bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-read sequencing unravels the complexity of structural variants inPRKNin two individuals with early-onset Parkinson’s disease
Authors: Cogan Guillaume , Daida Kensuke , Billingsley Kimberley J. , Tesson Christelle , Forlani Sylvie , Jornea Ludmila , Arnaud Lionel , Tissier Laurene , LeGuern Eric , Singleton Andrew B. , Ferrien Mélanie , Gervais Bernard Hélène , Lesage Suzanne , Blauwendraat Cornelis , Brice Alexis
Published: May 2024

Background

PRKNbiallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinson’s disease (PD). However, the variants responsible for suspectedPRKN-PD individuals are not always identified with standard genetic testing.

Objectives

Identify the genetic cause in two siblings with aPRKN-PD phenotype using long-read sequencing (LRS).

Methods

The genetic investigation involved standard testing using successively multiple ligation probe amplification (MLPA), Sanger sequencing, targeted sequencing, whole-exome sequencing and LRS.

Results

MLPA and targeted sequencing identified one copy of exon four inPRKNbut no other variants were identified. Subsequently, LRS unveiled a large deletion encompassing exon 3 to 4 on one allele and a duplication of exon 3 on the second allele; explaining the siblings’ phenotype. MLPA could not identify the balanced rearrangement of exon 3.

Conclusions

This study highlights the potential utility of long-read sequencing in the context of unsolved typicalPRKN-PD individuals.
Assessment of 3D hemi-diaphragmatic motion via free-breathing dynamic MRI in pediatric thoracic insufficiency syndrome
Authors: Hosseini Mahdie , Udupa Jayaram K. , Hao You , Tong Yubing , Wu Caiyun , Akhtar Yusuf , Al-Noury Mostafa , Shaghaghi Shiva , McDonough Joseph M. , Biko David M. , Gogel Samantha , Mayer Oscar H. , Cahill Patrick J. , Torigian Drew A. , Anari Jason B.
Published: May 2024

Purpose

Thoracic insufficiency syndrome (TIS) affects ventilatory function due to spinal and thoracic deformities limiting lung space and diaphragmatic motion. Corrective orthopedic surgery can be used to help normalize skeletal anatomy, restoring lung space and diaphragmatic motion. This study employs free-breathing dynamic MRI (dMRI) and quantifies the 3D motion of each hemi-diaphragm surface in normal and TIS patients, and evaluates effects of surgical intervention.

Materials and Methods

In a retrospective study of 149 pediatric patients with TIS and 190 healthy children, we constructed 4D images from free-breathing dMRI and manually delineated the diaphragm at end-expiration (EE) and end-inspiration (EI) time points. We automatically selected 25 points uniformly on each hemi-diaphragm surface, calculated their relative velocities between EE and EI, and derived mean velocities in 13 homologous regions for each hemi-diaphragm to provide measures of regional 3D hemi-diaphragm motion. T-testing was used to compare velocity changes before and after surgery, and to velocities in healthy controls.

Results

The posterior-central region of the right hemi-diaphragm exhibited the highest average velocity post-operatively. Posterior regions showed greater velocity changes after surgery in both right and left hemi-diaphragms. Surgical reduction of thoracic Cobb angle displayed a stronger correlation with changes in diaphragm velocity than reduction in lumbar Cobb angle. Following surgery, the anterior regions of the left hemi-diaphragm tended to approach a more normal state.

Conclusion

Quantification of regional motion of the 3D diaphragm surface in normal subjects and TIS patients via free-breathing dMRI is feasible. Derived measurements can be assessed in comparison to normal subjects to study TIS and the effects of surgery.
Using group norms to promote acceptance of HIV testing during household tuberculosis contact investigation: A household-randomized trial
Authors: Armstrong-Hough Mari , Gupta Amanda J. , Ggita Joseph , Nangendo Joan , Katamba Achilles , Davis J. Lucian
Published: May 2024

Background

HIV status awareness and linkage to care are critical for ending the HIV epidemic and preventing tuberculosis (TB). Among household contacts of persons with TB, HIV greatly increases the risk of incident TB and death. However, almost half of household contacts in routine settings decline HIV test offers during routine contact investigation. We evaluated a brief social-behavioral norming intervention to increase acceptance of HIV testing during household TB contact investigation.

Methods

We carried out a household-randomized, controlled trial to evaluate the effect of the norming strategy among household contacts of persons with pulmonary TB in Kampala, Uganda (ClinicalTrials.gov#NCT05124665). Community health workers (CHW) visited homes of persons with TB to screen contacts for TB symptoms and offer free, optional, oral HIV testing. Households were randomized (1:1) to usual care or the norming strategy. Contacts were eligible if they were ≥ 15 years old, self-reported to be HIV-negative, and living in a multi-contact household. The primary outcome, the proportion of contacts accepting HIV testing, was analyzed using an intention-to-treat approach, using a mixed-effects model to account for clustering by household. We assessed HIV testing yield as a proportion of all contacts tested.

Results

We randomized 328 contacts in 99 index households to the norming strategy, of whom 285 (87%) contacts were eligible. We randomized 224 contacts in 86 index households to the usual strategy, of whom 187 (84%) contacts were eligible. Acceptance of HIV testing was higher in the intervention arm (98% versus 92%, difference +6%, 95%CI +2% to +10%, p=0.004). Yield of HIV testing was 2.1% in the intervention arm and 0.6% in the control arm (p=0.22).

