bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation
Authors: Nakano Kenta , Goto Motohito , Fukuda Satsuki , Yanobu-Takanashi Rieko , Yabe Shigeharu G. , Shimizu Yukiko , Sakuma Tetsushi , Yamamoto Takashi , Shimoda Masayuki , Okochi Hitoshi , Takahashi Riichi , Okamura Tadashi
Published: August 2024

Background.

For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term.

Methods.

We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγcnull (NOG) mice (Ins1C96Y/C96Y
NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice.

Results.

All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation.

Conclusions.

The Ins1

C96Y/C96Y
NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.
Mobility and growth in confined spaces are important mechanisms for the establishment of Bacillus subtilis in the rhizosphere
Authors: Engelhardt Ilonka C. , Holden Nicola , Daniell Tim J. , Dupuy Lionel X.
Published: August 2024

The rhizosphere hosts complex and abundant microbiomes whose structure and composition are now well described by metagenomic studies. However, the dynamic mechanisms that enable micro-organisms to establish along a growing plant root are poorly characterized. Here, we studied how a motile bacterium utilizes the microhabitats created by soil pore space to establish in the proximity of plant roots. We have established a model system consisting of Bacillus subtilis and lettuce seedlings co-inoculated in transparent soil microcosms. We carried out live imaging experiments and developed image analysis pipelines to quantify the abundance of the bacterium as a function of time and position in the pore space. Results showed that the establishment of the bacterium in the rhizosphere follows a precise sequence of events where small islands of mobile bacteria were first seen forming near the root tip within the first 12–24 h of inoculation. Biofilm was then seen forming on the root epidermis at distances of about 700–1000 µm from the tip. Bacteria accumulated predominantly in confined pore spaces within 200 µm from the root or the surface of a particle. Using probabilistic models, we could map the complete sequence of events and propose a conceptual model of bacterial establishment in the pore space. This study therefore advances our understanding of the respective role of growth and mobility in the efficient colonization of bacteria in the rhizosphere.
Dorsoventral comparison of intraspecific polymorphisms in the butterfly wing pattern using a convolutional neural network
Authors: Amino Kai , Hirakasa Tsubasa , Yago Masaya , Matsuo Takashi
Published: August 2024

Butterfly wing patterns exhibit notable differences between the dorsal and ventral surfaces, and morphological analyses of them have provided insights into the ecological and behavioural characteristics of wing colour patterns. Conventional methods for dorsoventral comparisons are constrained by the need for homologous patches or shared features between two surfaces, limiting their applicability across species. We used a convolutional neural network (CNN)-based analysis, which can compare images of the dorsal and ventral surfaces without focusing on homologous patches or features, to detect dorsoventral bias in intraspecific polymorphisms such as sexual dimorphism (SD) and female-limited mimetic polymorphism (FMP). Using specimen images of 29 butterfly species from the Yaeyama Islands, Japan, we first showed that the level of SD calculated by CNN-based analysis corresponded well with traditional assessments of SD, demonstrating the validity of the method. Dorsoventral biases were widely detected, particularly in SD, which tended to bias dorsally. This supports the conventional hypothesis that sexual selection acts more strongly on the dorsal surface. In contrast, the FMP analysis showed no significant bias. Our findings highlight CNN-based analysis as a versatile technique for dorsoventral comparisons, suggesting that broader species sampling could reveal general patterns of selection acting differentially on the two surfaces.
Sensitivities in associating land-system archetypes with sustainability metrics: Insights from simulations
Authors: Varma Varun , Evans Paul M , Bütikofer Luca , Goodwin Cecily E D , Pywell Richard F , Redhead John W , Storkey Jonathan , Bullock James M , Mead Andrew
Published: August 2024

Archetypes of land- and socio-ecological systems, generated using unsupervised classification methods, enable the assimilation of complex environmental and socio-economic information. Such simplification has considerable potential to feed into decision support systems for sustainability planning. But, the usefulness of archetypes depends on how well they relate to sustainability criteria, such as ecosystem service (ES) delivery, that are external to the input datasets employed for archetype generation. Sensitivities in such post-hoc association analyses, and the associated utility of the archetype framework in a decision support context, remain unexplored. Here we emulated post-hoc association analysis procedures using simulated socio-ecological datasets and ES response variables. Our simulations revealed a substantial influence on analysis performance from (1) the number of variables used as inputs in archetype generation, (2) the correlation structure of input datasets, (3) the type and distribution of input variables, and (4) the functional form (linear or non-linear) characterising the relationship between ES variables and their predictors. We observed near-identical performance when archetypes were generated using K-means clustering and Self-Organising Maps (SOMs) – two commonly used archetype classification methods. Further, better archetype classifier performance did not guarantee better discrimination of ES value distributions between archetypes. Our results suggest that designing a framework to generate archetypes for sustainability planning, and the selected methodological choices therein, should place greater emphasis on what the archetypes will be used for in downstream analyses, and not focus solely on archetype classifier performance. This would better ensure the identification of archetypes adaptable to a diverse array of sustainability indicators and sufficiently robust for monitoring decision outcomes over time.
mosGraphGPT: a foundation model for multi-omic signaling graphs using generative AI
Authors: Zhang Heming , Huang Di , Chen Emily , Cao Dekang , Xu Tim , Dizdar Ben , Li Guangfu , Chen Yixin , Payne Philip , Province Michael , Li Fuhai
Published: August 2024

