bluuebunny/crossref_metadata_2025 huggingface dataset:
PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis
Authors: Sisson Thomas H. , Osterholzer John J. , Leung Lisa , Basrur Venkatesha , Nesvizhskii Alexey , Subbotina Natalya , Warnock Mark , Torrente Daniel , Virk Ammara Q , Horowitz Jeffrey C. , Migliorini Mary , Strickland Dudley K. , Kim Kevin K. , Huang Steven K. , Lawrence Daniel A.
Published: August 2024

Plasminogen activator inhibitor-1 (PAI-1) has been previously shown to promote lung fibrosis via a mechanism that requires an intact vitronectin (VTN) binding site. In the present study, employing two distinct murine fibrosis models, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a previously unrecognized profibrotic PAI-1-protein interaction involving the VTN-binding site for PAI-1. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorlA) as the most highly enriched PAI-1 interactor in the fibrosing lung. We next investigated the role of SorlA in pulmonary fibrosis and found that SorlA deficiency protected against lung scarring in a murine model. We further show that, while VTN deficiency does not influence fibrogenesis in the presence or absence of PAI-1, SorlA is required for PAI-1 to promote scarring. These results, together with data showing increased SorlA levels in human IPF lung tissue, support a novel mechanism through which the potent profibrotic mediator PAI-1 drives lung fibrosis and implicate SorlA as a new therapeutic target in IPF treatment.
Variability of 7K and 11K SomaScan plasma proteomics assays
Authors: Candia Julián , Fantoni Giovanna , Delgado-Peraza Francheska , Shehadeh Nader , Tanaka Toshiko , Moaddel Ruin , Walker Keenan A. , Ferrucci Luigi
Published: August 2024

SomaScan is an aptamer-based proteomics assay designed for the simultaneous measurement of thousands of human proteins with a broad range of endogenous concentrations. The 7K SomaScan assay has been recently expanded into the new 11K version. Following up on our previous assessment of the 7K assay, here we expand our work on technical replicates from donors enrolled in the Baltimore Longitudinal Study of Aging. By generating SomaScan data from a second batch of technical replicates in the 7K version, as well as additional intra- and inter-plate replicate measurements in the new 11K version using the same donor samples, this work provides useful precision benchmarks for the SomaScan user community. Beyond updating our previous technical assessment of the 7K assay with increased statistics, here we estimate inter-batch variability, we assess inter- and intra-plate variability in the new 11K assay, we compare the observed variability between the 7K and 11K assays (leveraging the use of overlapping pairs of technical replicates), and explore the potential effects of sample storage time (ranging from 2 to 30 years) in the assays’ precision.
The Influence of Shoreline Residential Development on Riparian and Littoral Habitats in the Belgrade Lakes of Maine
Authors: Bevier Catherine R. , Cole F. Russell , Gimond Manuel , Rueger Bruce F.
Published: August 2024

Residential development of lake shoreland can be accomplished with minimal negative impact to riparian and littoral habitat complexity, biological diversity, lake water quality, and general ecosystem health by using landscaping best practices. Preserving a heterogeneous and stratified vegetated buffer along the shoreline helps reduce erosion and nutrient runoff. In our study, we compared characteristics of undisturbed reference, developed but buffered, and developed but unbuffered properties along shorelines of three lakes in the Belgrade Lakes region of south central Maine, USA. Features of riparian habitats associated with reference and buffered developed sites were generally more similar to each other than to unbuffered developed sites. Significantly less shading along the shoreline, fewer trees and tall shrubs in buffer areas, and narrower buffer strips along the shoreline occurred on unbuffered developed sites compared to buffered developed sites. The degree of substrate embeddedness, aufwuchs cover, and amount of woody structure were more similar for littoral habitats adjacent to undeveloped reference and buffered developed sites than for unbuffered developed sites. These findings represent important validation for the use of landscaping best management practices that mimic natural landscape patterns to minimize the influence of shoreland residential development on lake ecosystem health. These practices should be promoted by lake protection programs and communicated to shoreline property owners.
Female Túngara Frogs Discriminate against the Call of Males Infected by Chytridiomycosis
Authors: Rodríguez-Brenes Sofía , Garza Sylvia F. , Ryan Michael J.
Published: August 2024

Species worldwide are disappearing in the most devastating mass extinction in human history and one of the six most profound extinctions in the history of life. Amphibians are greatly affected, approximately one third of living species are threatened, and many others are extinct. One of the main causes of amphibian species extinctions and population declines is the emerging infectious disease chytridiomycosis, caused by the fungusBatrachochytrium dendrobatidis(Bd). Although some species are somewhat tolerant of the disease, the non-lethal effects of the infection with Bd and their short or long term consequences are poorly understood. In these species there is the potential for behavioral responses to mitigate the spread of the fungus. Here we show that in túngara frogs, infection status influences the males’ mating calls. These infection-induced changes in the quality of males’ mating calls ultimately reduce the calls’ attractiveness to females making females less likely to respond to and thus mate with infected males. More broadly, our results imply that females might avoid mating with disease-infected males by assessing the acoustic signal only, and that such recruitment of behavioral responses might potentially ameliorate some of the effects of this sixth mass extinction.

