bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Druggable Site on GRP78 at the GRP78-SARS-CoV-2 Interface and Compounds to Disrupt that Interface
Authors: Lazou Maria , Hutton Jonathan R. , Chakravarty Arijit , Joseph-McCarthy Diane 
Published: September 2023

AbstractSARS-CoV-2, the virus that causes COVID-19, led to a global health emergency that claimed the lives of millions. Despite the widespread availability of vaccines, the virus continues to exist in the population in an endemic state which allows for the continued emergence of new variants. Most of the current vaccines target the spike glycoprotein interface of SARS-CoV-2, creating a selection pressure favoring viral immune evasion. Antivirals targeting other molecular interactions of SARS-CoV-2 can help slow viral evolution by providing orthogonal selection pressures on the virus. GRP78 is a host auxiliary factor that mediates binding of the SARS-CoV-2 spike protein to human cellular ACE2, the primary pathway of cell infection. As GRP78 forms a ternary complex with SARS-CoV-2 spike protein and ACE2, disrupting the formation of this complex is expected to hinder viral entry into host cells. Here, we developed a model of the GRP78-spike protein-ACE2 complex. We then used that model together with hot spot mapping of the GRP78 structure to identify the putative binding site for spike protein on GRP78. Next, we performed structure-based virtual screening of known drug/candidate drug libraries to identify binders to GRP78 that are expected to disrupt spike protein binding to the GRP78, and thereby preventing viral entry to the host cell. A subset of these compounds have previously been shown to have some activity against SARS-CoV-2. The identified hits are starting points for the further development of novel SARS-CoV-2 therapeutics, potentially serving as proof-of-concept for GRP78 as a potential drug target for other viruses.
Chronic optogenetic activation of hippocampal pyramidal neurons replicates the proteome footprint of Alzheimer’s disease-like pathology
Authors: Keramidis Iason , Samiotaki Martina , Sansonetti Romain , Alonso Johanna , Papanikolopoulou Katerina , Koninck Yves De 
Published: September 2023

AbstractNeuronal overexcitability can elicit synaptic changes, leading to neuronal hyperactivity and abnormal neural circuit processing. Such network disruption impairs neuronal function and survival, initiating neurodegeneration and Alzheimer’s disease (AD). Yet, the sequence of synaptic changes resulting from excessive neuronal activity remains elusive. We employed optogenetics to induce sustained neuronal hyperactivity in the hippocampi of wild-type and AD-like 5xFAD mice. Surprisingly, after a month of daily optogenetic stimulation, the proteomic profiles of photoactivated wild-type and 5xFAD mice exhibited remarkable similarity. Proteins involved in translation, protein transport, autophagy, and notably in the AD pathology were upregulated in wild-type mice. Conversely, both glutamatergic and GABAergic synaptic proteins were downregulated. These hippocampal proteomic and signaling alterations in wild-type mice resulted in spatial memory loss and augmented Αβ42 secretion. Collectively, these findings indicate that sustained neuronal hyperactivity alone replicates proteome changes seen in AD-linked mutant mice. Therefore, prolonged neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with AD.
Systemic 4-1BB stimulation augments extrafollicular memory B cell formation and recall responses duringPlasmodiuminfection
Authors: Caloba Carolina , Sturtz Alexandria J. , Lyons Taylor A. , John Lijo , Ramachandran Akshaya , Minns Allen M. , Cannon Anthony M. , Whalley Justin P. , Watts Tania H. , Kaplan Mark H. , Lindner Scott E. , Vijay Rahul 
Published: September 2023

SummaryT-dependent germinal center (GC) output, comprising plasma cells (PC) and memory B cells (MBC), is crucial for the clearance ofPlasmodiuminfection and protection against reinfection. In this study, we examined the effect of an agonistic antibody targeting 4-1BB (CD137), a member of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF), during experimental malaria. Here we show that exogenous 4-1BB stimulation, despite delaying the effector GC response, surprisingly enhanced humoral memory recall and protection from reinfection. Single cell RNA and ATAC sequencing of MBCs from mice that received 4-1BB stimulation revealed distinct populations with transcriptional and epigenetic signatures indicative of superior recall and proliferative potential. Importantly, our results indicate that the effects of 4-1BB stimulation are dependent on IL-9R signaling in B cells but independent of parasite load during primary infection. Our study proposes an immunomodulatory approach to enhance the quality of the MBC pool, providing superior protection during infection and vaccination, particularly in the context of malaria.
Microbial metabolic potential of hydrothermal vent chimneys along the Submarine Ring of Fire
Authors: Murray Laura , Fullerton Heather , Moyer Craig L. 
Published: September 2023

