bluuebunny/crossref_metadata_2025 huggingface dataset:
Appearance of green tea compounds in plasma following acute green tea consumption is modulated by the gut microbiome in mice
Authors: Sterrett John D. , Quinn Kevin D. , Doenges Katrina A. , Nusbacher Nichole M. , Levens Cassandra L. , Armstrong Mike L. , Reisdorph Richard M. , Smith Harry , Saba Laura M. , Kuhn Kristine A. , Lozupone Catherine A. , Reisdorph Nichole A.
Published: July 2024

Studies have suggested that phytochemicals in green tea have systemic anti-inflammatory and neuroprotective effects. However, the mechanisms behind these effects are poorly understood, possibly due to differential metabolism of phytochemicals resulting from variation in gut microbiome composition. To unravel this complex relationship, our team utilized a novel combined microbiome analysis and metabolomics approach applied to low complexity microbiome (LCM) and human colonized (HU) gnotobiotic mice treated with an acute dose of powdered matcha green tea. A total of 20 LCM mice received 10 distinct human fecal slurries for an n=2 mice per human gut microbiome; 9 LCM mice remained un-colonized with human slurries throughout the experiment. We performed untargeted metabolomics on green tea and plasma to identify green tea compounds that were found in plasma of LCM and HU mice that had consumed green tea. 16S ribosomal RNA gene sequencing was performed on feces of all mice at study end to assess microbiome composition. We found multiple green tea compounds in plasma associated with microbiome presence and diversity (including acetylagmatine, lactiflorin, and aspartic acid negatively associated with diversity). Additionally, we detected strong associations between bioactive green tea compounds in plasma and specific gut bacteria, including associations between spiramycin andGemmiger, and between wildforlide andAnaerorhabdus. Additionally, some of the physiologically relevant green tea compounds are likely derived from plant-associated microbes, highlighting the importance of considering foods and food products as meta-organisms. Overall, we describe a novel workflow for discovering relationships between individual food compounds and composition of the gut microbiome.

Importance

Foods contain thousands of unique and biologically important compounds beyond the macro- and micro-nutrients listed on nutrition facts labels. In mammals, many of these compounds are metabolized by the community of microbes in the colon. These microbes may impact the thousands of biologically important compounds we consume; therefore, understanding microbial metabolism of food compounds will be important for understanding how foods impact health. We used metabolomics to track green tea compounds in plasma of mice with and without complex microbiomes. From this, we can start to recognize certain groups of green tea-derived compounds that are impacted by mammalian microbiomes. This research presents a novel technique for understanding microbial metabolism of food-derived compounds in the gut, which can be applied to other foods.
MYC Binding Near Transcriptional End Sites Regulates Basal Gene Expression, Read-Through Transcription and Intragenic Contacts
Authors: Wang Huabo , Ma Bingwei , Stevens Taylor , Knapp Jessica , Lu Jie , Prochownik Edward V.
Published: July 2024

The MYC oncoprotein regulates numerous genes involved in cellular processes such as cell cycle and mitochondrial and ribosomal structure and function. This requires heterodimerization with its partner, MAX, and binding to specific promoter and enhancer elements. Here, we show that MYC and MAX also bind near transcriptional end sites (TESs) of over one-sixth of all annotated genes. These interactions are dose-dependent, evolutionarily conserved, stabilize the normally short-lived MYC protein and regulate expression both in concert with and independent of MYC’s binding elsewhere. MYC’s TES binding occurs in association with other transcription factors, alters the chromatin landscape, increases nuclease susceptibility and can alter transcriptional read-through, particularly in response to certain stresses. MYC-bound TESs can directly contact promoters and may fine-tune gene expression in response to both physiologic and pathologic stimuli. Collectively, these findings support a previously unrecognized role for MYC in regulating transcription and its read-through via direct intragenic contacts between TESs and promoters.
Influence of truthful and misleading instructions on statistical learning across the autism spectrum
Authors: Angeletos Chrysaitis Nikitas , Seriès Peggy
Published: July 2024

Bayesian studies of perception have documented how the brain learns the statistics of a new environment and uses them to interpret sensory information. Impairments in this process have been hypothesised to be central to autism spectrum disorders. However, very few such studies have differentiated between implicit and explicit learning. We manipulated the instructions given before a cue-stimulus association task to investigate their effects on statistical learning. The task was conducted online, in 335 participants with varying autistic traits. In the implicit condition, where no information was provided, participants acquired weak prior beliefs about the task regularities. Conversely, explicit information about the presence of regularities resulted in strong priors, correctly reflecting the task’s statistics, regardless of the information’s veracity. Contrary to our hypothesis, autistic traits did not correlate with the influence of priors in any condition.