Lay summary

Chytridiomycosis is an amphibian disease well known for its lethal effects. Túngara frogs are infected in nature, but seem to be resistant to the disease. Here we show that chytridiomycosis has non-lethal behavioral effects on túngara frogs. Females discriminate against infected males by assessing only their acoustic signal. The mating call of a male that is not infected with the disease is more attractive to females than the call of that same male when he is infected.
Turning microglia neuroprotective: Towards connexin43-specific therapy of Alzheimer’s disease
Authors: Su Yixun , Li Hui , Zhang Wenjie , Tao Shi , Wang Qi , Zhou Mi , Tang Yong , Chen Hui , Verkhratsky Alexei , Zha Zhengbao , Niu Jianqin , Yi Chenju
Published: August 2024

Alzheimer’s disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role of microglia in AD pathology, particularly in the early stages, is well acknowledged, although cell-specific therapeutic targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls microglial reactivity in AD, thus being a promising therapeutic target. We discovered a marked increase in Cx43 protein in the periplaque microglia in the post-mortem tissue from AD patients. Subsequently, using the APPswe/PS1dE9mouse model of AD, we demonstrated that microglial Cx43 operating as hemichannels influences microglial function, which in turn affects β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifted microglia to neuroprotective phenotype, which promoted the microglia-plaque interaction while suppressing the neurotoxic microglial signature, thereby mitigating the progression of AD. Following this lead, we developed a novel formulation of a small molecule peptide, lipid nanoparticle-delivered molecule TAT-Cx43266-283(TAT-CX43@LNPs), which selectively blocks Cx43 hemichannels. Our preclinical trial demonstrated its efficacy in delaying and rescuing β-amyloid-related neuropathology and cognitive impairment in AD mice. This study provides strong evidence to progress our novel drug into clinical trials and translate it to disease-preventing (when administered in the early disease stages) and disease-modifying agents.
Unifying regulatory motifs in endocrine circuits
Authors: Raz Moriya , Glass David S. , Milo Tomer , Kohanim Yael Korem , Karin Omer , Tendler Avichai , Mayo Avi , Alon Uri
Published: August 2024

In this study we identify unifying design principles in human endocrine systems. We find that 43 hormone systems, controlling diverse physiological functions, fall into 5 classes of circuits with shared structure – thus only a small number of the possible circuits actually occur. Each class uses a different regulatory logic to perform specific dynamical functions, such as homeostasis, acute input-output response or adjustable set points. The circuits employ interactions on two timescales: hormone secretion on the scale of minutes-hours and growth and shrinkage of endocrine gland mass on the scale of months, which impacts the amount of hormone the glands secrete. This two-timescale principle recurs in several classes of circuits, including the most complex class, which has an intermediate gland, the pituitary. We analyze the pituitary circuit in detail and find tradeoffs between endocrine amplification, buffering of hypersecreting tumors, and rapid response times. These unifying principles of regulation build a foundation for systems endocrinology.
Towards Principled Modeling Of Coronary Artery Calcium Scores With Zero-Inflated Regression
Authors: Shrikumar Avanti , Fathieh Sina , Figtree Gemma A. , Grieve Stuart M.
Published: August 2024

Abstract

The Coronary Artery Calcium Score (CACS) is a widely-used measure of Coronary Artery Disease (CAD). The primary use of CACS is to identify subclinical CAD and estimate risk of future cardiovascular events such as acute myocardial infarction. The development of coronary atherosclerosis is well known to be accelerated in response to risk factors such as age, hypertension, hypercholeterolaemia and smoking. However, there is substantial variability in an individual’s susceptibility or resistance to CAD against these risk factors. Quantifiying the deviation from “expected” CACS provides an novel opportunity to inform multi-omic and similar unbiased discovery of new markers and mechanisms of CAD trained against CT imaging. Standard linear regression struggles to model CACS due to the high prevalence of zeros (which reflect the absence of measurable coronary plaque). Prior works have variously handled this by discarding measurements with CACS of zero or by binning the CACS into broad categorical groups. Such approaches discard meaningful data, motivating the need for a more principled approach to handling the data distribution. In this work, we explored zero-inflated regression as a possible approach to modeling CACS using a cohort of patients from the BioHEART-CT study, and devised metrics to validate performance. We identified zero-inflated negative binomial regression, zero-inflated gamma regression and zero-inflated lognormal regression as promising approaches for handling the distributional properties of CACS, where the best method to use can vary depending on the dataset considered. A key contribution of our work is to demonstrate how these models can also estimate the percentile of the observed CACS relative to the distribution that would be expected after controlling for the inputs, thereby avoiding the need for data-hungry binning-based approaches.
Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade
Authors: Mathews Ian T. , Saminathan Priyanka , Henglin Mir , Liu Mingyue , Nadig Namratha , Fang Camille , Mercader Kysha , Chee Serena J. , Campbell Allison M. , Patel Abhijit A. , Tiwari Saumya , Watrous Jeramie D. , Ramesh Karthik , Dicker Martina , Dao Khoi , Meyer Melissa A. , Jousilahti Pekka , Havulinna Aki S. , Niiranen Teemu , Salomaa Veikko , Joosten Leo A.B. , Netea Mihai G. , Zheng Pan , Kronenberg Mitchell , Patel Sandip Pravin , Gutkind J. Silvio , Ottensmeier Christian , Long Tao , Kaech Susan M. , Hedrick Catherine C. , Cheng Susan , Jain Mohit , Sharma Sonia
Published: August 2024

Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementationin vivosuppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.
IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional brain changes
Authors: Labus Jennifer S , Delgadillo Desiree R. , Cole Steve , Wang Chencai , Naliboff Bruce , Chang Lin , Ellingson Benjamin M. , Mayer Emeran A.
Published: August 2024

Background & Aims

Clinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood. We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs).

Methods

A cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression.

Results

The high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms.

Conclusions

The findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.
Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene underlies a neurodevelopmental disorder
Authors: Pérez Baca María del Rocío , Palomares Bralo María , Vanhooydonck Michiel , Hamerlinck Lisa , D’haene Eva , Leimbacher Sebastian , Jacobs Eva Z. , De Cock Laurenz , D’haenens Erika , Dheedene Annelies , Malfait Zoë , Vantomme Lies , Silva Ananilia , Rooney Kathleen , Santos-Simarro Fernando , Lleuger-Pujol Roser , García-Miñaúr Sixto , Losantos-García Itsaso , Menten Björn , Gestri Gaia , Ragge Nicola ,   ZFHX4 consortium, Sadikovic Bekim , Bogaert Elke , Syx Delfien , Callewaert Bert , Vergult Sarah
Published: August 2024

8q21.11 microdeletions encompassing the gene encoding transcription factor ZFHX4, have previously been associated by us with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 57 individuals, 52 probands and 5 affected family members, with protein truncating variants (n=36), (micro)deletions (n=20) or an inversion (n=1) affectingZFHX4with variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions andZFHX4intragenic loss-of-function variants largely overlap, identifying ZFHX4 as the main driver for the microdeletion syndrome, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions only. We identify ZFHX4 as a transcription factor that is increasingly expressed during human brain development and neuronal differentiation. Furthermore, ZFHX4 interacting factors identified via IP-MS in neural progenitor cells, suggest an important role for ZFHX4 in cellular and developmental pathways, especially during histone modifications, cytosolic transport and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds with the promoter regions of genes with crucial roles in embryonic, neuron and axon development. Since loss-of-function variants inZFHX4are found with consistent dysmorphic facial features, we investigated whether the disruption ofzfhx4causes craniofacial abnormalities in zebrafish. First-generation (F0)zfhx4crispant zebrafish, (mosaic) mutant forzfhx4loss-of-function variants, have significantly shorter Meckel’s cartilages and smaller ethmoid plates compared to control zebrafish. Furthermore, behavioral assays show a decreased movement frequency in thezfhx4crispant zebrafish in comparison with control zebrafish larvae. Although further research is needed, ourin vivowork suggests a role for zfhx4 in facial skeleton patterning, palatal development and behavior.
Cost effectiveness of adopting a postoperative delirium risk prediction tool with non-pharmacological delirium prevention interventions for surgical patients
Authors: Graves Nicholas , Boettger Soenke , Zozmann Martin , Franziska Maja , Stocker Reto
Published: August 2024

Background

Postoperative delirium arises among older surgical patients. Screening followed by prevention efforts are recommended. A risk prediction tool has been developed yet the performance and whether adoption is cost-effective are unknown.

Objective

To estimate the expected change to ‘total costs’ and ‘health benefits’ measured by quality adjusted life years from a decision to adopt PIPRA plus for screening purpose to find at-risk individuals who are then offered non-pharmacological interventions to reduce risks of postoperative delirium.

Design

Cost effectiveness modelling study that draws on a range of relevant data sources.

Setting

Swiss healthcare system.

Subjects

Surgical inpatients aged 60 or older, excluding cardiac and intracranial surgeries.

Methods

A decision tree model was used to capture the events likely to impact on cost and health outcomes. Information was harvested from a prospective before-after study and augmented with other relevant data sources. Probabilistic sensitivity analysis was undertaken to reveal the probability that adoption was cost effective against a stated maximum willingness to pay threshold for decision making in Switzerland.