ABSTRACTHydrothermal vents host a diverse community of microorganisms that utilize chemical gradients from the venting fluid for their metabolisms. The venting fluid can solidify to form chimney structures that these microbes adhere to and colonize. These chimney structures are found throughout many different locations in the world’s oceans. In this study, comparative metagenomic analyses of microbial communities on five chimney structures from around the Pacific Ocean were elucidated focusing on the core taxa and genes that are characteristic for each of these hydrothermal vent chimneys, as well as highlighting differences among the taxa and genes found at each chimney due to parameters such as physical characteristics, chemistry, and activity of the vents. DNA from the chimneys was sequenced, assembled into contigs, annotated for gene function, and binned into metagenome-assembled genomes, or MAGs. Genes used for carbon, oxygen, sulfur, nitrogen, iron, and arsenic metabolism were found at varying abundances at each of the chimneys, largely from either Gammaproteobacteria or Campylobacteria. Many taxa had an overlap of these metabolic genes, indicating that functional redundancy is critical for life at these hydrothermal vents. A high relative abundance of oxygen metabolism genes coupled with low carbon fixation genes could be used as a unique identifier for inactive chimneys. Genes used for DNA repair, chemotaxis, and transposases were found to be at higher abundances at each of these hydrothermal chimneys allowing for enhanced adaptations to the ever-changing chemical and physical conditions encountered.IMPORTANCEThe metabolic byproducts of microorganisms that form and reside in hydrothermal vent chimneys facilitate nutrient cycling in both the hydrothermal vent ecosystem and throughout the world’s oceans. Diverse communities of microbes utilize chemicals in the venting fluid to gain energy and biomass. Here, metagenomic and amplicon sequencing was used to identify metabolism genes to better understand the metabolic potential of chimneys. The combination of genes detected in this study sheds light on hydrothermal vent chimneys’ community structure and metabolic potential throughout the Pacific Ocean.
Click editing enables programmable genome writing using DNA polymerases and HUH endonucleases
Authors: da Silva Joana Ferreira , Tou Connor J. , King Emily M. , Eller Madeline L. , Ma Linyuan , Rufino-Ramos David , Kleinstiver Benjamin P. 
Published: September 2023

AbstractGenome editing technologies that install diverse edits can widely enable genetic studies and new therapeutics. Here we develop click editing, a genome writing platform that couples the advantageous properties of DNA-dependent DNA polymerases with RNA-programmable nickases (e.g. CRISPR-Cas) to permit the installation of a range of edits including substitutions, insertions, and deletions. Click editors (CEs) leverage the “click”-like bioconjugation ability of HUH endonucleases (HUHes) with single stranded DNA substrates to covalently tether “click DNA” (clkDNA) templates encoding user-specifiable edits at targeted genomic loci. Through iterative optimization of the modular components of CEs (DNA polymerase and HUHe orthologs, architectural modifications, etc.) and their clkDNAs (template configurations, repair evading substitutions, etc.), we demonstrate the ability to install precise genome edits with minimal indels and no unwanted byproduct insertions. Since clkDNAs can be ordered as simple DNA oligonucleotides for cents per base, it is possible to screen many different clkDNA parameters rapidly and inexpensively to maximize edit efficiency. Together, click editing is a precise and highly versatile platform for modifying genomes with a simple workflow and broad utility across diverse biological applications.
Notch3 deletion regulates HIV-1 gene expression and systemic inflammation to ameliorate chronic kidney disease
Authors: Thornton Mackenzie , Sommer Nicole , McGonigle Mercedes , Ram Anil Kumar , Yerrathota Sireesha , Ehirim Henrietta , Chaturvedi Aakriti , Phan Johnny Dinh , Chakraborty Anubhav , Chakravarthi Praveen V , Gunewardena Sumedha , Tyagi Mudit , Talreja Jaya , Wang Tao , Singhal Pravin , Tran Pamela V , Fields Timothy A , Ray Patricio E , Dhillon Navneet K , Sharma Madhulika 
Published: September 2023