Author Summary

Perception is greatly influenced by the brain’s prior knowledge of the environment, through a process calledBayesian inference. Recent theories of psychiatric disorders and particularly autism view them as impairments in this process. A crucial aspect of this process is how individuals form their knowledge of the environment. However, previous studies have not differentiated between learning that occurs when participants are aware of what they are learning and learning that happens implicitly. In the present study, we conducted an experiment with four conditions, each varying in terms of what participants were trying to learn and whether they were aware of the general form of the regularities. Our findings revealed that participants form much stronger beliefs about the regularities when they are informed about their presence. Additionally, we discovered that participants with strong autistic traits did not differ in their beliefs about the regularities in any of the conditions.
Feeding status modulates diel vertical migration of zooplankton via effects on circadian rhythms
Authors: Berger Cory A , Tarrant Ann M.
Published: July 2024

Diel vertical migration (DVM) of aquatic animals is arguably the largest migration on Earth, and occurs each day in most marine and freshwater ecosystems. DVM is influenced directly by factors such as light, food, and predator abundance, but is also regulated by internal circadian clocks. Untangling the mechanistic controls of DVM, and the relative importance of external versus endogenous cues, has been hampered by a lack of experimental systems. Here, we leverage advances in animal tracking software to develop an imaging system allowing us to quantify the positions of dozens of individual copepods (Acartia tonsa) at sub-second resolution over multiple days. We use this approach to characterize group-level diel behavioral patterns at much higher resolution than has previously been possible. We find that behavioral rhythms entrain to light cycles and regular feeding and persist during constant conditions (darkness, no feeding), indicating true circadian regulation and establishingA. tonsaas an experimental system for DVM. We test the hypothesis that food availability impacts DVM by acting as an entraining cue for circadian rhythms. Daytime-restricted feeding weakens circadian behavioral rhythms compared to nighttime-restricted feeding, illustrating that food availability can impact DVM indirectly via effects on internal clocks in zooplankton. Our results provide a detailed view of zooplankton populations over diel cycles, establish a mechanism by which temporal variation in food supply can affect zooplankton migrations, and lay the groundwork for new experimental studies of circadian behavior.
Improving biodiversity in Central and Eastern European domestic gardens needs regionally scaled strategies
Authors: Varga-Szilay Zsófia , Barševskis Arvīds , Benedek Klára , Bevk Danilo , Jojczyk Agata , Krištín Anton , Růžičková Jana , Jelaska Lucija Šerić , Veromann Eve , Vilumets Silva , Fetykó Kinga Gabriela , Szövényi Gergely , Pozsgai Gábor
Published: July 2024

Amid ongoing urbanisation and increasing anthropogenic activities, domestic gardens, while they cannot replace undisturbed habitats, play a valuable role in enhancing urban biodiversity by supplementing green areas and improving landscape connectivity. Moreover, biodiversity-friendly gardens also improve human well-being and foster connections between nature and people. To study these benefits, we distributed an online questionnaire between 2022 and 2023, and used a scoring system to evaluate the ecological value of gardens, garden owners’ motivations, and pesticide use habits. We used machine learning to explore how these indices interact and what sociodemographic factors drive them across nine Central and Eastern European (CEE) countries. Additionally, we explored the differences and similarities between the ecological values of gardens and gardening practices in building high biodiversity. Our findings reveal significant variability both between and within countries, across all three indices with Romania faring low and Czechia reaching high scores in all three indices. Domestic pesticide use was ubiquitous across all CEE and largely unaffected by sociodemographic factors. However, increased time spent with gardening was associated with reduced pesticide use and a greater potential for fostering high biodiversity. Garden owners over 55 tended to follow and uphold longstanding conventional practices and thus lowered both pesticide and garden index scores. The local-scale differences we observed emphasise the need for regionally tailored guidelines for biodiversity-friendly gardening over standardized regulations across Europe. Optimal strategies for effective environmental educational and community programs can be developed based on local biodiversity and the three indices used in this study. To maximize their impact and meet local needs, these programs should educate garden owners about the environmental and health effects of pesticides and offer comprehensive biodiversity-related information across all regions and social strata. This is particularly crucial in Central and Eastern Europe (CEE), where such initiatives are currently underrepresented.

Highlights

Domestic gardens can enhance biodiversity and support human well-being.

Study conducted across nine Central and Eastern European countries.

Significant variability both between and within countries in gardening practices.

Improving biodiversity in domestic gardens needs regionally scaled strategies.

