bluuebunny/crossref_metadata_2025 huggingface dataset:
Neighborhood Deprivation, Genetic Predisposition, and Life Satisfaction: Evidence from the German Twin Family Panel
Authors: Harerimana Nadia V. , Liu Yixuan , Ruks Mirko
Published: December 2024

Both genes and the neighborhood are important for life satisfaction; however, there is little research on gene-environment interactions (GxE) that examines how the effect of genetic endowments varies as a function of the environmental context with life satisfaction as the outcome. This study investigated how neighborhood deprivation moderates the effects of genetic predisposition on life satisfaction. Using data from the German Twin Family Panel (TwinLife), we identified 760 dizygotic (DZ) twins and employed twin fixed-effect models to assess the GxE effects on life satisfaction. The findings reveal that the polygenic score (PGS) for subjective well-being is positively associated with life satisfaction. The effect of PGS for subjective well-being on life satisfaction is strongest for individuals living in moderately deprived areas, while it is weaker for those living in highly deprived and less deprived areas. Thus, there are signs of compensation in less deprived areas and, particularly, diathesis-stress/triggering in highly deprived areas.
Outcome-Driven Microscopy: Closed-Loop Optogenetic Control of Cell Biology
Authors: Passmore Josiah B. , Rates Alfredo , Schröder Jakob , van Laarhoven Menno T. P. , Hellebrekers Vincent J. W. , van Hoef Henrik G. , Geurts Antonius J. M. , van Straaten Wendy , Nijenhuis Wilco , Berger Florian , Smith Carlas S. , Smal Ihor , Kapitein Lukas C.
Published: December 2024

Smart microscopy is transforming biological imaging by integrating real-time analysis with adaptive acquisition to enhance imaging efficiency. Whereas many emerging implementations are event-driven and focus on on-demand data acquisition to reduce phototoxicity, we here present ‘outcome-driven’ microscopy, which combines smart microscopy with optogenetics to achieve subcellular spatiotemporal control of biology to predefined outcomes. We validate this approach using light-based control of cell migration and nucleocytoplasmic transport, and demonstrate unprecedented spatiotemporal control over cellular behaviour.
Twelve-Month Outcomes of Faricimab for Patients With Sub-optimally Responsive Diabetic Macular Oedema in a UK Tertiary Referral Centre
Authors: El-Badawi Kamal , Scrivens Benjamin , Eke Oluwaniyi , Ismail Rehab , Kobayter Lina , Salvatore Serena
Published: December 2024

Purpose

Evaluating 12-month visual and anatomical outcomes after switching to faricimab in diabetic macular oedema (DMO) patients with sub-optimal response to aflibercept 2mg.

Patients and methods

Sixty-two eyes of fifty patients were enrolled in this retrospective study at a UK tertiary referral centre. This consisted of DMO patients with sub-optimal response to aflibercept 2mg who were switched to faricimab. Four loading injections of faricimab were given at monthly intervals, followed by a treat-and-extend regime. The sub-optimal response was defined as CST >325 microns or >20% from best CST despite aflibercept 2mg at less than or equal to 8 weekly intervals(≤q8w) having completed a loading dose of aflibercept 2 mg (6 injections at monthly intervals). Outcome measures were best-recorded visual acuity (BRVA), central subfield thickness (CST), and treatment intervals.

Results

Baseline BRVA was 67.6 (±11.8) letters and CST was 406.4 (±105.9) µm, and the mean treatment interval was 6.5 (±1.8) weeks. At baseline, 24.2% of eyes were treated every 4 weeks (q4w), 19.4% every 6 weeks (q6w), and 56.5% every 8 weeks (q8w). After the 4thfaricimab loading dose, 54 patients continued on treat-and-extend faricimab. BRVA improved to 70.4 (±12.7) letters (p=0.007) while CST reduced to 372.8 (±132.0)µm (p=0.070). The mean injection interval improved to 7.4 (±2.6), 95%CI[0.1, 2.9]weeks. Subjects were followed up for 57.1 (±19.7) weeks, with a mean of 7.92 (±2.53) faricimab injections. At the latest follow-up, BRVA was stable at 68.7 (±14.6)(p=0.918) letters. CST had reduced further to 343.1 (±117.5) µm(p=0.034). Treatment intervals at the latest follow-up were: 3.2% q4w, 9.7% q6w, 30.6% q8w, 3.2% q10w, 11.3% q12w, 1.6% q14w, 6.5% q16w, with 53.2% on ≥q8w. The mean injection interval had also improved to 9.2 (±3.1) weeks(p=0.122).

Conclusion

In this study, DMO patients with sub-optimal response to aflibercept 2mg experienced improved anatomical outcomes and extended treatment intervals while maintaining vision by switching to faricimab.
Distinct DNA Methylation Signatures in Maternal Blood Reveal Unique Immune Cell Shifts in Preeclampsia and the Pregnancy-Postpartum Transition
Authors: Jamshed Laiba , Smith Keaton W , Wilson Samantha L
Published: December 2024

