bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the generation time for influenza transmission using household data in the United States
Authors: Chan Louis Yat Hin , Morris Sinead E. , Stockwell Melissa S. , Bowman Natalie M. , Asturias Edwin , Rao Suchitra , Lutrick Karen , Ellingson Katherine D. , Nguyen Huong Q. , Maldonado Yvonne , McLaren Son H. , Sano Ellen , Biddle Jessica E. , Smith-Jeffcoat Sarah E. , Biggerstaff Matthew , Rolfes Melissa A. , Talbot H. Keipp , Grijalva Carlos G. , Borchering Rebecca K. , Mellis Alexandra M. ,   RVTN-Sentinel Study Group
Published: August 2024

The generation time, representing the interval between infections in primary and secondary cases, is essential for understanding and predicting the transmission dynamics of seasonal influenza, including the real-time effective reproduction number (Rt). However, comprehensive generation time estimates for seasonal influenza, especially post the 2009 influenza pandemic, are lacking. We estimated the generation time utilizing data from a 7-site case-ascertained household study in the United States over two influenza seasons, 2021/2022 and 2022/2023. More than 200 individuals who tested positive for influenza and their household contacts were enrolled within 7 days of the first illness in the household. All participants were prospectively followed for 10 days completing daily symptom diaries and collecting nasal swabs, which were tested for influenza via RT-PCR. We analyzed these data by modifying a previously published Bayesian data augmentation approach that imputes infection times of cases to obtain both intrinsic (assuming no susceptible depletion) and realized (observed within household) generation times. We assessed the robustness of the generation time estimate by varying the incubation period, and generated estimates of the proportion of transmission before symptomatic onset, infectious period, and latent period. We estimated a mean intrinsic generation time of 3.2 (95% credible interval, CrI: 2.9-3.6) days, with a realized household generation time of 2.8 (95% CrI: 2.7-3.0) days. The generation time exhibited limited sensitivity to incubation period variation. Estimates of the proportion of transmission that occurred before symptom onset, the infectious period, and the latent period were sensitive to variation in incubation periods. Our study contributes to the ongoing efforts to refine estimates of the generation time for influenza. Our estimates, derived from recent data following the COVID-19 pandemic, are consistent with previous pre-pandemic estimates, and will be incorporated into real-time Rt estimation efforts.
Assessing early detection ability through spatial arrangements in environmental surveillance for poliovirus: a simulation-based study
Authors: Asakura Toshiaki R. , O'Reilly Kathleen M
Published: August 2024

Detecting the circulation of poliovirus in its early stages is paramount for swift public health action. Environmental surveillance (ES) is the testing of sewage samples for the presence of poliovirus and has the potential to enhance early detection capabilities. However, the establishment and maintenance of ES sites incur costs and necessitate human resources, underscoring the consideration of ES scale and site selection. Here, we aim to assess the early detection ability of ES by varying the number and location of ES sites using the simulation-based approach. We developed a stochastic meta-population model among unimmunised children aged under 5 years old and used geographic and demographic characteristics of South Africa as a case study of a non-endemic country, assuming a single introduction of wild poliovirus serotype 1. We constructed six scenarios by combining three importation risk distributions (predicated on population size, approximations of international inbound travel volume and border crossing volume) with two ES site layout strategies: one proportionate to population size and another focusing on importation risk via land border crossings. We showed that a modest number of strategically positioned ES sites can achieve a high early detection ability when assumed importation risks were geographically confined. In contrast, when importation risks were dispersed, the effectiveness of ES was diminished. Our sensitivity analyses suggested that the strategy to implement ES across large areas with low sampling frequency consistently resulted in a better early detection ability against various importation scenarios than one to implement ES in limited areas with high sampling frequency. Although we acknowledge the challenges of translating our simulated outcomes for real-world situations, our study has implications for deciding the scale and site selection of ES.
Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces
Authors: Yamamoto Erin A. , Koike Seiji , Wong Caitlyn , Dennis Laura E. , Luther Madison N. , Scatena Avery , Khambadkone Seva , Iliff Jeffrey J. , Lim Miranda M. , Levendovszky Swati R. , Elliott Jonathan E. , Barisano Giuseppe , Müller-Oehring Eva M. , Morales Angelica M. , Baker Fiona C. , Nagel Bonnie J. , Piantino Juan
Published: August 2024

Background and Purpose

An association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI).

Materials and Methods

This analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3).

Results

On average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a person’s BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a person’s average BMI was associated with a 0.021 mm3/cm3increase in MV-PVS volume (p<0.001).

Conclusion

This longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a person’s mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.
Dysregulated Cholesterol Metabolism with Anomalous PI3K/Akt/mTOR pathway Predicts Poor Carboplatin Response in High Grade Serous Ovarian Cancer
Authors: Mahapatra Elizabeth , Saha Arka , Nag Niraj , Gope Animesh , Thakur Debanjan , Vernekar Manisha , Chakrabarti Jayanta , Basu Mukta , Pal Amit , Sengupta Sanghamitra , Mukherjee Sutapa
Published: August 2024

Rapidly escalating High-Grade Serous Ovarian Cancer (HGSOC) incidences, relapse, and mortalities result from failed carboplatin therapy. In this regard, reprogrammed cholesterol metabolism arising from deregulated PI3K/Akt/mTOR signaling aggravates HGSOCs to evade carboplatin. Therefore, we designed a pilot study to ascertain their clinical relevance in determining the carboplatin response of HGSOC tumors.

