bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends in cognitive function before and after myocardial infarction : findings from the China Health and Retirement Longitudinal Study
Authors: Zhu Sijia , Shang Jing , Dong Jianye , Chen Qingmei , Hua Jianian 
Published: August 2023

AbstractObjectivesIncident stroke was associated with cognitive dysfunction after stroke and even before stroke. However, cognitive trends prior to myocardial infarction (MI) and the timeline of cognitive decline in a few years following incident MI remain unclear, especially among the Chinese population. We aimed to evaluate whether MI was associated with cognitive change both before and after MI in China.MethodsThis cohort study included 11287 participants without baseline heart problems or stroke from the China Health and Retirement Longitudinal Study. The exposure was self-reported MI. The outcomes were scores of cognitive function in five domains, which reflected abilities of episodic memory, visuospatial abilities, orientation, attention and calculation, and global cognition as a summary measure. Linear mixed models explored cognitive function before and after incident MI among the MI participants and the cognitive trends of participants free of MI.ResultsDuring the 7-year follow-up, 421 individuals (3.7% of 11287, mean [SD] age, 60.0 [9.0] years; 59.1% female) experienced MI events. The cognitive scores of participants of both the MI group and the control group without MI declined gradually due to aging. The annual decline rate of the MI group before incident MI was similar to that of the control group during the whole follow-up period. Incident MI was not associated with acute cognitive decline in all five cognitive domains. Moreover, MI did not accelerate the cognitive decline rate after MI compared with the pre-MI cognitive trends. The decline rate of cognitive function after MI was similar to the rate before MI.ConclusionsDifferent from stroke, participants who had an MI did not show steeper cognitive decline before MI. MI was not associated with acute cognitive decline and accelerated long-term decline after MI. Future studies are needed to learn the mechanisms behind the different patterns of cognitive decline between MI and stroke.
Delays in accessing high-quality care for newborns in East Africa: An analysis of survey data in Malawi, Mozambique, and Tanzania
Authors: Niehaus Lori , Sheffel Ashley , Kalter Henry , Amouzou Agbessi , Koffi Alain , Munos Melinda K. 
Published: August 2023

AbstractBackgroundDespite the existence of evidence-based interventions, substantial progress in reducing neonatal mortality is lagging, indicating that small and sick newborns (SSNs) are likely not receiving the care they require to survive and thrive. The “three delays model” provides a framework for understanding the challenges in accessing care for SSNs. However, the extent to which each of the delays impacts access to care for SSNs is not well-understood. To fill this evidence gap, we explored the impact of each of the three delays on access to care for SSNs in Malawi, Mozambique, and Tanzania.MethodsSecondary analyses of data from three different surveys served as the foundation of this study. To understand the impact of delays in the decision to seek care (delay 1) and the ability to reach an appropriate point of care (delay 2), we investigated time trends in place of birth disaggregated by facility type and explored care-seeking behaviors for newborns who died. To understand the impact of delays accessing high-quality care after reaching a facility (delay 3), we measured facility readiness to manage care for SSNs and used this measure to adjust institutional delivery coverage for SSN care readiness.FindingsCoverage of institutional deliveries was substantially lower after adjusting for facility readiness to manage SSN care, with decreases of 30 percentage points (pp) in Malawi, 14pp in Mozambique, and 24pp in Tanzania. While trends suggest more SSNs are born in facilities, substantial gaps remain in facilities’ capacities to provide lifesaving interventions. In addition, exploration of care-seeking pathways revealed that a substantial proportion of newborn deaths occurred outside of health facilities, indicating barriers in the decision to seek care or ability to reach an appropriate source of care may also prevent SSNs from receiving these interventions.ConclusionsInvestments are needed to overcome delays in accessing high quality care for the most vulnerable newborns – those who are born small or sick. As more mothers and newborns access health services in low- and middle-income countries, ensuring that life-saving interventions for SSNs are available at the locations where newborns are born and seek care after birth is critical.
Tau phosphorylated at serine 356 is associated with Alzheimer’s disease pathology and can be lowered in mouse and human brain tissue using the NUAK inhibitor WZ4003
Authors: Taylor Lewis W. , Simzer Elizabeth M. , Pimblett Claire , Lacey-Solymar Oscar T.T. , McGeachan Robert I. , Meftah Soraya , Rose Jamie L. , Spires-Jones Maxwell P. , Catterson James H. , Koch Henner , Liaquat Imran , Clarke Jonathan H. , Skidmore John , Booker Sam A. , Brennan Paul M. , Spires-Jones Tara L. , Durrant Claire S. 
Published: August 2023