1.0

Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by immune dysregulation and significant risks to maternal and fetal health. While current management relies on high-risk patient monitoring and early diagnosis, these methods are costly and burdensome, especially for low-risk pregnancies. There is a pressing need for non-invasive tools to predict and monitor PE. DNA methylation (DNAm) is a type of DNA modification that influences gene expression, and has been associated with immune cell dynamics and PE pathogenesis. This study explores whether DNAm-based immune cell composition profiling can provide insights into PE-related immune dysregulation. We conducted a search in the Gene Expression Omnibus (GEO) for DNA methylation datasets using Illumina 27K, 450K, and EPIC arrays from maternal blood in both healthy and PE pregnancies. We found two studies that met our criteria, involving a total of 24 healthy pregnancies and 14 with PE. To estimate the composition of immune cells (including CD8T, CD4T, Monocytes, Natural Killer, Neutrophils, Eosinophils, and B cells) based on DNA methylation data, we employed the R package EpiDISH. We used a linear model to compare statistical differences in the proportions of immune cells between PE cases and the control group. Longitudinal trends were also examined to capture immune cell shifts from pregnancy to postpartum. We found that monocyte proportions were significantly reduced in preeclamptic pregnancies compared to normotensive pregnancies (p=0.013). No significant differences were observed in other immune cell types, including T cells, B cells, neutrophils, eosinophils, and natural killer cells. Longitudinal analyses revealed substantial immune cell shifts in the postpartum period, including increased monocytes, B cells, CD4+ T cells, and CD8+ T cells, emphasizing the importance of gestational age in immune dynamics. These findings support DNAm profiling as a valuable tool for understanding immune cell dynamics in PE. Reduced monocyte proportions in PE highlight the role of immune dysregulation in its pathogenesis. Longitudinal sampling provides additional insights into the evolution of immune changes throughout pregnancy and postpartum, offering potential for developing predictive and monitoring tools for PE. Future studies with larger, more diverse cohorts are essential to refine the utility of DNAm in pregnancy complications.
The CCL17-CCR4 axis is critical for mutant STAT6-mediated microenvironmental remodelling and therapeutic resistance in Relapsed/Refractory Diffuse Large B Cell Lymphoma
Authors: Abraham Madelyn J. , Guilbert Cynthia , Gagnon Natascha , Goncalves Christophe , Benoit Alexandre , Rys Ryan N. , Preston Samuel E. J , Morin Ryan D. , Miller Wilson H. , Johnson Nathalie A. , del Rincon Sonia V. , Mann Koren K.
Published: December 2024

Relapsed and refractory Diffuse Large B Cell Lymphoma (rrDLBCL) presents a significant challenge in hematology-oncology, with approximately 30-40% of DLBCL patients experiencing relapse or resistance to treatment. This underscores the urgent need to better understand the molecular mechanisms governing therapeutic resistance. Signal Transducer and Activator of Transcription 6 (STAT6) has been previously identified as a gene with recurrent D419 gain-of-function mutations in rrDLCBL. When STAT6D419mutations are present in DLBCL tumour cells, we have demonstrated that transcription of the chemokine CCL17 (aka TARC) is increased, and tumours have increased infiltration of CD4+ T cells. However, the significance of increased T cell infiltration had not been determined. In the present study, we developed a mouse model of STAT6D419Nmutant DLBCL, that recapitulates the critical features of human STAT6D419mutant DLBCL, including increased expression of phospho-STAT6, increased CD4+ T cell invasion, and resistance to doxorubicin treatment. With this model, we found CD4+ T cells in STAT6D419Ntumours have higher expression of the receptor for CCL17, CCR4. Usingex vivofunctional assays we demonstrate that STAT6D419Ntumour cells are directly chemoattractive to CCR4+ CD4+ T cells, and when CCR4 is inhibited using a small molecule antagonist, CD4+ T cells in STAT6D419Ntumours are reduced and STAT6D419Ntumours regain therapeutic sensitivity to doxorubicin. Using PhenoCycler imaging of human rrDLBCL samples, we find that STAT6D419tumours indeed have increased expression of phospho-STAT6+ and increased cellular interactions between phospho-STAT6+ tumour cells and CD4+/ CCR4+ CD4+ T cells. Thus, our data identify CCR4 as an attractive therapeutic target in STAT6D419mutant rrDLBCL.
The pyrethroid insecticide deltamethrin disrupts neuropeptide and monoamine signaling pathways in the gastrointestinal tract
Authors: White Alexandria C. , Krout Ian N. , Mouhi Sabra , Chang Jianjun , Kelly Sean D. , Caudle W. Michael , Sampson Timothy R.
Published: December 2024

Enteroendocrine cells (EECs) are a rare cell type of the intestinal epithelium. Various subtypes of EECs produce distinct repertoires of monoamines and neuropeptides which modulate intestinal motility and other physiologies. EECs also possess neuron-like properties, suggesting a potential vulnerability to ingested environmental neurotoxicants. One such group of toxicants are pyrethroids, a class of prevalent insecticides used residentially and agriculturally. Pyrethroids agonize voltage-gated sodium channels (VGSCs), inducing neuronal excitotoxicity, and affect the function of monoamine-producing neurons. Given their anatomical location at the interface with the environment and their expression of VGSCs, EECs likely represent a vulnerable cell-type to oral pyrethroid exposure. In this study, we used the EEC cell line, STC-1 cells, to evaluate the effects of the common pyrethroid deltamethrin on the functional status of EECs. We find that deltamethrin impacts both expression of serotonergic pathways and inhibits the adrenergic-evoked release of an EEC hormone, GLP-1,in vitro. In a mouse model of oral exposure, we found that deltamethrin induced an acute, yet transient, loss of intestinal motility, in both fed and fasted conditions. This constipation phenotype was accompanied by a significant decrease in peripheral serotonin production and an inhibition of nutrient-evoked intestinal hormone release. Together, these data demonstrate that deltamethrin alters monoaminergic signaling pathways in EECs and regulates intestinal motility. This work demonstrates a mechanistic link between pyrethroid exposure and intestinal impacts relevant to pyrethroid-associated diseases, including inflammatory bowel disease, neurodegenerative disease, and metabolic disorders.
Cassini: Streamlined and Scalable Method for in situ profiling of RNA and Protein
Authors: Lapique Nicolas , Kim Michael , Thom Nicholas , Nadaf Naeem M. , Pineda Juan , Macosko Evan Z.
Published: December 2024

