bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-dose vitamin D3in the treatment of complicated severe acute malnutrition in Pakistan: a double-blind randomised controlled trial (ViDiSAM)
Authors: Saleem Javeria , Zakar Rubeena , Butt Muhammad Salman , Kaleem Rameeza , Chaudhary Asif , Chandna Jaya , Jolliffe David A , Piper Joseph , Abbas Zaigham , Tang Jonathan C Y , Fraser William D , Freemantle Nick , Prendergast Andrew J , Martineau Adrian R 
Published: July 2024

ABSTRACTWe have previously shown that high-dose vitamin D3improved weight gain and neurodevelopmental indices in children receiving standard therapy for uncomplicated severe acute malnutrition (SAM). We conducted a randomised placebo-controlled trial to determine whether two oral doses of 200,000 international units (IU) vitamin D3would benefit children aged 6-59 months receiving standard therapy for complicated SAM in Lahore, Pakistan. The primary outcome was mean weight-for-height or -length z-score (WHZ) at 2-month follow-up. Secondary efficacy outcomes were mean WHZ at 6-month follow-up and mean lean mass index, Malawi Development Assessment Tool (MDAT) scores and serum 25-hydroxyvitamin D (25[OH]D) concentrations at 2- and 6-month follow-up. 259 children were randomised (128 to vitamin D, 131 to placebo), of whom 251 (96.9%) contributed data to analysis of the primary outcome. At 2-month follow-up, participants allocated to vitamin D had significantly higher mean serum 25(OH)D concentrations than those allocated to placebo (adjusted mean difference [aMD] 100.0 nmol/L, 95% confidence interval [CI] 72.2 to 127.8 nmol/L). This was not associated with an inter-arm difference in mean WHZ (aMD 0.02, 95% CI −0.20 to 0.23), or in any other anthropometric or neurodevelopmental outcome assessed at 2- or 6-month follow-up overall. The intervention was safe. In conclusion, high-dose vitamin D3elevated mean serum 25(OH)D concentrations in children receiving standard therapy for complicated SAM in Pakistan, but did not influence any anthropometric or neurodevelopmental outcome studied. The trial was registered atClinicalTrials.govwith the identifierNCT04270643.
Eye Movement Variations in Indoor, Outdoor, and Reading Scenarios and their Implications for Myopia
Authors: Li Qi , Zhou Chao , Liu Tingting , Han Yingxiang , Wang Dajiang , Wang Xiaofei 
Published: July 2024

ABSTRACTPurposeTo quantitatively measure eye movement behaviors in indoor, outdoor, and reading scenarios to understand their potential link to myopia.MethodsForty-one healthy adult subjects freely viewed indoor and outdoor scenes and performed reading activities using virtual reality (VR). Eye movement data were recorded with the built-in eye tracker of the VR headset (HTC Vive Pro Eye). Gaze and fixation data were calculated and reported for eight regions of the visual field.ResultsIndoor scenes exhibited a more pronounced downward gaze than outdoor environments. Significant differences (p < 0.05) in gaze and fixation behaviors were observed between reading and other scenarios. In region 8 (peripheral inferior visual field), the median (1st quartile, 3rd quartile) number of gaze points were 816 (463, 1175), 1123 (743, 1497), and 1705 (966, 2382) for outdoor, indoor and reading scenarios, respectively. Similarly, fixation behavior counts were 4 (1, 9), 7 (1, 11), and 39 (22, 54), respectively.ConclusionsDownward gaze and fixation behaviors are more prevalent in reading and indoor environments. Given that downwards eye movements can induce instantaneous axial elongation, our results suggested a potential biomechanical pathway for myopia progression through optic nerve traction and ocular tissue remodeling. This study underscores the need for further research to explore the specific role of eye movement behaviors in the progression of myopia, especially in real-life settings.
Integrated proteasomal and lysosomal activity shape mTOR-regulated proteome remodeling
Authors: Cui Danica S. , Webster Samantha M. , Davis Joseph H. 
Published: July 2024