Non-NACT HGSOC (n=31) subjects were classified into optimum, borderline, and high cohorts based on blood cholesterol levels which positively correlated with their relative tissue cholesterol content. TCGA database showed that mutations in specific PI3K/Akt/mTOR candidates including cholesterol metabolism regulators (SREBP1, SREBP2, SRB-1, STAR, HMGCR) and prosurvival effectors (Akt, mTOR, p70S6K, P38MAPK, HIF-1α, COX2, VEGF) are characteristic to HGSOCs. We discerned dysregulations (expressions/activity) in SREBP2, SRB-1, STAR, and HMGCR along with Akt/pAktThr308, mTOR/pmTORSer2448, p70S6K, P38MAPK, HIF-1α, COX2, and VEGF proteins within high cohort. Herein, poorly differentiated tumors with escalated HMGCR activity overproduced cholesterol thereby rigidifying their cell membranes to restrain Pt-DNA adduct retention. With a carboplatin IC50of 5.23µM, high cohort tumors generated lesser drug-induced ROS and espoused unaltered mitochondrial-membrane depolarization and DNA damage profiles. These parameters were moderately altered in the borderline-HGSOC cohort possessing relatively less rigid membranes and a lower carboplatin IC50of 2.78µM. Accordingly, borderline and high cohorts were respectively denoted as intermediate responder and non-responder of carboplatin. On the contrary, the cholesterol-deficient optimum cohort (IC50-1.59µM) with fluid membranes was a carboplatin responder group.

Our study established the candidature of abnormal cholesterol and PI3K/Akt/mTOR (protein-level) statuses as predictive markers to screen HGSOCs for carboplatin responses before therapy.
Manipulating rice canonical Gα and extra-large G protein subunits for improved agronomic traits
Authors: Cantos Christian F. , Assmann Sarah M.
Published: August 2024

Rice productivity is fundamentally linked to its architecture, governed by signaling networks including those based on heterotrimeric G proteins. In this study, we investigated the individual gene impacts and genetic interactions of the canonical Gα gene (RGA1), and the non-canonical extra-large Gα genes (OsXLG1, OsXLG3a, OsXLG3b, OsXLG4) in controlling plant architecture. We generatedOsXLGmutants using CRISPR/Cpf1 gene editing in Nipponbare (WT) andd1, a Nipponbare null mutant ofRGA1. We then phenotyped 25 different genotypes in the greenhouse for 19 different agronomic traits. In wild type (WT), mutations inRGA1,OsXLG3a,OsXLG3b, orOsXLG4, as well as any combination of Gα genes, resulted in a shorter stature, a desirable trait. Mutations inOsXLG1andOsXLG4increased the number of spikelets and grains per panicle, showcasing advantageous traits that led to higher yield. Mutations inOsXLG3a,OsXLG3b, any combination ofOsXLGs, or anyOsXLGcombined with thed1mutation, reduced seed production and yield. Flag leaf width was the only trait influenced solely by RGA1.RGA1transcript abundance in theosxlgmutants was positively correlated with height, culm length, panicle exsertion, and harvest index, implicating OsXLG regulation ofRGA1expression as an underlying mechanism. Overall, increasedRGA1expression is correlated with more favorable reproductive traits but less favorable vegetative traits. Our study reveals the complex interaction of RGA1 and OsXLGs within the signaling networks that shape rice architecture, from vegetative to post-harvest stages. Our results suggest modulation ofRGA1, OsXLG1, OsXLG3a,orOsXLG4expression as strategies to enhance yield.
Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma
Authors: Yates Josephine , Mathey-Andrews Camille , Park Jihye , Garza Amanda , Gagné Andréanne , Hoffman Samantha , Bi Kevin , Titchen Breanna , Hennessey Connor , Remland Joshua , Shannon Erin , Camp Sabrina , Balamurali Siddhi , Cavale Shweta Kiran , Li Zhixin , Raghawan Akhouri Kishore , Kraft Agnieszka , Boland Genevieve , Aguirre Andrew J. , Sethi Nilay S. , Boeva Valentina , Van Allen Eliezer
Published: August 2024

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.
Suppression of glycolysis decreases sugar-induced cell death in Saccharomyces cerevisiae
Authors: Valiakhmetov Airat Ya.
Published: August 2024

