bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution Genome Assembly and Population Genetic Study of the Endangered MapleAcer pentaphyllum(Sapindaceae): Implications for Conservation Strategies
Authors: Li Xiong , Jiang Li-Sha , Deng Heng-Ning , Yu Qi , Ju Wen-Bin , Feng Yu , Xu Bo
Published: August 2024

Acer pentaphyllumDiels (Sapindaceae), a highly threatened maple endemic to dry-hot valleys of the Yalong River in western Sichuan, China, requires urgent conservation efforts due to its extremely rarity and restricted distribution. In this study, we present a high-quality chromosome-level reference genome ofA. pentaphyllum(626 Mb, 2n = 26), comprising 70.64% repetitive sequences and 38,540 protein-coding genes. Phylogenetic analysis shows thatA. pentaphyllumdiverged from a clade consisting ofA. yangbienseandA. saccharumin the late Eocene (∼37.83 Ma). In the genome ofA. pentaphyllum, genes involved in responding to external environmental change have undergone expansion and positive selection, potentially reflecting its adaptive strategies. While no recent independent whole-genome duplication events were detected, a recent rapid amplification of transposable elements was observed. Population genomic analysis of 227 individuals from 28 populations revealed low genetic diversity (1.04 ± 0.97 × 10−3) compared to other woody species. Phylogeographic patterns suggest an upstream colonization along the Yalong River, with two severe population bottlenecks correlating with major Pleistocene climatic transitions. In addition, most populations exhibit high inbreeding and genetic load, particularly those at range edges (TKX, CDG, TES). Based on these genomic insights, we propose targeted conservation strategies, including genetic rescue measures, to safeguard this unique maple species. These findings not only contribute to the preservation ofA. pentaphyllumbut also enhance our understanding of plant adaptation to extreme environments and the impacts of climate change on species with restricted distributions.
Diminished social memory and hippocampal correlates of social interactions in chronic social defeat stress susceptibility
Authors: Larosa Amanda , Zhang Tian Rui , Wong Alice S. , Cyrus Y. H. Fung , Long Xiong Ling Yun (Jenny) , Fung Benjamin C. M. , Wong Tak Pan
Published: August 2024

Background

The susceptibility to chronic stress has been associated with depression, a mood disorder which highly implicates the hippocampus. Hippocampal contribution to stress susceptibility has been supported by findings in mice following chronic social defeat stress (CSDS). However, little is known of the role of hippocampal activity in determining the development of stress susceptibility.

Methods

We used the UCLA miniscope to longitudinally measure the activity of dorsal CA1 hippocampal neurons across CSDS. Apart from examining the representation of social information by these neurons, we also compared social memory in mice that were susceptible or resilient to CSDS.

Results

We observed more stable dCA1 correlates of social interaction and social memory in CSDS resilience. Such changes were absent in CSDS susceptible mice and accompanied by greater social memory impairments.

Conclusions

CSDS susceptibility may be supported by hippocampal social cognitive processes, reflected in diminished hippocampal representations of social information and a greater impairment in social memory.
Neural basis of concurrent deliberation toward a choice and degree of confidence
Authors: Vivar-Lazo Miguel , Fetsch Christopher R.
Published: August 2024

ABSTRACT

Decision confidence plays a key role in flexible behavior and (meta)cognition, but its underlying neural mechanisms remain elusive. To uncover the latent dynamics of confidence formation at the level of population activity, we designed a decision task for nonhuman primates that measures choice, reaction time, and confidence with a single eye movement on every trial. Monkey behavior was well fit by a bounded accumulator model instantiating parallel processing of evidence, rejecting a serial model in which the choice is resolved first followed by post-decision accumulation for confidence. Neurons in area LIP reflected concurrent accumulation, exhibiting covariation of choice and confidence signals across the population, and within-trial dynamics consistent with parallel updating at near-zero time lag. The results demonstrate that monkeys can process a single stream of evidence in service of two computational goals simultaneously—a categorical decision and associated level of confidence—and illuminate a candidate neural substrate for this ability.
Timing anti-PD-L1 checkpoint blockade immunotherapy to enhance tumor irradiation
Authors: Lee Steve Seung-Young , Pagacz Joanna , Averbek Sera , Scholten David , Liu Yue , Kron Stephen J.
Published: August 2024

Background

The ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs) including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFNγ-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects.

Methods

Flank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5 or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers.ResultsIn both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned toward baseline by 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation.