In the expanding field of spatial genomics, numerous methods have emerged to decode biomolecules in intact tissue. Advanced techniques based on combinatorial decoding can resolve thousands of features in a reasonable time but are often constrained by either the prohibitive costs associated with commercial platforms or the complexity of developing custom instruments. Alternatively, sequential detection methods, like single-molecule FISH, are easier to implement but offer limited multiplexing capability or signal amplification. Here, we introduce Cassini, a new approach for straightforward, cost-effective multiplexed measurements of mRNA and protein features simultaneously. Cassini leverages rolling circle amplification (RCA), known for its robust amplification and remarkable stability even after intense stripping, to serially detect each feature in under 20 minutes of total experimental time. The method also enables simultaneous immunostaining with either fluorophore-conjugated or DNA-barcoded antibodies, through an optimized immunostaining buffer. In a single overnight run, we show that Cassini can quantify 32 features (comprising both RNA and proteins) with sensitivity similar to state-of-the-art FISH techniques. We provide a comprehensive protocol alongside an online probe-design platform (cassini.me), aiming to enhance accessibility and user-friendliness. With our open-source solution, we aspire to empower researchers to uncover the nuances of spatial gene expression dynamics across diverse biological landscapes.
Characterization of both major histocompatibility complex classes in a wild social mammal: the banded mongoose
Authors: Schubert Nadine , Nichols Hazel J. , Mwanguhya Francis , Businge Robert , Kyambulima Solomon , Mwesige Kenneth , Cant Michael A. , Winternitz Jamie C.
Published: December 2024

The major histocompatibility complex’s (MHC) role in the vertebrate adaptive immune response and its exceptional polymorphism make it a key target for studying adaptive gene evolution. However, previous studies on carnivore MHC have mostly focused on populations which experienced a severe bottleneck or are of general conservation concern. Hence, sample sizes are often small and generalizations about MHC diversity are unreliable. Furthermore, studies often focus on one MHC class and do not cover the whole peptide binding groove of the MHC molecule. Here, we characterize MHC class I (MHC-I) exon 2 and 3, encoding both the α1- and α2-domain of the MHC-I molecule, as well as MHC-II DRB exon 2 for a large sample (N = 282-485) of a wild mammal of least conservation concern, the banded mongoose. We found that MHC-I generally showed higher allelic diversity and polymorphism compared to MHC-II, which is in line with findings in humans that show higher diversifying selection acting on MHC-I. However, MHC-I exon 3 showed the lowest diversity, possibly due to its different role in generating the peptide binding groove of the class I molecule compared to exon 2. Moreover, we found selection to act more strongly on MHC-I exon 2 (domain α1) than exon 3 (domain α2). Despite frequent inbreeding, phylogenetic comparative analysis showed banded mongooses to have MHC diversity levels comparable with other carnivores of least concern. Phylogenetic analysis indicated a longer evolutionary trajectory for MHC-II compared to MHC-I as well as species-specific gene duplication of nonclassical sequences of MHC-I clustering with classical sequences. Trans-species polymorphism was detected for nonclassical MHC-I sequences suggesting homology or convergent evolution for these genes. Our study is the first to characterize both MHC classes of a social, wild carnivore using a high throughput sequencing approach with a large sample size and thereby provides the basis for further investigation of MHC structure and function within the banded mongoose and other carnivores.
Effect of Redcurrant (Ribes rubrum) fruit powder on patients with COVID-19, A randomized double-blinded clinical trial
Authors: Pirmorad Azadeh Ahmadi , Ebadipour Sakineh , Amiri-Sadeghan Amir , Zarredar Habib , Asadi Milad , khalili Majid , Sharifi Akbar
Published: December 2024

Introduction

COVID-19 has affected many people worldwide. Effective treatments have been reported using medicinal plants which their multi functionality may beneficial. Considering the importance of innate immune response and pathologic effect of cytokine storm in COVID-19 patients, this study examined the effect of Redcurrant (Ribes rubrum) fruit powder capsules on inflammatory cytokines of IL-6 and TNFα as primary objectives. Moreover, its effect on the COVID-19 patients’ recovery symptoms was evaluated.

Methods

We analyzed the clinical effect on recovery symptoms, hematological parameters, and the serum levels of interlucin-6 and TNFα in the placebo-controlled and treated patients with Redcurrant fruit powder.

Results

Redcurrant fruit powder capsules significantly decreased pro-inflammatory cytokines of IL-6 and TNF-α, and reduced the clinical recovery time of COVID-19 and fatigue (from 7.3 ± 2.09 to 2.9 ± 1.28 days) as well as cough (from 5.67 ± 2.4 to 2.4 ± 1.7) days compared to the control group.