AbstractTau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK) related enzyme NUAK1 been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimer’s disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD post-mortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in anex vivosystem that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype specific effects, we found that WZ4003 results in a culture-phase dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.
Dopaminergic D2 receptor modulation of striatal cholinergic interneurons contributes to sequence learning
Authors: Chancey Jessica Hotard , Kellendonk Christoph , Javitch Jonathan A. , Lovinger David M. 
Published: August 2023

AbstractLearning action sequences is necessary for normal daily activities. Medium spiny neurons (MSNs) in the dorsal striatum (dStr) encode action sequences through changes in firing at the start and/or stop of action sequences or sustained changes in firing throughout the sequence. Acetylcholine (ACh), released from cholinergic interneurons (ChIs), regulates striatal function by modulating MSN and interneuron excitability, dopamine and glutamate release, and synaptic plasticity. Cholinergic neurons in dStr pause their tonic firing during the performance of learned action sequences. Activation of dopamine type-2 receptors (D2Rs) on ChIs is one mechanism of ChI pausing. In this study we show that deleting D2Rs from ChIs by crossing D2-floxed with ChAT-Cre mice (D2Flox-ChATCre), which inhibits dopamine-mediated ChI pausing and leads to deficits in an operant action sequence task and lower breakpoints in a progressive ratio task. These data suggest that D2Flox-ChATCre mice have reduced motivation to work for sucrose reward, but show no generalized motor skill deficits. D2Flox-ChATCre mice perform similarly to controls in a simple reversal learning task, indicating normal behavioral flexibility, a cognitive function associated with ChIs.In vivoelectrophysiological recordings show that D2Flox-ChatCre mice have deficits in sequence encoding, with fewer dStr MSNs encoding entire action sequences compared to controls. Thus, ChI D2R deletion appears to impair a neural substrate of action chunking. Virally replacing D2Rs in dStr ChIs in adult mice improves action sequence learning, but not the lower breakpoints, further suggesting that D2Rs on ChIs in the dStr are critical for sequence learning, but not for driving the motivational aspects of the task.Significance statementThe role of striatal projection neurons in encoding action sequences has been extensively studied, and cholinergic interneurons play a central role in striatal physiology, but we do not yet understand how cholinergic interneurons contribute to action sequencing. Using a combination of mouse genetics, behavior, andin vivoelectrophysiology this work shows that genetic deletion of D2 receptors from striatal cholinergic interneurons disrupts the learning, performance, and encoding of action sequences, without changing general locomotion or motor skill learning. Virally replacing D2 receptors specifically in dorsal striatal cholinergic interneurons is sufficient to rescue the sequence behavior. Our observations may be useful in understanding and treating movement disorders in which dopamine and acetylcholine are imbalanced.
Effort cost of reaching prompts vigor reduction in older adults
Authors: Summerside Erik M. , Courter Robert J. , Shadmehr Reza , Ahmed Alaa A. 
Published: August 2023

AbstractAs people age, they move slower. Is age-related reduction in vigor a reflection of a reduced valuation of reward by the brain, or a consequence of increased effort costs by the muscles? Here, we quantified cost of movements objectively via the metabolic energy that young and old participants consumed during reaching and found that in order reach at a given speed, older adults expended more energy than the young. We next quantified how reward modulated movements in the same populations and found that like the young, older adults responded to increased reward by initiating their movements earlier. Yet, their movements were less sensitive to increased reward, resulting in little or no modulation of reach speed. Lastly, we quantified the effect of increased effort on how reward modulated movements in young adults. Like the effects of aging, when faced with increased effort the young adults responded to reward primarily by reacting faster, with little change in movement speed. Therefore, reaching required greater energetic expenditure in the elderly, suggesting that the slower movements and reactions exhibited in aging are partly driven by an adaptive response to an elevation in the energetic landscape of effort. That is, moving slower appears to be a rational economic consequence of aging.Significance statementHealthy aging coincides with a reduction in speed, or vigor, of walking, reaching, and eye movements. Here we focused on disentangling two opposing sources of aging-related movement slowing: reduced reward sensitivity due to loss of dopaminergic tone, or increased energy expenditure movements related to mitochondrial or muscular inefficiencies. Through a series of three experiments and construction of a computational model, here we demonstrate that transient changes in reaction time and movement speed together offer a quantifiable metric to differentiate between reward- and effort-based alterations in movement vigor. Further, we suggest that objective increases in the metabolic cost of moving, not reductions in reward valuation, are driving much of the movement slowing occurring alongside healthy aging.
Mosquitoes escape looming threats by actively flying with the bow-wave induced by the attacker
Authors: Cribellier Antoine , Camilo Leonardo Honfi , Goyal Pulkit , Muijres Florian T. 
Published: August 2023

