PTC patients were divided into three subgroups: continuous RAI uptake (ID), loss of uptake at the first I-131 treatment (iDF) and lost gradually (iDG). Proteomic profiling and targeted next-generation sequencing were performed on primary lesions. The incidence of gene mutations and fusions was compared across groups. Bioinformatic analysis was subsequently conducted to identify the differentially expressed proteins and enriched pathways.ResultsForty-eight PTC patients with recurrence and/or metastasis were included. The expression profiles of the RR-PTC and control groups were similar. In the subgroup comparison, enriched pathways related to MAPK and TNF signaling were associated with negative I-131 uptake and tumor tolerance with positive I-131 uptake. TheBRAFV600Emutation was less common in the ID group, whereas theTERTpromoter mutation was more common in the iDF group.NCOA4-RETfusion was more common in the ID group.ConclusionThe present study constructed the first proteomic profile of RR-PTC. The identified proteins and pathways may be promising biomarkers and drug targets. Gene alterations can aid in the early diagnosis of RR-PTC.
The exit of naïve pluripotency contains a lipid metabolism-induced checkpoint for genome integrity
Authors: de Souza Roshni A. , Barneda David , Karimlou Donja , Bovee Nick G.P. , Zheng Yuhan , Kahlman Eveline J.E.M. , Novo Clara Lopes , Ellis James K. , Leeke Bryony J. , Bangalore Megha Prakash , Liu Zijing , Sousa Bebiana C. , Lopez-Clavijo Andrea F. , Jansen Joop H. , Barahona Mauricio , Percharde Michelle , Keun Hector C. , Christian Mark , Marks Hendrik , Azuara Véronique 
Published: September 2024

AbstractPluripotent progenitors undergo dramatic cellular and biochemical transformations during peri-implantation development. These large-scale reprogramming events are fundamental for subsequent differentiation, but how they are integrated and co-ordinated with the preservation of genome integrity remain unknown. Here, we uncover a metabolism-induced telomere checkpoint that takes place in pluripotent progenitors as they form rosette-like epithelial structures. We show that the glycolytic switch at the exit of naïve pluripotency is preceded by an acceleration of mitochondrial respiration andde novolipogenesis, fuelling the accumulation of lipid droplets required for morphogenesis. We find that downstream of these CIDEA-promoted metabolic events is the induction of ZSCAN4, a key pluripotency-associated regulator of telomere stability. Surprisingly, the build-up of lipid droplets corresponds to a transient shortening of telomeres, which triggers the activation of an elongation mechanism via ZSCAN4. Thus, telomere homeostasis can be safeguarded as essential lipid metabolic reprogramming unfolds to drive developmental progression.
Anti-tubercular potential and pH-driven mode of action of salicylic acid derivatives
Authors: Laudouze Janïs , Francis Thomas , Forest Emma , Mies Frédérique , Bolla Jean-Michel , Crauste Céline , Canaan Stéphane , Shlyonsky Vadim , Santucci Pierre , Cavalier Jean-François 
Published: September 2024

AbstractIn the search for new anti-tuberculosis drugs with novel mechanisms of action, we evaluated the antimycobacterial activity of a panel of eight phenolic acids against four pathogenic mycobacterial model species, includingM. tuberculosis. We demonstrated that salicylic acid (SA), as well as the iodinated derivatives 5-iodo-salicylic acid (5ISA) and 3,5-diiodo-salicylic acid (3,5diISA), displayed promising antitubercular activities. Remarkably, using a genetically encoded mycobacterial intrabacterial pH reporter, we describe for the first time thatSA, 5ISA, 3,5diISAand the anti-inflammatory drug aspirin (ASP) act by disrupting the intrabacterial pH homeostasis ofM. tuberculosisin a dose-dependent manner underin vitroconditions mimicking the endolysosomal pH of macrophages. In contrast, the structurally related second-line anti-TB drug 4-aminosalicylic acid (PAS) had no pH-dependent activity and was strongly antagonized by L-methionine supplementation, thereby suggesting distinct modes of action. Finally, we propose thatSA, ASPand its two iodinated derivatives could restrictM. tuberculosisgrowth in a pH-dependent manner by acidifying the cytosol of the bacilli; therefore, making such compounds very attractive for further development.
Transient Notch Activation Converts Pluripotent Stem Cell-Derived Cardiomyocytes Towards a Purkinje Fiber Fate
Authors: Gonzalez David M. , Dariolli Rafael , Moyett Julia , Song Stephanie , Shewale Bhavana , Bliley Jacqueline , Clarke Daniel , Ma’ayan Avi , Rentschler Stacey , Feinberg Adam , Sobie Eric , Dubois Nicole C. 
Published: September 2024