ABSTRACTThe crucial growth regulator mTOR is suppressed during nutrient limitation, which reduces protein synthesis and activates the ubiquitin-proteasome system (UPS) and lysosomal degradation pathways. Whereas these pathways have been extensively studied individually, their integrated dynamics, including the interplay between protein synthesis and degradation, and the coordination between lysosomal and UPS pathways, remain underexplored. Here, we couple stable isotope pulse-labeling and mass spectrometry to quantify and kinetically model proteome dynamics following mTOR inhibition in cultured human cells. Using a combination of genetics and pharmacological inhibitors, we identify proteins strictly degraded by one pathway, those that undergo multimodal degradation, and others that can flexibly access the proteasome or lysosome subject to the availability of either. Our data resource, comprised of ∼5.2 million proteomic measurements, reveals that the UPS and lysosomal pathway operate with disparate kinetics, and highlights the rapid nature of lysosomal degradation. Additionally, we observe that cells coordinate the synthesis and degradation of translation initiation and elongation factors, leading to preferential synthesis from key classes of mRNA transcripts. Taken together, this work illuminates the complex, integrated pathways influencing proteostasis when mTOR is inhibited, provides a rich resource detailing the kinetics of protein synthesis and degradation, and establishes a robust methodology for measuring proteome dynamics on a per-protein basis in the context of cellular stress.
Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor
Authors: O’Brien Darragh P , Jones Hannah BL , Shi Yuqi , Guenther Franziska , Vendrell Iolanda , Viner Rosa , Brennan Paul E , Mead Emma , Zarganes-Tzitzikas Tryfon , Davis John B , Pinto-Fernández Adán , England Katherine S , Murphy Emma J , Turnbull Andrew P , Kessler Benedikt M 
Published: July 2024

ABSTRACTInhibition of the mitochondrial deubiquitinating enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson’s Disease and mitophagy-related disorders. We have integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small molecule containing a cyanopyrrolidine reactive group,USP30-I-1. The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells. Enzyme kinetics and Hydrogen Deuterium eXchange mass spectrometry (HDX-MS) infers that the inhibitor binds tightly to regions surrounding the USP30 catalytic cysteine and positions itself to form a binding pocket along the thumb and palm domains of the protein, thereby interfering its interaction with ubiquitin substrates. A comparison to a non-covalent USP30 inhibitor containing a benzosulfonamide scaffold revealed a slightly different binding mode closer to the active site Cys77, which may provide the molecular basis for improved selectivity towards USP30 against other members of the DUB enzyme family. Our results highlight advantages in developing covalent inhibitors, such asUSP30-I-1, for targeting USP30 as treatment of disorders with impaired mitophagy.
CryptosporidiumOocyst Wall Proteins are true oocyst wall proteins, with COWP8 functioning to hold the inner and outer layers of the oocyst wall together
Authors: Bacchetti Ross , Stevens Sarah , Lemgruber Leandro , Gonzalez Oliva Mariana Azevedo , Sands Emma M , Alexandrou Konstantinos , Tinti Michele , Robinson Lee , Hanna Jack C , Seizova Simona , Goddard Peyton , Vassalli Massimo , Pawlowic Mattie C 
Published: July 2024

AbstractCryptosporidiosis is a significant cause of diarrhoeal disease contributing to substantial morbidity and mortality for the immunocompromised and for young children, especially those who are malnourished. There are no vaccines available and no effective treatments for these patients. Another challenge is thatCryptosporidiaare waterborne and resistant to common water treatments including chlorination.Cryptosporidiaare transmitted as an oocyst that is made up of a hardy oocyst wall that protects four parasites. Little is understood about how the oocyst is constructed, its composition, and the how it resists chlorination. A family of predictedCryptosporidiumOocyst Wall Proteins (COWPs) was identified from the genome. Using a genetic approach, we confirm that all members of the COWP family localise to the oocyst wall. Our studies indicate that COWP2, 3 and 4 localise specifically to the oocyst “suture”, a zipper-like structure on the oocyst wall from which parasites emerge during infection. In parasites lacking COWP8, we observe that the inner and outer layers of the oocyst wall are no longer associated suggesting a role for COWP8 in oocyst wall morphology. Despite loss of COWP8, these transgenic parasites are viable, unchanged in mechanical strength, and retain resistance to chlorination. This work sets the foundation for future exploration ofCryptosporidiumtransmission.
EGFR does not directly interact with cortical actin: A SRRF’n’TIRF Study
Authors: Pandey Shambhavi , Wohland Thorsten 
Published: July 2024