Conclusions

Optimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.
Rapid phenotypic and genotypic change in a laboratory schistosome population
Authors: Jutzeler Kathrin S. , Platt Roy N. , Li Xue , Morales Madison , Diaz Robbie , Le Clec’h Winka , Chevalier Frédéric D. , Anderson Timothy J.C.
Published: August 2024

Background

Genomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites,Mycobacterium tuberculosisandSalmonellaspp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The BrazilianSchistosoma mansonipopulation SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocysts number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a ∼10x increase in cercarial production and ∼4x increase in worm burden.

Methods

To determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes.

Results

While SmLE allele frequencies remained stable over the eight-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles rose in the SmBRE population from 0 to 41-46% across the genome between September and October 2021, documenting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s= ∼0.23) drove replacement of low fitness SmBRE with high fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4 where SmBRE alleles remained at high frequency.

Conclusions

We were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize fixed single nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge.
Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers
Authors: Takeda Mitsunobu , Theardy Madelaine S. , Sorokin Alexey , Coker Oluwadara , Kanikarla Preeti , Chen Shuaitong , Yang Zecheng , Nguyen Phuoc , Wei Yongkun , Yao Jun , Wang Xiaofei , Yan Liang , Jin Yanqing , Cai Yiming , Paku Masakatsu , Chen Ziheng , Li Kara Z. , Citron Francesca , Tomihara Hideo , Gao Sisi , Deem Angela K. , Zhao Jun , Wang Huamin , Hanash Samir , DePinho Ronald A , Maitra Anirban , Draetta Giulio F. , Ying Haoqiang , Kopetz Scott , Yao Wantong
Published: August 2024

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.
Neural mechanisms of credit assignment for delayed outcomes during contingent learning
Authors: Witkowski Phillip P. , Rondot Lindsay , Kurth-Nelson Zeb , Garvert Mona M. , Dolan Raymond J , Behrens Timothy E. J. , Boorman Erie D.
Published: August 2024

Adaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (lFPC). Our results indicate that lFPC holds previous causal choices in a “pending” state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making.
Therapeutic potential of red blood cell-derived extracellular vesicles in reducing neuroinflammation and protecting against retinal degeneration
Authors: Sekar Rakshanya , Cioanca Adrian V. , Yang Yilei (Evelyn) , Kamath Karthik Shantharam , Carroll Luke , Natoli Riccardo , Wooff Yvette
Published: August 2024

Neuroinflammation is a pathological process mediated through immune cell activation and pro-inflammatory cytokine release, resulting in neuronal cell death. In the central nervous system (CNS), neuroinflammation is a characteristic feature underlying the onset and progression of retinal and neurodegenerative diseases. Targeting neuroinflammation to reduce neuronal cell death and protect against visual and cognitive declines is therefore a key therapeutic strategy. However, due to the complex and multi-faceted nature of these diseases, to date there has been little therapeutic success with single target approaches insufficient to tackle widespread and multi-pathway inflammatory cascades. Furthermore, as the retina and brain reside within immune-privileged environments, a major challenge in treating these diseases is producing and delivering a therapeutic that, in itself, does not exacerbate inflammation. Extracellular vesicles (EV), derived from red blood cells (RBC EV), present a promising solution to overcome these hurdles, due to their innate ability to cross blood-tissue barriers, biocompatible nature, and their broad anti-inflammatory properties to modulate complex neuroinflammatory pathways.

This study therefore investigated the therapeutic potential of RBC EV in mediating neuroinflammation using anin-vivophoto-oxidative damage model of retinal degeneration as a model for CNS neuroinflammation. In this work, we developed a novel incubation pipeline using N1 medium supplement and superoxide dismutase (SOD) supplementation to promote the production of safe, neuroprotective, and anti-inflammatory RBC EV. Delivery of RBC EVin vivo, was shown to be safe with strong penetration across all retinal layers. Further, therapeutic administration of RBC EV via local intravitreal injection significantly reduced inflammation and cell death and preserved retinal function. Notably, strong safety and therapeutic efficacy was also demonstrated in the retina following systemic (intraperitoneal) administration, highlighting a potential game-changing approach for less-invasive therapeutic delivery to the CNS. Finally, multi-omic analyses andin vitrofindings supported an anti-inflammatory mechanism-of-action, with RBC EV modulating pro-inflammatory cytokine release, including those known to be involved in the pathogenesis of retinal and neurodegenerative diseases.