Reducing pesticide use and increasing awareness are key.
SARS-CoV-2 entry and fusion are independent of ACE2 localization to lipid rafts
Authors: Bolland William , Marechal Inès , Petiot Chloé , Porrot Françoise , Guivel-Benhassine Florence , Casartelli Nicoletta , Schwartz Olivier , Buchrieser Julian
Published: July 2024

Membrane fusion occurs at the early stages of SARS-CoV-2 replication, during entry of the virus, and later during the formation of multinucleated cells called syncytia. Fusion is mediated by the binding of the viral Spike protein to its receptor ACE2. Lipid rafts are dynamic nanodomains enriched in cholesterol and sphingolipids. Rafts can act as platforms for entry of dìerent viruses by localizing virus receptors, and attachment factors to the same membrane microdomains. Here, we first demonstrate that cholesterol depletion by methyl-beta-cyclodextrin inhibits Spike mediated fusion and entry. To further study the role of ACE2 lipid raft localization in SARS-CoV-2 fusion and entry, we design a GPI-anchored ACE2 construct. Both ACE2 and ACE2-GPI proteins are similarly expressed at the plasma membrane. Through membrane flotation assays, we show that in dìerent cell lines, ACE2-GPI localises predominantly to raft domains of the plasma membrane while ACE2 is non-raft associated. We then compare the ability of ACE2 and ACE2-GPI to permit SARS-CoV-2 pseudovirus entry and syncytia formation and replication of dìerent viral variants. We find little dìerence in the two proteins. Our results demonstrate that SARS-CoV-2 entry and fusion are a cholesterol dependent and raft-independent process.

IMPORTANCE

Rafts are often exploited by viruses and used as platforms to enhance their entry into the cell or spread from cell-to-cell. The membrane localization of ACE2 and the role of lipid rafts in SARS-CoV-2 entry and cell-to-cell spread is poorly understood. The function of lipid rafts in viral fusion is often studied through their disruption by cholesterol-depleting agents. However, this process may have ò-target impacts on viral fusion independently of lipid-raft disruption. Therefore, we created an ACE2 construct that localizes to lipid rafts using a GPI anchor. Conversely, wild-type ACE2 was non-raft associated. We find that the localization of ACE2 to lipid rafts does not modify the fusion dynamics of SARS-CoV-2.
Estimating cis and trans contributions to differences in gene regulation
Authors: Hallgrímsdóttir Ingileif B. , Carilli Maria , Pachter Lior
Published: July 2024

We describe a coordinate system and associated hypothesis testing framework for determining whethercisortransregulation is responsible for differences in gene expression between two homozygous strains or species.
Distinct genetic profiles influence body mass index between infancy and adolescence
Authors: Wang Geng , McEwan Samuel , Zeng Jian , Haile-Mariam Mekonnen , Yengo Loic , Goddard Michael E , Kemper Kathryn E , Warrington Nicole M
Published: July 2024

Body mass index (BMI) changes throughout life with age-varying genetic contributions. We aimed to investigate the genetic contribution to BMI across early life using repeated measures from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Random regression modelling was used to estimate the genetic covariance matrix (Kg) of BMI trajectories from ages one to 18 years with 65,930 repeated BMI measurements from 6,291 genotyped ALSPAC participants. TheKgmatrix was used to estimate SNP-based heritabilityat yearly intervals from 1-18 years and genetic correlations across early life. We also performed an eigenvalue decomposition ofKgto identify age-varying genetic patterns of BMI. Finally, we investigated the impact of a polygenic score derived from adult BMI on the estimated genetic components across early life. Thewas relatively constant across early life, between 23-30%. The genetic contribution to BMI in early childhood is different to that in later childhood, indicated by the diminishing strength of genetic correlation across different ages. The eigenvalue decomposition revealed that the primary axis of variation (explaining 89% of the genetic variance inKg) increases with age from zero and reaches a plateau in adolescence, while the second eigenfunction (explaining around 9% ofKg) represents factors with opposing effects on BMI between early and later ages. Adjusting for the adult BMI polygenic score attenuated thefrom late childhood; for example,is 29.8% (SE=6.5%) at 18 years of age and attenuates to 14.5% (SE=6.3%) after adjusting for the adult BMI polygenic score. Although common genetic variation explains around 23-30% of BMI variability across early life, our findings indicate that there is a different genetic profile operating during infancy compared to later childhood and adolescence.
Lost in Transplantation: Characterizing Racial Gaps in Physician Organ Offer Acceptance
Authors: Adam Hammaad , Bermea Rene S. , Yang Ming Ying , Celi Leo Anthony , Ghassemi Marzyeh
Published: July 2024

Background.

There are known racial disparities in the organ transplant allocation system in the United States. However, prior work has yet to establish if transplant center decisions on offer acceptance—the final step in the allocation process— contribute to these disparities.

Objective

To estimate racial differences in the acceptance of organ offers by transplant center physicians on behalf of their patients.

Design

Retrospective cohort analysis using data from the Scientific Registry of Transplant Recipients (SRTR) on patients who received an offer for a heart, liver, or lung transplant between January 1, 2010 and December 31, 2020.

Setting

Nationwide, waitlist-based.

Patients

32,268 heart transplant candidates, 102,823 liver candidates, and 25,780 lung candidates, all aged 18 or older.

Measurements

1) Association between offer acceptance and two race-based variables: candidate race and donor-candidate race match; 2) association between offer rejection and time to patient mortality.