Conclusion

Redcurrant fruit powder might be a promising herbal treatment of COVID-19, and since no considerable side effect is observed in short-term usage, it might be beneficial to start treatment as early as possible in suspected cases of COVID-19.
Widespread genetic testing control inherited polycystic kidney disease in cats
Authors: Ukawa Hisashi , Kida Akane , Ataka Kai , Horie Ryo , Matsumoto Yuki
Published: December 2024

A genetic variant ofPKD1in cats, which causes polycystic kidney disease (PKD), is a target for direct-to-consumer genetic testing to assess PKD risk; however, its effect on genetic structure in cat populations remains unexplored. Therefore, in this study, we aimed to examine the changes in feline PKD and thePKD1variant across breeds and over time using a large dataset of 110,325 insured and 61,968 genetic-tested cats from 14 breeds. Results revealed that thePKD1variant frequency significantly decreased, with a reduction of 42.6% before 2019 and after 2022. Systematic genomic analysis revealed no differences in genetic structure or inbreeding levels. The effective population size of cats with thePKD1variant decreased between points. Overall, these findings highlight the potential of direct-to-consumer genetic testing in promoting more optimized breeding practices and enhancing feline welfare.
Anti-inflammatory assessment of zinc oxide nanoparticles mediatedAframomum citratum(C. Pereira) K. Schum (Zingiberaceae) in Wistar rats
Authors: Eya’ane Meva Francois , Nga Essama Denise Murielle , Nguemfo Edvige Laure , Bamal Hans-Denis , Ntoumba Agnes Antoinette , Ebanda Kedi Phillipe Belle , Yen Beglau Thi Hai , Tako Djimefo Alex Kevin , Djuidje Annie Guilaine , Tchatchouang Geordamie Chimi , Nanga Chick Christian , Nyuyfoni Gildas Fonye , Tchangou Njimou Armel Florian , Madeleine Evouna Danielle Ines , Mintang Fongang Armel Ulrich , Janiak Christoph
Published: December 2024

Introduction

Zinc oxide nanoparticles (ZnONPs) have been synthesized using a wide range of techniques, including green chemistry, because of their versatility, cost effectiveness, and environmentally friendly nature, offering thereby interesting and inexpensive therapeutic options. This study aimed to develop zinc oxide nanoparticles as an anti-inflammatory agent usingAframomum citratumseed extract.

Methodology

ZnONPs were prepared by the reaction between zinc nitrate and an alkalineaqueous extract ofA. citratumseeds. The isolated nanoparticles were then characterized using UV-Vis, FTIR, SEM/EDX, PXRD and TEM techniques. The toxicological profile was assessed at a limited dose of 2000 mg/kg in rats, and methods for heat denaturation of egg albumin, stabilization of red blood cell membranes and inhibition of carrageenan-induced plantar oedema were studied to assess anti-inflammatory properties.

Results

The formation of ZnONPs was observed by a color change and the appearance of the plasmon resonance peak at 360 nm in the UV-Vis spectrum while FTIR confirmed the presence of secondary metabolites; SEM confirmed the presence of multiform aggregates, and TEM visualize point like particles. EDS confirmed the presence of Zn atoms within the synthetized material. The toxicological profile studied showed no harmful signs; zinc oxide nanoparticles synthesized fromA. citratumseed extract showed high inhibition percentages of 86 (1mg/mL); 77 (0.6mg/mL) and 79(1mg/mL) when subjected to inhibition of heat-induced egg albumin denaturation, red cell membrane stabilization and oedema induction by carrageenan respectively, not significatively different compared with diclofenac sodium as positive controls.

Conclusion

Zinc oxide nanoparticles synthesized and characterized fromA. citratumseed extract act as a potent anti-inflammatory agent and are devoid of acute oral toxicity.
Using a Multilingual AI Care Agent to Reduce Disparities in Colorectal Cancer Screening: Higher FIT Test Adoption Among Spanish-Speaking Patients
Authors: Bhimani Meenesh , Baker R. Hal , Ausin Markel Sanz , Meixiong Gerald , Lasko Rae , Raglow-Defranco Mariska , Miller Alex , Mukherjee Subhabrata , Godil Saad , Cook Anderson , Agnew Jonathan D. , Atreja Ashish
Published: December 2024

Background

Colorectal cancer (CRC) screening rates remain disproportionately low among Hispanic and Latino populations. While artificial intelligence (AI) has shown promise in healthcare delivery, its impact on health equity remains unclear.

Objective

To evaluate the effectiveness of a bilingual generative AI voice agent outreach program in engaging Spanish-speaking patients for CRC screening compared to English-speaking patients.

Methods

We conducted a retrospective analysis of AI-powered outreach calls for CRC screening at a large integrated health system serving central Pennsylvania and northern Maryland in September 2024. The study included 1,878 patients (517 Spanish-speaking, 1,361 English-speaking) eligible for colorectal cancer screening. The AI care agent conducted personalized phone calls in the patient’s preferred language to discuss screening and facilitate fecal immunochemical test (FIT) kit requests. The primary outcome was FIT test opt-in rate. Secondary outcomes included call connect rates and duration.

Results

Spanish-speaking patients demonstrated significantly higher engagement across all measures compared to English-speaking patients: FIT test opt-in rates (18.2% vs. 7.1%, p<0.001), connect rates (88.8% vs. 53.3%, p<0.001), and call duration (6.05 vs. 4.03 minutes, p<0.001). In multivariate analysis, Spanish language preference remained an independent predictor of FIT test opt-in (adjusted OR 2.012, 95% CI 1.340-3.019, p<0.001) after controlling for demographic and other factors (gender, age, state of residence, and call duration).

Conclusions

Contrary to concerns about technology exacerbating disparities, AI-powered outreach achieved significantly higher engagement among Spanish-speaking patients. These findings suggest that language-concordant AI interactions may help address healthcare disparities and improve preventive care engagement in traditionally underserved populations.
Epidemiology ofVibrio CholeraeInfections in the Households of Cholera Patients in the Democratic Republic of the Congo: PICHA7 Prospective Cohort Study
Authors: George Christine Marie , Sanvura Presence , Namunesha Alves , Bisimwa Jean-Claude , Endres Kelly , Felicien Willy , Williams Camille , Trivedi Shubhanshi , Davis Kilee L. , Perin Jamie , Sack David A. , Bengehya Justin , Maheshe Ghislain , Cikomola Cirhuza , Bisimwa Lucien , Leung Daniel T. , Mwishingo Alain
Published: December 2024

Background

The aim of this prospective cohort study is to build evidence on transmission dynamics and risk factors forVibrio choleraeinfections in cholera patient households.