Generative pretrained models represent a significant advancement in natural language processing and computer vision, which can generate coherent and contextually relevant content based on the pre-training on large general datasets and fine-tune for specific tasks. Building foundation models using large scale omic data is promising to decode and understand the complex signaling language patterns within cells. Different from existing foundation models of omic data, we build a foundation model,mosGraphGPT, for multi-omic signaling (mos) graphs, in which the multi-omic data was integrated and interpreted using a multi-level signaling graph. The model was pretrained using multi-omic data of cancers in The Cancer Genome Atlas (TCGA), and fine-turned for multi-omic data of Alzheimer’s Disease (AD). The experimental evaluation results showed that the model can not only improve the disease classification accuracy, but also is interpretable by uncovering disease targets and signaling interactions. And the model code are uploaded via GitHub with link:https://github.com/mosGraph/mosGraphGPT
Enhanced pollen tube performance at high temperature contributes to thermotolerant fruit production in tomato
Authors: Yimga Ouonkap Sorel V. , Palaniappan Meenakshisundaram , Pryze Kelsey , Jong Emma , Ali Mohammad Foteh , Styler Benjamin , Almasaud Rasha Althiab , Harkey Alexandria F. , Reid Robert W. , Loraine Ann E. , Smith Steven E. , Muday Gloria K. , Pease James B. , Palanivelu Ravishankar , Johnson Mark A.
Published: August 2024

Rising temperature extremes during critical reproductive periods threaten the yield of major grain and fruit crops. Flowering plant reproduction depends on development of sufficient numbers of pollen grains and on their ability to generate a cellular extension, the pollen tube, which elongates through the pistil to deliver sperm cells to female gametes for double fertilization. These critical phases of the life cycle are sensitive to temperature and limit productivity under high temperature (HT). Previous studies have investigated the effects of HT on pollen development, but little is known about how HT applied during the pollen tube growth phase affects fertility. Here, we used tomato as a model fruit crop to determine how HT affects the pollen tube growth phase, taking advantage of cultivars noted for fruit production in exceptionally hot growing seasons. We found that exposure to HT solely during the pollen tube growth phase limits fruit biomass and seed set more significantly in thermosensitive cultivars than in thermotolerant cultivars. Importantly, we found that pollen tubes from the thermotolerant Tamaulipas cultivar have enhanced growthin vivoandin vitrounder HT. Analysis of the pollen tube transcriptome’s response to HT allowed us to develop hypotheses for the molecular basis of cellular thermotolerance in the pollen tube and we define two response modes (enhanced induction of stress responses, and higher basal levels of growth pathways repressed by heat stress) associated with reproductive thermotolerance. Importantly, we define key components of the pollen tube stress response identifying enhanced ROS homeostasis and pollen tube callose synthesis and deposition as important components of reproductive thermotolerance in Tamaulipas. Our work identifies the pollen tube growth phase as a viable target to enhance reproductive thermotolerance and delineates key pathways that are altered in crop varieties capable of fruiting under HT conditions.

Abstract Figure
Clinical efficacy landscaping in genetic obesity: A meta-analysis in Prader Willi syndrome (PWS)
Authors: Sarkar Manish , Horsten Henning von , Milunov Dimitrije , Lefebvre Nathalie Barreto , Saha Soham
Published: August 2024

Abstract

Genetic obesity such as Prader Willi syndrome (PWS) is a multifaceted condition influenced by various elements, including genetic predisposition, environmental factors, and behavioral components. This meta-analysis explored the reported efficacy of therapeutics in clinical trials for PWS by evaluating clinical endpoints reached in the course of the study and the adverse events observed for each. We looked at GLP1 receptor mediated and non-GLP1 receptor mediated therapies and compared their performance in study arms across time and standard of care. In addition, we estimated the present market shares across different obesity and diabetes assets which have been tested against PWS. In conclusion, the study points to two key readouts. First, existing obesity and diabetes assets are not effective for genetic obesity such as PWS. The unmet needs remain high. Second, the markets for obesity and diabetes are in a stage of expansion. A collaborative approach to therapy development for genetic obesity is required to improve the quality of life for affected individuals.
iSODA: A Comprehensive Tool for Integrative Omics Data Analysis in Single- and Multi-Omics Experiments
Authors: Olivier-Jimenez Damien , Derks Rico J. E. , Harari Oscar , Cruchaga Carlos , Ali Muhammad , Ori Alessandro , Di Fraia Domenico , Cabukusta Birol , Henrie Andy , Giera Martin , Mohammed Yassene
Published: August 2024