Conclusion

A norming intervention significantly improved uptake of HIV testing among household contacts of persons with TB.

Funding/Support

This work was supported by the Center for Interdisciplinary Research on AIDS (P30MH062294) and the Fogarty International Center of the National Institutes of Health (R21TW011270). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other sponsors.
Mapping the Global Landscape of Task Shifting and Sharing: A Bibliographic Analysis from 1970 to 2022
Authors: Das Shukanto , Grant Liz
Published: May 2024

Task shifting and sharing (TS/S) are strategies for redistributing healthcare services from more specialised to less-qualified providers. It aims to optimise service delivery, particularly in resource-constrained settings with workforce shortages. Our paper provides an overview of the global landscape of TS/S research, examining the geographic distribution, publication trends, variation in descriptors for TS/S and the disease focus of articles on TS/S. We searched five databases in October 2022, namely Medline, CINAHL Plus, Elsevier, Global Health and Google Scholar. Our bibliographic analysis included 2,072 articles related to TS/S. We extracted data on the countries where the studies were based, the terminology used to describe task redistribution, and the specific disease focus of the publications. The findings were then visualised and analysed to uncover trends and insights. The results revealed that TS/S research has been most extensively conducted in certain African and South Asian countries, particularly South Africa, India, Uganda, Kenya and Malawi. The terminology used to describe task redistribution varied, with “task shifting” being the most common term (66.0%), followed by “task sharing” (24.0%), “task delegation” (6.0%), and “task shifting and sharing” (3.9%). The disease focus of the publications was diverse, with HIV (n=450) and depression (n=375) being the most studied conditions, A major proportion of articles (42.5%) did not carry a disease focus, instead concentrated on broader health systems strengthening and policy issues. In conclusion, our study offers insights into the global landscape of TS/S research, highlighting the geographic disparities, terminology nuances and disease-specific applications. We believe our findings can inform future research and practice, including the need for standardisation of terminology, targeted implementation efforts, expansion of disease-specific applications and a focus on comprehensive systems strengthening. By addressing these considerations, stakeholders can optimise the impact of TS/S strategies and improve healthcare delivery and outcomes globally.
Optimizing Spatial Distribution of Wastewater-Based Disease Surveillance to Advance Health Equity
Authors: Daza–Torres Maria L. , Montesinos-López J. Cricelio , Herrera César , García Yury E. , Naughton Colleen C. , Bischel Heather N. , Nuño Miriam
Published: May 2024

In 2022, the US Centers for Disease Control and Prevention commissioned the National Academies of Sciences, Engineering, and Medicine to assess the role of community-level wastewater-based disease surveillance (WDS) beyond COVID-19. WDS is recognized as a promising mechanism for promptly identifying infectious diseases, including COVID-19 and other novel pathogens. An important conclusion drawn from this initiative is that it is crucial to maintain equity and expand access to maximize the advantages of WDS for marginalized communities. To address this need, we propose an optimization framework that focuses on the strategic allocation of wastewater monitoring resources at the wastewater treatment plant level. The framework’s purpose is to obtain a balanced spatial distribution, inclusive population coverage, and efficient representation of vulnerable communities in allocating resources for WDS. This study offers an opportunity to improve wastewater surveillance by tailoring location selection strategies to address specific priorities, improving decision-making in public health responses.
Numerical Cincinnati Stroke Scale versus Stroke Severity Screening Tools for the Prehospital Determination of LVO
Authors: Wagstaff Holden M. , Crowe Remle P. , Youngquist Scott T. , Stoecklein H. Hill , Treichel Ali , He Yao , Majersik Jennifer J.
Published: May 2024

Background

Previous research demonstrated that the numerical Cincinnati Prehospital Stroke Scale (CPSS) identifies large vessel occlusion (LVO) at similar rates compared to a limited number of stroke severity screening tools. We aimed to compare numerical CPSS to additional stroke scales using a national EMS database.

Methods

Using the ESO Data Collaborative, the largest EMS database with hospital linked data, we retrospectively analyzed prehospital patient records for the year 2022. Stroke and LVO diagnoses were determined by ICD-10 codes from linked hospital discharge and emergency department records. Prehospital CPSS was compared to the Cincinnati Stroke Triage Assessment Tool (C-STAT), the Field Assessment Stroke Triage for Emergency Destination (FAST-ED), and the Balance Eyes Face Arm Speech Time (BE-FAST). The optimal prediction cut-points for LVO screening were determined by intersecting the sensitivity and specificity curves for each scale. To compare the discriminative abilities of each scale among those diagnosed with LVO, we used the area under the receiver operating curve (AUROC).

Results

We identified 17,442 prehospital records from 754 EMS agencies with ≥ 1 documented stroke scale of interest: 30.3% (n=5,278) had a hospital diagnosis of stroke, of which 71.6% (n=3,781) were ischemic; of those, 21.6% (n=817) were diagnosed with LVO. CPSS score ≥ 2 was found to be predictive of LVO with 76.9% sensitivity, 68.0% specificity, and AUROC 0.787 (95% CI 0.722-0.801). All other tools had similar predictive abilities, with sensitivity / specificity / AUROC of: C-STAT 62.5% / 76.5% / 0.727 (0.555-0.899); FAST-ED 61.4% / 76.1%/ 0.780 (0.725-0.836); BE-FAST 70.4% / 67.1% / 0.739 (0.697-0.788).