Methods

Household contacts of cholera patients were observed for 1-month after the index cholera patient was admitted to a health facility for stool, serum, and water collection in urban Bukavu in South Kivu, Democratic Republic of the Congo. AV. choleraeinfection was defined as aV. choleraebacterial culture positive result during the 1-month surveillance period and/or a four-fold rise in aV. choleraeO1 serological antibody from baseline to the 1-month follow-up.

Results

Twenty-seven percent of contacts (134 of 491) of cholera patients had aV. choleraeinfection during the surveillance period. Twelve percent (9 of 77) of cholera patient households had a stored water sample withV. choleraeby bacterial culture, and 7% (5 of 70) had a water source sample withV. cholerae. Significant risk factors for symptomaticV. choleraeinfections among contacts were stored food left uncovered (Odds Ratio (OR): 2.39, 95% Confidence Interval (CI): 1.13, 5.05) and younger age (children <5 years) (OR: 2.09, 95% CI: 1.12, 3.90), and a drinking water source with >1 colony forming unitE.coli/ 100mL (OR: 3.59, 95% CI: 1.46, 8.84) forV. choleraeinfections.

Conclusions

The findings indicate a high risk of cholera among contacts of cholera patients in this urban cholera endemic setting, and the need for targeted water treatment and hygiene interventions to prevent household transmission ofV. cholerae.

In this prospective cohort study in the Democratic Republic of the Congo, the majority of cholera patient households had multipleVibrio choleraeinfected household members and both source water and stored drinking water samples hadV. cholerae.
Bacteriophage Kil peptide folds into a predicted helix-turn-helix structure to disruptEscherichia colicell division
Authors: Naha Arindam , Cameron Todd A. , Margolin William
Published: December 2024

FtsZ, a eukaryotic tubulin homolog and an essential component of the bacterial divisome, is the target of numerous antimicrobial compounds as well as proteins and peptides, most of which inhibit FtsZ polymerization dynamics. We previously showed that the Kil peptide from bacteriophage λ inhibitsEscherichia colicell division by disrupting FtsZ ring assembly, and this inhibition requires the presence of the essential FtsZ membrane anchor protein ZipA. To investigate Kil’s molecular mechanism further, we employed truncation mutants and molecular modeling to identify the minimal residues necessary for its activity. Modeling suggests that Kil’s core segment folds into a helix-turn-helix (HTH) structure. Deleting either the C-terminal 11 residues or the N-terminal 5 residues of Kil still allowed inhibition ofE. colicell division, but removing both termini nearly abolished this activity, indicating that a minimal region within the Kil HTH core is essential for its function. Another Kil-like peptide from a closely related enterobacterial phage also disrupts FtsZ ring assembly and requires ZipA for this activity. Consistent with its broader activity against FtsZ, λ Kil was able to efficiently inhibit cell division of a uropathogenicE. coli(UPEC) strain. Understanding the function of Kil and similar peptides can potentially reveal additional ways to target FtsZ for antimicrobial therapies as well as elucidate how FtsZ functions in bacterial cell division.
Quantitative Genetics of Microbiome Mediated Traits
Authors: Week Bob , Ralph Peter L. , Tavalire Hannah F. , Cresko William A. , Bohannan Brendan J. M.
Published: December 2024

Multicellular organisms host a rich assemblage of associated microorganisms, collectively known as their “microbiomes”. Microbiomes have the capacity to influence their hosts’ fitnesses, but the conditions under which such influences contribute to evolution are not clear. This is due in part to a lack of a comprehensive theoretical framework for describing the combined effects of host and associated microbes on phenotypic variation. Here we begin to address this gap by extending the foundations of quantitative genetic theory to include host-associated microbes, as well as alleles of hosts, as factors that explain quantitative host trait variation. We introduce a way to partition host-associated microbiomes into componenents relevant for predicting a microbiome-mediated response to selection. We then apply our general framework to a simulation model of microbiome inheritance to illustrate principles for predicting host trait dynamics, and to generalize classical narrow and broad sense heritabilities to account for microbial effects. We demonstrate that microbiome-mediated responses to host selection can arise from various transmission modes, not solely vertical, with the contribution of non-vertical modes depending on host life history. Our work lays a foundation for integrating microbiome-mediated host variation and adaptation into our understanding of natural variation.
Causal considerations can determine the utility of machine learning assisted GWAS
Authors: Mukherjee Sumit , McCaw Zachary , Amar David , Dey Rounak , Soare Thomas , Xu Kaiwen , Somineni Hari ,   insitro Research Team, Eriksson Nicholas , O’Dushlaine Colm
Published: December 2024

Machine Learning (ML) is increasingly employed to generate phenotypes for genetic discovery, either by imputing existing phenotypes into larger cohorts or by creating novel phenotypes. While these ML-derived phenotypes can significantly increase sample size, and thereby empower genetic discovery, they can also inflate the false discovery rate (FDR). Recent research has focused on developing estimators that leverage both true and machine-learned phenotypes to properly control the type-I error. Our work complements these efforts by exploring how the true positive rate (TPR) and FDR depend on the causal relationships among the inputs to the ML model, the true phenotypes, and the environment.