Omics technologies including genomics, proteomics, metabolomics, and lipidomics allow profound insights into health and disease. Thanks to plummeting costs of continuously evolving omics analytical platforms, research centers collect multi-omics data more routinely. They are, however, confronted with the lack of a versatile software solution to harmoniously analyze single-omics data and merge and interpret multi-omics data. We have developed iSODA, an interactive web-based application for the analysis of single-as well as multi-omics omics data. The software tool emphasizes intuitive, interactive visualizations designed for user-driven data exploration. Researchers can filter and normalize their datasets and access a variety of functions ranging from simple data visualization like volcano plots and PCA, to advanced functional analyses like enrichment analysis for proteomics and saturation analysis for lipidomics. For insights from integrated multi-omics, iSODA incorporates Multi-Omics Factor Analysis – MOFA, and Similarity Network Fusion – SNF. All results are presented in interactive plots with the possibility of downloading plots and associated data. The ability to adapt the imported data on-the-fly allows for tasks such as removal of outlier samples or failed features, various imputation strategies, or data normalization. The modular design allows for extensions with new analyses and plots. The software is accessible underhttp://isoda.online/.

Abstract Figure

Graphical summary for iSODA showcasing some application examples, the data import, the single-omics and multi-omics modules.
The genome assembly ofRhabditoides inermisfrom a complex microbial community reveals further evidence for parallel gene family expansions across multiple nematodes
Authors: Rödelsperger Christian , Röseler Waltraud , Athanasouli Marina , Wighard Sara , Herrmann Matthias , Sommer Ralf J.
Published: August 2024

Background

Free-living nematodes such asCaenorhabditis elegansandPristionchus pacificusare powerful model systems for linking specific traits to their underlying genetic basis. To trace the evolutionary history of a candidate gene, a robust phylogenomic framework is indispensable.

Results

In this work, we generated a near chromosome-scale genome assembly of the nematodeRhabditoides inermiswhich had previously been proposed as the sister group of the family Diplogastridae to whichP. pacificusbelongs. The genome was assembled from a complex microbial community that consists of multiple bacteria and a fungus of the genusVanrija. TheR. inermisgenome has five chromosomes that likely arose from recent fusions of different Nigon elements. Phylogenomic analysis groupedR. inermiswithin a clade includingC. elegans,Mesorhabditis belariand other rhabditids and thus, did not support a sister group relationship betweenR. inermisand the family Diplogastridae. Comparative genomic analyses identified abundant lineage-specific orthogroups which reveal evidence for parallel expansions of environmentally responsive gene families.

Conclusions

Our work demonstrates the value of theR. inermisgenome as a resource for future phylogenomic analysis and for studying gene family evolution.
Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN)
Authors: Pea Antonio , He Xiaotong , Upstill-Goddard Rosie , Luchini Claudio , Santana Leonor Patricia Schubert , Dreyer Stephan , Duthie Fraser , Jamieson Nigel B. , McKay Colin J. , Dickson Euan J. , Pulvirenti Alessandra , Rebus Selma ,   Genomics Innovation Alliance,   Scottish Genome Partnership, Piccoli Paola , Sperandio Nicola , Lawlor Rita T. , Milella Michele , Froeling Fieke E. M. , Salvia Roberto , Scarpa Aldo , Bainkin Andrew V. , Wedge David C. , Chang David K.
Published: August 2024

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies.
Predicting reproductive phenology of wind-pollinated trees via PlanetScope time series
Authors: Song Yiluan , Katz Daniel S.W. , Zhu Zhe , Beaulieu Claudie , Zhu Kai
Published: August 2024