Taken together, these findings highlight the broad applicability of RBC EV in treating neuroinflammation in the CNS, presenting a scalable and effective treatment approach for these currently untreatable diseases.
PLSKO: a robust knockoff generator to control false discovery rate in omics variable selection
Authors: Yang Guannan , Menkhorst Ellen , Dimitriadis Evdokia , Lê Cao Kim-Anh
Published: August 2024

The knockoff framework, combined with variable selection procedure, controls false discovery rate (FDR) without the need for calculatingp−values. Hence, it presents an attractive alternative to differential expression analysis of high-throughput biological data. However, current knockoff variable generators make strong assumptions or insufficient approximations that lead to FDR inflation when applied to biological data.

We propose Partial Least Squares Knockoff (PLSKO), an efficient and assumption-free knockoff generator that is robust to varying types of biological omics data. We compare PLSKO with a wide range of existing methods. In simulation studies, we show that PLSKO is the only method that controls FDR with sufficient statistical power in complex non-linear cases. In semi-simulation studies based on real data, we show that PLSKO generates valid knockoff variables for different types of biological data, including RNA-seq, proteomics, metabolomics and microbiome. In preeclampsia multi-omics case studies, we combined PLSKO with Aggregation Knockoff to address the randomness of knockoffs and improve power, and show that our method is able to select variables that are biologically relevant.
Sequential mosaic variants inKRASandSTAT5Bassociated with a mixed phenotype of two acquired errors of immunity
Authors: Forkgen Julia , Masle-Farquhar Etienne , Fontaine Yves , Russell Amanda , Ji Shannon , Peters Timothy J , Qiao Zhen , Geaghan Michael , Jackson Katherine JL , Hammond Jillian M , Deveson Ira W , David Clementine , Lemberg Daniel A , Gupta Nitin , Fuentes-Bolanos Noemi , Mustjoki Satu , Hwa Vivian , Tangye Stuart G , Gray Paul E , Siggs Owen M
Published: August 2024

Mosaic genetic variation has been implicated in the pathogenesis of both malignant and non-malignant immunological disease. Here, we report a unique case of postnatal acquisition of a gain-of-function (GoF)KRASvariant, with an additional GoFSTAT5Bvariant, in a woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. Targeted amplicon sequencing revealed widespread distribution of both variants in key immune cell populations, and in historical blood and tissue samples, with the emergence of both variants coinciding with the time of clinical presentation. Short- and long-read single cell RNA sequencing of patient cells highlighted a unique population of monocytes, with a broad distribution of both variants, and dysregulated cytokine signaling pathways. Flow cytometry revealed dysregulated STAT signaling, and the presence of a distinct population of highly granular CD24+ cells. Taken together with the clinical presentation, these findings led to a diagnosis of combined RAS-associated autoimmune leukoproliferative disorder (RALD) and non-clonalSTAT5BGoF disease. To our knowledge, this is the first reported combination of two distinct acquired errors of immunity causing a mixed clinical phenotype, and highlights the importance of considering acquired monogenic diseases within a broader genomic context.
Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: a population cohort study
Authors: Hu Yuqi , Gao Le , Zhou Lingyue , Liu Wenlong , Wei Cuiling , Liu Boyan , Sun Qi , Tian Wenxin , Chu Rachel Yui Ki , Song Song , Cheng Franco Wing Tak , Chan Joe Kwun Nam , Ng Amy Pui Pui , Lo Heidi Ka Ying , Lee Krystal Chi Kei , Chang Wing Chung , Wong William Chi Wai , Chan Esther Wai Yin , Wong Ian Chi Kei , Chai Yi , Lai Francisco Tsz Tsun
Published: August 2024

Background

Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is unclear due to the absence of cohort studies.

Methods

We extracted data from a territory-wide public healthcare database in Hong Kong to build a retrospective cohort of anonymized patients aged 18+ with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least two prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated.

Results

In total, 9,965 patients were included, with 834 clozapine users, who had a significant IRR of 2.22 (95% CI 1.52, 3.34) for HM compared to olanzapine users. Absolute rate difference was estimated to be 57.40 (95% CI 33.24, 81.55) per 100,000 person-years. Findings were consistent across sub-groups by age and sex in terms of effect size, although the IRR was non-significant for those aged 65 or older. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers.

Conclusion

Absolute rate difference in HM incidence was very small although there is a twofold elevated rate. Pharmacotherapies with clozapine may consider this potential rare risk in addition to known side effects.
Evaluation of the effect of auto-transplanted tooth for repairing maxillary sinus perforation compared to traditional flap repair
Authors: Liao Fenglin , Zhang Biao , Zhong Haoyan
Published: August 2024

Objective

The purpose of this study is to compare the outcomes of using auto-transplanted tooth and flap for repairing sinus perforation after tooth extraction. The aim is to provide a new reference for selecting appropriate repair methods for maxillary sinus perforation.