Although 30 years have passed since the description of sugar-induced cell death (SICD), the specific molecular mechanism that triggers this process remains unclear. This paper attempts to shed light on the relationship between SICD and glucose catabolism. Deletion of the TPS1 gene resulted in a 44% suppression of SICD and a 75% reduction in the number of cells with excess ROS. The suppression was comparable to the suppression of SICD (38%) and ROS (71%) with deletion of the HXK2 gene. Since HXK2 is the first enzyme in the glycolytic pathway, the effect of two other key glycolytic enzymes on SICD was tested. Deletion of the TDH3 gene (glyceraldehyde-3-phosphate dehydrogenase) resulted in a 39% suppression of SICD and ROS by 48%. Inhibition of Tdh3p with 1 mM iodoacetamide also suppressed SICD by 67% and ROS by 58%. Deletion of the PFK1 (phosphofructokinase 1) gene resulted in a complete block of SICD (97%), but unexpectedly resulted in a significant increase in the number of cells with excess ROS. All strains tested (except ΔPFK1) showed increased glucose consumption, suggesting that redistribution of glucose fluxes between glycolysis and the pentose phosphate shunt is a key regulator of SICD development.
Species-specific interactions with apex carnivores yield unique benefits and burdens for mesocarnivores
Authors: Binder Wesley , Rabe Jack , Lowe Zoe , Scott Gordon , Lacey Claire , King Eliza , Stahler Daniel R. , Chakrabarti Stotra
Published: August 2024

Mesocarnivores must balance the negative (competition) and positive (carrion provisioning) effects of dominant apex carnivores to coexist in shared landscapes. How mesocarnivores navigate such top-down effects have typically been examined through a risk-reward lens. However, the risks accrued by mesocarnivores might not be even across all apex-mesocarnivore pairings in multi-carnivore systems, and instead can be mediated through species-specific interactions. Using remote-camera surveys from 2021-2023, we estimated apex (wolf, cougar) and mesocarnivore (red fox, coyote) spatial overlap, occupancy, temporal activity, and fine-scale behaviors in northern Yellowstone National Park, USA. Additionally, we monitored GPS-collared wolf and cougar predation from 2016-2023 and recorded red fox and coyote mortalities and scavenging events at these locations. Red foxes and coyotes were ubiquitous in our study area with high naive occupancy, despite abundant wolves and cougars. Coyote occupancy was positively associated with wolf occupancy, but exhibited marginal avoidance of cougars. Photo-detection probabilities of both mesocarnivores doubled in the 24 hours following apex carnivore detections, with the exception of coyotes following cougars. Overall latency of coyote detections was longest following cougar detections and shortest following wolves, while foxes exhibited no such difference. Further, coyotes were most active when wolves and cougars were collectively least active. Red foxes were nocturnal and appeared less sensitive to wolf and cougar activities, but avoided coyote peak times. Coyotes were more prevalent scavengers than red foxes at apex carnivore kills, but scavenging often had lethal consequences. We found that when wolves kill coyotes, it was typically when coyotes attempted to scavenge from wolf kills, while cougars killed and consumed coyotes as prey. Thus wolves act as competitors for coyotes, while cougars are both predators and competitors. This distinction possibly explains coyote avoidance of cougars but attraction to wolves. Mesocarnivores in Yellowstone leverage foraging benefits from associating with apex carnivores. However, these benefits are burdened by associating with wolves and cougars whose contrasting hunting modes and habitat preferences yield separate risks. Disparate costs to mesocarnivores contingent upon apex carnivore behavior offer novel insights into carnivore community ecology, and call for a more nuanced analysis of trophic interactions.
Brain and gonadal genes are differentially expressed inBicyclus anynanabutterfly larvae that learned a heritable novel food odor preference
Authors: Gowri V. , Tian Shen , Monteiro Antónia
Published: August 2024

Bicyclus anynanabutterfly larvae learn to prefer novel odors added to their plant food and transmit those learned preferences to the next generation. However, the molecular mechanisms regulating the inheritance of this acquired preference remain unexplored. Here we examined how larval diet affected gene expression patterns in the larval brain as well as the gonads of adults to explore a potential genetic basis of this inheritance. We fedB. anynanalarvae leaves coated with a novel banana odor (isoamyl acetate), or with a control solution, and performed five choice assays on individual larvae during their development to identify individuals that showed a majority preference for the treatment odor they were fed with. We then dissected male and female larval brains, adult spermatophores, or adult oocytes from those individuals, and profiled mRNA in all tissues and micro-RNA (miRNA) expression in oocytes only. Our results show that there are 83 differentially expressed genes (DEGs) across all tissue types in odor and control groups, of which 23 play roles in metabolism, transcription, response to various chemical stimuli, and olfactory pathways. MiRNAs did not differ in expression across diet treatments, but we discovered 57 novel miRNAs in oocytes. The DEGs in gonads are potential epigenetic factors that can regulate the inheritance of a learned odor preference. Still, caution is required as there was no overlap between DEGs across male and female brains, as well as male and female gonads.
Entropy production constrains information throughput in gene regulation
Authors: Gehri Maximilian , Stelzl Lukas , Koeppl Heinz
Published: August 2024