Conclusion

The less complex CPSS exhibited comparable performance to three frequently employed LVO detection tools. EMS agency leadership, medical directors, stroke system directors, and other stroke leaders may consider the complexity of stroke severity instruments and challenges with ensuring accurate recall and consistent application when selecting which instrument to implement. Use of the simpler CPSS may enhance compliance with the utilization of LVO screening instruments while maintaining the accuracy of prehospital LVO determination.
TOMOMAN: a software package for large scale cryo-electron tomography data preprocessing, community data sharing, and collaborative computing
Authors: Khavnekar Sagar , Erdmann Philipp S. , Wan William
Published: May 2024

Cryo-electron tomography (cryo-ET) and subtomogram averaging (STA) are becoming the preferred methodologies for investigating subcellular and macromolecular structures in native or near-native environments. While cryo-ET is amenable to a wide range of biological problems, these problems often have data processing requirements that need to be individually optimized, precluding the notion of a one-size-fits-all processing pipeline. Cryo-ET data processing is also becoming progressively more complex due to an increasing number of packages for each processing step. Though each package has its own strengths and weaknesses, independent development and different data formats makes them difficult to interface with one another. TOMOMAN (TOMOgram MANager) is an extensible package for streamlining the interoperability of packages, enabling users to develop project-specific processing workflows. TOMOMAN does this by maintaining an internal metadata format and wrapping external packages to manage and perform preprocessing, from raw tilt-series data to reconstructed tomograms. TOMOMAN can also export this metadata between various STA packages. TOMOMAN also includes tools for archiving projects to data repositories; allowing subsequent users to download TOMOMAN projects and directly resume processing where it was previously left off. By tracking essential metadata, TOMOMAN streamlines data sharing, which improves reproducibility of published results, reduces computational costs by minimizing reprocessing, and enables distributed cryo-ET projects between multiple groups and institutions. TOMOMAN provides a way for users to test different software packages to develop processing workflows that meet the specific needs of their biological questions and to distribute their results with the broader scientific community.
Elucidating the Impact ofHypericum alpestreExtract and L-NAME on the PI3K/Akt Signaling Pathway in A549 Lung Adenocarcinoma Cells
Authors: Javrushyan Hayarpi , Ginovyan Mikayel , Petrosyan Gayane , Qocharyan Mery , Harutyunyan Tigran , Gevorgyan Smbat , Karabekian Zaruhi , Maloyan Alina , Avtandilyan Nikolay
Published: May 2024

Plants within theHypericaceaefamily have been traditionally used for their medicinal properties, showcasing a wide range of effects such as antibacterial, antiviral, and antioxidant qualities.Hypericum alpestre(HA) extracts have exhibited significant cytotoxicity against various cancer cell lines. The phenolic compounds found in HA extracts have attracted attention for their potential in cancer prevention. L-NAME, known for its ability to inhibit nitric oxide synthase (NOS) activity, has emerged as a promising approach in cancer therapy. However, the precise molecular mechanisms underlying the anticancer effects of HA and L-NAME remain unclear. This study aims to clarify the impact of HA and L-NAME on the PI3K/Akt signaling pathway in A549 lung adenocarcinoma cells, with a specific focus on TNFa/COX-2 and VEGFa/MMP-2 pathways.In silicoanalysis, they identified the compounds with the highest affinity for PI3K/Akt, a finding validated by subsequentin vitroexperiments. Furthermore, the combination of herbs and L-NAME exhibited superior efficacy compared to the herb and 5-FU combination, as evidenced by the promotion of apoptosis. Both the herb alone and the combination of the herb with L-NAME demonstrated inhibitory effects on the TNFa/COX-2 and VEGFa/MMP-2 pathways. This therapeutic approach is hypothesized to operate through the PI3k/Akt cell signaling pathway. A better understanding of the interaction between HA polyphenols and PI3K/Akt signaling could pave the way for novel therapeutic strategies against cancer, including drug-resistant tumors.
parafac4microbiome: Exploratory analysis of longitudinal microbiome data using Parallel Factor Analysis
Authors: van der Ploeg G.R. , Westerhuis J.A. , Heintz-Buschart A. , Smilde A.K.
Published: May 2024

Studies investigating microbial temporal dynamics are increasingly common, leveraging longitudinal designs that collect microbial abundance data across multiple time points from the same subjects. Traditional exploratory approaches like Principal Component Analysis (PCA) fail to fully utilize this structure. By organizing data as a three-way array—subjects as rows, microbial abundances as columns, and time points as the third dimension—multi-way methods such as Parallel Factor Analysis (PARAFAC) can better capture temporal and structural patterns. This study demonstrates Parallel Factor Analysis (PARAFAC) as a method to explore longitudinal microbiome data using three exemplary studies.

In the first example, a long time series of in vitro microbiomes, PARAFAC identifies primary time-resolved variations. The second example, a longitudinal infant gut microbiome study, shows that PARAFAC can distinguish subject groups and enhance comparative analysis, even with moderate missing data. In the third example, a gingivitis intervention study of the oral microbiome, PARAFAC enables the identification of microbial subcommunities of interest through post-hoc clustering.