Results

Black race was associated with significantly lower odds of offer acceptance for livers (OR=0.93, CI: 0.88-0.98) and lungs (OR=0.80, CI: 0.73-0.87). Donor-candidate race match was associated with significantly higher odds of offer acceptance for hearts (OR=1.11, CI: 1.06-1.16), livers (OR=1.10, CI: 1.06-1.13), and lungs (OR=1.13, CI: 1.07-1.19). Rejecting an offer was associated with lower survival times for all three organs (heart hazard ratio=1.16, CI: 1.09-1.23; liver HR=1.74, CI: 1.66-1.82; lung HR=1.21, CI: 1.15-1.28).

Limitations

Our study analyzed the observational SRTR dataset, which has known limitations.

Conclusion

Offer acceptance decisions are associated with inequity in the organ allocation system. Our findings demonstrate the additional barriers that Black patients face in accessing organ transplants and demonstrate the need for standardized practice, continuous distribution policies, and better organ procurement.
Single-molecule live-cell RNA imaging with CRISPR-Csm
Authors: Xia Chenglong , Colognori David , Jiang Xueyang , Xu Ke , Doudna Jennifer A.
Published: July 2024

High-resolution, real-time imaging of RNA is essential for understanding the diverse, dynamic behaviors of individual RNA molecules in single cells. However, single-molecule live-cell imaging of unmodified endogenous RNA has not yet been achieved. Here, we present single-molecule live-cell fluorescencein situhybridization (smLiveFISH), a robust approach that combines the programmable RNA-guided, RNA-targeting CRISPR-Csm complex with multiplexed guide RNAs for efficient, direct visualization of single RNA molecules in a range of cell types, including primary cells. Using smLiveFISH, we tracked individual endogenousNOTCH2andMAP1BmRNA transcripts in living cells and identified two distinct localization mechanisms: co-translational translocation ofNOTCH2mRNA at the endoplasmic reticulum, and directional transport ofMAP1BmRNA toward the cell periphery. This method has the potential to unlock principles governing the spatiotemporal organization of native transcripts in health and disease.
Multiomic analyses uncover immunological signatures in kidney transplantation
Authors: Tinel Claire , Varin Alexis , Anglicheau Dany , Callemeyn Jasper , De Loor Jetty , Gwinner Wilfried , Marquet Pierre , Rabant Marion , Sauvaget Virginia , Loon Elisabet Van , Lamarthée Baptiste , Naesens Maarten
Published: July 2024

Identifying biomarkers in kidney transplant patients is essential for early detection of rejection, personalized treatment and improved overall outcomes. It improves our ability to monitor the health of the transplanted organ and tailor interventions to the specific needs of each patient. Here we compiled a multicenter, multiomic dataset of the kidney transplant landscape. Using multi-omics factor analysis (MOFA), we sought to uncover sources of biological variability in patients’ blood, urine and allograft at the epigenetic and transcriptomic levels. MOFA reveals multicellular immune signatures characterized by distinct monocyte, natural killer and T cell substates explaining a large proportion of inter-patient variance. We also identified specific factors that reflect allograft rejection, complement activation or induction treatment. Factor 1 mainly explained the molecular variations in patients’ circulation and discriminated antibody-mediated rejection from T-cell mediated rejection. Factor 2 captured some of the molecular variation occurring within the allograft and associated with complement/monocytes crosstalk. Factor 4 captured the impact of ATG induction. These data provide proof-of-concept of MOFA’s ability to reveal multicellular immune profiles in kidney transplantation, opening up new directions for mechanistic, biomarker and therapeutic studies.
Neural mass modelling reveals that hyperexcitability underpins slow-wave sleep changes in children with epilepsy
Authors: Dunstan Dominic M , Chan Samantha YS , Goodfellow Marc
Published: July 2024

Objective

The relationship between sleep and epilepsy is important but imperfectly understood. We sought to understand why children with epilepsy have altered sleep homeostasis.

Methods

We used neural mass models to replicate sleep EEG recorded from 15 children with focal lesional epilepsies and 16 healthy age-matched controls.

Results

The models revealed that sleep EEG differences are driven by enhanced firing rates in the neuronal populations of patients, which arise predominantly due to enhanced excitatory synaptic currents. These differences were more marked in patients who had seizures within 72 hours after the sleep recording. Furthermore, models inferred from patients resided closer in parameter space to models of a typical seizure rhythm.

Significance

These results demonstrate that brain mechanisms relating to epilepsy manifest in the interictal EEG in slow-wave sleep, and that EEG recorded from patients can be mapped to synaptic deficits that may explain their predisposition to seizures. Neural mass models inferred from sleep EEG data have the potential to generate new biomarkers to predict seizure occurrence or inform treatment decisions.

1.

