bluuebunny/crossref_metadata_2025 huggingface dataset:
scDiffEq: drift-diffusion modeling of single-cell dynamics with neural stochastic differential equations
Authors: Vinyard Michael E. , Rasmussen Anders W. , Li Ruitong , Klein Allon M. , Getz Gad , Pinello Luca
Published: December 2023

Single-cell sequencing measurements facilitate the reconstruction of dynamic biology by capturing snapshot molecular profiles of individual cells. Cell fate decisions in development and disease are orchestrated through an intricate balance of deterministic and stochastic regulatory events. Drift-diffusion equations are effective in modeling single-cell dynamics from high-dimensional single-cell measurements. While existing solutions describe the deterministic dynamics associated with the drift term of these equations at the level of cell state, diffusion is modeled as a constant across cell states. To fully understand the dynamic regulatory logic in development and disease, models explicitly attuned to the balance between deterministic and stochastic biology are required. To address these limitations, we introduce scDiffEq, a generative framework for learning neural stochastic differential equations that approximate biology’s deterministic and stochastic dynamics. Using lineage-traced single-cell data, we demonstrate that scDiffEq offers an improved reconstruction of cell trajectories and prediction of cell fate from multipotent progenitors during hematopoiesis. By impartingin silicoperturbations to multipotent progenitor cells, we find that scDiffEq accurately recapitulates the dynamics of CRISPR-perturbed hematopoiesis. We generalize this approach beyond lineage-traced or multi-time point datasets to model the dynamics of single-cell data from a single time point. Using scDiffEq, we simulate high-resolution developmental cell trajectories, which can model their drift and diffusion, enabling us to study their time-dependent gene-level dynamics.
Reward circuit function and treatment outcome following vALIC deep brain stimulation in treatment-resistant depression
Authors: Runia N. , van de Mortel L.A. , Smith C. L. C. , Bergfeld I.O. , de Kwaasteniet B.P. , Luigjes J. , van Laarhoven J. , Notten P. , Beute G. , van den Munckhof P. , Schuurman P.R. , Denys D.A.J.P. , van Wingen G.A.
Published: December 2023

Depression is associated with abnormal functioning of the reward circuit. Several deep brain stimulation (DBS) targets for treatment-resistant depression (TRD) directly modulate white matter bundles of the reward circuit. Here we investigated whether baseline reward processing in the brain is associated with ventral anterior limb of the internal capsule (vALIC) DBS outcome and whether vALIC DBS changes neural activity in the reward circuit.

We studied fifteen patients with TRD who performed a monetary reward task during functional magnetic resonance imaging (fMRI) before vALIC DBS surgery, after DBS parameter optimization, and during a sham-controlled crossover phase. DBS devices were switched off during scanning for MRI safety reasons. Additionally, fifteen matched healthy controls were investigated twice to account for test-retest effects. We investigated brain responses to reward anticipation, loss anticipation, reward feedback and loss feedback.

Results showed that lower baseline nucleus accumbens activation during loss anticipation and higher baseline caudate nucleus and midcingulate cortex activation during reward feedback processing were associated with worse DBS outcome. No significant changes in reward processing were observed following vALIC DBS in comparison to healthy controls or after active compared to sham stimulation. Instead, increased middle frontal gyrus responses following DBS to loss feedback was associated with better DBS outcome.

These results suggest that DBS efficacy in TRD is related to individual differences in reward circuit functioning at baseline and to changes in middle frontal gyrus responses following DBS.
What factors predict ambulance pre-alerts to the emergency department? Analysis of routine data from 3 UK ambulance services
Authors: Sampson Fiona , Pilbery Richard , Herbert Esther , Goodacre Steve , Bell Fiona , Spaight Rob , Rosser Andy , Webster Peter , Millins Mark , Pountney Andy , Coster Joanne , Long Jaqui , O’Hara Rachel , Foster Alexis , Miles Jamie , Turner Janette , Boyd Aimee
Published: December 2023

Objective

Ambulance clinicians use pre-alert calls to advise emergency departments (EDs) of the arrival of patients requiring immediate review or intervention. Consistency of pre-alert practice is important in ensuring appropriate EDs response. We used routine data to describe pre-alert practice and explore factors affecting variation in practice.

Methods

We undertook an observational study using a linked dataset incorporating 12 months’ ambulance patient records, ambulance clinician data and emergency call data for three UK ambulance services. We used LASSO regression to identify candidate variables for multivariate logistic regression models to predict variation in pre-alert use, analysing clinician factors (role, experience, qualification, time of pre-alert during shift), patient factors (NEWS2 score, clinical working impression, age, sex) and hospital factors (receiving ED, ED handover delay status).