ABSTRACTThe epidermal growth factor receptor (EGFR) governs pivotal signaling pathways in cell proliferation and survival, with mutations implicated in numerous cancers. The organization of EGFR on the plasma membrane (PM) is influenced by the lipids and the cortical actin (CA) cytoskeleton. Despite the presence of a putative actin-binding domain (ABD) spanning 13 residues, a direct interaction between EGFR and CA has not been definitively established. While disrupting the cytoskeleton can impact EGFR behavior, suggesting a connection, the influence of the static actin cytoskeleton has been found to be indirect. Here, we investigate the potential interaction between EGFR and CA, as well as the extent to which CA regulates EGFR’s distribution on the PM using SRRF’n’TIRF, a spatiotemporal super-resolution microscopy technique that provides sub-100 nm resolution and ms-scale dynamics from the same dataset. To label CA, we constructed PMT-mEGFP-F-tractin, which combines an inner leaflet targeting domain PMT, fluorescent probe mEGFP, and the actin-binding protein F-tractin. In addition to EGFR-mEGFP, we included two control constructs: a) an ABD deletion mutant, EGFRΔABD-mEGFP serving as a negative control, and b) EGFR-mApple-F-tractin, where F-tractin is fused to the C-terminus of EGFR-mApple, serving as the positive control. We find that EGFR-mEGFP and EGFRΔABD-mEGFP show similar membrane dynamics, implying that EGFR-mEGFP dynamics and organization are independent of CA. EGFR dynamics show CA dependence when F-tractin is anchored to the cytoplasmic tail. Together, our results demonstrate that EGFR does not directly interact with the CA in its resting and activated state.SIGNIFICANCESRRF’n’TIRF is a spatiotemporal super-resolution microscopy technique that allows for the investigation of plasma membrane-cytoskeleton interactions. We investigate how cortical actin (CA) influences the dynamic behavior and structural organization of EGFR, employing specific probe targeting CA structure and dynamics. Our results suggest that EGFR, whether in its resting or activated state, does not directly bind to or interact with the CA. Any influence of CA on EGFR is indirect through membrane modulating activities of CA.
A facile chemical strategy to synthesize precise AAV-protein conjugates for targeted gene delivery
Authors: Pham Quan , Glicksman Jake , Shahraeini Sadegh , Han Boyang , Jewel Delilah , Loynd Conor , Singha Roy Souyma Jyoti , Chatterjee Abhishek 
Published: July 2024

AbstractThe efficacy of current gene therapy approaches using adeno associated virus (AAV) vectors is limited by the poor control over their tissue tropism. Untargeted AAV vectors require high doses to achieve therapeutic efficacy, which is associated with toxic off-target impacts and increased therapeutic costs. The ability to reprogram existing AAV vectors to selectively transduce target tissues is essential to develop next-generation human gene therapies that are safer, more efficacious, and less expensive. Using selective and high-affinity antibodies and antibody-like proteins to retarget existing AAV vectors to bind novel cell-surface receptors offers an attractive and modular approach to reprogram their tropism. However, attaching these proteins onto the complex and delicate AAV capsids remains challenging. Here, we report a versatile chemical strategy to covalently attach recombinant proteins onto the capsid of AAV, using a combination of genetic code expansion and bioorthogonal conjugation chemistry. This method is efficient, and allows precise control over the site and stoichiometry of protein attachment onto the AAV capsid, enabling systematic optimization of the resulting conjugate. Using this approach, we generated conjugates of AAV2 with an anti-HER2 nanobody and a full-length anti-HER2 IgG, which show highly efficient and selective gene delivery into HER2+ cancer cells. Remarkably, the optimized AAV2-nanobody conjugate facilitated efficient transduction of HER2+ tumor xenograft in mice with little off-target gene expression, including in the liver. Programmable synthesis of AAV-protein conjugates using this method offers a promising new strategy to rationally engineer next-generation gene therapy vectors.
Fine Tuning Genetic Circuits via Host Context and RBS Modulation
Authors: Chan Dennis Tin Chat , Winter Lena , Bjerg Johan , Krsmanovic Stina , Baldwin Geoff S. , Bernstein Hans C. 
Published: July 2024