Key Points

The mechanisms that differentiate children with epilepsy from controls during slow-wave sleep can be understood using a mathematical model.

The observed spectral power shifts in patients are predominately explained by greater excitatory synaptic currents.

These differences in currents place patients’ models closer to seizure rhythms.

Ultimately, this framework could help foster the development of biomarkers to guide intervention in epilepsy.
Dynamic Individual Prediction of Conversion from Mild Cognitive Impairment to Probable Alzheimer’s Disease using Joint Modeling
Authors: Mouiha Abderazzak , Potvin Olivier , Duchesne Simon ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

Background

We propose a joint model predicting the risk of conversion from MCI to AD that considers the association between biomarker evolution and disease progression.

Methods

We selected 814 MCI subjects (285 progressives, 529 stables) who had at least four follow-up MRI visits from the ADNI dataset. The values of Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) were used as a surrogate of time. A mixed linear model was fitted for bilateral hippocampal volumes (HC) versus ADAS-Cog, education, age and sex and a Cox model for risk progression. The association between HC evolution and risk conversion was estimated by fitting a joint model.

Results

Our results show (1) significant association (p< .0001, C.I.= [0.0864; 0.1217]) between bilateral HC and risk of conversion; (2) on average, the risk of progression increased as HC decreased; and (3) the individual prediction of the risk is dynamic, i.e., updated at each follow-up. The AUC of our model for the whole group increased to reach 0.789 at the last follow-up.

Conclusions

Applicable to AD and generalizable to other biomarkers and covariates, this joint methodology has a direct application in the clinical estimation of individual risk.
Evaluating acute medical service performance against assessment time metrics: the Society for Acute Medicine Benchmarking Audit 2023 (SAMBA23)
Authors: Atkin Catherine , Subbe Chris , Holland Mark , Varia Ragit , Cooksley Tim , Gebril Adnan , Kennedy Adrian , Knight Thomas , Lasserson Daniel
Published: July 2024

Performance within acute medicine services is impacted by ongoing pressures on acute care services. Data from the Society for Acute Medicine Benchmarking Audit 2023 (SAMBA23), was used to assess performance of acute medicine services compared to key clinical quality indicators, comparing performance by initial assessment location. Data was analysed for 8213 unplanned attendances across 161 hospitals. Comparing by initial assessment location, performance against the clinical quality indicators was unchanged from 2022. Only 29% of daytime arrivals assessed within the Emergency Department received consultant review within target times. Delays were seen in transfer between acute care locations. 29% of patients requiring admission were not admitted to the AMU. There is ongoing variation in acute medical service performance nationally, with significant delays in patient access to appropriate assessment locations.
A comparative analysis of the prevalence of suicidal ideation among depressed and non-depressed pregnant women in rural Bangladesh
Authors: Mumu Rifa Tamanna , Shaikh Md Parvez , Mitra Dipak Kumar
Published: July 2024

Background

More than 300 million people all over the world succumbed to depressive disorders in 2015. 680 per 100,000 expectant mothers worldwide bear suicidal ideation during the antenatal period. Despite suicidal ideation being a consequence of antenatal depression, there is a scarcity of information on the prevalence of suicidal ideation in depressed and non-depressed pregnant women in rural Bangladesh.

Objective

This study is directed to evaluate the point prevalence of suicidal ideation and compare the prevalence between depressed and non-depressed pregnant women in rural Bangladesh.

Method

A cross-sectional study was performed in Lohagara, a rural subdistrict in Bangladesh between January 08 and 17, 2024. 351 pregnant women of various trimesters were recruited for the study. The Bengali-translated version of the Edinburgh Postnatal Depression Scale (EPDS) and another structured questionnaire were used for data collection. Data analyses were done by STATA version 17.

Result

The point prevalence of suicidal ideation is 11.4% (95% CI: 8.5% to 15.2%). It reveals a similarity between depressed and non-depressed pregnant women. The prevalence of suicidal thoughts in antenatally depressed women accounts for 10.2% (95% CI: 6.1% to 16.6%) and in non-depressed pregnant women it is 12.2% (95% CI: 8.4% to 17.3%) -obtained after analysis.

Conclusion

The considerable prevalence of suicidal thoughts among depressed and non-depressed rural pregnant women in Bangladesh underscores the necessity of ensuring additional counseling, care, and support to expectant mothers during their antepartum.
Structural insight into sodium ion pathway in the bacterial flagellar stator from marineVibrio
Authors: Nishikino Tatsuro , Takekawa Norihiro , Kishikawa Jun-ichi , Hirose Mika , Kojima Seiji , Homma Michio , Kato Takayuki , Imada Katsumi
Published: July 2024