Biological signal processing typically requires energy, leading us to hypothesize that a cell’s information processing capacity is constrained by its energy dissipation. Signals and their processing mechanisms are often modeled using Markovian chemical reaction networks (CRNs). To enable rigorous analysis, we review and reformulate stochastic thermodynamics for open CRNs, utilizing Kurtz’s process-based formulation. In particular, we revisit the identification of the energy dissipation rate with the entropy production rate (EPR) at the non-equilibrium steady state (NESS). We also highlight potential inconsistencies in traditional formulations for generic Markov processes when applied to open CRNs, which may lead to erroneous conclusions about equilibrium, reversibility, and the EPR. Additionally, we review the concepts of mutual information (MI) and directed information (DI) between continuous-time trajectories of CRNs, which capture the transmission of spatiotemporal patterns. We generalize existing expressions for the MI, originally accounting for transmission between two species, to now include transmission between arbitrary subnetworks. A rigorous derivation of the DI between subnetworks is presented. Based on channel coding theorems for continuous-time channels with feedback, we argue that directed information is the appropriate metric for quantifying information throughput in cellular signal processing. To support our initial hypothesis within the context of gene regulation, we present two case studies involving small promoter models: a two-state nonequilibrium promoter and a three-state promoter featuring two activation levels. We provide analytical expressions of the directed information rate (DIR) and maximize them subject to an upper bound on the EPR. The maximum is shown to increase with the EPR.
Autism spectrum disorder common variants associated with regional lobe volume variations at birth: cross-sectional study in 273 European term neonates in developing Human Connectome Project
Authors: Le Hai , Fenchel Daphna , Dimitrakopoulou Konstantina , Patel Hamel , Curtis Charles , Cordero-Grande Lucilio , Edwards David A. , Hajnal Joseph , Tournier J-Donald , Deprez Maria , Cullen Harriet
Published: August 2024

Increasing lines of evidence suggest cerebral overgrowth in autism spectrum disorder (ASD) children in early life, but few studies have examined the effect of ASD common genetic variants on brain volumes in a general paediatric population. This study examined the association between ASD polygenic risk score (PRS) and volumes of the frontal, temporal, parietal, occipital, fronto-temporal and parieto-occipital lobes in 273 term-born infants of European ancestry in the developing Human Connectome Project. ASD PRS was positively associated with frontal (β = 0.027, pFDR = 0.04) and fronto-temporal (β = 0.024, pFDR = 0.01) volumes, but negatively with parietal (β = -0.037, pFDR = 0.04) and parieto-occipital (β = -0.033, pFDR = 0.01) volumes. This preliminary result suggests potential involvement of ASD common genetic variants in early structural variations linked to ASD.
Reassessing the management of uncomplicated urinary tract infection: A retrospective analysis using machine learning causal inference
Authors: Jones Noah C , Shih Ming-Chieh , Healey Elizabeth , Zhai Chen Wen , Advani Sonali D , Smith-McLallen Aaron , Sontag David , Kanjilal Sanjat
Published: August 2024

Background Uncomplicated urinary tract infection (UTI) is a common indication for outpatient antimicrobial therapy. National guidelines for the management of uncomplicated UTI were published by the Infectious Diseases Society of America in 2011, however it is not fully known the extent to which they align with current practices, patient diversity, and pathogen biology, all of which have evolved significantly in the time since their publication. Objective We aimed to re-evaluate efficacy and adverse events for first-line antibiotics (nitrofurantoin, and trimethoprim-sulfamethoxazole), versus second-line antibiotics (fluoroquinolones) and versus alternative agents (oral β-lactams) for uncomplicated UTI in contemporary clinical practice by applying machine learning algorithms to a large claims database formatted into the Observational Medical Outcomes Partnership (OMOP) common data model. Outcomes Our primary outcome was a composite endpoint for treatment failure, defined as outpatient or inpatient re-visit within 30 days for UTI, pyelonephritis or sepsis. Secondary outcomes were the risk of 4 common antibiotic-associated adverse events: gastrointestinal symptoms, rash, kidney injury and C. difficile infection. Statistical methods We adjusted for covariate-dependent censoring and treatment indication using a broad set of domain-expert derived features. Sensitivity analyses were conducted using OMOP-learn, an automated feature engineering package for OMOP datasets. Results Our study included 57,585 episodes of UTI from 49,037 patients. First-line antibiotics were prescribed in 35,018 (61%) episodes, second-line antibiotics were prescribed in 21,140 (37%) episodes and alternative antibiotics were prescribed in 1,427 (2%) episodes. After adjustment, patients receiving first-line therapies had an absolute risk difference of -2.1% [95% CI -2.9% to -1.6%] for having a revisit for UTI within 30 days of diagnosis relative to second-line antibiotics. First-line therapies had an absolute risk difference of -6.6% [95% CI -9.4% to -3.8%] for 30-day revisit compared to alternative β-lactam antibiotics. Differences in adverse events were clinically similar between first and second line agents, but lower for first-line agents relative to alternative antibiotics (-3.5% [95% CI -5.9% to -1.2%]). Results were similar for models built with OMOP-learn. Conclusion Our study provides support for the continued use of first-line antibiotics for the management of uncomplicated UTI. Our results also provide proof-of-principle that automated feature extraction methods for OMOP formatted data can emulate manually curated models, thereby promoting reproducibility and generalizability.
Berberine is a novel mitochondrial calcium uniporter (MCU) inhibitor that disrupts MCU-EMRE assembly
Authors: Zhao Haixin , Chen Siqi , Cao Nian , Wu Wenjun , Liu Guangqin , Gao Jun , Chen Jiayi , Li Ting , Lu Dingyi , Zeng Lingmin , Zhu Haizhen , Zhang Weina , Xia Qing , Li Teng , Zhou Tao , Zhang Xue-Min , Li Ai-Ling , Pan Xin
Published: August 2024