Airborne pollen triggers allergic reactions which result in public health consequences. A better understanding of flowering and pollen phenology could improve airborne pollen predictions and reduce pollen exposure. Data on the timing of flowering and pollen release are needed to improve models of airborne pollen concentrations, but existingin-situdata collection efforts are expensive and spatially sparse. Satellite-based estimates of plant phenology could potentially enable large-scale data collection, but it is difficult to detect the reproductive phenology of wind-pollinated flowers from space. Here, we infer the reproductive phenology of wind-pollinated plants usingPlanetScopetime series with a spatial resolution of 3 m and a daily revisit cycle, complemented byin-situflower and pollen observations, leveraging the correlation between vegetative and reproductive phenology. On the individual tree level, we extracted PlanetScope-derived green-up time and validated its correlation to flowering time using flower observations in a national-scale observatory network. Scaling up to the city level, we developed a novel approach to characterize pollen phenology from PlanetScope-derived vegetative phenology, by optimizing two tuning parameters: the threshold of green-up or green-down and the time lag between green-up/down and flowering. We applied this method to seven cities in the US and seven key wind-pollinated tree genera, calibrated by measurements of airborne pollen concentrations. Our method characterized pollen phenology accurately, not only in-sample (Spearman correlation: 0.751, nRMSE: 13.5%) but also out-of-sample (Spearman correlation: 0.691, nRMSE: 14.5%). Using the calibrated model, we further mapped the pollen phenology landscape within cities, showing intra-urban heterogeneity. Using high spatiotemporal resolution remote sensing, our novel approach enables us to infer the flowering and pollen phenology of wind-pollinated plant taxa on a large scale and a fine resolution, including areas with limited priorin-situflower and pollen observations. The use of PlanetScope time series therefore holds promise for developing process-based pollen models and targeted public health strategies to mitigate the impact of allergenic pollen exposure.
Myeloid-instructed CD14+CD4+T cells within the tumor microenvironment are associated with TNF⍺ signaling and prolonged survival in non-small cell lung cancer
Authors: Marceaux Claire , Yokote Kenta , Gayevskiy Velimir , Batey Daniel , Tarasova Ilariya , Choux Laurie , Riley Lucy , Ribera Nina Tubau , Hywood Jack , Christie Michael , Antippa Phillip , Speed Terence P , Rogers Kelly L. , Phipson Belinda , Asselin-Labat Marie-Liesse
Published: August 2024

Immune cells from the adaptive and innate immune systems coexist in the tumor immune microenvironment (TME) to mediate tumor cell immunosurveillance and prevent tumor relapse. Relapse-free survival after surgical resection is heterogeneous in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of non-small cell lung cancer. Yet, little is known about the composition and spatial organisation of the TME that could explain the different prognoses for lung cancer patients. Using spatial multi-omics analyses, we show that LUAD and LUSC have distinct TMEs and that neutrophil-enriched tumors are associated with worse survival, while the accumulation of myeloid-instructed CD14+T cells in the tumor core was associated with prolonged patient survival. CD14+CD4+T cells express prototypic markers of myeloid cells and were found to be clonally expanded tumor-specific activated T cells. TNFα signaling was activated in tumors with high infiltration of CD14+CD4+T cells in the tumor core. Our results demonstrate that innate immune cells impact adaptive immune cell activity to support the deployment of discrete T cell populations with anti-tumor activity.
Anodal tsDCS restores the structure and function of the disrupted proprioceptive Ia synapses on spinal motoneurons in the SOD1 G93A mouse model of ALS
Authors: Jankowiak T. , Cholewiński M. , Kryściak K. , Krok E. , Grycz K. , Bączyk M.
Published: August 2024

An imbalance between cells’ intrinsic excitability and synaptic excitation levels is the basis of spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a restoration of the deficient Ia synaptic excitation of spinal MNs was achieved by applying acute trans-spinal direct current stimulation (tsDCS) to presymptomatic SOD1 G93A mice. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 animals can provoke spinal MN neuroplasticity and reduce the disease burden. Anodal, cathodal or sham polarisation of 100 µA was applied to P30-P35 SOD1 G93A mice; passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of polarized animals was used to test the impact of our intervention on Ia synapse morphology, MN intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs, coupled with a significant upregulation of vesicular glutamate transporter levels and GlurR4 subunits of AMPA receptors at the Ia synapse. On the other hand, cathodal polarisation failed to induce any significant alteration to Ia synapse morphology but did increase both peak and plateau input resistance and recovered the abnormal paired-pulse ratio. Unexpectedly, the changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular pathways ctivity and did not decrease the disease burden. Altogether our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which nevertheless appears insufficient to alter disease dynamics.

Highlights

14-days of trans-spinal direct current stimulation (tsDCS) alters the electrophysiological properties and morphology of Ia proprioceptive synapses on spinal MNs in SOD1 G93A mouse model of ALS

Anodal (depolarising) tsDCS increases MN synaptic excitation and restores the postsynaptic elements of the Ia synapse

Cathodal (hyperpolarising) tsDCS increases MN input resistance but does not impact Ia synapse morphology

Both anodal and cathodal tsDCS fail to significantly modify the cellular burden of the disease
Heat Shock Factor Regulation of Antimicrobial Peptides Expression Suggests a Conserved Defense Mechanism Induced by Febrile Temperature in Arthropods
Authors: Xiao Bang , Chen Shihan , Wang Yue , Liao Xuzheng , He Jianguo , Li Chaozheng
Published: August 2024