Results

From the dataset of 1,363,274 patients conveyed to ED, 142,795 (10.5%) were pre-alerted, of whom only a third were for conditions with clear pre-alert pathways (e.g. sepsis, STEMI, major trauma). Casemix (illness acuity score, clinical diagnostic impression) was the strongest predictor of pre-alert use but male patient gender, clinician role, receiving hospital, and hospital turnaround delay at receiving hospitals were also statistically significant predictors, after adjusting for casemix. There was no evidence of higher pre-alert rates in the final hour of shift.

Conclusions

Pre-alert decisions are determined by factors other than illness acuity and clinical diagnostic impression. Research is required to determine whether our findings are reproducible elsewhere and why non-clinical factors (e.g. patient gender) may influence pre-alert practice.
A randomized sham-controlled trial of transcranial and intranasal photobiomodulation in Japanese patients with mild cognitive impairment and mild dementia due to Alzhimer’s disease: a protocol
Authors: Yokoi Yuma , Inagawa Takuma , Yamada Yuji , Matsui Makoto , Tomizawa Asumi , Noda Takamasa
Published: December 2023

Introduction

Photobiomodulation (PBM) is a novel strategy for cognitive enhancement by improving brain metabolism and blood flow. It is potentially beneficial for patients with Alzheimer’s disease (AD). We present a study protocol for a randomised controlled trial designed to evaluate the efficacy and safety of PBM.

Method and analysis

This is a single-centre, parallel-group, randomised, sham-controlled study. We enrol patients with mild cognitive impairment or dementia due to AD and assigned them to receive either active or sham stimulation at home for 12 weeks, with three sessions per week (20 minutes each). The stimulation involves invisible near-infrared light delivered by five applicators (one in a nostril, one on the frontal scalp, and three on the occipital scalp). The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale–cognition from baseline to Week 12. We will also measure cognitive function, activity of daily living, behavioural and psychological symptoms, and caregiver burden. We will collect data at clinics at baseline and Week 12 and remotely at home. We estimate a sample size of 30 (20 active and 10 sham) based on an expected mean difference of −6.9 and an SD of 4.8. We use linear models for the statistical analysis.

Ethics and dissemination

The National Center of Neurology and Psychiatry Clinical Research Review Board (CRB3200004) approved this study. The results of this study will be published in a scientific peer-reviewed journal.

Trial registration details Japan Registry of Clinical Trials jRCTs032230339.

ARTICLE SUMMARY

Strengths and limitations of this study

This study aims to investigate the impact of PBM on the cognitive function and quality of life of patients diagnosed with mild cognitive impairment or dementia, using a well-defined sample population.

A potential limitation of this study is that it is conducted at a single centre and does not adequately assess the long-term outcomes of PBM.
Optimizing Glycemic Control in Type 1 Diabetic Patients using a Deep Learning-Based Artificial Pancreas with a Secure Glucagon and Insulin Delivery System
Authors: Singh Rohan , Rao Raj R.
Published: December 2023

Type 1 diabetes impacts millions worldwide, with some patients facing rapid fluctuations in their blood sugar levels. These fluctuations can negatively impact an individual’s quality of life and if untreated, can lead to nerve damage, coma, and death. While current methods have helped address hyperglycemia (high blood sugar), there has been less success with hypoglycemia (low blood sugar) and glucagon administration. To bridge this gap, an artificial pancreas with a novel insulin and glucagon pump was developed. Initiating the system, a personalized mobile app enables users to input meal carbohydrate and insulin bolus data. The data is then transmitted to a deep learning model that incorporates Continuous Glucose Monitor readings, along with carbohydrate and insulin data from the app. The two-layer Long Short-Term Memory network, developed in Python, accurately forecasts blood sugar levels on Ohio University’s OhioT1DM patient dataset and the UVa/Padova simulation’s data for a 30 minute-interval. An algorithm then utilizes the predictions to calculate optimal insulin and glucagon doses using metabolization formulas. To ensure system security, data is transmitted through a cloud-based MQ Telemetry Transport server and secured with industry-standard authentication and encryption methods. Finally, a microcontroller-based prototype accurately dispenses insulin and glucagon doses. The system kept in-silico patients at optimal levels for 38% longer and reduced dangerous levels by 22% compared to conventional controllers on an FDA-approved preclinical trial alternative simulation. By addressing both hypo and hyperglycemia, this real-time medical device can be a transformative tool for individuals with diabetes, enabling them to live healthier and more fulfilling lives.
BRI1-mediated removal of seed coat H3K27me3 marks is a brassinosteroid-independent process
Authors: Pankaj Rishabh , Lima Rita B. , Luo Guan-Yu , Ehlert Sinah , del Toro-de León Gerardo , Bente Heinrich , Finger Pascal , Sato Hikaru , Figueiredo Duarte D.
Published: December 2023