The mitochondrial calcium uniporter (MCU) complex mediates Ca2+entry into mitochondrial, which plays a crucial role in regulating cellular energy metabolism and apoptosis. Dysregulation of MCU is implicated in various diseases, such as neurodegenerative disorders, cardiac diseases and cancer. Despite its importance, developing specific and clinically viable MCU inhibitors has been challenging. Here, we identify Berberine, a well-established drug with a documented safety profile, as a potent MCU inhibitor through a virtual screening of an FDA-approved drug library. Berberine localizes within mitochondria and directly binds to the juxtamembrane loop domain of MCU. This binding disrupts the interaction of MCU with its essential regulator, EMRE, thereby inhibiting rapid Ca2+entry into the mitochondria. Notably, Berberine pretreatment reduces mitochondrial Ca2+overload and mitigate ischemia/reperfusion-induced myocardial injury in mice. Our findings establish Berberine as a potent MCU inhibitor, offering a safe therapeutic strategy for diseases associated with dysregulated mitochondrial calcium homeostasis.
The first assembled chromosome-level genome of an individual from Karnataka, India
Authors: mhatre Anisha , Chindarkar Yash , Ganesh Apoorva , Thakare Aditi , Mishra Prakruti , Ravindran Febina , Sharma Aditya , Srinivasan Subhashini , Choudhary Bibha
Published: August 2024

We present the first chromosome level assembled genome of an individual from Karnataka, India (KIn1) using de novo assembly of 12x coverage of PacBio HiFi reads generated in-house and 30x Hi-C data from the most ethnically related individual to KIn1 from Andhra Pradesh (HG04712) publicly available under International Genome Sample Resource (IGSR). We achieved an N50 of 137 Mb and an L50 of 9, which are very close to the maximum achievable N50 of 147 Mb and minimum achievable L50 of 8 respectively for human genomes. A comparison of the KIn1 assembly with assemblies of four other individual genomes from a Puerto Rican (PR1), Ashkenazi (Ash1), Hans Chinese (Hans1) and Northern European (T2T) reported to date from resources like IGSR and/or Genome in a Bottle (GIBR) collections, shows that the longest scaffolds from KIn1 cover 80-90% of the reference chromosomes and exhibit near collinearity. We find unique inversion in chromosome 7 euchromatic region and other major translocations in chr17 and 20 in KIin1. We also produced a chromosome level assembly for another individual from Punjab, Lahore (HG03492) for use in our comparison. The analysis of variants among select IGSR individuals using the KIn1 assembly as a reference, reveals that the Indian Telugu from UK (ITU) population in IGSR is ethnically closest to KIn1, followed by the Srilankan Tamil from UK (STU) as representatives of South Asian ancestry.
Pix2Path: Integrating Spatial Transcriptomics and Digital Pathology with Deep Learning to Score Pathological Risk and Link Gene Expression to Disease Mechanisms
Authors: Fu Xiaonan , Chen Yan
Published: August 2024

Spatial transcriptomics (ST) provides high-resolution mapping of gene expression within tissues, and integrating ST with digital pathology can offer unprecedented insights into the molecular mechanisms underlying various diseases. However, existing methods primarily focus on aligning these two distinct datasets, often neglecting the causal connections between spatial gene activity and pathological phenotype. We introduce Pix2Path, a deep learning-based approach utilizing conditional generative adversarial networks (cGANs), to bridge the gap between spatial transcriptomics and digital pathology. Pix2Path can process data from various spatial transcriptomics (ST) technologies, assess pathological risk scores across different conditions, and supports a leave-one-out spatial in silico gene perturbation strategy. As demonstrated in AD Aβ plaques pathology, this approach allows to link gene expression changes to tissue morphology and pathology without relying on predefined conditions, providing a new perspective on understanding disease mechanisms.
Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance
Authors: Angel Marcela Riveros , Seguin Bernard , Lohr Christiane V , Beer Tomasz , Feliciano John , Ramsey Stephen A. , Thomas George V
Published: August 2024

Prostate cancer continues to be one of the most lethal cancers in men. While androgen-deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrate an androgen indifferent phenotype, characterized by low androgen receptor and neuroendocrine associated genes. Notably, we identified two genes, ISG15 and AZGP1 that were consistently up- and downregulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P, and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these 5 genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signaling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.
Automatic detection of seizures within zebrafish larvae epilepsy models using single-channel electroencephalography
Authors: Delaney Connor , Wei Qi , Peixoto Nathalia
Published: August 2024