Results

Patients in both phases of the study were similar. Costs were lower by 3075CHF (SD 997) per patient with the adoption of the risk screening tool and there was a modest gain to health benefits of 0.01 QALY (SD 0.026). There was a 100% probability that adoption would be cost saving and a 91% probability that adoption would be cost-effective.

Conclusions

We provide early-stage evidence that a decision to adopt the risk screening tool and offer risk reducing interventions will be cost-effective.

Key points

Many surgical patients suffer from post operative delirium.

Screening and early intervention can reduce risks and improve outcomes.

It is important to establish whether screening and early intervention is cost effective.
Dynamic and prognostic proteomic associations with FEV1decline in chronic obstructive pulmonary disease
Authors: Ruvuna Lisa , Hijazi Kahkeshan , Guzman Daniel E. , Guo Claire , Loureiro Joseph , Khokhlovich Edward , Morris Melody , Obeidat Ma’en , Pratte Katherine A. , DiLillo Katarina M. , Sharma Sunita , Kechris Katerina , Anzueto Antonio , Barjaktarevic Igor , Bleecker Eugene R. , Casaburi Richard , Comellas Alejandro , Cooper Christopher B. , DeMeo Dawn L. , Foreman Marilyn , Flenaugh Eric L. , Han MeiLan K. , Hanania Nicola A. , Hersh Craig P. , Krishnan Jerry A. , Labaki Wassim W. , Martinez Fernando J. , O’Neal Wanda K. , Paine Robert , Peters Stephen P. , Woodruff Prescott G. , Wells J Michael , Wendt Christine H. , Arnold Kelly B. , Barr R. Graham , Curtis Jeffrey L. , Ngo Debby , Bowler Russell P. ,   SPIROMICS, COPDGene and MESA-Lung Investigators
Published: August 2024

Rationale

Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need.

Objective

Identify prognostic and dynamic plasma protein biomarkers of COPD progression.

Methods

We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1(prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways.

Measurements and Main Results

The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins.

Conclusion

We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.
Delineating Drug Class and Target-Specific Adverse Events of Kinase Inhibitors
Authors: Schweickart Annalise , Somani Juhi , Theisen Ryan , Sahni Navriti , Cichońska Anna , Rahman Rayees
Published: August 2024

Kinase inhibitors are a successful category of therapeutics used in treating diseases such as cancer, autoimmunity, and neurodegeneration. Despite their efficacy, these drugs often present clinically relevant adverse events that can limit their therapeutic utility or lead to their failure in clinical trials. The adverse event profile of a kinase inhibitor can be explained by its off- and on-target binding profile. Unfortunately, there are limited resources to couple inhibition of a specific kinase to clinical adverse events. Discerning which adverse events can be attributed to a specific kinase, and which are more generally caused by the kinase inhibitor drug class, is crucial for designing next-generation drugs that avoid toxicity and enhance clinical viability. By integrating adverse event incident data from the FDA Adverse Events Reporting Database with machine learning-predicted molecular binding profiles, we developed a statistical method that associates specific adverse events with potent inhibition of certain kinases. We also identify general adverse events inherent to the kinase inhibitor class. We validate our model through an extensive literature review of known kinase-adverse event pairs, comparison with the OnSIDES drug label side effect dataset, and prospective prediction of adverse events of recently approved kinase inhibitors. We show that our method can recapitulate well-established kinase-toxicity associations and identify previously unreported kinases associated with adverse events.
Hydrogen Sulfide (H₂S)-Producing Oral Bacteria May Protect Against COVID-19
Authors: Vaishnani Meghalbahen , Modi Anupama , Chauhan Kshipra , Parekh Bhavin
Published: August 2024

COVID-19 mortality rates have varied dramatically across the globe. Yet the reasons behind these disparities remain poorly understood. While recent research has linked gut microbes to these variations, the role of oral bacteria, a main port of entry for the coronavirus, remains unexplored.We investigated the relationship between oral microbiota and COVID-19 mortality rates across eightcountries. Raw sequencing data of 16S rRNA regions from oral microbiota in 244 healthy subjects from eight countries were obtained from public databases. We employed a generalized linear model (GLM) to predict COVID-19 mortality rates using oral microbiota composition. GLM revealed that high abundances of hydrogen sulfide (H₂S)-producing bacteria, particularly Treponema, predicted low COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering using a combination of LIGER and t-SNE yielded four oral microbiome "orotypes." Orotypes enriched in H₂S-producing bacteria coincided with lower mortality rates, while orotypes harboring Haemophilus or Rothia were associated with increased vulnerability. To validate our findings, we analyzed influenza mortality data from the same countries, observing similar protective trends. Our findings suggest that oral bacteria-produced H₂S may serve as a critical initial defense against SARS-CoV-2 infection.H₂S from oral bacteria may prevent infection through antiviral activity, blocking ACE2 receptors, suppressing cytokines, and boosting antioxidants. This highlights the oral microbiome’s role in COVID-19 outcomes and suggests new preventive and therapeutic strategies.