Methods and materials

This study involved 19 patients with sinus perforation who underwent treatment at the Department of Oral Surgery, Hospital of Stomatology Wuhan University, from March 2021 to September 2022. The study included two groups: a test group with 11 cases where perforation of the maxillary sinus mucosa greater than 5 mm was found during autologous tooth transplantation, and a control group with 8 cases where maxillary sinus mucosa perforation greater than 5 mm was found during tooth extraction. Clinical examination and radiographic examination were taken at 2 weeks, 1, 3, 6, and 12 months post-surgery of two groups. The two-year survival probability of the AT group was assessed using Kaplan-Meier survival analysis.

Results

The success rate of the auto-transplantation (AT) group was 72.7% (8/11), while the success rate of the flap transfer (FT) group was 100%. Upon analysis, it was found that the survival probability of AT group was significantly lower when the gingival index(GI) score was 2 (51.8%), in comparison to when it was 0 or 1 (100%).

Conclusion

The study findings demonstrated that the utilization of auto-transplanted teeth yielded a favorable outcome in restoring maxillary sinus perforation, suggesting its viability as a potential option.
Health losses attributable to anthropogenic climate change
Authors: Carlson Colin J. , Mitchell Dann , Gibb Rory , Stuart-Smith Rupert F. , Carleton Tamma , Lavelle Torre E. , Lippi Catherine A. , Lukas-Sithole Megan , North Michelle A. , Ryan Sadie J. , Shumba Dorcas Stella , Chersich Matthew , New Mark , Trisos Christopher H.
Published: August 2024

Despite widespread consensus that climate change poses a serious threat to global public health, very few studies have isolated the specific contributions of human-caused climate change to changes in morbidity and mortality. Here, we systematically review over 3,600 abstracts, and identify a dozen end-to-end impact attribution studies on human health outcomes published between 2016 and 2023. Based on these studies, we find that estimates of attributable mortality range from 10 to over 271,000 deaths, depending on timescale, spatial extent, climate hazard, and cause of death. We calculate that this loss of life amounts to up to US$ trillions in monetary value when using standard valuation approaches. So far, end-to-end attribution studies capture only a small fraction of the presumed global burden of climate change, with few studies addressing infectious and non-communicable diseases, and no subnational or event-specific studies focused on a location outside of Europe and the United States. However, the field of health impact attribution is poised to explode in the next decade, putting unprecedented pressure on policymakers to take action for human health.
Clinical, social, and economic impacts of colorectal cancer screening with the multi-target stool-DNA test: 10-year experience - a simulated study
Authors: Estes Chris , Dehghani Mohammad , Ozbay A. Burak , Vahdat Vahab , Limburg Paul J. , Brooks Durado
Published: August 2024

Introduction

In the United States, colorectal cancer (CRC) remains a substantial public health challenge, with approximately 150,000 new cases diagnosed annually. Guidelines from organizations such as the United States Preventive Services Task Force (USPSTF) recommend several screening strategies, including endoscopic, radiologic, and stool-based options such as the multi-target stool DNA (mt-sDNA) test. In this analysis, we analyzed the estimated clinical, social, and economic impacts of mt-sDNA screening over the inaugural 10-year period for test availability.

Methods

To assess the effectiveness of CRC screenings with the mt-sDNA test, published rates of advanced precancerous lesions (APL) and cancer prevalence by stage, as well as the transition rate of APL to CRC for the average-risk population in the US were used for a simulated population. The mt-sDNA test’s sensitivity and specificity for APL and CRC were derived from previously published data. To assess the economic impact of screening with mt-sDNA compared to colonoscopy, we utilized data from literature regarding the time and resources required to prepare and complete each test. Furthermore, the costs of treatment according to the stage of colorectal cancer are considered, to show the value of CRC prevention and early detection.

Results

Our analysis indicates that mt-sDNA screening detected an estimated 98,000 cases of CRC and 525,000 individuals were found to have APLs, precursors to CRC. When using 10-year survival rate from CRC, it is estimated that the mt-sDNA test led to more than 34,000 patients surviving due to earlier intervention compared to no screening. Furthermore, the mt-sDNA test demonstrated approximately $22.3 billion cost savings compared to no screening, including an estimated $9.7 billion in cancer treatment costs through early CRC detection and an additional $12.6 billion resulting from cancer prevention through APL detection and management.