AbstractCardiac Purkinje fibers form the most distal part of the ventricular conduction system. They coordinate contraction and play a key role in ventricular arrhythmias. While many cardiac cell types can be generated from human pluripotent stem cells, methods to generate Purkinje fiber cells remain limited, hampering our understanding of Purkinje fiber biology and conduction system defects. To identify signaling pathways involved in Purkinje fiber formation, we analyzed single cell data from murine embryonic hearts and compared Purkinje fiber cells to trabecular cardiomyocytes. This identified several genes, processes, and signaling pathways putatively involved in cardiac conduction, including Notch signaling. We next tested whether Notch activation could convert human pluripotent stem cell-derived cardiomyocytes to Purkinje fiber cells. Following Notch activation, cardiomyocytes adopted an elongated morphology and displayed altered electrophysiological properties including increases in conduction velocity, spike slope, and action potential duration, all characteristic features of Purkinje fiber cells. RNA-sequencing demonstrated that Notch-activated cardiomyocytes undergo a sequential transcriptome shift, which included upregulation of key Purkinje fiber marker genes involved in fast conduction such asSCN5A, HCN4 and ID2,and downregulation of genes involved in contractile maturation. Correspondingly, we demonstrate that Notch-induced cardiomyocytes have decreased contractile force in bioengineered tissues compared to control cardiomyocytes. We next modified existingin silicomodels of human pluripotent stem cell-derived cardiomyocytes using our transcriptomic data and modeled the effect of several anti-arrhythmogenic drugs on action potential and calcium transient waveforms. Our models predicted that Purkinje fiber cells respond more strongly to dofetilide and amiodarone, while cardiomyocytes are more sensitive to treatment with nifedipine. We validated these findingsin vitro, demonstrating that our new cell-specificin vitromodel can be utilized to better understand human Purkinje fiber physiology and its relevance to disease.
Structural and functional analysis of cancer-associated missense variants in the retinoblastoma protein (Rb) pocket domain
Authors: Castro Anthony , Ruiz-Rivera Alfredo , Moorman Chad C. , Wolf-Saxon Emma R. , Mims Hailey N. , Vasquez-Meza Vanessa I. , Rangel Matthew A. , Loera Marcos M. , Bond Ian , Buchanan Seth B. , Villarreal Estela , Tripathi Sarvind , Rubin Seth M. , Burke Jason R. 
Published: September 2024

ABSTRACTThe retinoblastoma tumor suppressor (Rb) is a multifunctional protein that primarily regulates the cell cycle but also has roles in cellular differentiation, DNA damage response and apoptosis. The loss of Rb is a key event in the development or progression of many cancers. Essential functions of Rb occur through its pocket domain, which is necessary for regulating binding interactions with E2F transcription factors and transcription repressors that bind via an LxCxE motif. The pocket domain is the most highly-conserved region of the multidomain protein, as well as the most frequent site of mutations. To understand what effects cancer missense mutations have on Rb’s pocket domain, we used fluorescence polarization and differential scanning fluorimetry to quantify changes, caused by 75 cancer-associated missense variants, to E2F transactivation domain (E2FTD) binding, LxCxE binding, and changes to the thermostability of the protein. We find that 43% of the missense variants we tested reduce Rb-E2FTDbinding. Many of these variants are not located at the E2F binding site, yet they destabilize the fold of the protein and show temperature-sensitive binding effects. We also find that 21% of tested mutations reduce LxCxE binding, and several mutations selectively disrupt either E2FTDor LxCxE binding. Protein X-ray crystallography of four missense variants reveals how different mutations destabilize the protein fold and inhibit E2FTDor LxCxE binding. Taken together, this work provides the first understanding of the multiple ways through which stability, structure and function of Rb’s pocket domain is altered by a large number of missense mutations seen in cancer.
Unsaturated lipids as key control points for caveola formation and disassembly
Authors: Wu Yeping , Lim Ye-Wheen , McMahon Kerrie-Ann , Martel Nick , Rae James , Lo Harriet P. , Gao Ya , Tillu Vikas , Larsson Elin , Lundmark Richard , Levic Daniel S. , Bagnat Michel , Lim Junxian , Fairlie David P. , Pol Albert , Collins Brett M. , Ariotti Nicholas , Hall Thomas E. , Parton Robert G. 
Published: September 2024

AbstractCaveolae are specialized plasma membrane domains with a unique lipid composition. Recent work has implicated lipid peroxidation in triggering caveola disassembly, releasing caveolar proteins to regulate the cellular response to oxidative stress. Here we investigated the role of specific lipid species in caveola formation and response to oxidative stress. Systematic screening of lipid enzymes identified ACSL4, a critical enzyme in the synthesis of polyunsaturated fatty acid-containing lipids, and enzymes involved in the biosynthesis of pro-ferroptotic ether lipids, as key regulators of caveola formation. Omega-6 fatty acids promoted efficient caveola formation, while their oxidation or displacement by omega-3 or monounsaturated fatty acids disrupted this process. Moreover, we found that omega-6 fatty acid-containing membrane lipids were required for oxidative stress-induced caveola disassembly. These findings unveil a new model for caveola formation, highlighting specific unsaturated lipids as essential caveolar components and key control points for caveola disassembly in response to an oxidizing environment.
The accessory domains of Phospholipase D regulate its localization and activity inDrosophilaphotoreceptors
Authors: Naik Amruta , Raghu Padinjat 
Published: September 2024