Graphical Abstract
Targeting OAS3 for reversing M2d infiltration and restoring anti-tumor immunity in pancreatic cancer
Authors: Zhang Shaopeng , Xu Ximo , Zhang Kundong , Lei Changzheng , Xu Yitian , Zhang Pengshan , Zhang Yuan , Gu Haitao , Huang Chen , Qiu Zhengjun
Published: August 2024

Abundant infiltration of tumor-associated macrophages (TAMs) within the tumor stroma plays a pivotal role in inducing immune escape in pancreatic cancer (PC). Lactate serves as a direct regulator of macrophage polarization and functions, although the precise regulation mechanism remain inadequately understood. Our study revealed that PC cells promote macrophage polarization towards the M2d phenotype through high lactate secretion. M2d is characterized by elevated secretion of IL-10 and VEGF-A, which diminish CD8+T cells cytotoxicity and promote tumor neoangiogenesis simultaneously. Additionally, we identify 2,5’-oligoadenylate synthase 3 (OAS3) as an essential regulator of M2d polarization, upregulated by PC cells via lactate/METTL3/OAS3 axis. METTL3 mediated m6A modification on OAS3 mRNA correlates with increased OAS3 expression in TAMs, which is associated with poorer prognosis in PC patients. OAS3 deficiency in macrophages substantially impairs IL-10highVEGF-AhighM2d polarization and their pro-tumor functions while enhancing the therapeutic efficacy of gemcitabine (Gem) and anti-PD-L1 mAb in humanized mouse models. In conclusion, OAS3 presents as a promising immune therapeutic target for reversing IL-10highVEGF-AhighM2d infiltration and restoring CD8+T cell mediated anti-tumor immunity in pancreatic cancer.
The role of a structured community health worker network in achieving malaria elimination goals in the Dominican Republic: an impact evaluation amid COVID-19 Disruptions
Authors: Michelén Ströfer Nicole , Tejada Bueno Natalia , Santos Félix María Yinet , Cruz Raposo Jose Luis , Lana Justin T. , Turbé Valérian , Cohen Justin M. , Napier Harriet
Published: August 2024

Community health workers (CHWs) can play a key role in malaria elimination through expanding access to malaria testing and treatment. The Dominican Republic, a low endemic country committed to eliminate malaria by 2025, implemented a structured malaria CHW network in the three main urban foci of Greater Santo Domingo. This research quantifies the networks’ contributions towards malaria elimination from its implementation in 2019 until 2022. The study highlights the impact of COVID-19 disruptions on CHWs’ performance and explores the network’s ability to bounce back from health systems’ shocks.

The performance of a malaria CHW network in Greater Santo Domingo, Dominican Republic was evaluated using weekly data collected from CHWs and routinely collected surveillance data from the Ministry of Public Health (MoH). We assess performance of CHWs by analyzing key variables such as (1) reporting compliance, (2) household visitation rates, (3) malaria rapid diagnostic tests performed, (4) malaria cases detected, and (5) time between symptom onset and malaria diagnosis. To evaluate the impact of COVID-19 on the network, CHW’s performance indicators are evaluated across three time periods (prior to, during, and after COVID-19 interruptions).

Results showed that over the evaluation period, reported malaria cases in study foci decreased from 1,243 cases in 2019 to 5 cases in 2023. CHWs diagnosed and treated over 43% of malaria cases in study foci before COVID-19 interruptions and 14% during interruptions. 83% of cases detected by CHWs were detected through active case detection, with 17% detected passively. CHWs detected malaria cases and initiated treatment 1.5 days earlier than health facilities and MoH personnel performing active case detection.

This evaluation provides evidence that a structured CHW network with clearly defined responsibilities and management protocol can assume a large proportion of malaria case management service provision, contribute to early malaria case detection, and help curb local malaria transmission. It adds to a growing body of research on the feasibility and benefits of CHW-led proactive household visitation. Despite interruptions such as the COVID-19 pandemic, concerted investment can sustain CHW program gains.
Coaching visits and supportive supervision for primary care facilities to improve malaria service data quality in Ghana: an intervention case study
Authors: Asiedu Amos , Haws Rachel A. , Mohammed Wahjib , Boye-Doe Joseph , Agblanya Charles , Ntumy Raphael , Malm Keziah , Boateng Paul , Tetteh Gladys , Oseni Lolade
Published: August 2024