Temperature is a critical factor influencing the outbreak and progression of viral diseases in organisms. Febrile temperatures have been shown to enhance immune competence and reduce viral replication in various species. However, the underlying mechanisms remain largely unknown. In this study, we investigate the molecular mechanisms by which elevated temperatures confer resistance to viral infections, focusing on the role of heat shock factor 1 (HSF1) in regulating antimicrobial effectors rather than the traditional target genes molecular chaperones. Using shrimpLitopenaeus vannameias a model, we demonstrate that febrile temperatures induce HSF1, which in turn upregulates antimicrobial peptides (AMPs) that target viral envelope proteins and inhibit viral replication. Importantly, this is the first to show that HSF1 directly binds to the heat shock elements (HSE) motifs of AMPs both in shrimp andDrosophila, suggesting this may be a conserved regulatory mechanism in arthropods. Additionally, our findings highlight the role of HSF1 beyond the classical heat shock response, revealing its critical function in modulating innate immunity. These insights provide new avenues for managing viral infections in aquaculture and other settings by leveraging environmental temperature control.
AROMHA Brain Health Test: A Remote Olfactory Assessment as a Screen for Cognitive Impairment
Authors: Jobin Benoît , Magdamo Colin , Delphus Daniela , Runde Andreas , Reineke Sean , Soto Alysa Alejandro , Ergun Beyzanur , Albers Alefiya Dhilla , Albers Mark W.
Published: August 2024

Cost-effective, noninvasive screening methods for preclinical Alzheimer’s disease (AD) and other neurocognitive disorders remain an unmet need. The olfactory neural circuits develop AD pathological changes prior to symptom onset. To probe these vulnerable circuits, we developed the digital remote AROMHA Brain Health Test (ABHT), an at-home odor identification, discrimination, memory, and intensity assessment.

The ABHT was self-administered among cognitively normal (CN) English and Spanish speakers (n=127), participants with subjective cognitive complaints (SCC; n=34), and mild cognitive impairment (MCI; n=19). Self-administered tests took place remotely at home under unobserved (among interested CN participants) and observed modalities (CN, SCC, and MCI), as well as in-person with a research assistant present (CN, SCC, and MCI).

Olfactory performance was similar across observed and unobserved remote self-administration and between English and Spanish speakers. Odor memory, identification, and discrimination scores decreased with age, and olfactory identification and discrimination were lower in the MCI group compared to CN and SCC groups, independent of age, sex, and education.

The ABHT revealed age-related olfactory decline, and discriminated CN older adults from those with cognitive impairment. Replication of our results in other populations would support the use of the ABHT to identify and monitor individuals at risk for developing dementia.
Transforming Childhood Vaccination Rates in Rural Egypt: A Case Study on Results-Based Management in Healthcare Programs
Authors: Shultz Tanya , Gabriel Sandra , Hussein Muhammad , Swint Jennifer , ElBoray Mona , Peter Amanda , Zeinhom Zahra , Abbas Hend , Anwar Samah , Zhang Wei
Published: August 2024

This case study examines the implementation of a results-based management (RBM) approach in a childhood vaccination program across rural Egypt. The project, initiated in 2020, aimed to address the persistently low immunization rates in remote areas by restructuring healthcare delivery and resource allocation.

The study details how the RBM framework was applied to set clear, measurable objectives, develop key performance indicators, and establish a robust monitoring and evaluation system. It highlights the innovative use of mobile health technologies for data collection and analysis, enabling real-time adjustments to the program strategy.

Over a three-year period, the initiative achieved a remarkable 40% increase in vaccination coverage, significantly reducing the incidence of preventable childhood diseases in the target regions. The case study explores the challenges encountered, including cultural barriers and logistical hurdles, and describes the adaptive management techniques employed to overcome these obstacles.

This research provides valuable insights into the effective application of RBM principles in resource-constrained settings, demonstrating how data-driven decision-making and stakeholder engagement can lead to substantial improvements in public health outcomes. The findings offer practical guidelines for healthcare managers and policymakers seeking to enhance the efficiency and impact of their programs in similar contexts.
Novel Amplicons based Method for Near-Full-Length Genome (NFLG) Sequencing of HIV-1 Group M Recombinant Forms
Authors: Moscona Roy , Wagner Tali , Geva Miranda , Bucris Efrat , Erster Oran , Zuckerman Neta S. , Mor Orna
Published: August 2024

Over the years the spread of HIV-1 across the globe resulted in the creation of multiple subtypes and new recombinant forms (RFs). While the pol gene region of the HIV-1 genome is used for resistance mutations analysis and initial detection of RFs, whole genome sequencing analysis is required to determine recombination events across the viral genome. Here, we present a novel robust near-full length genome (NFLG) sequencing approach for the sequencing of HIV-1 genomes, out of clinical whole blood samples. This method has been successfully tested for various HIV-1 subtypes and RFs.