AbstractPhospholipase D (PLD) is activated during the response of animal cells to a large number of extracellular signals including growth factors, hormones and other extracellular stimuli. The product of PLD activity, phosphatidic acid (PA) is thought to act as a signalling molecule in cells. Since both the substrate, phosphatidylcholine and product phosphatidic acid (PA) are membrane anchored lipids, the precise localization and activation of PLD at specific locations in cells is critical. Here we report that that the precise localization ofDrosophilaPLD (dPLD) in photoreceptors is critical to maintain the structure of these cells during illumination. This localization of dPLD is dependent on its N-terminal PH domain; deletion of the PH domain (dPLDΔPH) results in mis localization of the protein, loss of functional activity anddPLDΔPHis unable to rescue the phenotypes ofdPLDloss of function. By contrast, deletion of the PX domain (dPLDΔPX) does not impact the localization of dPLD but enhances the functional activity of the protein. Thus the PH and PX domains of dPLD regulate its localization and activity respectively.
Whole-brain dynamics and hormonal shifts throughout women’s lifespan: From reproductive stages to menopausal transition and beyond
Authors: Escrichs Anira , Avila-Varela Daniela , Patow Gustavo , Pletzer Belinda , Ritter Petra 
Published: September 2024

ABSTRACTNeuroimaging studies have identified significant age-related disruptions in whole-brain dynamics, yet the influence of women’s reproductive stages and associated hormonal shifts remains underexplored. This study leverages resting-state fMRI data from the Human Connectome Project in Aging to examine brain dynamics through five reproductive stages: reproductive, late reproductive, perimenopause, early postmenopause, and late postmenopause. Our results indicate that the late reproductive stage is characterized by the highest dynamical complexity across whole-brain and resting-state networks, while brain dynamics significantly decline at menopause onset. Additionally, we employ machine learning classifiers using two approaches: (1) brain dynamics alone and (2) brain dynamics combined with follicle-stimulating hormone (FSH) and estradiol (brain-hormone model). Both models accurately distinguished reproductive stages, but the brain-hormone model outperformed the brain dynamics model. Key predictors included decreased estradiol, increased FSH, and altered brain dynamics in later life stages. These results offer a framework for assessing brain health across women’s reproductive lifespan.
Mouse PAW: reverse-translating the FINGER multimodal lifestyle intervention enhances synaptic plasticity and cognition in adult wild type female mice
Authors: Alanko Vilma , Eroli Francesca , Végvári Ákos , Solomon Alina , Hartmann Tobias , Nilsson Per , Kivipelto Miia , Maioli Silvia , Matton Anna 
Published: September 2024

AbstractBackgroundTargeting multiple risk factors through preventive interventions can halt the onset or progression of dementia. The clinical efficacy of this approach was shown in the multimodal FINGER trial, yet knowledge of the underlying biological mechanisms is limited. In the current study, we applied for the first time a multimodal lifestyle intervention in mice to study effects on cognition and associated molecular pathways.MethodsWe have established a novel experimental model, the lifestyle intervention PAW (Prevention ofAlzheimer’s by a Multimodal Lifestyle Protocol –Working-mechanisms for Memory Gains) in mice. In this model, we combined different modalities of intervention aiming to achieve synergistic effects. The animals were given access to running wheels (voluntary exercise), Fortasyn Connect (a medical food that slows disease progression in early Alzheimer’s disease), and they were subjected to cognitive training in an IntelliCage environment (PAW group). To separately investigate the effects of pharmacological vascular management as a preventive measure, another group of mice was given Atorvastatin and Enalapril (cholesterol and blood pressure lowering pharmaceuticals, respectively) dosed in the diet (Pharma group). Control mice were housed in normal conditions. We included 12 wild type C57BL/6J female mice 6.5 months of age per group. The full intervention lasted for 8 weeks. Blood pressure was measured at baseline and the end of the intervention. All mice underwent a battery of behavioural testing after the eight weeks of intervention. Hippocampi were dissected for proteomics analysis.ResultsDuring the intervention, the PAW group actively participated in the intervention by learning the different cognitive training programs and by using the running wheels. At the end of the intervention, the PAW group showed a lowering of blood pressure to a similar extent as in the Pharma group (systolic 158 mmHg to 139 mmHg,p= 0.003, and 163 mmHg to 136 mmHg,p= 0.042, respectively). Furthermore, the PAW group displayed a better short-term spatial working memory compared to the control group as assessed by the spontaneous alternation in the Y maze test (66.5% and 56.7%, respectively,p= 0.036). Proteomic analysis of the hippocampi and downstream bioinformatic analysis revealed that several pathways were upregulated in the PAW mice including synaptogenesis (Z = 4.27,p= 1.26E–18) and glutamate binding, activation of AMPA receptors and synaptic plasticity (Z = 3.74,p= 3.16E–19).ConclusionsOur findings suggest that the PAW model effectively mimics the clinical effects of multimodal lifestyle dementia prevention, and further demonstrates the activation of hippocampal-specific molecular drivers of memory gains.