Conclusion

Clinical availability, adoption, and growth of stool-based CRC screening have significantly increased overall screening rates in the US. It is estimated that mt-sDNA utilization will continue to grow, providing a home-based CRC screening solution for millions of screen-eligible US adults over the next decade and beyond.
Arterial spin labeling as a promising alternative to FDG-PET for clinical diagnosis of patients with disorders of consciousness
Authors: Han Junrong , Duncan Niall W. , Huang Likai , Lee Chia , Yang Che-Ming , Wu Yen-Chien , Chen David Yen-Ting , Lane Timothy J.
Published: August 2024

Objective: To evaluate the potential of arterial spin labeling (ASL) as an alternative to FDG-PET in the diagnosis of disorders of consciousness (DOC), we conducted a comparative study of the two modalities. Methods: A total of 36 DOC patients (11 female; mean age = 49.67 ± 14.54 years) and 17 healthy control (HC) participants (9 female; mean age = 31.9 ± 9.6 years) underwent both FDG-PET scans that measure metabolism via glucose uptake and ASL scans that measure cerebral blood flow (CBF). CBF and metabolism in DOC and HC were compared, globally and for seven functional networks. Comparability of the two modalities was estimated using Spearman partial correlation for both global and network levels. Furthermore, a support vector machine (SVM) algorithm was used to train two classifiers to distinguish DOC patients from HC with normalized CBF or metabolism values from the seven networks. Performance of these classifiers was first evaluated through leave-one-subject-out (LOSO) cross-validation within their respective modalities. Subsequently, cross-modal validation was conducted: testing the ASL-trained classifier with PET data (ASL-to-PET validation) and vice versa (PET-to-ASL validation). Performance of each classifier was assessed using receiver operating characteristic (ROC) analysis, with area under the curve (AUC) as the metric. Results: Both modalities showed agreement in decreased CBF and metabolism in DOC patients compared to HC, at both global and network levels. The global brain and most networks showed significant positive partial correlation between CBF and metabolism. SVM classifiers, utilizing activity from seven networks as features, performed well in the both LOSO cross-validation (ASL-trained classifier: accuracy = 83.02%, AUC = 0.95; PET-trained classifier: accuracy = 98.12%, AUC = 0.98) and cross-modal validation (ASL-to-PET validation: accuracy = 84.90%, AUC =0.92; PET-to-ASL validation: accuracy = 73.58%, AUC = 0.93). Conclusion: Our results demonstrate that ASL provides information comparable to FDG-PET for DOC patients; moreover, classifiers trained on ASL data perform comparably well to those trained on FDG-PET data. Therefore, ASL could be a valuable alternative to FDG-PET in the clinical diagnosis of DOC, especially in light of its advantages: ease of acquisition, avoidance of radiation exposure, brevity of scanning time, and lower-cost.
PyPlaque: an Open-source Python Package for Phenotypic Analysis of Virus Plaque Assays
Authors: De Trina , Andriasyan Vardan , Yakimovich Artur
Published: August 2024

Virological plaque assays are the primary method for quantifying infectious particles in a suspension, achieved by incubating a serial dilution of the virus with a monolayer of indicator cells. Existing software tools for quantification of plaque assay images lack modularity, show measurements disagreements or are closed-source - a common hurdle in BioImage analysis. We introduce PyPlaque, an open-source Python package focusing on flexibility and modularity rather than a bulky graphic user interface. Unlike previous methods, an abstracted architecture using object-oriented programming allows accommodation of various experimental containers and specimen carriers as data structures while focusing on phenotype-specific information. Aligned with the logical flow of experimental design and desired quantifications, it delivers insights at multiple granularity levels, facilitating detailed analysis. We demonstrate how this approach allows to focus on alleviating the disagreement in measurements. Furthermore, similar design is generalisable to diverse datasets in various biological contexts that fit our structural paradigm.
Persistent changes in nociceptor translatomes govern hyperalgesic priming in mouse models
Authors: Sankaranarayanan Ishwarya , Kume Moeno , Mohammed Ayaan , Mwirigi Juliet M , Inturi Nikhil Nageswar , Munro Gordon , Petersen Kenneth A , Tavares-Ferreira Diana , Price Theodore J
Published: August 2024

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identifiedGpr88as upregulated andMetrnas downregulated. We confirmed a functional role for these genes, wherein a GPR88 agonist causes pain only in primed mice and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.
Incomplete lytic cycle of a widespreadBacteroidesbacteriophage leads to the formation of defective viral particles
Authors: Vendrell-Fernández Sol , Beamud Beatriz , Abou-Haydar Yasmina , Am de Sousa Jorge , Burlaud-Gaillard Julien , Kornobis Etienne , Raynal Bertrand , Vinh Joelle , Bikard David , Ghigo Jean-Marc
Published: August 2024