Many bacteria swim in liquid or swarm on surface using the flagellum rotated by a motor driven by specific ion flow. The motor consists of the rotor and stator, and the stator converts the energy of ion flow to mechanical rotation. However, the ion pathway and the mechanism of stator rotation coupled with specific ion flow are still obscure. Here, we determined the structures of the Na+-driven stator ofVibrio, namely PomAB, in the presence and absence of sodium ions and the structure with its specific inhibitor, phenamil, by cryo-electron microscopy. The structures and following functional analysis revealed the sodium ion pathway, the mechanism of ion selectivity, and the inhibition mechanism by phenamil. We propose a model of sodium ion flow coupled with the stator rotation based on the structures. This work provides insights into the molecular mechanisms of ion specificity and conversion of the electrochemical potential into mechanical functions.
Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate
Authors: Li Hang , Ji Shengwei , Ariefta Nanang R. , Galon Eloiza May S. , El-Sayed Shimaa AES , Do Thom , Jia Lijun , Sakaguchi Miako , Asada Masahito , Nishikawa Yoshifumi , Qin Xin , Liu Mingming , Xuan Xuenan
Published: July 2024

Babesiosis is a disease brought on by intraerythrocytic parasites of the genusBabesia. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs againstBabesia. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainlyPlasmodiumandToxoplasma. This study evaluated the growth-inhibiting properties of CIP againstBabesiaspp. and investigated the mechanism of CIP onB. gibsoni. The half inhibitory concentration (IC50) values of CIP against thein vitrogrowth ofB. bovisandB. gibsoniwere 20.2 ± 1.4 nM and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth ofB. microtiandB. rodhaini in vivo.Resistance was conferred by L921V and L921I mutations inBgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP againstBgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3-fold and 2.4-fold decrease inBgATP4L921VandBgATP4L921Icompared to that ofBgATP4WT, respectively. Anin silicoinvestigation revealed reductions in affinity for CIP binding toBgATP4L921VandBgATP4L921Icompared toBgATP4WT. Resistant strains showed no significant cross-resistance to atovaquone (ATO) or tafenoquine (TQ), with less than a onefold change in IC50values. Combining CIP with TQ effectively eliminatedB. microtiinfection in SCID mice, no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an anti-babesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome resistance and achieve complete parasite clearance.
2,3-bis (phenylamino) quinoxaline - containing compounds display potent activity against Methicillin-resistantStaphylococcus aureus,Enterococcus faecalisand their biofilms
Authors: Padalino Gilda , Duggan Katrina , Mur Luis A. J. , Maillard Jean-Yves , Brancale Andrea , Hoffmann Karl F.
Published: July 2024

Antimicrobial resistance remains a global challenge threatening the ability to control diseases caused by bacterial infections. Here, we explored the antimicrobial activity of 2,3-N,N-diphenyl quinoxaline derivatives against representative Gram-positive, Gram-negative andMycobacteriumspecies. Two quinoxaline derivatives (compounds25and31) demonstrated particularly potent activity against mostStaphylococcus aureus,Enterococcus faeciumandEnterococcus faecalisstrains tested (MIC values between 0.25 to 1 mg/l). These compounds also demonstrated potent antibacterial activity against methicillin-resistantS. aureus(MRSA) and vancomycin-resistantE. faecium/E. faecalis(VRE) strains. Against an extensive panel of clinically relevant isolates, they further showed comparable or better activity to four currently used antibiotics (vancomycin, teicoplanin, daptomycin and linezolid). Finally, they performed better in preventingS. aureusandE. faecalisbiofilm formation when compared to several other antibiotics. In conclusion, these two quinoxaline derivatives have promising activities that could be further explored as part of efforts to identify urgently needed new antibacterial agents.
Maternal dietary deficiency in choline reduced levels of MMP-2 levels in blood and brain tissue of male offspring mice
Authors: Esfandiarei Mitra , Strash Shawn G.U. , Covaleski Amanda , Ille Sharadyn , Li Wei-dang , Jadavji Nafisa M.
Published: July 2024

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It’s well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tubein utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diets prior to and during pregnancy and lactation. When offspring were 3-months of age, ischemic stroke was induced. One and half months later blood and brain tissue were collected. We measured levels of matrix-metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and report reduced levels of MMP-2 in both, with no changes observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.
Two for tau: Automated model discovery reveals two-stage tau aggregation dynamics in Alzheimer’s disease
Authors: Stockman Charles A. , Goriely Alain , Kuhl Ellen ,   and the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-βplaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction-diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a twoterm ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-βpositive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-βand tau than previously postulated. In line with the amyloid-tau dual pathway hypothesis, our results show that the presence of toxic amyloid-βinfluences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.
Secondary metabolites and their impact on symbiotic interactions in the ambrosia fungusGeosmithia eupagioceri
Authors: Kolařík Miroslav , Stodůlková Eva , Kajzrová Soňa , Semerád Jaroslav , Hubert Jan , Kuzma Marek , Šulc Miroslav , Císařová Ivana , Jašica Andrej , Wennrich Jan-Peer , Hulcr Jiří , Flieger Miroslav
Published: July 2024