Effective decision-making for malaria prevention and control depends on timely, accurate, and appropriately analyzed and interpreted data. Poor quality data reported into national health management information systems (HMIS) prevent managers at the district level from planning effectively for malaria in Ghana. We analyzed reports from data coaching visits and follow-up supervision conducted to 231 health facilities in six of Ghana’s 16 regions between February and November 2021. The visits targeted health workers’ knowledge and skills in malaria data recording, HMIS reporting, and how managers visualized and used HMIS data for planning and decision making. A before-after design was used to assess how data coaching visits affected data documentation practices and compliance with standards of practice, quality and completeness of national HMIS data, and use of facility-based malaria indicator wall charts for decision-making at health facilities. The percentage of health workers demonstrating good understanding of standards of practice in documentation, reporting and data use increased from 72 to 83% (p<0.05). At first follow-up, reliability of HMIS data entry increased from 29 to 65% (p<0.001); precision increased from 48 to 78% (p<0.001); and timeliness of reporting increased from 67 to 88% (p<0.001). HMIS data showed statistically significant improvement in data completeness (from 62 to 87% (p<0.001)) and decreased error rate (from 37 to 18% (p<0.001)) from baseline to post-intervention. By the second follow-up visit, 98% of facilities had a functional data management system (a 26-percentage-point increase from the first follow-up visit, p<0.0001), 77% of facilities displayed wall charts, and 63% reported using data for decision-making and local planning. There are few documented examples of data coaching to improve malaria surveillance and service data quality. Data coaching provides support and mentorship to improve data quality, visualization, and use, modeling how other malaria programs can use HMIS data effectively at the local level.
Utility of thromboelastography to assess the effect of anticoagulation reversal in intracranial hemorrhage
Authors: Zepeski A , Faine BA , Ghannam M , Olalde HM , Wendt L , Naidech A , Mohr NM , Leira EC
Published: August 2024

Background

Intracranial hemorrhage (ICH) is a serious complication associated with oral anticoagulant use and is associated with significant morbidity and mortality. Although anticoagulation reversal agents are utilized as standard of care, practitioners are limited in their ability to assess degree of anticoagulation reversal for direct oral anticoagulants (DOACs). There is a clinical need identify biomarkers to assess anticoagulation status in patients with DOAC-associated ICH to ensure hemostatic efficacy of anticoagulation reversal agents in the acute setting. The purpose of this study was to assess the utility of thromboelastography (TEG) to assess the impact of anticoagulation reversal in patients presenting to the emergency department (ED) with DOAC-associated ICH.

Methods

We conducted a prospective, observational cohort study in adult patients presenting to the ED with acute DOAC-associated ICH. Patients were excluded if last DOAC dose was >48 hours prior to hospital arrival, if they experienced polytrauma, were pregnant, incarcerated, had a history of hepatic failure or coagulopathy, or received anticoagulation reversal with products other than prothrombin complex concentrates (PCCs). We collected baseline TEG samples from participants prior to anticoagulation reversal, as well as 30-minutes, 12-hours, and 24-hours post-reversal. TEG samples were also collected from participants who transferred to our facility after reversal at ED presentation, as well as 12- and 24-hours post-reversal.

Results

Pre-reversal TEG was collected on 10 participants prior to DOAC reversal. A significant decrease in TEG R-time was observed at 30 minutes post-reversal. R-time increased at 12- and 24-hours to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index.

Conclusions

TEG R-time may be able to detect a change in anticoagulation activity of DOACs in ICH after anticoagulation reversal. R-time decreases acutely after anticoagulation reversal and rebounds at 12- and 24-hours post-reversal.
Generation of biobased, biodegradable non-woven straw mats for multiple environmentally friendly uses
Authors: Gressel Jonathan , Hoffmann Sigal
Published: August 2024

Two billion tons of grains straws are produced annually, most of which has a negative ecological value. A small proportion is fed to ruminants as a low calory roughage. Grain straws had been burnt to prevent pathogen spores from over-wintering, now requiring greater fungicide use if left on soil surface, or more fertilizer use when the straw is plowed under and then binds nutrients. Lignin from paper making had been dumped, but is now finding limited uses, including as a glue in plywood manufacture. We propose to find the right ratio of lignin and other biodegradable adhesives coated on straw along with ascertaining the optimal pressures and temperatures for binding the adhesives and them cross-link straw fibers into mats.