Researchers continue to pursue new drugs capable of treating intractable, or drug- resistant, epilepsy as a large number of patients do not see a reduction in the number of seizures from current treatments. To quicken the pace of drug research, zebrafish (Danio rerio) have been utilized as a model organism for testing anticonvulsant drugs before clinical trials. However, the lengthy task of labeling electroencephalography (EEG) data slows the pace of this line of research and limits its full potential. This study investigated the creation of automatic seizure detection algorithms for electroencephalogram data recorded from seizure-induced zebrafish to detect seizure, artifact, and neurotypical events. Four unique seizure detection algorithms were proposed and implemented based on k-nearest neighbor (KNN), support vector machine (SVM), and artificial neural network (ANN) classifiers. These four techniques were tested using the same input features and their results compared. The best-performing algorithm was identified as the Single Stage KNN with an 83.8% accuracy, followed by the Single Stage ANN with an 80.3% accuracy. The results indicate that a single-stage, multiclass classification architecture may be beneficial to automatically labeling epilepsy data, thus enhancing efficiency. Furthermore, the results for the algorithms which separate the multiclass classification into a series of binary classifications suggest that there are advantages in research and clinical settings to implement a detection algorithm that can delineate neurotypical and non-neurotypical data to assist with manual labeling.
Navigating the Urban River: Transcriptomic Responses of Freshwater Fish to Multiple Anthropogenic Stressors
Authors: Escobar-Sierra Camilo , Lampert Kathrin P.
Published: August 2024

Urbanization imposes multiple anthropogenic stressors on freshwater ecosystems, affecting aquatic species’ physiological responses. This study explores the transcriptomic responses of the freshwater fishCottus rhenanusto various stressors in an urban river system. RNA sequencing of fish from multiple stations revealed significant seasonal variations in gene expression, with a higher number of differentially expressed genes (DEGs) observed in the summer. Fish at the station experiencing the highest anthropogenic pressure showed notable responses, particularly during warmer months, with enriched pathways related to metabolism, oxidative stress, and immune responses. Key findings include the activation of metabolic stress pathways and immune system genes, such as IL-17 and MAPK pathways, influenced by high temperatures, salinity, and low oxygen levels. Pathway enrichment analyses highlight the impact of temperature and salinity on oxidative stress and osmoregulation, revealing the critical role of the transportome in adapting to salinity changes. These findings showcase the complex interactions between stressors and physiological responses, emphasizing the need for integrated conservation strategies to manage urban stream ecosystems.
Muscle Fibroblasts and Stem Cells Stimulate Motor Neurons in An Age and Exercise-Dependent Manner
Authors: Soendenbroe Casper , Schjerling Peter , Bechshoeft Cecilie J.L. , Svensson Rene B. , Schaeffer Laurent , Kjaer Michael , Chazaud Benedicte , Jacquier Arnaud , Mackey Abigail L.
Published: August 2024

Exercise preserves neuromuscular function in ageing through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant in skeletal muscle and reside close to neuromuscular junctions, but their relative roles in motor neuron maintenance remain undescribed. Using direct co-cultures of embryonic rat motor neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation of the motor neuron transcriptome, with FIB generally favoring neuron growth and cell migration and MuSC favoring production of ribosomes and translational machinery. Conditioned medium from FIB was superior to MuSC in preserving motor neurons and increasing their maturity. Lastly, we established the importance of donor age and exercise status and found an age-related distortion of motor neuron and muscle cell interaction that was fully mitigated by lifelong physical activity. In conclusion, we show that human muscle FIB and MuSC synergistically stimulate the growth and viability of motor neurons, which is further amplified by regular exercise.
Interplay between chemotaxis, quorum sensing, and metabolism regulatesEscherichia coli-SalmonellaTyphimurium interactionsin vivo
Authors: Laganenka Leanid , Schubert Christopher , Barthel Manja , Nguyen Bidong D. , Näf Jana , Lobriglio Thomas , Hardt Wolf-Dietrich
Published: August 2024

Motile bacteria use chemotaxis to navigate complex environments like the mammalian gut. These bacteria sense a range of chemoeffector molecules, which can either be of nutritional value or provide a cue for the niche best suited for their survival and growth. One such cue molecule is the intra- and interspecies quorum sensing signaling molecule, autoinducer-2 (AI-2). Apart from controlling collective behavior ofEscherichia coli, chemotaxis towards AI-2 contributes to its ability to colonize the murine gut. However, the impact of AI-2-dependent niche occupation byE. colion interspecies interactionsin vivois not fully understood.

Here, using the C57BL/6J mouse infection model, we show that chemotaxis towards AI-2 contributes to nutrient competition and thereby affects colonization resistance conferred byE. coliagainst the enteric pathogenSalmonella entericaserovar Typhimurium (S.Tm). LikeE. coli,S.Tm also relies on chemotaxis, albeit not towards AI-2, to compete against residingE. coliin a gut inflammation-dependent manner. Finally, by using a barcoded mutant library pool ofS.Tm, we analyzed how AI-2 signaling inE. coliaffects the central metabolism ofS.Tm. AI-2-dependent niche colonization byE. colispecifically affected the fitness ofS.Tm mutants deficient in fumarate respiration (ΔdcuABC) or mannose (ΔmanA) utilization. Our findings thus provide important insights into AI-2-mediatedE. coli-S.Tm interactions during gut infection.