Seed development in angiosperms starts with double fertilization, where two paternal sperm cells fertilize the maternal gametes. This leads to the formation of the embryo and of the endosperm. These fertilization products are enveloped by the maternally-derived seed coat, the development of which is inhibited prior to fertilization by the Polycomb Repressive Complex 2 (PRC2). This complex deposits the repressive histone mark H3K27me3, whose removal is necessary for seed coat formation. Here, we show that JUMONJI-type (JMJ) histone demethylases are expressed in the seed coats ofArabidopsis thaliana(Arabidopsis) and are necessary for its formation. We propose that JMJ activity is coupled to Brassinosteroid (BR) function, as BR effectors physically recruit JMJ proteins to target loci. Consistent with this, we show that loss of BR biosynthesis and signaling leads to seed coat defects, and that loss of the main BR receptor, BRI1, results in H3K27me3 hypermethylation. Moreover, our data points to BRI1 mediating H3K27me3 removal independently of BRs, while a different receptor, BRL3, likely regulates seed coat formation in a BR-dependent manner. We thus propose a model where seed coat development relies on canonical and non-canonical functions of BR receptors.
Specific inhibition of α-synuclein oligomer generation and toxicity by the chaperone domain Bri2 BRICHOS
Authors: Adam Laurène , Kumar Rakesh , Arroyo-Garcia Luis Enrique , Molenkamp Willem Hendrik , Nowak Jan Stanislaw , Klute Hannah , Farzadfard Azad , Alkenayeh Rami , Nielsen Janni , Biverstål Henrik , Otzen Daniel E. , Johansson Jan , Abelein Axel
Published: December 2023

Understanding the molecular mechanisms of neurodegenerative diseases and finding efficient treatments have been major priorities for research and society, yet new therapeutic approaches remain essential to face the socio-economic burden caused by these devastating diseases. Protein misfolding and aggregation are involved in several neurodegenerative disorders, such as α-synuclein (αSyn) implicated in Parkinson’s disease. Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti-amyloid Bri2 BRICHOS domain, can be used to target αSyn-associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominately suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), in addition to fibril-end elongation. This mechanism implies a drastic decrease of the oligomer generation rate. Besides targeting secondary nucleation sites on the fibril surface, BRICHOS directly binds to oligomeric αSyn species. Further, usingex vivoexperiments, BRICHOS effectively diminishes αSyn fibril-related toxicity to hippocampal electrophysiology. Our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to αSyn neurotoxicity and have the potential as protein-based treatments against neurodegenerative disorders.
Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma
Authors: Roux Cecilia , Hamer Sian , Shea Abigail , Chen Emilia , Sadr Ayeh Sadat , English Christie , Sahoo Sarthak , Allo Anido Alejandro , Che Harvey , Chesler Louis , Jolly Mohit Kumar , Morgan Michael David , Bruna Alejandra
Published: December 2023

In paediatric cancers like neuroblastoma, limited genetic diversity emphasizes the role of phenotypic heterogeneity in driving malignancy. We investigated this phenomenon using experimental evolution and single-cell techniques in neuroblastoma preclinical models. Our findings reveal that neuroblastoma cells navigate multistable phenotypic landscapes, named plasticity systems. These finely regulate their topology and dynamics enabling tolerance, persistence, and regrowth in response to treatment. While preferential killing of adrenergic cells (ADRN), notably under cisplatin treatment, enriches drug-tolerant persister (DTP) populations with mesenchymal (MES) properties, we also observed phenotypic transitions contributing to DTP entry and exit. Additionally, single-cell-derived clone experiments unveiled a spectrum of heritable plasticity traits linked to functional properties, influencing DTP behaviour. Mathematical modelling supports the critical role of all cell phenotypes in evolutionary adaptation. Collectively, our study depicts plasticity systems as key early cancer drivers of adaptive evolution in neuroblastoma through regulating the multistability and dynamics of phenotypic landscapes. These insights underscore the necessity of decoding plasticity for advancing long-term therapeutic effectiveness.
Nanos2+cells give rise to germline and somatic lineages in the sea anemoneNematostella vectensis
Authors: Denner Andreas , Steger Julia , Ries Alexander , Morozova-Link Elizaveta , Ritter Josefine , Haas Franziska , Cole Alison G. , Technau Ulrich
Published: December 2023