These slowly-biodegradable mats can be as: 1. Filters surrounding fish pens, binding pollutants from fish excrements, which are metabolized along with the straw by periphyton into material edible by fish as well as zooplankton eaten by fish. These filter mats may also prevent the movement of parasites into or out of the pens; 2. Mats used for erosion control on bare slopes until vegetated; 3. As insulation material in construction, where the carbon will be sequestered for decades; 4. As a compostable packaging material replacing polystyrene and bubble wrap; 5. Weed-preventing soil covering in organic and conventional agriculture. Such mats can be doped with ammonium and potassium as well as calcium and magnesium to be slowly released as fertilizer. Thus, by combining a negative environmental value waste materials with an adhesive we can generate mats that have very positive environmental benefits.
PneumoBrowse 2: An integrated visual platform for curated genome annotation and multiomics data analysis ofStreptococcus pneumoniae
Authors: Janssen Axel B. , Gibson Paddy S. , Bravo Afonso M. , de Bakker Vincent , Slager Jelle , Veening Jan-Willem
Published: August 2024

Streptococcus pneumoniaeis an opportunistic human pathogen responsible for high morbidity and mortality rates. Extensive genome sequencing revealed its large pangenome, serotype diversity, and provided insight into genome dynamics. However, functional genome analysis has lagged behind, as that requires detailed and time-consuming manual curation of genome annotations, and integration of genomic and phenotypic data. To remedy this, PneumoBrowse was presented in 2018; a user-friendly interactive online platform, which provided the detailed annotation of theS. pneumoniaeD39V genome, alongside transcriptomic data. Since 2018, many new studies onS. pneumoniaegenome biology and protein functioning have been performed. Here, we present PneumoBrowse 2 (https://veeninglab.com/pneumobrowse), fully rebuilt in JBrowse 2. We updated annotations for transcribed and transcriptional regulatory features in the D39V genome. We added genome-wide data tracks for high-resolution chromosome conformation capture (Hi-C) data, chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-Seq), ribosome profiling, CRISPRi-seq gene essentiality data and more. Additionally, we included 18 phylogenetically diverseS. pneumoniaegenomes and their annotations. By providing easy access to diverse high-quality genome annotations, and links to other databases (including UniProt and AlphaFold), PneumoBrowse 2 will further accelerate research and development into preventive and treatment strategies, through increased understanding of the pneumococcal genome.

Graphical abstract
Cultivar-specific fungicide resistance emerges during a growing season in field populations ofZymoseptoria tritici
Authors: Talas Firas , Stapley Jessica , McDonald Bruce A.
Published: August 2024

Zymoseptoria triticicauses the most damaging wheat disease in Europe, septoria tritici blotch (STB). In Europe, STB is controlled mainly by fungicides and fungicide resistance is frequently reported. While fungicide resistance is thought to emerge mainly from standing genetic variation within field populations ofZ. tritici, few studies have attempted to quantify the degree of fungicide resistance occurring at the field scale and to measure changes in frequencies of resistant strains following fungicide applications during a single growing season. Even fewer studies have considered the effects of different wheat cultivars on the emergence of fungicide resistance. We measured EC50 values for 1005 strains ofZ. triticisampled at two time points from 17 different wheat cultivars growing in a replicated field experiment that was treated with combinations of five different fungicides three times during the growing season. We found that field populations ofZ. triticican maintain a very high diversity in fungicide sensitivity phenotypes despite three fungicide treatments, with as much diversity found within a single field during a single growing season as has been described across all of Europe over several years. Multidrug resistance to two or more fungicides was found in 18.9% of the tested strains. We discovered that wheat cultivars that were more resistant to STB tended to be colonized byZ. triticistrains that exhibited higher fungicide resistance. We also found that specific wheat cultivars selected for resistance to specific active ingredients. Overall, our findings illustrate the many challenges associated with designing fungicide treatment programs that aim to reduce selection for fungicide resistance when confronted with a pathogen likeZ. triticithat has a very high evolutionary potential.
Rapid Raman spectroscopy-based test for antimicrobial resistance
Authors: Mushenkov Vladimir , Zhigalova Ksenia , Denisov Pavel , Gordeev Alexey , Lukyanov Dmitry , Kukushkin Vladimir , Priputnevich Tatiana , Zavyalova Elena
Published: August 2024

Antimicrobial resistance is one of the top global health threats. In 2019, antimicrobial resistance was associated with 4.95 million deaths, of which 1.97 million were caused by drug resistant infections directly. The main subset of AMR is the antibiotic resistance, that is resistance of bacteria to antibiotic treatment. Traditional and most commonly used antibiotic susceptibility tests are based on detection of bacterial growth and its inhibition in the presence of an antimicrobial. These tests typically take over 1-2 days to perform, so empirical therapy schemes are often administered before the proper testing. Rapid tests for antimicrobial resistance are necessary to optimize the treatment of bacterial infection. Here we combine MTT test with Raman spectroscopy to provide 1.5-hour long test for minimal inhibitory concentrations determination. SeveralE.coliandK.pneumoniaestrains were tested with three types antibiotics, including ampicillin from penicillin family, kanamycin from aminoglycoside family and levofloxacin from fluoroquinolone family. The test provided the same minimal inhibitory concentrations as traditional Etest confirming its robustness.
Discovery and Engineering of a New BvCas12a Nuclease for Mammalian Genome Editing and Nucleic Acid Detection
Authors: SHEN Xuechun , HUANG Lei , WANG Dan , LIU Chuan , CHEN Ke , LI Baitao , QI Chen , ZOU Yuanqiang , XIAO Liang , JIANG Yuan , LAN Hongxia , ZHENG Yue
Published: August 2024