These examples highlight PARAFAC’s broad applicability for analyzing longitudinal microbiome data across diverse environments. The approach is implemented in the R packageparafac4microbiome, available on CRAN, providing researchers with accessible tools for similar analyses.

Importance

Understanding how microbiomes change over time can give us valuable insights into their role in health and disease. Many traditional methods like Principal Component Analysis (PCA) miss important patterns in data collected over time, but Parallel Factor Analysis (PARAFAC) helps uncover these trends in a much clearer way. Using this approach, we were able to identify key changes in microbiomes across different settings, like lab experiments, the infant gut, and the mouth. PARAFAC also works well even when some data is missing, which is a common issue. To make this tool accessible, we’ve included it in a user-friendly R package, enabling other researchers to analyze microbiome dynamics in their own studies and explore how these changes might influence health and treatments.
Genetic modification of the shikimate pathway to reduce lignin content in switchgrass (Panicum virgatumL.) significantly impacts plant microbiomes
Authors: Liu Shuang , Chou Ming-Yi , Benucci Gian Maria Niccolò , Eudes Aymerick , Bonito Gregory
Published: May 2024

Switchgrass (Panicum virgatumL.) is considered a sustainable biofuel feedstock, given its fast-growth, low input requirements, and high biomass yields. Improvements in bioenergy conversion efficiency of switchgrass could be made by reducing its lignin content. Engineered switchgrass that expresses a bacterial 3-dehydroshikimate dehydratase (QsuB) has reduced lignin content and improved biomass saccharification due to the rerouting of the shikimate pathway towards the simple aromatic protocatechuate at the expense of lignin biosynthesis. However, the impacts of this QsuB trait on switchgrass microbiome structure and function remains unclear. To address this, wildtype and QsuB engineered switchgrass were grown in switchgrass field soils and samples were collected from inflorescences, leaves, roots, rhizospheres, and bulk soils for microbiome analysis. We investigated how QsuB expression influenced switchgrass-associated fungal and bacterial communities using high-throughput Illumina MiSeq amplicon sequencing of ITS and 16S rDNA. Compared to wildtype, QsuB engineered switchgrass hosted different microbial communities in roots, rhizosphere, and leaves. Specifically, QsuB engineered plants had a lower abundance of arbuscular mycorrhizal fungi (AMF). Additionally, QsuB engineered plants had fewerActinobacteriotain root and rhizosphere samples. These findings may indicate that changes in the plant metabolism impact both organismal groups similarly, or potential interactions between AMF and the bacterial community. This study enhances understanding of plant-microbiome interactions by providing baseline microbial data for developing beneficial bioengineering strategies and by assessing non-target impacts of engineered plant traits on the plant microbiome.
Discovering Intron Gain Events in Humans through Large-Scale Evolutionary Comparisons
Authors: Hoh Celine , Salzberg Steven L
Published: May 2024

The rapid growth in the number of sequenced genomes makes it possible to search for the appearance of entirely new introns in the human lineage. In this study, we compared the genomic sequences for 19,120 human protein-coding genes to a collection of 3493 vertebrate genomes, mapping the patterns of intron alignments onto a phylogenetic tree. This mapping allowed us to trace many intron gain events to precise locations in the tree, corresponding to distinct points in evolutionary history. We discovered 584 intron gain events, all of them relatively recent, in 514 distinct human genes. Among these events, we explored the hypothesis that intronization was the mechanism responsible for intron gain. Intronization events were identified by locating instances where human introns correspond to exonic sequences in homologous vertebrate genes. Although apparently rare, we found three compelling cases of intronization, and for each of those we compared the human protein sequence and structure to homologous genes that lack the introns.
Dark exposure reduces high-frequency hearing loss in C57BL/6J mice
Authors: Jendrichovsky Peter , Lee Hey-Kyoung , Kanold Patrick O.
Published: May 2024

Plastic changes in the brain are primarily limited to early postnatal periods. Recovery of adult brain plasticity is critical for the effective development of therapies. A brief (1-2 week) duration of visual deprivation (dark exposure, DE) in adult mice can trigger functional plasticity of thalamocortical and intracortical circuits in the primary auditory cortex suggesting improved sound processing. We tested if DE enhances the ability of adult mice to detect sounds. We trained and continuously evaluated the behavioral performance of mice in control and DE conditions using automated home-cage training. Consistent with age-related peripheral hearing loss present in C57BL/6J mice, we observed decreased performance for high-frequency sounds with age, which was reduced by DE. In CBA mice with preserved peripheral hearing, we also found that DE enhanced auditory performance in low and mid frequencies over time compared to the control.
Design of a genetically programmable and customizable protein scaffolding system for the hierarchical assembly of robust, functional macroscale materials
Authors: Zhang Ruijie , Kang Sun-Young , Gaascht Francois , Pena Eliana L. , Dannert Claudia Schmidt-
Published: May 2024