AbstractAntiretroviral therapy (ART) has decreased HIV-1 associated morbidity. However, despite ART, immune cells remain latently infected and slowly release viral proteins, leading to chronic inflammation and HIV-1 associated comorbidities. New strategies are needed to target viral proteins and inflammation. We found activation of Notch3 in several renal cells of the HIV-1 mouse model (HIV-Tg26) and in patients with HIV associated Nephropathy. We hypothesized that targeting Notch3 activation constitutes an effective therapy for HIV-related chronic kidney diseases (HIV-CKD). We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3 months, HIV-Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality rate. Bulk RNA sequencing revealed that N3KO not only reduced renal infiltrating cells but significantly reduced the expression of HIV genes. Moreover, Notch3 activated the HIV-promoter and induction of HIV-1 resulted in increased Notch3 activation indicating a feedback mechanism. Further, bone marrow derived macrophages (BMDMs) from HIV-Tg26 mice showed activation of Notch3 indicating systemic effects. Consistent with that, systemic levels of TNF-α, MCP-1 and other inflammatory chemokines and cytokines were reduced in Tg-N3KO mice. Thus, Notch3 inhibition/deletion has a dual therapeutic effect in HIV-CKD and may extend to other HIV-related pathologies.
Leveraging long-term smartwatch data to inform Parkinson’s disease progression, subtypes, and risk
Authors: Schalkamp Ann-Kathrin , Peall Kathryn J , Harrison Neil A , Escott-Price Valentina , Sandor Cynthia 
Published: September 2023

AbstractUse of digital sensors to passively collect long-term, longitudinal data offers a step change in our ability to monitor Parkinson’s disease (PD). However, to date the evaluation of long-term digital sensor data has been neglected in favour of evaluating short-term data collected in controlled settings. To address this, we combined longitudinal clinical and biological assessment data from the Parkinson’s Progression Marker Initiative (PPMI) cohort with long-term (mean: 485 days) at-home digital monitoring data collected with the Verily Study Watch. We then derived digital timeseries components leveraging the long-term monitoring of the PPMI. We found three key findings: Firstly, that these digital timeseries components correlated with the rate of progression of motor (r = 0.23, p-value = 8.5×10-3, r = 0.26, p-value = 2.2×10-3) and autonomic symptoms (r = −0.23, p-value = 8.2×10-3), impairments in daily living (r = 0.26, p-value = 2.5×10-3), increase in medication requirements and complications (r = −0.25, p-value = 4.2×10-3), and rate of increase in cerebrospinal fluid (CSF) tau (ptau: r = 0.28, p-value = 2.6×10-3; ttau: r = 0.34, p-value = 1.2×10-4). Second, we derived digitally informed subtypes of PD and found higher similarity with CSF (0.35) and DaTscan (0.35) subtypes than has been found for previously published subtypes (CSF: 0.31±0.01, DaTscan: 0.31±0.02). Finally, we showed that long-term digital monitoring can inform PD risk and sensitively detect individuals with probable prodromal PD. Our findings highlight the wealth of application areas for digital sensors in PD research.
Working Memory Gating in Obesity: Insights from a Case-Control fMRI Study
Authors: Herzog Nadine , Hartmann Hendrik , Janssen Lieneke K. , Waltmann Maria , Deserno Lorenz , Fallon Sean J. , Horstmann Annette 
Published: September 2023