Author Summary

Both chemotaxis and AI-2 quorum sensing systems have been extensively studied inEscherichia coli. Despite our understanding of these systems at a molecular levelin vitro, their physiological relevancein vivo, particularly in the context of mammalian gut colonization, remains less explored. Building on our previous work on the role of chemotaxis and AI-2 signaling inE. coligut colonization, we investigated their roles in interspecies interactions. Specifically, we examined how AI-2-dependent colonization byE. coliaffects its competition with the enteric pathogenSalmonella entericaserovar Typhimurium (S.Tm) and the metabolic requirements forS.Tm growth.

Our data show that AI-2 signaling contributes to colonization resistance ofE. coliagainstS.Tm. AlthoughS.Tm also requires chemotaxis to grow efficiently inE. coli-colonized mice, this is independent of its ability to sense AI-2. Notably, AI-2-dependent niche occupation byE. colialteredS.Tm metabolism at different stages of infection. Collectively, our findings highlight how AI-2 signaling in one species can affect the metabolism of its interaction partnersin vivo.
Electron tomography visualization of HIV-1 virions trapped by fusion inhibitors to host cells in infected tissues
Authors: Ladinsky Mark S. , Zhu Li , Ullah Irfan , Uchil Pradeep D. , Kumar Priti , Kay Michael S. , Bjorkman Pamela J.
Published: August 2024

HIV-1 delivers its genetic material to infect a cell after fusion of the viral and host cell membranes, which takes place after the viral envelope (Env) binds host receptor and co-receptor proteins. Binding of host receptor CD4 to Env results in conformational changes that allow interaction with a host co-receptor (CCR5 or CXCR4). Further conformational rearrangements result in an elongated pre-hairpin intermediate structure in which Env is anchored to the viral membrane by its transmembrane region and to the host cell membrane by its fusion peptide. Although budding virions can be readily imaged by electron tomography (ET) of HIV-1–infected tissues and cultured cells, virions that are fusing (attached to host cells via pre-hairpin intermediates) are not normally visualized, perhaps because the process of membrane fusion is too fast to capture by EM. To image virions during fusion, we used fusion inhibitors to prevent downstream conformational changes in Env that lead to membrane fusion, thereby trapping HIV-1 virions linked to target cells by prehairpin intermediates. ET of HIV-1 pseudovirions bound to CD4+/CCR5+TZM-bl cells revealed presumptive pre-hairpin intermediates as 2-4 narrow spokes linking a virion to the cell surface. To extend these results to a more physiological setting, we used ET to image tissues and organs derived from humanized bone marrow, liver, thymus (BLT) mice infected with HIV-1 and then treated with CPT31, a high-affinity D-peptide fusion inhibitor linked to cholesterol. Trapped HIV-1 virions were found in all tissues studied (small intestine, mesenteric lymph nodes, spleen, and bone marrow), and spokes representing pre-hairpin intermediates linking trapped virions to cell surfaces were similar in structure and number to those seen in the previous pseudovirus and cultured cell ET study.

IMPORTANCE

Trapped and untrapped HIV-1 virions, both mature and immature, were distinguished by localizing spokes via 3D tomographic reconstructions of HIV-1 infected and fusion-inhibitor treated tissues of humanized mice. The finding of trapped HIV-1 virions in all tissues examined demonstrates a wide distribution of the CPT31 inhibitor, a desirable property for a potential therapeutic. In addition, the presence of virions trapped by spokes, particularly in vascular endothelial cells, demonstrates that fusion inhibitors can be used as markers for potential HIV-1-target cells within tissues, facilitating the mapping of HIV-1 target cells within the complex cellular milieu of infected tissues.
Implementing arbitrary multimode continuous-variable quantum gates with fixed non-Gaussian states and adaptive linear optics
Authors: Hanamura Fumiya , Asavanant Warit , Nagayoshi Hironari , Sakaguchi Atsushi , Ide Ryuhoh , Fukui Kosuke , van Loock Peter , Furusawa Akira
Published: August 2024

Non-Gaussian quantum gates are essential components for optical quantum information processing. However, the efficient implementation of practically important multimode higher-order non-Gaussian gates has not been comprehensively studied. We propose a measurement-based method to directly implement general, multimode, and higher-order non-Gaussian gates using only fixed non-Gaussian ancillary states and adaptive linear optics. Compared to existing methods, our method allows for a more resource-efficient and experimentally feasible implementation of multimode gates that are important for various applications in optical quantum technology, such as the two-mode cubic quantum nondemolition gate or the three-mode continuous-variable Toffoli gate, and their higher-order extensions. Our results will expedite the progress toward fault-tolerant universal quantum computing with light.