Using a simulation-based framework, we study architectures in which the machine-learned proxy phenotype is derived from biomarkers (i.e. inputs) either causally up-stream or downstream of the target phenotype. We show that no inflation of the false discovery rate occurs when the proxy phenotype is generated from upstream biomarkers, but that false discoveries can occur when the proxy phenotype is generated from downstream biomarkers. Next, we show that power to detect variants truly associated with the target phenotype depends on its heritability and correlation with the proxy phenotype. However, the source of the correlation is key to evaluating a proxy phenotype’s utility for genetic discovery. We demonstrate that evaluating machine-learned proxy phenotypes using out-of-sample predictive performance (e.g. phenotypic correlation) provides a poor lens on utility. This is because overall predictive performance does not differentiate between genetic and environmental correlation. In addition to parsing these properties of machine-learned phenotypes via simulations, we further illustrate them using real-world data from the UK Biobank.
The methane-cycling microbiome in intact and degraded permafrost soils of the pan-Arctic
Authors: Wang Haitao , Lindemann Erik , Liebmann Patrick , Varsadiya Milan , Svenning Mette Marianne , Waqas Muhammad , Petters Sebastian , Richter Andreas , Guggenberger Georg , Barta Jiri , Urich Tim
Published: December 2024

The methane-cycling microbiomes in Arctic permafrost-affected soils play crucial roles in the production and consumption of this important greenhouse gas. However, little is known about the distributions of Arctic methanogens and methanotrophs across the regional scale and along the vertical soil profile, as well as their responses to the widespread permafrost thaw. Using a unique sample set from nine different locations across the pan-Arctic, we identified methanogen and methanotroph phylotypes in 729 datasets of 16S rRNA gene amplicons.

In 621 samples of intact permafrost soils across the pan-Arctic, only 22 methanogen and 26 methanotroph phylotypes were identified. Relative abundances of both functional groups varied significantly between sites and soil horizons. Only four methanogen phylotypes were detected at all locations, with the hydrogenotrophicMethanobacterium lacusdominating. Remarkably, the permafrost soil methane filter was almost exclusively comprised of a few phylotypes closely related to the obligate methanotrophic speciesMethylobacter tundripaludum.

In degraded permafrost sites in Alaska,M. tundripaludumalso dominated the methanotroph microbiome in the wet site. However, in dry, water-drained former permafrost site,Methylocapsaphylotypes, closely related with the atmospheric methane oxidizing bacteria, were exclusively found and dominant, indicating a massive restructuring of the methanotroph guild that consequently resulted in functional changes from a soil methane filter to an atmospheric methane sink.

This study provides first insights into the identity and intricate spatial distribution of methanotrophs and methanogens in permafrost soils at a pan-Arctic scale and their responses to different water status after permafrost degradation. These findings point towards a few key microbes particularly relevant for future studies on Arctic CH4dynamics in a warming climate and that under future dry conditions more atmospheric CH4uptake in Arctic upland soils might happen.
Embryonic exposures to flame retardant tetrabromobisphenol A (TBBPA) disrupts dorsoventral patterning in zebrafish
Authors: Senarath Pathirajage Kanchaka , Serradimigni Rosemaria , Sharma Sunil , Dasgupta Subham
Published: December 2024

Tetrabromobisphenol A (TBBPA), a widely used flame retardant in commercial products such as synthetic textiles, plastics, and electronics poses potential toxicity risks through indoor exposure. This study aims to leverage zebrafish as a model to study TBBPA impacts on zebrafish dorsoventral patterning—a process that lays the foundation of an embryo’s axial determination and localization of specific tissues and organs. Zebrafish embryos were exposed to varying concentrations of TBBPA (0-10 µM) at either 0.75- or 6-hours post-fertilization (hpf) and phenotyped at 8 or 24 hpf. Following this, whole-mount immunohistochemistry (IHC) was conducted out to quantify various proteins important in the BMP signaling pathway, epithelial-to-mesenchymal transition (EMT) and ectoderm and mesoderm germ layers. Importantly, these assessments were done at environmentally relevant concentrations ranging down to nM and pM levels. Our data showed a significant concentration-dependent increase in ventralization phenotypes, marked by enlarged blood island area, coupled with a disruption of the ventral-to-dorsal gradient of pSMAD protein levels, indicating BMP signaling disruptions. Perturbations in epithelial-to-mesenchymal transition (EMT), as evidenced by changes in E- and N-cadherin expression and Snail2 transcription factor levels, indicated impaired cell migration on TBBPA exposures. We then interrogated if TBBPA impacts germ layers and structures derived from specific germ layers. We observed significant concentration-dependent changes in levels of Sox2 and Sox10- both indicators of neural crest cell formation and differentiation from the ectoderm. We also observed a significant reduction of Tbx16- a marker of paraxial mesodermal cells. Collectively, both these data show TBBPA-induced impact on germ layers. Finally, we examined specific cell types derived from ectoderm and mesoderm and showed TBBPA-induced inhibition of cartilage development (derived from ectodermal neural crest cells) and blood cell development (derived from mesodermal cells). Our findings collectively demonstrate that TBBPA-induced disruptions in early developmental signaling and dorsoventral patterning may contribute to systemic toxicity in zebrafish embryos. Importantly, we see these disruptions at environmentally relevant concentrations, reinforcing the importance of continued interrogation of TBBPA in targeting early embryogenesis.
Dissociating Contributions of Theta and Alpha Oscillations from Aperiodic Neural Activity in Human Visual Working Memory
Authors: van Engen Quirine , Chau Geeling , Smith Aaron , Adam Kirsten , Donoghue Thomas , Voytek Bradley
Published: December 2024