In all animals, stem cell populations of varying potency facilitate regeneration and tissue homeostasis. Notably, germline stem cells in both vertebrates and invertebrates express highly conserved RNA-binding proteins, such asnanos, vasaandpiwi. Interestingly, in animals, which are capable of whole-body regeneration, such as poriferans, hydrozoans and planarians, these genes are also expressed in somatic multi- and pluripotent stem cells, which led to the proposal that they had an ancestral role in all stem cells. While multi- and pluripotent interstitial stem cells have been identified in hydrozoans, they have not unambiguously been demonstrated in other cnidarian classes. Therefore, it is currently unclear if these stem cell systems share a common evolutionary origin or have been adapted individually in different lineages as homoplasy. We therefore aimed to characterize stem cells expressing conserved stem cell marker genes in the sea anemoneNematostella vectensis, to gain insight of shared traits governing the regulation of this enigmatic cell type. Through single cell transcriptomics, we identify cell populations expressing the germline associated markerspiwi1andnanos2in the soma and germline. Transgenic reporter genes reveal a lineage giving rise to somatic cells, consistent with a role as a multipotent stem cell population. Cell proliferation studies show that a fraction ofnanos2+reporter cells are cycling and CRISPR/Cas9 mediated gene knockout show thatnanos2+progenitor cells are indispensable for male and female germline maintenance inNematostella. This suggestsnanosandpiwigenes have a conserved role in somatic and germline stem cells in cnidarians.
An improved haplotype resolved genome reveals more rice genes
Authors: Abdullah Muhammad , Furtado Agnelo , Masouleh Ardashir Kharabian , Okemo Pauline , Henry Robert
Published: December 2023

The rice reference genome (Oryza sativa ssp. japonica cv. Nipponbare) has been an important resource in plant science. We now report an improved and haplotype resolved genome sequence based upon more accurate sequencing technology. This improved assembly includes regions missing in earlier genomes sequences and the annotation of more than 3,000 new genes due to greater sequence accuracy.
Application of slow-controlled release fertilizer coordinates the carbon flow in carbon-nitrogen metabolism to effect rice quality
Authors: Jiang Zhengrong , Chen Qiuli , Liu Dun , Tao Weike , Gao Shen , Li Jiaqi , Lin Chunhao , Zhu Meichen , Ding Yanfeng , Li Weiwei , Li Ganghua , Sakr Soulaiman , Xue Lihong
Published: December 2023

Slow-controlled release fertilizers are experiencing a popularity in rice cultivation due to their effectiveness in yield and quality with low environmental costs. However, the underlying mechanism by which these fertilizers regulate grain quality remains inadequately understood. This study investigated the effects of five fertilizer management practices on rice quality in a two-year field experiment: CK, conventional fertilization, and four applications of slow-controlled release fertilizer (UF, urea formaldehyde; SCU, sulfur-coated urea; PCU, polymer-coated urea; BBF, controlled-release bulk blending fertilizer). In 2020 and 2021, the yields of UF and SCU groups showed significant decreases when compared to conventional fertilization, accompanied by a decline in nutritional quality. Additionally, PCU group exhibited poorer cooking and eating qualities. However, BBF group achieved increases in both yield (10.8 t hm−2and 11.0 t hm−2) and grain quality reaching the level of CK group. The sufficient nitrogen supply in both the PCU and BBF groups during the grain-filling stage led to a greater capacity for the accumulation of proteins and amino acids in the PCU group compared to starch accumulation. Intriguingly, BBF group showed better carbon-nitrogen metabolism than that of PCU group. The optimal nitrogen supply present in BBF group suitable boosted the synthesis of amino acids involved in the glycolysis/ tricarboxylic acid cycle, thereby effectively coordinating carbon-nitrogen metabolism. The application of the new slow-controlled release fertilizer, BBF, is advantageous in regulating the carbon flow in the carbon-nitrogen metabolism to enhance rice quality.
dAux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to α-synuclein degradation
Authors: Zhang Shiping , Wang Linfang , Yi Shuanglong , Tsai Yu-ting , Wang Honglei , Li Shuhua , Wang Ruiqi , Liu Yang , Yan Wei , Liu Chang , He Kai-Wen , Ho Margaret S.
Published: December 2023

Glia serve as double-edged swords to modulate neuropathology in Parkinson’s disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating α-synuclein (α-syn) inclusions, remains elusive. Here we present evidence that dAuxilin (dAux), theDrosophilahomolog of the PD risk factor Cyclin G-associated kinase (GAK), regulates the lysosomal degradation of α-syn in glia. Lack of glial Gak/dAux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including α-syn. Whereas α-syn accumulated prominently in lysosomes devoid of glial dAux, levels of injected α-syn preformed fibrils also further enhanced in the absence of microglial Gak. Mechanistically, dAux mediates phosphorylation at the serine 543 of Vha44, the V1C subunit of the vacuolar H+-ATPase (V-ATPase), regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial dAux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling the V-ATPase assembly for lysosomal α-syn degradation in glia. Targeting the clearance of glial α-syn inclusions via this lysosomal pathway could potentially be a therapeutical approach to ameliorate the disease progression in PD.
Development of Pial Collaterals by Extension of Pre-existing Artery Tips
Authors: Kumar Suraj , Ghosh Swarnadip , Shanavas Niloufer , Sivaramakrishnan Vinayak , Dwari Manish , Das Soumyashree
Published: December 2023