Ambrosia fungi colonize freshly dead trees, sequester nutrients, and serve as nutritional source for ambrosia beetles in exchange for dispersal. A key aspect of this symbiosis is the ability of fungi to colonize and dominate the wood around the beetle tunnels, forming a monospecific nutritional mycelium in the beetle gallery. Hypotheses for these dynamics include active beetle management, fungal inoculation priority, and the fungus’s chemical ecology facilitating resource capture and competition. The ecological role of allelochemicals produced by ambrosia fungi is unknown, although they may suppress microbes while being harmless to beetles, which has potential medical or food technology applications. This study presents a comprehensive analysis of secondary metabolites from the ambrosia fungusGeosmithia eupagioceri(Ascomycota: Hypocreales). Eight extracellular compounds were identifiedin vitro: 5-hydroxymethyl-2-furancarboxylic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 4-hydroxyphenylacetic acid (4-HPA), 4-HPA methyl ester, tyrosol, and thymine. Most compounds show cross-taxon activity, suppressing the growth of bacteria, fungi, a nematode, and a mite. We have shown that often overlooked chemically simple compounds may have activities leading to increased fitness of beetle hosts, including previously unconsidered activity against mites and nematodes. For the first time, we point out that these compounds also have the previously unconsidered potential to modulate the physiology of their producer (by inducing symbiotic morphology by quorum sensing mechanisms), the beetle host and associated microbes through synergism. Furthermore, we have shown that the ambrosia fungi have biotechnological potential in the search for growth suppressors of microorganisms and invertebrates, not toxic to humans.

IMPORTANCE

Bark and ambrosia beetles and their microbial symbionts play crucial roles in forest ecosystems by aiding in the decomposition of dead trees, nutrient cycling, and habitat creation. However, they can cause extensive damage to both natural and planted forests by killing trees. Our study has led to a fundamental shift in the understanding of interactions between beetle symbiotic fungi and the environment, mediated by secondary metabolites. Newly, we show that these substances can not only be antimicrobial but also suppress the growth of mites, nematodes, but also can modulate the physiology of the producer fungus and potentially the host beetle and associated microbes. Our study, although conducted on a relatively artificial system with the need for validation on other lineages of ambrosia fungi, suggests entirely new research directions in the understanding of bark beetle holobiont and ambrosia beetles.
Trace elements increase replicability of microbial growth
Authors: Nadig Amit Shimoga , Gross Rotem , Bollenbach Tobias , Ansmann Gerrit
Published: July 2024

Trace elements are often omitted from chemically defined growth media. From established properties of trace elements, we deduce that this omission makes experiments unnecessarily sensitive to unavoidable contamination with trace elements. We confirm this experimentally by growing eleven bacterial strains in high replicate with and without supplementing trace elements, keeping all other conditions as fixed as possible to isolate the effect of trace elements. We find that supplementing trace elements considerably reduces variability of growth even in this benign scenario, and we argue that typical experimental setups exacerbate this. We discuss implications for the design and use of trace-element supplements, and in particular argue that their use should be standard practice, as they can reduce variability of almost all experiments using chemically defined media, taking a step towards greater precision and replicability in microbiology.
The evolution of an individual-like dispersive stage in colonial siphonophores
Authors: Mańko Maciej K. , Munro Catriona , Leclère Lucas
Published: July 2024

Evolutionary transitions between individual and colonial organisms remain enigmatic. Siphonophores, abundant pelagic cnidarians, exhibit a complex colony structure composed of repeated individual (zooid) clusters called cormidia. Many siphonophores release their posterior-most cormidia as independent fragments known as eudoxids, ensuring sexual reproduction. However, the mechanisms of eudoxid production and its evolutionary origins are unknown. Using live imaging, immunohistochemistry and pharmacological inhibition we provide a mechanistic understanding of eudoxid formation. We demonstrate that eudoxid release is controlled by a dedicated muscle and involves tissue remodeling, leading to the formation of an integrated dispersive unit with specific behaviors and a different buoyancy. We show that eudoxids and parental colonies often have different spatial or temporal distributions, suggesting niche partitioning. We infer that eudoxids evolved once through the concomitant evolution of multiple cormidium subparts. This study reveals how the acquisition of an individual-like dispersal stage, through muscle evolution and colony modification, contributed to the ecological success of a primary carnivore in marine planktonic ecosystems.