The method is based on an in-house developed set of 32 pan-genotypic primer pairs, divided into two pools, each containing 16 primer pairs covering the entire HIV-1 genome. Two parallel multiplex PCR reactions were used to generate 32 overlapping DNA fragments spanning the HIV-1 genome. Nextera XT protocol was used to obtain barcoded DNA libraries, which were sequenced with the Illumina Miseq platform using a V3 kit. A consensus sequence was determined for each sample and was used to define recombination events across the genome. For this aim, a combined analysis of several computational tools including HIV BLAST, phylogenetic analysis, RIP, SimPlot++ and jpHMM were employed. Overall, plasma samples from 33 patients suspected to carry RFs and 2 different, known pure subtypes controls, were included in this study. Genome coverage varied between RFs, while the gag and pol genes were nearly fully covered, the highly variable env gene region was not. Yet, these NFLG analyses enabled the identification of recombination events genome wide.

In summary, we describe a methodology for HIV-1 NFLG sequencing, which is based on partially overlapping, multiple PCR fragments, spanning the HIV-1 genome. Additionally, this newly refined method was compared to HIV-1 NFLG results of PCR-free metagenomic sequencing and proved to obtain greater coverage of the HXB2 reference genome. Yet, further testing and validation on a larger cohort is required. Still, this method enables sequencing of 20 different patient samples in a single MiSeq sequencing run and was used for the characterization of different HIV-1 RFs and pure subtypes circulating in Israel.
Syncing Strategy and Execution: A Systematic Review of Public Health Preparedness Policy Implementation
Authors: Swint Jennifer , Zhang Wei , Marrison Amanda , Gabriel Sandra
Published: August 2024

Background

The gap between public health preparedness and response policies and their practical implementation remains a critical challenge in global health security. This systematic review synthesizes evidence on barriers to effective policy implementation and identifies strategies for bridging this policy- practice gap.

Methods

We systematically searched six electronic databases for peer-reviewed studies published between 2000 and 2023 focusing on the implementation of public health preparedness and response policies. Study quality was assessed using the Mixed Methods Appraisal Tool (MMAT) and AMSTAR-2.

Results

Of 2,456 initially identified studies, 87 met the inclusion criteria. Studies addressed various public health emergencies, including infectious disease outbreaks (n=41, 47.1%), natural disasters (n=23, 26.4%), and man-made disasters (n=8, 9.2%). Key barriers to policy implementation included organizational factors (76 studies, 87.4%), resource constraints (72 studies, 82.8%), and communication challenges (68 studies, 78.2%). Promising strategies for bridging the gap included adaptive management approaches (38 studies, 43.7%), participatory policy development (35 studies, 40.2%), and integrated information systems (31 studies, 35.6%). Only 23 studies (26.4%) were assessed as high quality, with limited quantitative evidence on strategy effectiveness.

Conclusions

While several promising strategies for bridging the policy-practice gap have been identified, there is a critical need for more rigorous evaluations of their effectiveness. Future research should focus on organizational reforms, flexible resource allocation, and leveraging emerging technologies to enhance policy implementation in public health preparedness and response.
The Effect of a Post-Bronchodilator FEV1/FVC<0.7 on COPD Diagnosis and Treatment: A Regression Discontinuity Design
Authors: Moffett Alexander T. , Halpern Scott D. , Weissman Gary E.
Published: August 2024

Background

Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend the diagnosis of chronic obstructive pulmonary disease (COPD) only in patients with a post-bronchodilator forced expiratory volume in 1 second to forced vital capacity ratio (FEV1/FVC) less than 0.7. However the impact of this recommendation on clinical practice is unknown.

Research Question

What is the effect of a documented post-bronchodilator FEV1/FVC<0.7 on the diagnosis and treatment of COPD?

Study Design and Methods

We used a national electronic health record database to identify clinical encounters between 2007 to 2022 with patients 18 years of age and older in which a post-bronchodilator FEV1/FVC value was documented. An encounter was associated with a COPD diagnosis if a diagnostic code for COPD was assigned, and was associated with COPD treatment if a prescription for a medication commonly used to treat COPD was filled within 90 days. We used a regression discontinuity design to measure the effect of a post-bronchodilator FEV1/FVC<0.7 on COPD diagnosis and treatment.