Pial collaterals provide protection from ischemic damage and improve prognosis of stroke patients. The origin or precise sequence of events underlying pial collateral development is unclear and has prevented clinicians from adapting new vascularization and regeneration therapies. We use genetic lineage tracing and intra-vital imaging of mouse brains at cellular resolution to show that during embryogenesis, pial collateral arteries develop from extension and anastomoses of pre-existing artery tips, in a VegfR2 dependent manner. This process of artery tip extension occurs on pre-determined microvascular tracks. Our data demonstrate that an arterial receptor, Cxcr4, earlier shown to drive artery cell migration and coronary collateral development, is dispensable for formation and maintenance of pial collateral arteries. Our study shows that collateral arteries of the brain are built by a unique mechanism, distinct from that of the heart.
Developmental arcs of plasticity in whole movement repertoires of a clonal fish
Authors: Ehlman Sean M. , Scherer Ulrike , Bierbach David , Stärk Luka , Beese Marvin , Wolf Max
Published: December 2023

Developmental plasticity at the behavioral repertoire level allows animals to incrementally adjust their behavioral phenotypes to match their environments through ontogeny, serving as a lynchpin between ecological factors that cue phenotypic adjustments and evolutionary forces that select upon emergent phenotypic variation. Quantifying the continuous arcs of plasticity throughout animals’ development, however, has often been prohibitively challenging. Here, we leverage recent advancements in high-resolution behavioral tracking and analysis to (i) track the behavior of 45 genetically identical fish clones (Poecilia formosa) reared in near-identical environments during their first four weeks of life at 0.2 s resolution and (ii) quantify the continuous arcs of plasticity across entire behavioral repertoires through development. Doing so, we are able to test one of the most fundamental theoretical predictions from Bayesian models of development that in stable (but initially unknown) environments, behavioral plasticity should gradually decrease from a maximum at the beginning of life. Using two approaches to measure plasticity across ontogeny, we first quantify plasticity in individual behavioral metrics before also developing a novel whole-repertoire approach that calculates plasticity as the degree of ‘behavioral entropy’ across a multi-dimensional behavioral phenotype space. We robustly find – despite experimentally matching as best as possible the assumptions of models that predict decreasing plasticity – a ∼two-week initial increase in plasticity in movement behaviors before plasticity subsequently decreased. Our results challenge a common intuition about the optimal developmental course of plasticity through early ontogeny, thereby also demonstrating the value of long-term behavioral tracking approaches for testing fundamental predictions on phenotypic development.

Significance statement

Behavioral plasticity across development may help animals adjust to uncertainty in moderately unpredictable environments. In stable environments, developing animals should gradually decrease this uncertainty through ontogeny, becoming less sensitive to incoming information (and thus less behaviorally plastic) as they age. This intuitive expectation of ‘old dog’ inflexibility to ‘new tricks’, however, has not been adequately tested with the long-term, highresolution datasets that would be ideal. Here, we achieve such a test and emphasize the significance of this study in (1) providing a novel method for quantifying multi-dimensional behavioral plasticity continuously across long-term, high-resolution behavioral timeseries and in (2) testing fundamental theory that links the temporal patterning of environmental conditions to evolved patterns of behavioral plasticity across development.
Clustering of HR+/HER2- breast cancer in an Asian cohort is driven by immune phenotypes
Authors: Pan Jia-Wern , Ragu Mohana , Chan Wei-Qin , Hasan Siti Norhidayu , Islam Tania , Teoh Li-Ying , Jamaris Suniza , See Mee-Hoong , Yip Cheng-Har , Rajadurai Pathmanathan , Looi Lai-Meng , Mohd Taib Nur Aishah , Rueda Oscar M. , Caldas Carlos , Chin Suet-Feung , Lim Joanna , Teo Soo Hwang
Published: December 2023

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR+/HER2-breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR+/HER2-breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR+/HER2-samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.
ganon2: up-to-date and scalable metagenomics analysis
Authors: Piro Vitor C. , Reinert Knut
Published: December 2023

The fast growth of public genomic sequence repositories greatly contributes to the success of metagenomics. However, they are growing at a faster pace than the computational resources to use them. This challenges current methods, which struggle to take full advantage of the massive and fast data generation. We propose a generational leap in performance and usability with ganon2, a sequence classification method that performs taxonomic binning and profiling for metagenomic analysis. It indexes large datasets with a small memory foot-print, maintaining fast, sensitive, and precise classification results. Based on the full NCBI RefSeq and its subsets, ganon2 indices are on average 50% smaller than state-of-the-art methods. Using 16 simulated samples from various studies, including the CAMI 1+2 challenge, ganon2 achieved up to 0.15 higher median F1-Score in taxonomic binning. In profiling, improvements in the F1-Score median are up to 0.35, keeping a balanced L1-norm error in the abundance estimation. ganon2 is one of the fastest tools evaluated and enables the use of larger, more diverse, and up-to-date reference sets in daily microbiome analysis, improving the resolution of results. The code is open-source and available with documentation athttps://github.com/pirovc/ganon.
5,6-dimethylxanthenone-4-acetic acid (DMXAA), a Partial STING Agonist, Competes for Human STING Activation
Authors: Temizoz Burcu , Shibahara Takayuki , Hioki Kou , Hayashi Tomoya , Kobiyama Kouji , Jann Lee Michelle Sue , Surucu Naz , Sag Erdal , Kumanogoh Atsushi , Yamamoto Masahiro , Gursel Mayda , Ozen Seza , Kuroda Etsushi , Coban Cevayir , Ishii Ken J.
Published: December 2023