Inspired by the properties of natural protein-based biomaterials, protein nanomaterials are increasingly designed with natural or engineered peptides, or with protein building blocks. Very few examples describe the design of functional protein-based materials for biotechnological applications that can be readily manufactured, are amenable to functionalization, and exhibit robust assembly properties for macroscale material formation. Here, we designed a protein-scaffolding system that self-assembles into robust, macroscale materials suitable for cell-free applications. By controlling the co-expression inE. coliof self-assembling scaffold building blocks with and without modifications for covalent attachment of cross-linking cargo proteins, hybrid scaffolds with spatially organized conjugation sites are overproduced that can be readily isolated. Cargo proteins, including enzymes, are rapidly cross-linked onto scaffolds for the formation of functional materials. We show that these materials can be used for the cell-free operation of a co-immobilized two-enzyme reaction and that the protein material can be recovered and reused. We believe that this work will provide a versatile platform for the design and scalable production of functional materials with customizable properties and the robustness required for biotechnological applications.
Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing
Authors: Steyaert Wouter , Sagath Lydia , Demidov German , Yépez Vicente A. , Esteve-Codina Anna , Gagneur Julien , Ellwanger Kornelia , Derks Ronny , Weiss Marjan , den Ouden Amber , van den Heuvel Simone , Swinkels Hilde , Zomer Nick , Steehouwer Marloes , O’Gorman Luke , Astuti Galuh , Neveling Kornelia , Schüle Rebecca , Xu Jishu , Synofzik Matthis , Beijer Danique , Hengel Holger , Schöls Ludger , Claeys Kristl G , Baets Jonathan , Van de Vondel Liedewei , Ferlini Alessandra , Selvatici Rita , Morsy Heba , Saeed Abd Elmaksoud Marwa , Straub Volker , Müller Juliane , Pini Veronica , Perry Luke , Sarkozy Anna , Zaharieva Irina , Muntoni Francesco , Bugiardini Enrico , Polavarapu Kiran , Horvath Rita , Reid Evan , Lochmüller Hanns , Spinazzi Marco , Savarese Marco ,   Solve-RD DITF-ITHACA,   Solve-RD DITF-Euro-NMD,   Solve-RD DITF-RND,   Solve-RD DITF-EpiCARE, Matalonga Leslie , Laurie Steven , Brunner Han G. , Graessner Holm , Beltran Sergi , Ossowski Stephan , Vissers Lisenka E.L.M. , Gilissen Christian , Hoischen Alexander
Published: May 2024

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single nucleotide variants (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions in extensively studied RD families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Rare Disease Network (ERN) experts. Of these, 21 families were affected by so-called ‘unsolvable’ syndromes for which genetic causes remain unknown, and 93 families with at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without genetic diagnosis despite extensive prior testing.

Clinical interpretation and orthogonal validation of variants in known disease genes yielded thirteen novel genetic diagnoses due tode novoand rare inherited SNVs, InDels, SVs, and STR expansions. In an additional four families, we identified a candidate disease-causing SV affecting several genes including anMCF2/FGF13fusion andPSMA3deletion. However, no common genetic cause was identified in any of the ‘unsolvable’ syndromes. Taken together, we found (likely) disease-causing genetic variants in 13.0% of previously unsolved families and additional candidate disease-causing SVs in another 4.3% of these families.

In conclusion, our results demonstrate the added value of HiFi long-read genome sequencing in undiagnosed rare diseases.
BRCA-DIRECT digital pathway for diagnostic germline genetic testing within a UK breast oncology setting: a randomised, non-inferiority trial
Authors: Torr B. , Jones C. , Kavanaugh G. , Hamill M. , Allen S. , Choi S. , Garrett A. , Valganon-Petrizan M. , MacMahon S. , Yuan L. , Way R. , Harder H. , Gold R. , Taylor A. , Gabe R. , Lucassen A. , Manchanda R. , Fallowfield L. , Jenkins V. , Gandhi A. , Evans D.G. , George A. , Hubank M. , Kemp Z. , Bremner S. , Turnbull C.
Published: May 2024

BACKGROUND

Genetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is an important step in the breast cancer diagnostic pathway. To expand capacity and reduce turnaround time, testing is increasingly offered within ‘mainstream’ oncology services, rather than via referral to clinical genetics. However, mainstream capacity is also stretched, as testing is offered to greater proportions of patients. Novel patient-centred pathways may offer opportunity for improved access.

PATIENTS AND METHODS

We recruited 1,140 women with unselected breast cancer to undergo germline genetic testing through the BRCA-DIRECT digital pathway; compromising at-home saliva sampling and consenting, with access to a digital dashboard to complete tasks and a genetic counselling telephone hotline.

Ahead of consenting to the test, participants were randomised to receive information about genetic testing digitally (569/1140, 49.9%) or via a pre-test genetic counselling consultation (571/1140, 50.1%). The primary outcome was uptake of genetic testing. We also measured patient knowledge, anxiety, and satisfaction, and conducted a healthcare professional survey.

RESULTS

1,001 (87.8%) participants progressed to receive their pre-test information and consented to testing. Uptake was higher within participants randomised to receive digital information compared with those randomised to a pre-test genetic counselling consultation (90.8% (95% CI: 88.5% to 93.1%) vs 84.7% (95% CI: 81.8% to 87.6%), p=0.002, adjusted for participant age and site). Non-inferiority was observed in relation to all other outcomes evaluated. Usage of the telephone hotline was modest (<20% of participants; 1,441 total minutes, 344 clinical minutes recorded) and, of 37 healthcare professionals surveyed, there was majority agreement that all elements of the pathway were equivalent to current standard-of-care.