Results

Among 27 817 clinical encounters, involving 18 991 patients, a post-bronchodilator FEV1/FVC<0.7 was present in 14 876 (53.4%). The presence of a documented post-bronchodilator FEV1/FVC<0.7 had a small effect on the probability of a COPD diagnosis, increasing by 6.0% (95% confidence interval [CI] 1.1% to 10.9%) from 38.0% just above the 0.7 cutoff to 44.0% just below this cutoff. The presence of a documented post-bronchodilator FEV1/FVC had no effect on the probability of COPD treatment (−2.1%, 95% CI−7.2% to 3.0%).

Interpretation

The presence of a documented post-bronchodilator FEV1/FVC<0.7 has only a small effect on the probability that a clinician will make a guideline-concordant diagnosis of COPD and has no effect on corresponding treatment decisions.
Toward Predicting Peripheral Artery Disease Treatment Outcomes Using Non-Clinical Data
Authors: Ramini Ali Al , Fallahtafti Farahnaz , TakallouIraklis Mohammad Ali , Pipinos Iraklis , Myers Sara , Alsaleem Fadi
Published: August 2024

Peripheral Artery Disease (PAD) significantly impairs quality of life and presents varying degrees of severity that correctly identifying would help choose the proper treatment approach and enable personalized treatment approaches. However, the challenge is that there is no single agreed-on measure to quantify the severity of a patient with PAD. This led to a trial-and-error approach to deciding the course of treatment for a given patient with PAD. This study uses non-clinical data, such as biomechanical data and advanced machine-learning techniques, to detect PAD severity levels and enhance treatment selection to overcome this challenge. Our findings in this paper lay the groundwork for a more data-driven, patient-centric approach to PAD management, optimizing treatment strategies for better patient outcomes.
Chemically induced dislocation and mutation of essential cytoskeletal proteins: A case study focusing on Coronin-A
Authors: Stange Maike B. , Großmann Robert , Flemming Sven , Grebe Markus , Beta Carsten
Published: August 2024

Actin is one of the most highly conserved proteins—the actin cytoskeleton or actin-like structures are found in all kingdoms of life. In this work, Coronin-A, a central player involved in actin dynamics, is considered as an example to compare the effect of four mutation strategies on its function inDictyostelium discoideum. Two distinct genetic knockout methods (selection-linked integration and classical gene disruption), RNAi knockdown, and sudden loss-of-function generated by chemically induced dislocation (CID) are compared and the cell lines are characterized according to actin dependent processes: appearance, development, and motility. These phenotypic features are affected to different degrees in the mutant cell lines, providing a basis to discuss the strengths and weaknesses of each approach. This comparative study highlights the advantages of the newly introduced selection-linked integration method to knock out genes over commonly used gene disruption, and for expressing a CID-based knock-sideways system under the native promotor of the protein of interest.
Active control of mitochondrial network morphology by metabolism driven redox state
Authors: Singh Gaurav , Vengayil Vineeth , Khanna Aayushee , Adhikary Swagata , Laxman Sunil
Published: August 2024

Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the Electron Transport Chain (ETC)— through complex I/II, or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC genetically or chemically, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively controls mitochondrial form.
Uncoupling the functional roles of Coronavirus Nsp1
Authors: Bäumlin Emilie , Andenmatten Dominic , Luginbühl Jonas , Lalou Aurélien , Schwaller Nino , Karousis Evangelos D.
Published: August 2024

When host cells are infected with coronaviruses, the first viral protein produced is Nsp1. This protein inhibits host protein synthesis and induces host mRNA degradation to enhance viral proliferation. Despite its critical role, the mechanism by which Nsp1 mediates cellular mRNA degradation remains unclear. In this study, we use cell-free translation to address how the host mRNA stability is regulated by Nsp1. We reveal that SARS-CoV-2 Nsp1 binding to the ribosome is enough to trigger mRNA degradation independently of ribosome collisions or active translation. MERS-CoV Nsp1 inhibits translation without triggering degradation, highlighting mechanistic differences between the two Nsp1 counterparts. Nsp1 and viral mRNAs appear to co-evolve, rendering viral mRNAs immune to Nsp1-mediated degradation in SARS-CoV-2, MERS-CoV and Bat-Hp viruses. By providing new insights into the mode of action of Nsp1, our study helps to understand the biology of Nsp1 better and find new strategies for therapeutic targeting against coronaviral infections.

Significance

Cell-free assays allow the decoupling of Nsp1-mediated translation inhibition from RNA degradation.

Nsp1 interaction with the ribosome is crucial for mRNA degradation, but active translation is not required.

SARS-CoV-2 Nsp1 induces mRNA degradation, while MERS-CoV Nsp1 inhibits translation without triggering degradation.