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA can not fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative—3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xhanthen-9one (HHMX)—that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced bySTINGgain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) inin vitroexperiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.
Influence of plant defense signaling and innate insect metabolic differences to the overall performance of fall armyworm (Spodoptera frugiperda) corn and rice strains on maize as a host
Authors: Israni Bhawana , Raguschke Bettina , Reichelt Michael , Gershenzon Jonathan , Vassão Daniel Giddings
Published: December 2023

The fall armyworm (FAW,Spodoptera frugiperda) is a well-known crop pest that feeds mainly on grasses. Separate strains are known to infest maize (corn) and rice that show varying degrees of developmental and metabolic differences, as well as reproductive isolation. Here we show that the greater performance of the corn compared to the rice strain on maize leaves may be explained by several factors. Maize plants respond to herbivory by the rice strain with greater levels of defense hormone signaling and greater accumulation of defensive benzoxazinoids. Moreover, measurements of the activity of a glucosyltransferase involved in benzoxazinoid metabolism and the transcript levels of the encoding gene revealed that the corn strain had higher benzoxazinoid detoxification potential than the rice strain. The two strains also exhibit constitutive differences in the expression of an alternate variant, with potential consequences for differential regulation of the glucosylation activity. These factors may account for the better performance of corn strain larvae on maize leaves, perhaps in combination with the other differences we found in maize defense metabolites after FAW herbivory by untargeted metabolomics.
A bovine pulmosphere model and multiomics analyses identify a signature of early host response toMycobacterium tuberculosisinfection
Authors: Bhaskar Vinay , Kumar Rishi , Praharaj Manas Ranjan , Gandham Sripratyusha , Maity Hemanta Kumar , Sarkar Uttam , Dey Bappaditya
Published: December 2023

Interactions between the tubercle bacilli and lung cells during the early stages of tuberculosis (TB) are crucial for disease outcomes. Conventional 2D cell culture inadequately replicates the multicellular complexity of lungs. We introduce a 3D pulmosphere model forMycobacterium tuberculosisinfection in bovine systems, demonstrating through comprehensive transcriptome and proteome analyses that these 3D structures closely replicate the diverse cell populations and abundant extracellular matrix proteins, emphasizing their similarity to thein vivopulmonary environment. While both avirulent BCG and virulentM. tuberculosis-infected pulmospheres exhibit commonalities in the upregulation of several host signaling pathways, distinct features such as upregulation of ECM receptors, neutrophil chemotaxis, interferon signaling, and RIG-1 signaling pathways characterize the unique early response to virulentM. tuberculosis. Moreover, a signature of seven genes/proteins, including IRF1, CCL5, CXCL8, CXCL10, ICAM1, COL17A1, and CFB, emerges as indicative of the early host response toM. tuberculosisinfection. Overall, this study presents a superiorex vivomulticellular bovine pulmosphere TB model, with implications for discovering disease biomarkers, enabling high-throughput drug screening, and improving TB control strategies.
CtBP2 triggers CCN1-induced metastatic dissemination of osteosarcoma cells in a non-hypoxic microenvironment
Authors: Patria Laura Di , Habel Nadia , Olaso Robert , Stefanovska Bojana , Fromigue Olivia
Published: December 2023

Osteosarcoma is the most prevalent pediatric solid bone tumor. These tumors are highly metastatic and frequently develop resistance to chemotherapy, leading to poor survival rate for patients. We found that C-terminal Binding Protein 2 (CtBP2) and Cysteine-rich protein 61 (CYR61/CCN1) expression level correlated positively in a panel of cell lines.In silicoanalysis of protein-protein interaction network revealed a link with stemness markers. We confirmed that CtBP2 influences stemness markers expression, cell clonogenicity, cell migration, matrix metalloproteinase activity and cell invasion. Surprisingly, using syngeneic tumor cells graft models, while induction of CtBP2 expression correlated with the metastatic dissemination process, it occurred only at the invasive front. Hypoxic conditions in central tumor region interfered with CtBP2 induction. Globally, we identify for the first time that CtBP2 is a required inducing factor in the CYR61-related metastatic progression of osteosarcoma. Moreover, we demonstrate that while CtBP2 is a downstream transcriptional target of CYR61 signaling cascade, it occurs only under non-hypoxic conditions. The present study suggests that CtBP2 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma.
The interacting effects of climate and land-use/land-cover changes on ecological communities
Authors: Thompson Kimberly L. , Chase Jonathan M. , Remelgado Ruben , Meyer Carsten
Published: December 2023