While visual working memory (WM) is strongly associated with reductions in occipitoparietal 8-12 Hz alpha power, the role of 4-7 Hz frontal midline theta power is less clear, with both increases and decreases widely reported. Here, we test the hypothesis that this theta paradox can be explained by non-oscillatory, aperiodic neural activity dynamics. Because traditional time-frequency analyses of electroencephalopgraphy (EEG) data conflate oscillations and aperiodic activity, event-related changes in aperiodic activity can manifest as task-related changes in apparent oscillations, even when none are present. Reanalyzing EEG data from two visual WM experiments (n = 74), and leveraging spectral parameterization, we found systematic changes in aperiodic activity with WM load, and we replicated classic alpha, but not theta, oscillatory effects after controlling for aperiodic changes. Aperiodic activity decreased during WM retention, and further flattened over the occipitoparietal cortex with an increase in WM load. After controlling for these dynamics, aperiodic-adjusted alpha power decreased with increasing WM load. In contrast, aperiodic-adjusted theta power increased during WM retention, but because aperiodic activity reduces more, it falsely appears as though theta “oscillatory” power (e.g., bandpower) is reduced. Furthermore, only a minority of participants (31/74) had a detectable degree of theta oscillations. These results offer a potential resolution to the theta paradox where studies show contrasting power changes. We identify novel aperiodic dynamics during human visual WM that mask the potential role that neural oscillations play in cognition and behavior.

Significance statement

Working Memory (WM) is our ability to hold information in mind without it being present in our external environment. Years of research focused on oscillatory brain dynamics to discover the mechanisms of WM. Here, we specifically look at oscillatory and non-oscillatory, aperiodic activity as measured with scalp EEG to test their significance in supporting WM. We challenge earlier findings regarding theta oscillations with our analysis approach, while replicating alpha oscillation findings. Furthermore, aperiodic activity is found to be involved in WM, over frontal regions in a task-general manner, and over anterior regions this activity is reduced with an increase the number of items that are remembered. Thus, we have identified novel aperiodic dynamics during human visual WM.
Stool processing methods for Xpert Ultra testing in childhood tuberculosis: A prospective, multi-country accuracy study
Authors: Jaganath Devan , Nabeta Pamela , Nicol Mark P. , Castro Robert , Wambi Peter , Zar Heather J. , Workman Lesley , Lodha Rakesh , Singh Urvashi B. , Bavdekar Ashish , Sanghavi Sonali , Trollip André , Mace Aurélien , Bonnet Maryline , Lounnas Manon , de Haas Petra , Tiemersma Edine , Alland David , Banada Padmapriya , Cattamanchi Adithya , Ruhwald Morten , Wobudeya Eric , Denkinger Claudia M. ,   the Stool H2H Study Team
Published: December 2024

Background

Centrifuge-free processing methods support stool Xpert Ultra testing for childhood tuberculosis (TB), but there are limited data on their accuracy, acceptability and usability.

Methods

We conducted a prospective evaluation of stool Xpert Ultra in India, South Africa, and Uganda with three methods: Stool Processing Kit (SPK), Simple One-Step (SOS), and Optimized Sucrose Flotation (OSF). Children <15 years old with presumptive TB had respiratory specimen testing with Xpert Ultra and culture. Stool was tested using Xpert Ultra after processing with each method. We compared the accuracy of each method to a microbiological reference standard (MRS) and a composite reference standard (CRS). We surveyed the laboratory staff to assess acceptability and usability of the methods.

Results

We included 607 children, of whom the median age was 3.5 years (IQR 1.3-7), 48% were female, and 15.5% were HIV positive. Against the MRS, the sensitivities of SPK, SOS and OSF were 36.9% (95% CI 28.6-45.8), 38.6% (95% CI 17.2-51), and 31.3% (95% CI 20.2-44.1), respectively. The specificities of SPK, SOS and OSF were 98.2% (95% CI 96.4-99.3), 97.3% (95% CI 93.7-99.1) and 97.1% (95% CI 93.3-99), respectively. Laboratory staff reported that the methods were acceptable and usable, but SOS was most feasible to implement in a peripheral facility. Sensitivity increased among children who were culture-positive (55-77.3%) and was low (13-16.7%) against the CRS.

Conclusions

Stool processing methods for Xpert Ultra were acceptable, usable, and performed similarly, with highest sensitivity among children with culture-positive TB.

KEY POINTS

In a multi-country diagnostic accuracy study for childhood pulmonary tuberculosis, three stool processing methods for Xpert Ultra were acceptable, usable and performed similarly. Sensitivity was lower than that of sputum Xpert Ultra, but improved in children with culture-positive disease.
Earlier timing of seasonal respiratory infections and seasonal mortality during the COVID-19 pandemic
Authors: Sieber Michael , Traulsen Arne
Published: December 2024

Seasonal respiratory infections typically surge within a limited time window, but the exact timing within a given year is hard to predict. The disruptions caused by the COVID-19 pandemic led to dramatic changes in the transmission dynamics of many pathogens, providing a unique opportunity to study the determinants and robustness of the seasonal timing of epidemics. Combining detailed data on acute respiratory infections from Germany with an epidemiological model, we analyzed changes in the timing of seasonal epidemics. The seasonal surge in infections occurred substantially earlier during the COVID-19 pandemic, and was reflected in a corresponding shift in the seasonality of all-cause mortality. We show that this is a consistent, but transient outcome of disrupted epidemic seasonality, predictable from basic epidemiological principles.
Self-reported Stress Perception in Breast Cancer Patients Treated with Integrative Metal Color Light Therapy: The LUCIA Study Protocol
Authors: Oei Shiao Li , Groß Jessica , Ganz Michaela , Streffer Charlotte , Grieb Gerrit , Freytag Lysander , Johnson Sophia , Schad Friedemann , Thronicke Anja
Published: December 2024