AbstractTo detect and escape from a looming threat, night-flying insects must rely on other senses than vision alone. Nocturnal mosquitoes have been described to escape looming objects in the dark, but how they achieve this is still unknown. Here, we show how night-active female malaria mosquitoes escape from a rapidly looming object that simulates the defensive action of a blood-host. By combining videography-based automatic tracking with numerical simulations of the attacker-induced airflow, we first show that night-flying mosquitoes use airflow-sensing to detect the danger and trigger their escape. Secondly, by combining these data with mechanistic movement modelling, we unravelled how mosquitoes control their escape manoeuvres: they actively steer away from the danger, and passively travel with the bow-wave produced by the attacker. Our results demonstrate that night-flying mosquitoes escaping from a looming object use the object-induced airflow both to detect the danger, and as fluid medium to move with for avoiding collision. This shows that the escape strategy of flying insects is more complex than previous visually-induces escape flight studies suggest. As mosquitoes are average-sized insects, a combined airflow-induced and visual-induced escape strategy is expected to be common amongst millions of flying insect species. Also, our research helps explain the high escape performance of mosquitoes from counterflow-based odour-baited mosquito traps. It can therefore provide new insights for the development of novel trapping techniques for integrative vector management.
Sedentary behavior may accelerate aging through impact on epigenome and transcriptome: lessons from muscle inactivation inDrosophilalarvae
Authors: Brener Avivit , Lorber Dana , Reuveny Adriana , Toledano Hila , Porat-Kuperstein Lilach , Lebenthal Yael , Weizman Eviatar , Olender Tsviya , Volk Talila 
Published: August 2023

AbstractAimThe biological mechanisms linking sedentary lifestyles and metabolic derangements are incompletely understood. Our animal model mimics sedentary behavior during early life, enabling us to explore the associated chromatin epigenetic and transcriptomic landscapes.MethodsDrosophilalarvae carrying a temperature-sensitive mutation in theshibire1(shi) gene were used.shihomozygous mutant larvae undergo instant arrest of muscle contraction at a restrictive temperature (30°C), without affecting other systems. Bothshiand control (y,w) larvae were held at permissive temperature (18°C), and transferred to restrictive temperature (30°C) for six hours. Larvae were then dissected, fixed, and double-labeled with antibodies specific for epigenetic marks of chromatin activation (H3K9ac) and repression (H3K27me3), and their fluorescence signal was quantified. In addition, whole genome analysis of RNA-Pol II binding to DNA in muscle-specific inactive, or control larvae was performed using muscle-specific targeted DamID (TaDa) protocol.ResultsInducing muscle inactivity inshilarvae at 300C yielded a significantly higher ratio between chromatin activation and repression, based upon H3K9ac/H3K27me3 signals (p=0.025), relative to all control groups for which this ratio was comparable (p=0.995). Furthermore, muscle inactivation led to altered Pol II binding to 121 out of 2010 genes (6%). The suppressed protein-coding genes included genes associated with longevity, DNA repair, muscle function, and ubiquitin-dependent proteostasis. In addition, a three-fold enrichment of genes coding for lncRNAs was noted in the muscle-inactive larvae.ConclusionInducing muscle inactivation exerted a multi-level impact upon chromatin, triggering an altered epigenetic balance, as well as downregulation of the transcriptional activity of genes essential for muscle function, carbohydrate metabolism, longevity and others. Extrapolating these findings to humans holds promise for establishing a molecular link between sedentary behavior and metabolic diseases.
Integration of Multiple Spatial Omics Modalities Reveals Unique Insights into Molecular Heterogeneity of Prostate Cancer
Authors: Zhang Wanqiu , Spotbeen Xander , Vanuytven Sebastiaan , Kint Sam , Sarretto Tassiani , Socciarelli Fabio , Vandereyken Katy , Dehairs Jonas , Idkowiak Jakub , Wouters David , Alvira Larizgoitia Jose Ignacio , Partel Gabriele , Ly Alice , Laat Vincent de , Q Mantas Maria José , Gevaert Thomas , Devlies Wout , Mah Chui Yan , Butler Lisa M , Loda Massimo , Joniau Steven , Moor Bart De , Sifrim Alejandro , Ellis Shane R. , Voet Thierry , Claesen Marc , Verbeeck Nico , Swinnen Johannes V. 
Published: August 2023