CONCLUSION

Findings demonstrate that standardised, digital information offers a non-inferior alternative to conventional genetic counselling consultation, and that an end-to-end patient-centred, digital pathway (supported by genetic counselling hotline) could feasibly be implemented into mainstream breast oncology settings.
Demonstration of a Decongestant Effect of “Coldamaris Akut” Compared to Saline Nasal Spray in Participants Suffering from Seasonal Allergic Rhinitis
Authors: Unger-Manhart Nicole , Morokutti-Kurz Martina , Zieglmayer Petra , Lemell Patrick , Savli Markus , Zieglmayer René , Dellago Hanna , Prieschl-Grassauer Eva
Published: May 2024

Purpose

Carrageenan-containing nasal sprays are known to alleviate symptoms of common cold and allergic symptoms by building a barrier against airborne intruders. The objective of this study was to develop a hyperosmolar nasal spray with barrier-forming properties and to demonstrate its decongestant effect in the context of allergic rhinitis.

Methods

The efficacy of the nasal spray components was first demonstratedin vitroby a virus replication inhibition, water absorption, and barrier assay. Clinical efficacy was assessed in a randomized, controlled, crossover trial, where adults with a history of severe seasonal allergic rhinitis were exposed to grass pollen allergens under controlled conditions for a total of 6 hours. Participants received either the carrageenan- and sorbitol containing nasal spray (CS) or saline solution (SS) after 1h45min of allergen exposure. After one week, participants repeated the exposure, receiving the treatment (CS or SS) they had not received before. The primary efficacy endpoint was the mean change in ’Nasal Congestion Symptom Score’ (NCSS) during the allergen exposure. Secondary efficacy endpoints were nasal airflow, nasal secretion, total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total respiratory symptom score (TRSS).

Results

Preclinical assays showed virus-blocking, barrier building and water withdrawing properties of the CS components. In the clinical study, a total of 46 participants were screened, 41 were randomized and 39 completed the study. There was no significant difference in mean NCSS change from pre- to post-treatment between CS and SS (mean difference of 0.02 [95% CI -0.19; 0.24] during the first 2 hours after treatment) when analyzed by intention-to-treat. However, nasal airflow increased over time after treatment with CS, while it declined after SS, leading to a growing difference in airflow between CS- and SS-treated participants (p=0.039 at 6:00h). The anterior nasal airflow increased after treatment in 23/38 (61%) of the CS treated participants, compared to only 13/38 (34%) of the SS treated participants (p=0.024). The mean nasal secretion over 2-6 h was reduced by 1.00 g or -25% after CS (p=0.003) compared to pre-treatment, while it was reduced by only -0.50 g after SS (p=0.137). No significant differences in TNSS, TOSS and TRSS were observed between CS and SS treatments.

Conclusion

CS builds a barrier at the mucosa against viruses and dust and is safe and effective in alleviating nasal congestion, nasal airflow and nasal secretion in adults with grass pollen allergy.

Trial registration

NCT04532762
High-resolution vector-borne disease infection risk mapping with Area-to-Point Poisson Kriging and Species Distribution Modeling
Authors: Moliński Szymon
Published: May 2024

Background

Disease infection data is usually aggregated and shared as a sum of infections in a given area over time. This data is presented as choropleth maps. The aggregation process protects privacy and simplifies decision-making but introduces visual bias for large areas and sparsely populated places. Moreover, aggregated areas of varying sizes cannot be simply used as the input for complex ecological models, which are based on data retrieved at higher resolution on regular grids. The issue is especially painful for vector-borne diseases, e.g. Lyme Disease, where infection risk is closely related to vector species and their ecological niche.

Methods

The paper presents the method of obtaining high-resolution risk maps using a pipeline with two components: (1) spatial disaggregation component, which transforms incidence rate aggregates into the point-support model using Area-to-Point Poisson Kriging, and (2) species distribution modeling component, which detects areas where ticks bite is more likely using MaxEnt model. The first component disaggregates Lyme Disease incidence rates summed over counties in Poland, Central Europe, in 2015. The second component uses ticks occurrence maps, Leaf Area Index, Normalized Difference Vegetation Index, Land Surface Temperature derived from Earth Observation satellites, and Digital Elevation Model.

The final weighted population-at-risk map is a product of both components outputs. The pipeline is built upon open source and open science projects, and it is reusable.

Results

The presented pipeline creates high-resolution risk maps: vector occurrence probability map, population-at-risk map, and weighted population-at-risk map which includes information about local infections and about vector species. The final maps have much better resolution than aggregated incidence rates. Visual bias for population-at-risk maps is removed, and unpopulated areas are not presented on the map.