Published by the American Physical Society
2024
Magnetic catalysis and diamagnetism from pion fluctuations
Authors: Mei Jie , Wen Rui , Mao Shijun , Huang Mei , Xu Kun
Published: August 2024

In the framework of the Nambu–Jona-Lasinio model beyond mean field approximation, the effects of pion fluctuations on (inverse) magnetic catalysis and magnetic susceptibility are studied. The negative magnetic susceptibility at low temperature is observed when contributions from both neutral and charged pions are taken into account. In the weak field approximation, it is observed that at finite temperature, the magnetic inhibition effect in the chiral limit, resulting from the difference between the transverse and longitudinal velocities of neutral pions, converts to weak magnetic catalysis when considering a nonzero current quark mass. Moreover, the magnetic catalysis is amplified by the charged pions. Therefore, no inverse magnetic catalysis is observed when considering pion fluctuations.

Published by the American Physical Society
2024
Lee-Yang theory of the superradiant phase transition in the open Dicke model
Authors: Brange Fredrik , Lambert Neill , Nori Franco , Flindt Christian
Published: August 2024

The Dicke model describes an ensemble of two-level atoms that are coupled to a confined light mode of an optical cavity. Above a critical coupling, the cavity becomes macroscopically occupied, and the system enters the superradiant phase. This phase transition can be observed by detecting the photons that are emitted from the cavity; however, it only becomes apparent in the limit of long observation times, while actual experiments are of a finite duration. To circumvent this problem, we here make use of recent advances in Lee-Yang theories of phase transitions to show that the superradiant phase transition can be inferred from the factorial cumulants of the photon emission statistics obtained during a finite measurement time. Specifically, from the factorial cumulants, we can determine the complex singularities of generating functions that describe the photon emission statistics, and by extrapolating their positions to the long-time limit one can detect the superradiant phase transition. We also show that the convergence points determine the tails of the large-deviation statistics of the photon current. Our paper demonstrates how phase transitions in the Dicke model and in other quantum many-body systems can be detected from measurements of a finite duration.

Published by the American Physical Society
2024
Reconstructing the spatial structure of quantum correlations in materials
Authors: Scheie Allen , Laurell Pontus , Dagotto Elbio , Tennant D. Alan , Roscilde Tommaso
Published: August 2024

Quantum correlations are a fundamental property of quantum many-body states. Yet they remain experimentally elusive, hindering certification of genuine quantum behavior, especially in quantum materials. Here we show that the momentum-dependent dynamical susceptibility measured via inelastic neutron scattering enables the systematic reconstruction of a general family of quantum correlation functions, which express the degree of quantum coherence in the fluctuations of two spins at an arbitrary mutual distance. Using neutron scattering data for the compound KCuF3—a system of weakly coupled S=1/2 Heisenberg chains—and numerically exact quantum Monte Carlo data, we show that quantum correlations possess a radically different spatial structure with respect to conventional correlations. Indeed, they exhibit a different emergent length scale—the quantum coherence length—which is finite at any finite temperature (including when long-range magnetic order develops). Moreover, we show theoretically that coupled Heisenberg spin chains exhibit a form of quantum monogamy, with a trade-off between quantum correlations along and transverse to the spin chains. These results highlight real-space quantum correlators as an informative, model-independent means of probing the underlying quantum state of real quantum materials.

Published by the American Physical Society
2024
Quantum and classical spin dynamics across temperature scales in the
S=1/2
Heisenberg antiferromagnet
Authors: Park Pyeongjae , Sala G. , Pajerowski Daniel M. , May Andrew F. , Kolopus James A. , Dahlbom D. , Stone Matthew B. , Halász Gábor B. , Christianson Andrew D.
Published: August 2024

Using the framework of semiclassical Landau-Lifshitz dynamics (LLD), we conduct a systematic investigation of the temperature-dependent spin dynamics in the S=1/2 Heisenberg square-lattice antiferromagnet (SAFM). By performing inelastic neutron scattering measurements on Zn2VO(PO4)2 (ZVPO) and corresponding finite-temperature spin dynamics simulations based on LLD, we present a comprehensive analysis that bridges quantum and classical spin dynamics over a broad temperature range. First, remarkable agreement between experimental data and LLD simulations is found in the paramagnetic phase of ZVPO, demonstrating the capability of LLD in accurately determining the spin Hamiltonian of S=1/2 systems and capturing the quantum-to-classical crossover of their spin dynamics. Second, by analyzing the discrepancies between the experimental data and the LLD simulations at lower temperatures, we determine the experimental temperature dependence of the quantum effects in the excitation spectrum of the S=1/2 SAFM: the quantum renormalization factor for the magnon energies and the quantum continuum above the one-magnon bands. Notably, the emergence of each quantum effect is found to correlate with the formation of three-dimensional long-range order. This work demonstrates the utility of LLD in gaining experimental insights into the temperature-induced modifications of quantum spin dynamics and their convergence towards classical expectations at higher temperatures. This motivates further applications to more challenging quantum antiferromagnets dominated by stronger quantum fluctuations.

Published by the American Physical Society
2024