Human activities continue to create land-use/land-cover (LULC) change across the Earth’s surface, and together with climate change, are major drivers of changes in biodiversity through time. However, the impacts of these spatiotemporally variable drivers on biodiversity change can be complex. We examined the effects of interactions between climate and LULC change on bird communities across the continental United States over nearly three decades. We analyzed temperature and precipitation data alongside data on tree-canopy, cropland, urban, and surface-water cover to understand how climate/LULC-change interactions influence species richness and abundance. Our results revealed stable or increasing trends in species richness, but a decline in overall abundance primarily from common species and a consequent increase in aspects of evenness of communities. We found that areas experiencing warming and drying climates exhibited increased species richness and slower declines in abundance. However, impacts of LULC change had contrasting effects on richness and abundance. Areas that experienced increasing tree-canopy cover over time had increasing trends in species richness, but exacerbated declines in abundance. On the other hand, areas with increasing cropland had moderated abundance declines, but more declining trends in richness. Finally, we found that the effects of climate/LULC-change interactions varied across the range of each pressure. While some interactions support a dominant role of climate change in structuring communities, others indicate that LULC change can mitigate or exacerbate the impact of climate change on biodiversity. Overall, our results highlight the importance of considering the direction and magnitude of each driver when assessing how climate and LULC interactions shape ecological communities.
Heterogeneous lineage-specific arginine deiminase expression within dental microbiome species
Authors: Mann Allison E. , Chakraborty Brinta , O’Connell Lauren M. , Nascimento Marcelle M. , Burne Robert A. , Richards Vincent P.
Published: December 2023

Arginine catabolism by the bacterial arginine deiminase system (ADS) has anticariogenic properties through the production of ammonia, which modulates the pH of the oral environment. Given the potential protective capacity of the ADS pathway, the exploitation of ADS competent oral microbes through pre- or probiotic applications is a promising therapeutic target to prevent tooth decay. To date, most investigations of the ADS in the oral cavity and its relation to caries have focused on indirect measures of activity, or on specific bacterial groups, yet the pervasiveness and rate of expression of the ADS operon in diverse mixed microbial communities in oral health and disease remains an open question. Here we use a multivariate approach, combining ultra-deep metatranscriptomic sequencing with paired metataxonomic andin vitrocitrulline quantification to characterize the microbial community and ADS operon expression in healthy and late-stage cavitated teeth. While ADS activity is higher in healthy teeth, we identify multiple bacterial lineages with upregulated ADS activity on cavitated teeth that are distinct from those found on healthy teeth using both reference-based mapping anddenovoassembly methods. Our dual metataxonomic and metatranscriptomic approach demonstrates the importance of species abundance for gene expression data interpretation and that patterns of differential expression can be skewed by low abundance groups. Finally, we identify several potential candidate probiotic bacterial lineages within species that may be useful therapeutic targets for the prevention of tooth decay and propose that the development of a strain-specific, mixed-microbial probiotic may be a beneficial approach given the heterogeneity of taxa identified here across health groups.

IMPORTANCE

Tooth decay is the most common preventable chronic disease, globally affecting more than two billion people. The development of caries on teeth is primarily a consequence of acid production by cariogenic bacteria that inhabit the plaque microbiome. Other bacterial strains in the oral cavity may suppress or prevent tooth decay by producing ammonia as a byproduct of the arginine deiminase metabolic pathway, increasing the pH of the plaque biofilm. While the benefits of arginine metabolism on oral health have been extensively documented in specific bacterial groups, the prevalence and consistency of ADS activity among oral bacteria in a community context remains an open question. In the current study, we use a multi-omics approach to document the pervasiveness of expression of the ADS operon in both health and disease to better understand the conditions in which ADS activity may prevent tooth decay.
Neurophysiological correlates of short-term recognition of sounds: Insights from magnetoencephalography
Authors: Serra E. , Lumaca M. , Brattico E. , Vuust P. , Kringelbach M. L. , Bonetti L.
Published: December 2023