Conclusions

The pipeline might be used for other vector-borne diseases. The final weighted population-at-risk map might be used as an input for another analytical model requiring high-resolution data placed over a regular grid. The pipeline removes visual bias and transforms aggregated data into a high-resolution point-support layer.
Reconstruction of artificial nuclei with nuclear import activity in living mouse oocytes
Authors: Yonezawa Nao , Shindo Tomoko , Oda Haruka , Kimura Hiroshi , Hiraoka Yasushi , Haraguchi Tokuko , Yamagata Kazuo
Published: May 2024

The cell nucleus is a dynamic structure repeating disassembly and reformation during mitosis. Reformation of the nucleus is essential for cell proliferation, and therefore, the factors required for nuclear reformation are fundamental for eukaryotes. Although various factors have been identified inin vitrosystems using frog egg extracts andin vivoimaging of somatic cells, little is known about the factors required for the formation of functional nuclear structures in living mouse eggs. To identify such factors, we used a reconstruction approach to construct an artificial nucleus around DNA in mouse eggs. T4 phage DNA (166 kbp) was microinjected into living mouse oocytes. Amounts of DNA injected and injection timing were examined to determine the conditions appropriate for the formation of functional nuclei. Microinjection of 100-500 ng/µl DNA during metaphase through telophase of the second meiosis, but not the subsequent interphase, was important for the formation of artificial nucleus. This T4 DNA-derived artificial nucleus had the structure of nuclear lamina and nuclear pore complexes, and nuclear transport activity, similar to natural nuclei. These results suggest that exogenous DNA can form a functional nucleus in mouse oocytes, regardless of the sequence or the source of DNA.
Exploring the genome-wide expression level of the bacterial strain belonging toBacillus safensis(MM19) againstPhomopsis viticola
Authors: Silme Ragıp Soner , Baysal Ömür , Can Ahmet , Kürüm Yiğit , Korkut Ahmet , Kırboga Kevser Kübra , Çetinkaya Agit
Published: May 2024

Introduction

Rhizobacteria has the suppression ability to compete with pathogenic microorganisms and help for plant immunity and defense mechanism. Their growth and survival in rhizosphere ensure biological balance in favor of the host plant.

Methods

In our study, with agar diffusion assays, we found a rhizobacterium species belonging toBacillus safensis, which can significantly suppressPhomopsis viticola. To elucidate the antagonistic mechanism, genome-wide gene expression profiling ofB. safensis(strain MM19) was performed in the presence and absence ofP. viticola. We used RNA-seq analysis to obtain a comprehensive overview of the responsiveB. safensiswhole gene expression classified according to biological and metabolic process toP. viticolaconcomitant growth in liquid culture.

Results

The differential gene expression profiles ofB. safensis(MM19) revealed significantly increased expression of prominent genes related to thiamine biosynthesis involving various metabolites and enzymes that play role in the suppression of mycelium growth and pathogen inhibition. Correspondingly, the expression of three major genes (HOG1, FUS3, SGI) involving in the virulence ofP. viticolawas followed using qPCR analysis. HOG1 was the highest expressed gene in the pathogen when it co-cultivated with MM19. Based on these findings, we performed molecular docking and dynamics analysis to explore the interaction between HOG1 and thiamine, besides expression of network analysis constructed using Cytoscape.

Discussion

The results proved that the functional genomic data related to thiamine biosynthesis and corresponding pathways ensure a priming role in the antagonistic behavior ofB. safensis(MM19) againstP. viticolaas a supporter for plant immunity.
In vivo reprogramming ofCaenorhabditis elegansleads to heterogeneous effects on lifespan
Authors: Kamaludeen Nibrasul , Mauge Yann , Mouridi Sonia El , Picó Sara , Vílchez-Acosta Alba , de Sousa João Agostinho , Pierron Marie , Praz Viviane , von Meyenn Ferdinand , Frøkjær-Jensen Christian , Ocampo Alejandro
Published: May 2024

In the last decade, cellular reprogramming of fully differentiated cells to pluripotent stem cells has become of great interest. Importantly, cellular reprogramming by expression of Oct4, Sox2, Klf4, and cMyc (OSKM) can ameliorate age-associated phenotypes in multiple tissues and extend lifespan in progeroid and aged wild-type mice. Surprisingly, the effects of in vivo reprogramming have not been deeply investigated in any other model organisms. Here, for the first time, we induce in vivo reprogramming inC. elegansusing a heat-inducible system at multiple developmental and adult stages. Similar to mice, expression of the reprogramming factors leads to premature death with different levels of toxicity at distinct developmental stages and aging. In vivo reprogramming inC. elegansmight represent a valuable tool to improve our understanding of development and in vivo reprogramming.
Does age protect against loss of tonotopy after acute deafness in adulthood?
Authors: Rosskothen-Kuhl Nicole , Green Sarah , Jakob Till F.
Published: May 2024

The mammalian auditory system develops a topographical organization of sound frequencies along its pathways, also called tonotopy, as a result of early auditory input. In contrast, sensory deprivation during early development results in no or only rudimentary tonotopic organization. This study addresses two questions: 1) How robust is the tonotopy when hearing fails in adulthood? 2) What role does age play at time of deafness? To address these questions, we deafened young and old adult rats with normal hearing. One month after deafness, both groups were unilaterally supplied with cochlear implants and electrically stimulated for two hours. The central auditory neurons, which were activated as a result of the local electrical intracochlear stimulation, were visualized using Fos staining. While the auditory system of young rats lost the tonotopic organization throughout the brainstem, the auditory system of the older rats mainly sustained its tonotopy. It can be proposed that neuronal plasticity prevails in the central auditory system of young adult rats, while neuronal stability prevails in the brains of aging rats. Consequently, age may be an important factor in protecting a hearing-experienced adult auditory system from a rapid loss of tonotopy when suffering from acute hearing loss. Furthermore, the study provides compelling evidence that acute deafness in young adult patients should be diagnosed as early as possible to prevent maladaptation of the central auditory system and thus achieve the optimal hearing outcome with a hearing prosthesis.
Two routes to value-based decisions in Parkinson’s disease: differentiating incremental reinforcement learning from episodic memory
Authors: Montaser-Kouhsari Leila , Nicholas Jonathan , Gerraty Raphael T. , Shohamy Daphna
Published: May 2024