Advances in metagenomics have led to the identification of new intestinal temperate bacteriophages. However, their experimental characterization remains challenging due to a limited understanding of their lysogenic-lytic cycle and the common lack of plaque formationin vitro. In this study we investigated the hankyphage, a widespread transposable phage of prominentBacteroidessymbionts. Hankyphages spontaneously produced virions in laboratory conditions even in the absence of inducer, but virions did not show any evidence of infectivity. To increase virion production and raise the chances of observing infection events, we identified a master repressor of the hankyphage lytic cycle, RepCHP, whose silencing amplified hankyphage gene expression, enhanced replicative transposition and virion production. However, attempts to infect or lysogenize new host cells with different capsular types remained unsuccessful. Transmission electron microscopy and capsid DNA sequencing revealed an abnormal virion morphology and incomplete DNA packaging of the hankyphage, suggesting that it cannot complete its assembly in laboratory conditions for reasons that are yet to be identified. Still, metavirome and phylogenetic analyses were suggestive of hankyphage horizontal transmission. We could also detect the activity of diversity-generating retroelements (DGRs) that mutagenize the hankyphage minor tail fiber, and likely contribute to its broad host range. This study sheds light on the life cycle of this this abundant intestinal bacteriophage and highlights important gaps in our understanding of the factors required for the completion of its life cycle. Elucidating this puzzle will be critical to gain a better understanding of the hankyphage biology and ecological role.
Using integrated wildlife monitoring for quantifying the impact of emerging Bagaza virus in red-legged partridges in Portugal, 2012-2024
Authors: Queirós João , Costa João Basso , de Mello Gonçalo , Fontoura-Goncalves Catarina , Höfle Úrsula , Górtazar Christian , Alves Paulo Célio , Acevedo Pelayo , Goncalves David
Published: August 2024

Bagaza virus, a vector-borne flavivirus that causes significant mortality in wild bird species, emerged in Portugal in September 2021. This study used integrated wildlife monitoring to quantify its impact on a natural population of red-legged partridge (Alectoris rufa) in southern Portugal. We constructed a baseline model of population dynamics prior to the outbreak (2012-2021) and used this model to predict population size in subsequent years (2022-2024). This model, which included population abundance and demographic data of red-legged partridge, as well as climatic variables, showed a strong fit to the observed data, and the difference between the predicted and observed population size in 2022 suggests a Bagaza-induced mortality rate of at least 59% (95% CI 52-66%). In addition to enabling the adaptive management of populations, our results demonstrate that integrated wildlife monitoring offers epidemiological insights for risk assessment, highlighting its role in proactive wildlife disease surveillance within the One Health framework.
Dynamic regulation of engineered T7 RNA polymerases by endogenous metabolites
Authors: Baumer Zachary T. , Newton Matilda , Löfstrand Lina , Paucar Genesis Nicole Carpio , Farny Natalie G. , Whitehead Timothy A.
Published: August 2024

For many enzymes, activity is regulated post-translationally by endogenous metabolites. Designing liganded control of essential activities like transcription would advance predictive control of biological processes, a fundamental goal of synthetic biology. Here we demonstrate that full-length, single subunit T7-derived RNA polymerases (T7 RNAP) can be controlled by physiologically relevant concentrations of indoles. We used rational design and directed evolution to identify T7 RNAP variants with minimal transcriptional activity in the absence of indole, and a 29-fold increase in activity with an EC50of 344µM. Indoles control T7-dependent gene expression exogenously, endogenously, and inter-cellularly. We also demonstrate indole-dependent bacteriophage viability and propagation intrans. Specificity of different indoles, T7 promoter specificities, and portability to different bacteria are shown. OurligandactivatedRNApolymerases (LARPs) represent a new chemically inducible platform immediately deployable for novel synthetic biology applications, including for modulation of synthetic co-cultures.
The pseudoenzyme β-amylase9 from Arabidopsis binds to and enhances the activity of α-amylase3: A possible mechanism to promote stress-induced starch degradation
Authors: Berndsen Christopher E , Storm Amanda R , Sardelli Angelina M , Hossain Sheikh R , Clermont Kristen R , McFather Luke M , Connor Mafe A , Monroe Jonathan
Published: August 2024