Teaser

Co-option of a muscle in siphonophores enabled life cycle complexification and ecological diversification
Haplotype-aware sequence alignment to pangenome graphs
Authors: Chandra Ghanshyam , Gibney Daniel , Jain Chirag
Published: July 2024

Modern pangenome graphs are built using haplotype-resolved genome assemblies. When mapping reads to a pangenome graph, prioritizing alignments that are consistent with the known haplotypes improves genotyping accuracy. However, the existing rigorous formulations for colinear chaining and alignment problems do not consider the haplotype paths in a pangenome graph. This often leads to spurious read alignments to those paths that are unlikely recombinations of the known haplotypes. In this paper, we develop novel formulations and algorithms for sequence-to-graph alignment and chaining problems. Inspired by the genotype imputation models, we assume that a query sequence is an imperfect mosaic of reference haplotypes. Accordingly, we introduce a recombination penalty in the scoring functions for each haplotype switch. First, we solve haplotype-aware sequence-to-graph alignment inO(|Q||E||H|)time, whereQis the query sequence,Eis the set of edges, and H is the set of haplotypes represented in the graph. To complement our solution, we prove that an algorithm significantly faster thanO(|Q||E||H|)is impossible under the strong exponential time hypothesis (SETH). Second, we propose a haplotype-aware chaining algorithm that runs inO(|H|Nlog⁡|H|N)time after graph preprocessing, whereNis the count of input anchors. We then establish that a chaining algorithm significantly faster thanO(|H|N)is impossible under SETH. As a proof-of-concept, we implemented our chaining algorithm in the Minichain aligner. By aligning sequences sampled from the human major histocompatibility complex (MHC) to a pangenome graph of 60 MHC haplotypes, we demonstrate that our algorithm achieves better consistency with ground-truth recombinations compared with a haplotype-agnostic algorithm.
Invariant amplitudes, unpolarized cross sections, and polarization asymmetries in neutrino-nucleon and antineutrino-nucleon elastic scattering
Authors: Borah Kaushik , Betancourt Minerba , Hill Richard J. , Junk Thomas , Tomalak Oleksandr
Published: July 2024

At leading order in weak and electromagnetic couplings, cross sections for (anti)neutrino-nucleon elastic scattering are determined by four nucleon form factors that depend on the momentum transfer Q2. Including radiative corrections in the Standard Model and potential new physics contributions beyond the Standard Model, eight invariant amplitudes are possible, depending on both Q2 and the (anti)neutrino energy Eν. We review the definition of these amplitudes and use them to compute both unpolarized and polarized observables including radiative corrections. We show that unpolarized accelerator neutrino cross-section measurements can probe new physics parameter space within the constraints inferred from precision beta decay measurements.

Published by the American Physical Society
2024
Observability of spin precession in the presence of a black-hole remnant kick
Authors: Borchers Angela , Ohme Frank , Mielke Jannik , Ghosh Shrobana
Published: July 2024

Remnants of binary black-hole mergers can gain significant recoil or kick velocities when the binaries are asymmetric. The kick is the consequence of the anisotropic emission of gravitational waves, which may leave a characteristic imprint in the observed signal. So far, only one gravitational-wave event supports a nonzero kick velocity: GW200129_065458. This signal is also the first to show evidence for spin precession. For most other gravitational-wave observations, spin orientations are poorly constrained as this would require large signal-to-noise ratios, unequal mass ratios, or inclined systems. Here we investigate whether the imprint of the kick can help to extract more information about the spins. We perform an injection and recovery study comparing binary black-hole signals with significantly different kick magnitudes, but the same spin magnitudes and spin tilts. To exclude the impact of higher signal harmonics in parameter estimation, we focus on equal-mass binaries that are oriented face-on. This is also motivated by the fact that equal-mass binaries produce the largest kicks and many observed gravitational-wave events are expected to be close to this configuration. We generate signals with henom4a, which includes mode asymmetries. These asymmetries are the main cause for the kick in precessing binaries. For comparison with an equivalent model without asymmetries, we repeat the same injections with henom. We find that signals with large kicks necessarily include large asymmetries, and these give more structure to the signal, leading to more informative measurements of the spins and mass ratio. Our results also complement previous findings that argued precession in equal-mass, face-on, or face-away binaries is nearly impossible to identify. In contrast, we find that in the presence of a remnant kick, even those signals become more informative and allow determining precession with signal-to-noise ratios observable already by current gravitational-wave detectors.

Published by the American Physical Society
2024
Directing entanglement spreading by means of a quantum East/West heterojunction structure
Authors: Chen Guanhua , Yao Yao
Published: July 2024

We extend the translationally invariant quantum East model to an inhomogeneous chain with East/West heterojunction structure. In analogy to the quantum diffusion of particles, we observe a plateaus-shaped entanglement entropy spreading in the heterojunction during time evolution that can be regarded as continuous cycles in a quantum heat engine. In order to figure out the possibility of manipulating the entanglement entropy as a quantum resource, the entropy growth is shown to be determined by the initial occupation and the site-dependent chemical potential, and the former is equivalent to an effective temperature. Through fine adjustment of these parameters, we discover the entanglement flow is simply superposed with those from two sources of the chain. An intriguing relation between our model and the traditional heat engines is subsequently established.

Published by the American Physical Society
2024