Patients with Parkinson’s disease are impaired at incremental reward-based learning. It is typically assumed that this impairment reflects a loss of striatal dopamine. However, many open questions remain about the nature of reward-based learning deficits in Parkinson’s. Recent studies have found that a combination of different cognitive and computational strategies contribute even to simple reward-based learning tasks, suggesting a possible role for episodic memory. These findings raise critical questions about how incremental learning and episodic memory interact to support learning from past experience and what their relative contributions are to impaired decision-making in Parkinson’s disease. Here we addressed these questions by asking patients with Parkinson’s disease (n=26) both on and off their dopamine replacement medication and age- and education-matched healthy controls (n=26) to complete a task designed to isolate the contributions of incremental learning and episodic memory to reward-based learning and decision-making. We found that Parkinson’s patients performed as well as healthy controls when using episodic memory, but were impaired at incremental reward-based learning. Dopamine replacement medication remediated this deficit while enhancing subsequent episodic memory for the value of motivationally relevant stimuli. These results demonstrate that Parkinson’s patients are impaired at learning about reward from trial-and-error when episodic memory is properly controlled for, and that learning based on the value of single experiences remains intact in patients with Parkinson’s disease.
Anchorage-independent cell proliferation promoted by fascin’s F-actin bundling
Authors: Isogai Tadamoto , Murali Vasanth Siruvallur , Zhou Felix , Wang Xinxin , Rajendran Divya , Perez-Castro Lizbeth , Venkateswaran Niranjan , Conacci-Sorrell Maralice , Danuser Gaudenz
Published: May 2024

The actin filament (F-actin) bundling protein fascin-1 is highly enriched in many metastatic cancers. Fascin’s contribution to metastasis have been ascribed to its enhancement of cell migration and invasion. However, mouse genetic studies clearly point to functions also in tumorigenesis, yet without mechanistic underpinnings. Here, we show that fascin expression promotes the formation of a non-canonical signaling complex that enables anchorage-independent proliferation. This complex shares similarities to focal adhesions and we refer to them as pseudo-adhesion signaling scaffolds (PASS). PASS are enriched with tyrosine phosphorylated proteins and require fascin’s F-actin-bundling activity for its assembly. PASS serve as hubs for the Rac1/PAK/JNK proliferation signaling axis, driven by PASS-associated Rac-specific GEFs. Experimental disruption of either fascin or RacGEF function abrogates sustained proliferation of aggressive cancersin vitroandin vivo. These results add a new molecular element to the growing arsenal of metabolic and oncogenic signaling programs regulated by the cytoskeleton architecture.
Supply chain collaboration, agility and firm performance: a case of manufacturing SMEs in India
Authors: Mahesh Prabhu H. , Srivastava Amit Kumar , Mukul Muthappa K.C.
Published: May 2024

Purpose

The dynamic business environment and intense competition have mandated agility in operations for manufacturing firms. Effective inter-organizational collaboration can make operations more agile. This paper develops an interpretive model to explore the effect of supply chain collaboration (SCC) on supply chain agility (SCA) and, subsequently, on business performance.

Design/methodology/approach

A hierarchical model that illustrates the relationship between SCC, SCA and firm performance components is developed using total interpretative structural modeling (TISM). Also, statistical validation of the model has been performed.

Findings

The results indicate that the vision and alertness of the firm on the strategic front promote collaboration between supply chain partners. This creates operational agility, helping the firm to absorb fluctuations in demand, thereby enhancing business performance.

Research limitations/implications

The opinion of most respondents was considered to develop the TISM framework over the fuzzy one, which necessitates a significantly more extensive data set. However, multiple discussions with participants can eliminate the prejudice of the majority approach. Also, the paper's development and validation were restricted to Indian manufacturing small and medium-sized enterprises (SMEs). The model can potentially be evaluated in large organizations to provide further insights.

Originality/value

The study blends the factors of SCC and SCA in a novel way to explain their combined impact on business performance. The TISM model addresses the “why” of theory development in addition to the “what” and “how” of it. Using triangulation in combination with the interpretative tool, this study additionally offers methodological value.
DRR pioneers: interview with Ben Wisner
Authors: Wisner Ben
Published: May 2024

Purpose

The transcript provides an overview of the development of the field and changing paradigms in this regard.

Design/methodology/approach

The transcript was developed in the context of a United Nations Office for Disaster Risk Reduction (UNDRR) project on the history of disaster risk reduction (DRR).

Findings

The transcript traces the initial discussions of how the At Risk book was conceived and presents new dimensions and challenges within the field.

Originality/value

The interview highlights the importance of the need to document the transitions, developments and paradigm changes in the field over time.