Starch accumulation in plant tissues provides an important carbon source at night and for regrowth after periods of dormancy and in times of stress. Both ɑ- and β-amylases (AMYs and BAMs, respectively) catalyze starch hydrolysis, but their functional roles are unclear. Moreover, the presence of catalytically inactive amylases that show starch excess phenotypes when deleted presents an interesting series of questions on how starch degradation is regulated. Plants lacking one of these catalytically inactive β-amylases, BAM9, were shown to have enhanced starch accumulation when combined with mutations in BAM1 and BAM3, the primary starch degrading BAMs in response to stress and at night, respectively. Importantly, BAM9 has been reported to be transcriptionally induced by stress through activation of SnRK1. Using yeast two-hybrid experiments, we identified the plastid-localized AMY3 as a potential interaction partner for BAM9. We found that BAM9 interacted with AMY3 in vitro and that BAM9 enhances AMY3 activity 3-fold. Modeling of the AMY3-BAM9 complex revealed a previously undescribed N-terminal structural feature in AMY3 that we call the alpha-alpha hairpin that could serve as a potential interaction site. Additionally, AMY3 lacking the alpha-alpha hairpin is unaffected by BAM9. Structural analysis of AMY3 showed that it can form a homodimer in solution and that BAM9 appears to replace one of the AMY3 monomers to form a heterodimer. Collectively these data suggest that BAM9 is a pseudoamylase that activates AMY3 in response to cellular stress, possibly facilitating starch degradation to provide an additional energy source for stress recovery.
Enhancement strategies for the microbial protein production of nitrogen-fixing hydrogen-oxidizing bacterial community
Authors: Wang Haoran
Published: August 2024

The feasibility and superiority of utilizing nitrogen-fixing hydrogen-oxidizing bacteria (NF-HOB) for microbial protein (MP) production have been proposed. This study simulated air as the source of nitrogen and oxygen and enhanced production efficiency by employing key strategies, including continuous gas supply, selecting a higher hydrogen-to-oxygen ratio, designing initial community structures and domestication, and exploring appropriate hydraulic retention times (HRT) in continuous culture. The results demonstrated that sequencing batch culture achieved an MP titer of 0.98 g/L, with N2fixation efficiency surpassing natural nodules by two orders of magnitude at 1.6 mg N2per g dry biomass per hour. Under an HRT of 48 hours, MP volumetric productivity reached 2.297 mg/(L·h), accompanied by a maximum biomass yield of 0.11 g CDW/g COD-H2. The high abundance of nitrogenase may provide crucial functional support, enabling the NF-HOB community to exhibit potential beyond previous understanding.
Using phylogenetic summary statistics for epidemiological inference
Authors: Núñez Rafael C. , Hart Gregory R. , Famulare Michael , Lorton Christopher , Herbeck Joshua T.
Published: August 2024

Since the coining of the term phylodynamics, the use of phylogenies to understand infectious disease dynamics has steadily increased. As methods for phylodynamics and genomic epidemiology have proliferated and grown more computationally expensive, the epidemiological information they extract has also evolved to better complement what can be learned through traditional epidemiological data. However, for genomic epidemiology to continue to grow, and for the accumulating number of pathogen genetic sequences to fulfill their potential widespread utility, the extraction of epidemiological information from phylogenies needs to be simpler and more efficient. Summary statistics provide a straightforward way of extracting information from a phylogenetic tree, but the relationship between these statistics and epidemiological quantities needs to be better understood. In this work we address this need via simulation. Using two different benchmark scenarios, we evaluate 74 tree summary statistics and their relationship to epidemiological quantities. In addition to evaluating the epidemiological information that can be inferred from each summary statistic, we also assess the computational cost of each statistic. This helps us optimize the selection of summary statistics for specific applications. Our study offers guidelines on essential considerations for designing or choosing summary statistics. The evaluated set of summary statistics, along with additional helpful functions for phylogenetic analysis, is accessible through an open-source Python library. Our research not only illuminates the main characteristics of many tree summary statistics but also provides valuable computational tools for real-world epidemiological analyses. These contributions aim to enhance our understanding of disease spread dynamics and advance the broader utilization of genomic epidemiology in public health efforts.

Author Summary

Our study focuses on the use of phylogenetic analysis to get valuable epidemiological insights. We conducted a simulation study to evaluate 74 phylogenetic summary statistics and their relationship to epidemiological quantities, shedding light on the potential of each of these statistics to quantify different characteristics of disease spread dynamics. Additionally, we assessed the computational cost of each statistic. This gives us additional information when selecting a statistic for a particular application. Our research is available through an open-source Python library. This work helps us enhance our understanding of phylogenetic tree structures and contributes to the broader application of genomic epidemiology in public health initiatives.
Effect and acceptability of co-created interventions linking public rehabilitation programs with civil society involvement for physical activity engagement – a convergent mixed methods pilot study
Authors: Thorsen Ida Kær , Midtgaard Julie , Hansen Marie Lønberg , Thomsen Katja , Søborg Henrik , Jensen Helle Oldrup , Almdal Thomas Peter , Lorenzen Janne Kunchel , Hansen Anders Blædel Gottlieb , Ried-Larsen Mathias
Published: August 2024