Cas12a is an RNA-guided endonuclease that has emerged as a powerful gene-editing tool. We have identified a novel Cas protein, BvCas12a, fromButyricimonas virosawith a 5’-TYTN protospacer adjacent motif (PAM). BvCas12a exhibits double-stranded DNA cleavage activityin vitroand genome editing activity in eukaryotic cells. Though the editing efficiency of BvCas12a is marginally lower than that of AsCas12a, the editing specificity of BvCas12a in eukaryotic cells is comparable or superior to that of AsCas12a. Moreover, BvCas12a exhibits substantial collateral activity and can detect HPV DNA effectively and accurately in conjunction with isothermal amplification, highlighting its potential in nucleic acid diagnostics. Furthermore, we have engineered BvCas12a to create two variants, BvCas12a-R (N549R, T606P) and BvCas12a-RVR (N549R, K555V, C559R, T606P). These variants recognize expanded 5’-YYN and 5’-YN PAMin vitro, respectively. Additionally, they exhibit higher editing activity than wild-type BvCas12a and recognize 5’-YYN PAMin vivoat all sites detected. In conclusion, we have identified a novel BvCas12a protein with high specificity and engineered two variants with broader PAM compatibility and improved genome editing efficiency. These findings offer a potent gene editing tool for application in scientific research, gene therapy, and nucleic acid diagnostics.
MYCN inhibits TrkC-mediated differentiation in neuroblastoma cells via disruption of the PKA signalling pathway
Authors: Maher Stephanie , Wynne Kieran , Zhernovkov Vadim , Halasz Melinda
Published: August 2024

Neuroblastoma is complex paediatric cancer with a spectrum of clinical outcomes ranging from spontaneous regression to aggressive metastatic disease. Low-risk patients often achieve over 90% survival with no or minimal treatment, while high-risk patients face less than 50% survival despite intensive multimodal therapy. Half of the high-risk cases harbour amplification of the MYCN oncogene. In addition to MYCN status, Trk receptors have also been linked to prognosis. TrkA expression is seen with low-risk cases while TrkB expression often occurs in MYCN-amplified NB. While TrkA and TrkB are well studied in NB, the role of TrkC is neuroblastomagenesis is not clear. Therefore, this study investigates the interplay between MYCN status and NT-3/TrkC signalling in neuroblastoma. Using a panel of neuroblastoma cell lines with varying MYCN levels, we found that TrkC activation leads to neuronal differentiation in MYCN non-amplified cells, whereas it promotes proliferation in MYCN-amplified cells. Temporal phosphoproteomics revealed differential activation of the PKA pathway, which was crucial for TrkC-mediated differentiation. Manipulating the PKA pathway altered cell fate outcomes, underscoring its role. In MYCN-amplified cells, MYCN knockdown increased PKA and CREB activity, shifting the phenotype towards differentiation. Analysis of neuroblastoma patient data showed lower expression of PKA pathway genes in MYCN-amplified tumours. Additionally, miR-221, upregulated by MYCN, was identified as a suppressor of the PKA/CREB pathway. These findings highlight the context-dependent nature of NT-3/TrkC signalling influenced by MYCN and suggest therapeutic potential in targeting the PKA pathway to induce differentiation of high-risk MYCN-amplified neuroblastoma.
A sticky Poisson Hidden Markov Model for solving the problem of over-segmentation and rapid state switching in cortical datasets
Authors: Li Tianshu , La Camera Giancarlo
Published: August 2024

The application of hidden Markov models (HMMs) to neural data has uncovered hidden states and signatures of neural dynamics that are relevant for sensory and cognitive processes. However, training an HMM on cortical data requires a careful handling of model selection, since models with more numerous hidden states generally have a higher likelihood on new (unseen) data. A potentially related problem is the occurrence of very rapid state switching after decoding the data with an HMM. The first problem can lead to overfitting and over-segmentation of the data. The second problem is due to intermediate-to-low self-transition probabilities and is at odds with many reports that hidden states in cortex tend to last from hundred of milliseconds to seconds. Here, we show that we can alleviate both problems by regularizing a Poisson-HMM during training so as to enforce large self-transition probabilities. We call this algorithm the ‘sticky Poisson-HMM’ (sPHMM). When used together with the Bayesian Information Criterion for model selection, the sPHMM successfully eliminates rapid state switching, outperforming an alternative strategy based on an HMM with a large prior on the self-transition probabilities. The sPHMM also captures the ground truth in surrogate datasets built to resemble the statistical properties of the experimental data.