Introduction

Many breast cancer patients benefit from appropriate oncological therapies, but also experience side effects or ongoing restrictions that have a significant impact on health-related quality of life. Non-Pharmaceutical Interventions (NPIs) such as sport, movement, art therapy, yoga or mindfulness-based stress reduction, can help to reduce distress and pain and support resilience strategies. Metal Colored Light (MCL) therapy, an integrative art therapy using metal colored glasses, has been used in the past to relieve symptoms, improve quality of life and support coping strategies. The LUCIA study aims for the first time to systematically investigate whether self-reported perception of stress can be influenced in breast cancer patients through a series of MCL.

Methods and analysis

The LUCIA-study will enroll 60 breast cancer patients treated with MCL therapy, which consists of nine individual MCL sessions per patient over a six-week period. The primary outcome is the analysis of self-reported stress perception of breast cancer patients using the National Comprehensive Cancer Network (NCCN) Distress Thermometer. Secondary endpoints include the Internal Coherence Scale (ICS) and quality of life using the European Organization for Research and Treatment of Cancer Questionnaire C30 (EORTC-QLQ-C30). Longitudinal changes in symptom burden will be assessed and multivariate analyses performed.

Ethics and disseminations

The present study is approved by the ethics committee of the Medical Association Berlin within the Network Oncology with the reference number Eth-27/10. The results will be presented at scientific conferences and published.

Trial registration number

The study was registered at the German Register for Clinical Trials under DRKS00013335 on 27/11/2017.

Strengths and limitations of this study

Self-reported stress perception of each participant in this LUCIA study will be evaluated before (T0) and after the Metal Colored Light (MCL) therapy (T1).

Changes in self-reported distress burden, internal coherence and health-related quality of life will be followed and asked three months (T2) and six months (T3) after T0.

Prospective evaluation of all participants.

Sources of bias and potential confounding can be limited through the use of multivariate analyses.

There is no direct control or placebo group and no blinding.
Neuropeptide-mediated temporal sensory filtering in a primordial nervous system
Authors: Wyss Livia S. , Bray Samuel R. , Wang Bo
Published: December 2024

Sensory filtering – prioritizing relevant stimuli while ignoring irrelevant ones – is crucial for animals to adapt and survive in complex environments. While this phenomenon has been primarily studied in organisms with complex nervous systems, it remains unclear whether simpler organisms also possess such capabilities. Here, we studied temporal information processing inSchmidtea mediterranea, a freshwater planarian flatworm with a primitive nervous system. Using long-term behavioral imaging and oscillatory ultraviolet (UV) light stimulations with rhythms matching the timescale of the animal’s short-term memory (∼minutes), we observed that planarians initially ignored rhythmic oscillations in UV intensity but eventually began tracking them after several cycles, demonstrating sensory filtering. We identified two neuropeptides, knockdown of which eliminated the initial ignoring phase and led to immediate stimulus-tracking, suggesting that these neuropeptides mediate an active sensory gating mechanism preventing response to transient fluctuations in stimuli. Notably, when UV stimulation was coupled with synchronous visible light oscillations, the planarians tracked the combined signals immediately, indicating that coherence across sensory modalities can override the initial gating. Our findings demonstrate that even simple nervous systems can filter temporal information and that this mechanism is mediated by neuropeptides. Unlike classical fast-acting small-molecule neurotransmitters, neuropeptides provide a slower, sustained, and global form of modulation that allows for more sophisticated control of sensory processing.

Significance statement

We show that simple nervous systems can use specific neuropeptides to achieve sensory filtering, a behavior previously thought to require complex brain architecture. This neuropeptide-mediated sensory gating mechanism reveals a fundamental role for neuropeptides in temporal information processing, offering insights into the mechanistic and evolutionary origins of attention-like behaviors.
Hyperactive PLCG1 drives non-canonical signaling to promote cell survival
Authors: Zeng Longhui , Zhang Xinyan , Xiong Yiwei , Sato Kazuki , Hajicek Nicole , Sondek John , Su Xiaolei
Published: December 2024

One of the long-standing questions in cell signaling field to identify and characterize key signaling nodes out of a complex network. Phospholipase Cγ1 (PLCG1) was identified as the most frequently mutated gene in adult T-cell leukemia/lymphoma, suggesting a critical function of PLCG1 in driving T cell activation. However, it remains unclear how these mutations regulate T cell physiology and pathology. Here we investigated three common leukemia/lymphoma associated mutations (R48W, S345F, and D1165H). We discovered that these mutations induced hyperactive T cell signaling and caused pro-survival phenotypes. PLCG1 mutants enhanced LAT condensation, calcium influx, and ERK activation. They promoted T cell proliferation, induced cell aggregation, and rendered resistance to vorinostat, an FDA-approved drug for cutaneous T-cell lymphoma. The resistance to vorinostat depended on ERK signaling and can be reversed with an ERK inhibitor. Mechanistically, alpha smooth muscle actin, which was specifically induced by PLCG1 mutants, directly bound PLCG1 to promote its activation. Together, these results demonstrated that hyperactive PLCG1 promoted T cell survival and drug resistance through inducing non-canonical signaling.