AbstractRecent advances in spatial omics methods are revolutionising biomedical research by enabling detailed molecular analyses of cells and their interactions in their native state. As most technologies capture only a specific type of molecules, there is an unmet need to enable integration of multiple spatial-omics datasets. This, however, presents several challenges as these analyses typically operate on separate tissue sections at disparate spatial resolutions. Here, we established a spatial multi-omics integration pipeline enabling co-registration and granularity matching, and applied it to integrate spatial transcriptomics, mass spectrometry-based lipidomics, single nucleus RNA-seq and histomorphological information from human prostate cancer patient samples. This approach revealed unique correlations between lipids and gene expression profiles that are linked to distinct cell populations and histopathological disease states and uncovered molecularly different subregions not discernible by morphology alone. By its ability to correlate datasets that span across the biomolecular and spatial scale, the application of this novel spatial multi-omics integration pipeline provides unprecedented insight into the intricate interplay between different classes of molecules in a tissue context. In addition, it has unique hypothesis-generating potential, and holds promise for applications in molecular pathology, biomarker and target discovery and other tissue-based research fields.
Inactivation oflmo0946(sif) induces the SOS response and MGEs mobilization and silences the general stress response and virulence program inListeria monocytogenes
Authors: Ładziak Magdalena , Prochwicz Emilia , Gut Karina , Gomza Patrycja , Jaworska Karolina , Ścibek Katarzyna , Młyńska-Witek Marta , Kadej-Zajączkowska Katarzyna , Lillebaek Eva M.S. , Kallipolitis Birgitte H. , Krawczyk-Balska Agata 
Published: August 2023

ABSTRACTBacteria have evolved numerous regulatory pathways to survive in changing environments. The SOS response is an inducible DNA damage repair system that plays an indispensable role in bacterial adaptation and pathogenesis. Here we report a discovery of the previously uncharacterized protein Lmo0946 as an SOS response interfering factor (Sif) in the human pathogenListeria monocytogenes.Functional genetic studies demonstrated thatsifis indespensible for normal growth ofL. monocytogenesin stress-free as well as multi-stress conditions, andsifcontributes to susceptibility to β-lactam antibiotics, biofilm formation and virulence. Absence of Sif promoted the SOS response and elevated expression of mobilome genes accompanied by mobilization of the A118 prophage and ICELm-1 mobile genetic elements (MGEs). These changes were found to be associated with decreased expression of general stress response genes from the σB regulon as well as virulence genes, including the PrfA regulon. Together, this study uncovers an unexpected role of a previously uncharacterized factor, Sif, as an inhibitor of the SOS response inL. monocytogenes.SUMMARYThis study uncovers an unexpected role of a previously uncharacterized factor, Sif, as an inhibitor of the SOS response inL. monocytogenes.
Oral StreptococciS. anginosusandS. mitisinduce distinct morphological, inflammatory, and metabolic signatures in macrophages
Authors: Kumar Sangeetha Senthil , Gunda Venugopal , Reinartz Dakota M. , Pond Kelvin , Raj Paul Victor Santiago , Johnson Michael D. L. , Wilson Justin E. 
Published: August 2023

AbstractOral streptococci are the pioneer colonizer and structural architect of the complex oral biofilm. Disruption of this architectural framework causes oral dysbiosis associated with various clinical conditions, including dental caries, gingivitis, and oral cancer. Among the genusStreptococcus,S. anginosusis associated with esophageal, gastric, and pharyngeal cancer tissues, whileS. mitisis correlated with oral cancer. However, no study has investigated mechanistic links between theseStreptococcus speciesand cancer-related inflammatory responses. To explore the underlying involvement ofS. anginosus and S. mitisin inflammation-associated cancer development, we investigated the innate immune response elicited byS. anginosusversusS. mitisusing the RAW264.7 macrophage cell line. Compared to untreated orS. mitisinfected macrophages,S. anginosusinfected macrophages exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2, accompanied by enhanced NF-κB activation. Mitostress analysis revealed an increased extracellular acidification rate in macrophages infected withS. anginosuscompared toS. mitis.Further, macrophages infected withS. anginosusfor 6h displayed upregulated aconitate decarboxylase, which catalyzes itaconate production. In contrast, no significant alterations were observed in succinate dehydrogenase that converts succinate to fumarate. At 24h,S. anginosusinduced significant shifts in succinate and itaconate, emphasizing a unique macrophage metabolic profile, and an augmented inflammatory response in response toS. anginosus.This study underscores the capacity ofS. anginosusto elicit a robust proinflammatory response in macrophages and opens new avenues of secretory immune metabolites in response to oral streptococci.ImportanceThe surge in head and neck cancer cases among individuals devoid of typical risk factors such as HPV infection, tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome’s influence on physiology, the oral microbiome, notably oral streptococci, a gatekeeper of systemic health, has been underappreciated in mucosal immunopathogenesis.S. anginosus,a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response toS. anginosuscompared to the early colonizerS. mitisas an initial ride towards understanding the impact of distinct oralStreptococcusspecies on the host immune response in the progression of OSCC.