AbstractComputational models and neurophysiological data propose that a ‘gating mechanism’ coordinates distractor-resistant maintenance and flexible updating of working memory contents: While maintenance of information is mainly implemented in the prefrontal cortex, updating of information is signaled by phasic increases in dopamine in the striatum. Previous literature demonstrates structural and functional alterations in these brain areas, as well as differential dopamine transmission among individuals with obesity, suggesting potential impairments in these processes. To test this hypothesis, we conducted an observational case-control fMRI study, dividing participants into groups with and without obesity based on their BMI. We probed maintenance and updating of working memory contents using a modified delayed match to sample task and investigated the effects of SNPs related to the dopaminergic system. While the task elicited the anticipated brain responses, our findings revealed no evidence for group differences in these two processes, neither at the neural level nor behaviorally. However, depending on Taq1A genotype, which affects dopamine receptor density in the striatum, participants with obesity performed worse on the task. In conclusion, this study does not support the existence of overall obesity-related differences in working memory gating. Instead, we propose that potentially subtle alterations may manifest specifically in individuals with a ’vulnerable’ genotype.
Gastric coagulation and postprandial amino acid absorption of milk is affected by mineral composition: a randomized crossover trial
Authors: van Eijnatten Elise J.M. , Roelofs Julia J.M. , Camps Guido , Huppertz Thom , Lambers Tim T. , Smeets Paul A.M. 
Published: September 2023

ABSTRACTBackgroundIn vitrostudies suggest that casein coagulation of milk is influenced by its mineral composition, and may therefore affect the dynamics of protein digestion, gastric emptying and appearance of amino acids (AA) in the blood, but this remains to be confirmedin vivo.ObjectiveThis study aimed to compare gastrointestinal digestion between two milks with the same total calcium content but different casein mineralization (CM).DesignFifteen males (age 30.9±13.8 y, BMI 22.5±2.2 kg/m2) participated in this randomized cross-over study with two treatments. Participants underwent gastric magnetic resonance imaging (MRI) scans at baseline and every 10 min up to 90 min after consumption of 600 ml milk with low or high CM. Blood samples were taken at baseline and up to 5 hours postprandially. Primary outcomes were postprandial plasma AA concentrations and gastric emptying rate. Secondary outcomes were postprandial glucose and insulin levels, gastric coagulation as estimated by image texture metrics, and appetite ratings.ResultsGastric content volume over time was similar for both treatments. However, gastric content image analysis suggested that the liquid fraction emptied quicker in the high CM milk, while the coagulum emptied slower. Relative to high CM, low CM showed earlier appearance of AAs that are more dominant in casein, such as proline (MD 4.18 µmol/L, 95%CI [2.38-5.98], p<0.001), while there was no difference in appearance of AAs that are more dominant in whey protein, such as leucine. The image texture metrics homogeneity and busyness differed significantly between treatments (MD 0.007, 95%CI [0.001, 0.012], p=0.022; MD 0.005, 95%CI [0.001, 0.010], p=0.012) likely because of a reduced coagulation in the low CM milk.ConclusionsMineral composition of milk can influence postprandial serum AA kinetics, likely due to differences in coagulation dynamics.
What are the most effective interventions to support children and young people bereaved by suicide in the family: a rapid review
Authors: Mann Mala , Kiseleva Meg , Searchfield Lydia , Mazzaschi Francesca , Jones Rhiannon , Lifford Kate , Weightman Alison , John Ann , Lewis Ruth , Edwards Rhiannon Tudor , Davies Jacob , Cooper Alison , Edwards Adrian 
Published: September 2023