5’UTR-specific protection of viral mRNAs from Nsp1 indicates a co-evolutionary adaptation between the two features
HIF1α controls steroidogenesis under acute hypoxic stress
Authors: Ariyeloye Stephen , Watts Deepika , Jaykar Mangesh , Ermis Cagdas , Krueger Anja , Kaden Denise , Stepien Barbara K. , Alexaki Vasileia Ismini , Peitzsch Mirko , Bechmann Nicole , El-Armouche Ali , Wielockx Ben
Published: August 2024

Background Hypoxia is a critical physiological and pathological condition known to influence various cellular processes, including steroidogenesis. While previous studies, including our own, have highlighted the regulatory effects of Hypoxia-Inducible Factor 1α (HIF1α) on steroid production, the specific molecular mechanisms remain poorly understood. This study investigates the role of hypoxia and HIF1α in steroid biosynthesis across multiple experimental models during acute exposure to low oxygen levels. Methods To assess the extent to which acute hypoxia modulates steroidogenesis, we employed several approaches, including the Y1 adrenocortical cell line, an ex vivo adrenal gland explant model, and a conditional HIF1α-deficient mouse line in the adrenal cortex. We focused on various regulatory patterns that may critically suppress steroidogenesis. Results In Y1 cells and adrenal gland explants, hypoxia induced the upregulation of specific microRNAs, leading to the suppression of mRNA levels of key steroidogenic enzymes and reduced steroid hormone production. The hypoxia/HIF1α-dependent induction of these microRNAs and the consequent modulation of steroid production were confirmed in vivo. Notably, using our conditional HIF1α-deficient mouse line, we found that the increase in miRNA expression under hypoxic conditions is directly dependent on HIF1α. Furthermore, the regulation of steroidogenic enzymes (e.g., StAR and Cyp11a1) and steroid production occurred at the level of protein translation, revealing an unexpected layer of control under hypoxic conditions in vivo. Conclusions These findings elucidate the molecular mechanisms underlying acute hypoxia-induced changes in steroid biosynthesis and may also be useful in developing new strategies for various steroid hormone pathologies.
Statistics in service of metascience: Measuring replication distance with reproducibility rate
Authors: Buzbas Erkan , Devezer Berna
Published: August 2024

Motivated by the recent putative reproducibility crisis, we discuss the relationship between replicability of scientific studies, reproducibility of results obtained in these replications, and the philosophy of statistics. Our approach focuses on challenges in specifying scientific studies for scientific inference via statistical inference, and is complementary to classical discussions in philosophy of statistics. We particularly consider the challenges in replicating studies exactly, using the notion of the idealized experiment. We argue against treating reproducibility as an inherently desirable property of scientific results, and in favor of viewing it as a tool to measure distance between an original study and its replications. To sensibly study the implications of replicability and results reproducibility on inference, such a measure of replication distance is needed. We present an effort to delineate such a framework here, addressing some challenges in capturing the components of scientific studies while identifying others as ongoing issues. We illustrate our measure of replication distance by simulations using a toy example. Rather than replications, we present purposefully planned modifications as an appropriate tool to inform scientific inquiry. Our ability to measure replication distance serves scientists in their search for replication-ready studies. We believe that likelihood-based and evidential approaches may play a critical role towards building a statistics that effectively serves the practical needs of science.
Apical Size Reduction by Macropinocytosis Alleviates Tissue Crowding
Authors: Bresteau Enzo , Suva Eve E , Revell Christopher , Hassan Osama A , Grata Aline , Sheridan Jennifer , Mitchell Jennifer , Arvantis Constandina , Korobova Farida , Woolner Sarah , Jensen Oliver , Mitchell Brian
Published: August 2024

Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report cell size reduction via macropinocytosis as an alternative mechanism. Macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane and driving a reduction in apical cell size that remodels the epithelium to alleviate crowding. We report that this mechanism regulates the long-term organization of developing epithelium in response to proliferation-induced crowding but also serves as an immediate response to acute external compression. In both cases, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
A mRNA Vaccine Encoding for a 60-mer G Glycoprotein Nanoparticle Elicits a Robust Neutralizing Antibodies Response Against the Nipah Virus
Authors: Brandys Pascal , Albariño César G , Jain Shilpi , Merenkova Irena , Schork Nicholas J , Deng Aihua , Valière Martine , Herold Jens
Published: August 2024

The Nipah virus is a zoonotic pathogen causing encephalitis and acute respiratory illness in humans with very high fatality rates. Here we report a novel messenger RNA vaccine that directly encodes for a nanoparticle displaying 60 head domains of the Nipah virus G (NiV G) glycoprotein that acts as a highly effective antigen. A vaccine encoding for the NiV G nanoparticle elicits high antibody titers against NiV G and a robust neutralizing antibody response with a pseudotyped Nipah virus system. We ultimately find that the proposed mRNA NiV G nanoparticle (mRNA NiV G-NP) provides a flexible platform for the development of vaccines that will likely be of great value in combatting future Nipah virus outbreaks.