Understanding the brain’s dynamic retrieval and updating of encoded information is a key focus in memory research. This study employed a same versus different auditory paradigm to investigate short-term auditory recognition within a predictive coding (PC) framework, concerning the perceptual interplay between experience-informed predictions and incoming sensory information. Using magnetoencephalography (MEG), we captured the neurophysiological correlates associated with a single-sound, short-term memory task. Twenty-six healthy participants were tasked with recognizing whether presented sounds were same or different compared to strings of standard stimuli. To prompt conscious memory retention, a white noise interlude separated these sounds from the standards. MEG sensor-level results revealed that recognition of same sounds elicited two significantly stronger negative components of the event-related field compared to different sounds. The first one was the N1, peaking 100ms post-sound onset, while the second one corresponded to a slower negative component arising between 300 and 600ms after sound onset. This effect was observed in several significant clusters of MEG sensors, especially temporal and parietal regions of the scalp. Conversely, different sounds produced scattered and smaller clusters of stronger activity than same sounds, peaking later than 600ms after sound onset. Source reconstruction using beamforming algorithms revealed the involvement of auditory cortices, hippocampus, and cingulate gyrus in both conditions. Overall, the results are coherent with PC principles and previous results on the brain mechanisms underlying auditory recognition, highlighting the relevance of early and later negative brain responses for successful prediction of previously listened sounds in the context of conscious short-term memory.
Paternally-induced environmental programming of placenta development, offspring birth weight and health phenotypes in a mouse model
Authors: Chen Elaine , da Cruz Raquel Santana , Nascimento Aallya , Joshi Meghali , Pereira Duane Gischewski , Dominguez Odalys , Fernandes Gabriela , Smith Megan , Paiva Sara P.C. , de Assis Sonia
Published: December 2023

Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male offspring developing both glucose intolerance and insulin resistance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.
Large Quantities of Bacterial DNA and Protein in Common Dietary Protein Source Used in Microbiome Studies
Authors: Bartlett Alexandria , Blakeley-Ruiz J. Alfredo , Richie Tanner , Theriot Casey M. , Kleiner Manuel
Published: December 2023

Diet has been shown to greatly impact the intestinal microbiota. To understand the role of individual dietary components, defined diets with purified components are frequently used in diet-microbiota studies. Many of the frequently used defined diets use purified casein as the protein source. Previous work indicated that this casein contains microbial DNA potentially impacting results of microbiome studies. Other diet-based microbially derived molecules that may impact microbiome measurements, such as proteins detected by metaproteomics, have not been determined for casein. Additionally, other protein sources used in microbiome studies have not been characterized for their microbial content. We used metagenomics and metaproteomics to identify and quantify microbial DNA and protein in a casein-based defined diet to better understand potential impacts on metagenomic and metaproteomic microbiome studies. We further tested six additional defined diets with purified protein sources with an integrated metagenomic-metaproteomic approach and show that contaminating microbial protein is unique to casein within the tested set as microbial protein was not identified in diets with other protein sources. We also illustrate the contribution of diet-derived microbial protein in diet-microbiota studies by metaproteomic analysis of stool samples from germ-free mice (GF) and mice with a conventional microbiota (CV) following consumption of diets with casein and non-casein protein. This study highlights a potentially confounding factor in diet-microbiota studies that must be considered through evaluation of the diet itself within a given study.

Importance

Many diets used in diet-microbiota studies use casein as the source of dietary protein. We found large quantities of microbial DNA and protein in casein-based diets. This microbial DNA and protein are resilient to digestion as it is present in fecal samples of mice consuming casein-based diets. This contribution of diet-derived microbial DNA and protein to microbiota measurements may influence results and conclusions and must therefore be considered in diet-microbiota studies. We tested additional dietary protein sources and did not detect microbial DNA or protein. Our findings highlight the necessity of evaluating diet samples in diet-microbiota studies to ensure that potential microbial content of the diet can be accounted for in microbiome measurements.
Physical constraints during Snowball Earth drive the evolution of multicellularity
Authors: Crockett William W. , Shaw Jack O. , Simpson Carl , Kempes Christopher P.
Published: December 2023

Molecular and fossil evidence suggest that complex eukaryotic multicellularity evolved during the late Neoproterozoic era, coincident with Snowball Earth glaciations, where ice sheets covered most of the globe. During this period, environmental conditions—such as sea water temperature and the availability of photosynthetically active light in the oceans—likely changed dramatically. Such changes would have had significant effects on both resource availability and optimal phenotypes. Here, we construct and apply mechanistic models to explore (i) how environmental changes during Snowball Earth and biophysical constraints generated selective pressures and (ii) how these pressures may have had differential effects on organisms with different forms of biological organization. By testing a series of alternate—and commonly debated—hypotheses, we demonstrate how multicellularity was likely acquired differently in eukaryotes and prokaryotes due to selective differences in the biophysical and metabolic regimes they experience: decreasing temperatures and resource-availability instigated by the onset of glaciations generated selective pressures towards smaller sizes in organisms in a diffusive regime and towards larger sizes in motile heterotrophs. These results suggest that changing environmental conditions during Snowball Earth glaciations gave multicellular eukaryotes an evolutionary advantage, paving the way for the complex multicellular lineages that followed.