Background

Public physical activity programs are time-limited and often lacking sufficient support for citizens to maintain physical activity engagement. In this project, municipal stakeholders; civil society organizations; citizens with type 2 diabetes (T2D), cardiovascular diseases (CVD), and/or obesity; and researchers were involved in the co-creation and implementation of interventions to support citizens in continuing physical activity engagement following a municipal rehabilitation program. The primary aim of this study was to investigate the effect of these interventions on physical activity engagement in civil society sports organizations. Secondary aims were to investigate acceptability and effect of these interventions on physical and mental health, and organizational development and collaboration.

Methods

This was a convergent mixed methods study using a quantitative prospective intervention study with a historic control group, and a qualitative descriptive study. These were analyzed separately and then integrated. Quantitative data from citizens were collected before; and 0, 3 and 6 months after ending their rehabilitation program. Outcomes included physical activity engagement in civil society organizations; and changes in objectively measured physical activity, physical and mental health. Qualitative data were collected among citizens, civil society, and municipal representatives. Themes included physical activity engagement, acceptability, and organizational development and collaboration.

Results

Among the 33 included citizens (58% women, median (25th; 75thpercentile) age of 67.6 (63.9; 74.1) years), six lived with T2D; nine with CVD; and 18 were obese. Of the 21 citizens who were not engaged in physical activities in civil society organizations before entering the rehabilitation program, 67% started and remained active at 6-month follow-up—significantly more than in the historic control group. Light physical activity increased by a mean (95% confidence interval) of 15.4 (2.3; 28.5) min/day from 0 to 6 months after the rehabilitation program; all other outcomes remained unchanged. This was assisted by experienced high acceptability of the linking interventions and strengthened collaboration between the municipal health center and civil society organizations.

Conclusions

The co-created interventions led to increased physical activity engagement in civil society organizations. This supports co-creation as a method to link municipal rehabilitation programs with physical activities in civil society organizations.

Trial registration

ClinicalTrials.gov:NCT05493345, 2022-08-05
Patterns of antidepressant prescribing in and around pregnancy: a descriptive analysis in the UK Clinical Practice Research Datalink
Authors: Martin Florence Z. , Sharp Gemma C. , Easey Kayleigh E. , Madley-Dowd Paul , Bowen Liza , Nimmo-Smith Victoria , Sadik Aws , Richardson Jonathan L. , Rai Dheeraj , Forbes Harriet
Published: August 2024

Objective

To describe the prevalence and patterns of antidepressant prescribing in and around pregnancy.

Design

Drug utilisation study.

Setting

Primary care in the United Kingdom (UK).

Population

Women with a pregnancy between 1996 and 2018 in the UK Clinical Practice Research Datalink (CPRD) GOLD Pregnancy Register.

Methods

Using primary care prescription records, we identified individuals who had been prescribed antidepressants in and around pregnancy and described changing prevalence of prescribing during pregnancy over time. We defined ‘prevalent’ or ‘incident’ antidepressant use, where ‘prevalent’ users were prescribed antidepressants both before and during pregnancy, and ‘incident’ users were newly prescribed antidepressants during pregnancy, then compared patterns of prescribing between these two groups. We also investigated characteristics associated with antidepressant discontinuation anytime during pregnancy and post-pregnancy prescribing.

Main outcome measures

Antidepressant prescribing during pregnancy.

Results

A total of 1,033,783 pregnancies were identified: 79,144 (7.7%) were prescribed antidepressants during pregnancy and 15,733 of these (19.9%) were ‘incident’ users. Antidepressant prescribing during pregnancy increased from 3.2% in 1996 to 13.4% in 2018. Most women, both ‘prevalent’ and ‘incident’ users, discontinued antidepressants anytime during pregnancy (54.8% and 59.9%, respectively). The majority of those who discontinued during pregnancy resumed in the 12 months after pregnancy (53.0%). Younger age, previous stillbirth, and higher deprivation were associated with more frequent discontinuation anytime during pregnancy.

Conclusions

Antidepressant use during pregnancy appears to be increasing in the UK. Most women discontinued antidepressants at some point before the end of pregnancy, but post-pregnancy resumption of antidepressants was common.

Funding

Wellcome Trust 218495/Z/19/Z.