AbstractBereavement by suicide is different from other forms of bereavement and needs specialised support. Children and young people who lost loved ones to suicide are more likely to suffer a complicated bereavement process and have poorer mental health.This review aims to assess the evidence for the effectiveness of interventions to support children and young people (up to the age of 24 years) bereaved by suicide. The review included evidence available up until 29 March 2023. Three studies were identified and all reported on group therapy interventions lasting between 10 and 14 weeks.Key findings and certainty of the evidenceReductions in anxiety and depressive symptoms were found in children who received the group interventions. However, due to the types of study designs used and limitations of the included studies, it is unclear if this is attributable to the interventions, so caution should be applied when generalising the results.The strongest evidence came from a non-randomised controlled study, in which children in the intervention group had significantly greater reduction of anxiety and depressive symptoms compared with children in the control group. However, this study was limited due to numbers of participants lost to follow-up.Research Implications and Evidence GapsFurther research is needed to develop interventions to support children and young people bereaved through death by suicide of a family member. Additional research is needed to evaluate the effectiveness and cost-effectiveness of planned interventions.Policy and Practice ImplicationsIt is difficult to draw firm conclusions due to the limited evidence and low quality of included studies. However, there are indications that group interventions may help to reduce anxiety and depressive symptoms in children bereaved by suicide. It will be important to develop guidance and standards of practice for these services based on best available evidence. All such services must use validated outcome measures as part of an integral evaluation process set up from service initiation.Funding statementThe Specialist Unit for Review Evidence was funded for this work by the Health and Care Research Wales Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government
An Innovative Visual Approach to Monitor Simultaneously Two Dimensions of Progress in Longevity: An Application to French and German Regions
Authors: Bonnet Florian , Klüsener Sebastian , Meslé France , Mühlichen Michael , Grigoriev Pavel 
Published: September 2023

AbstractBackgroundBoth enhancing life expectancy as well as diminishing inequalities in lifespan among social groups represent significant goals for public policy. However, there is a lack of methodological tools to simultaneously monitor progress in both dimensions. Additionally, there is a consensus that absolute and relative inequalities in lifespan must be scrutinized together.MethodsWe introduce a novel graphical representation that combines national mortality rates with social inequalities, considering both absolute and relative measures. We use French and German data stratified by place of residence to illustrate this representation.ResultsFor all-age mortality we detect for France a rather continuous pace of decline in both mortality levels and variation. In Germany, substantial progress was made in the 1990s, which was mostly driven by convergence between eastern and western Germany, followed by a period with less progress. Age-specific analyses reveal for Germany some worrying regional divergence trends at ages 35-74 in recent years. This is particularly pronounced among women.ConclusionOur novel visual approach allows evaluating easily the dynamics of societal progress in terms of longevity, and facilitates meaningful comparisons between populations, even when their current mortality rates differ. The methods we employ can be reproduced easily in any country with longitudinal mortality data stratified by relevant socio-economic information or regions. It is both useful for scientific analyses as well as policy advice.Key messagesWhat is already known on this topicImproving life expectancy as well as reducing social inequalities in longevity are major public policy objectives. However, there is a lack of proper methodological tools to evaluate progress on these objectives.What this study addsThis study proposes an innovative graphical representation that combines national mortality and social inequalities in both absolute and relative terms in order to assess the dynamics of societal progress in longevity and make relevant comparisons between populations whose mortality rates are not at the same level nowadays.How this study might affect research, practice or policyMethods are freely and easily reproducible for all countries with longitudinal mortality data stratified by socio-economic information or geographic regions.
Adopting orphan receptors: group IX/X transition metals as potential ligands of zebrafish Tlr4 homologs
Authors: Fox Aaron P.D. , Lee Tracy S. , Mithaiwala Sakina N. , Pollock Niall M. , Bhavsar Amit P. , Allison W. Ted 
Published: September 2023

AbstractTLR4 is the prototype immune receptor and central to infection defence via detecting lipopolysaccharide (LPS). Surprisingly, the impacts of LPS upon the TLR4 homologs in zebrafish, an important animal model, are equivocal and the function of TLR4 homologs across all fishes remains debatable. Recent work suggests zebrafish Tlr4 mediates ototoxic responses to a platinum-based chemotherapeutic. This prompts our hypothesis that Tlr4 detects group IX/X transition metals and thus has conserved roles with human TLR4 mediating allergic responses to nickel. Here, we use the larval zebrafish lateral line model to demonstrate (sub-)micromolar Ni, Co and Pt are ototoxic in a dose-dependent manner. TLR4 homologs are required for this toxicity because Tlr4 knockdown via CRISPR significantly reduced the metals’ impacts by ∼50%. Moreover, zebrafish Tlr4 was sufficient to mediate inflammatory responses to metals when expressed in a human cell line. These data are consistent with the notion that mediating responses to transition metals was a function of TLR4 homologs in the last common ancestor of fish and mammals, and begins to resolve the function(s) of TLR4 homologs in the zebrafish animal model of disease.