SUMMARYThe choice of organism to host a genetic circuit – the chassis – is often defaulted to model organisms due to their amenability. The chassis-design space has therefore remained underexplored as an engineering variable. In this work, we explored the design space of a genetic toggle switch through variations in nine ribosome binding sites compositions and three host contexts, creating 27 circuit variants. Characterization of performance metrics in terms of toggle switch output and host growth dynamics unveils a spectrum of performance profiles from our circuit library. We find that changes in host-context causes large shifts in overall performance, while modulating ribosome binding sites leads to more incremental changes. We find that a combined ribosome binding site and host-context modulation approach can be used to fine tune the properties of a toggle switch according to user-defined specifications, such as towards greater signaling strength, inducer sensitivity or both. Other auxiliary properties, such as inducer tolerance, are also exclusively accessed through changes in host-context. We demonstrate here that exploration of the chassis-design space can offer significant value, reconceptualizing the chassis-organism as an important part in the synthetic biologist’s toolbox with important implications for the field of synthetic biology.GRAPHICAL ABSTRACT
Data sharing in cancer research: A qualitative study exploring community members’ preferences
Authors: Johnston Elizabeth A. , Bourdaniotis Xanthia E. , Ayre Susannah K. , Zajdlewicz Leah , Beesley Vanessa L. , Goodwin Belinda C. 
Published: July 2024

AbstractAdvancements in cancer treatment and survivorship rely on participation in research and access to health records. This study explored preferences for data access and sharing in 14 workshops with 42 community members, most of whom were a cancer survivor or carer. Various scenarios for data access and sharing were presented and discussed, with participants’ preferences summarized using descriptive statistics. Reasons underlying these preferences were identified through a thematic analysis of workshop transcripts. Most participants indicated a willingness for researchers to use their self-reported data and current health records for a specific research project (86%). Many were also willing for their self-reported data and current (62%) or all future (44%) heath records to be shared with other researchers for use in other studies if made aware of this. Willingness to consent to data access and sharing data in cancer research was influenced by: (i) the potential for data sharing to advance medical discoveries and benefit people impacted by cancer in the future, (ii) transparency around researchers’ credibility and their intentions for data sharing, (iii) level of ownership and control over data sharing, and (iv) protocols for privacy and confidentiality in data sharing. Based on these themes, we present practical strategies for optimizing data access and sharing in cancer research.
Systematic review of natural language processing (NLP) applications in magnetic resonance imaging (MRI)
Authors: Mahmeed Gazal , Brin Dana , Konen Eli , Nadkarni Girish N , Klang Eyal 
Published: July 2024

AbstractBackgroundAs MRI use grows in medical diagnostics, applying NLP techniques could improve management of related text data. This review aims to explore how NLP can augment radiological evaluations in MRI.MethodsWe conducted a PubMed search for studies that applied NLP in the clinical analysis of MRI, including publications up to January 4, 2024. The quality and potential bias of the included studies were assessed using the QUADAS-2 tool.ResultsTwenty-six studies published between April 2010 and January 2024, covering more than 160k MRI reports were analyzed. Most of these studies demonstrated low to no risk of bias of the NLP. Neurology was the most frequently studied specialty, with twelve studies, followed by musculoskeletal (MSK) and body imaging. Applications of NLP included staging, quantification, and disease diagnosis. Notably, NLP showed high precision in tumor staging classification and structuring of free-text reports.ConclusionNLP shows promise in enhancing the utility of MRI. However, there is a need for prospective studies to further validate NLP algorithms in real-time clinical and operational scenarios and across various radiology specialties, which could lead to broader applications in healthcare.
Computerized analysis of the eye vasculature in a mass dataset of digital fundus images: the example of age, sex and primary open-angle glaucoma
Authors: Fhima Jonathan , Eijgen Jan Van , Reiner-Benaim Anat , Beeckmans Lennert , Abramovich Or , Stalmans Ingeborg , Behar Joachim A. 
Published: July 2024

AbstractObjectiveTo develop and validate an automated end-to-end methodology for analyzing retinal vasculature in large datasets of digital fundus images (DFIs), aiming to assess the influence of demographic and clinical factors on retinal microvasculature.DesignThis study employs a retrospective cohort design to achieve its objectives.ParticipantsThe research utilized a substantial dataset consisting of 115,237 digital fundus images obtained from individuals undergoing routine eye examinations. There was no inclusion of a separate control group in this study.MethodsThe proposed methodology integrates multiple stages: initial image quality assessment, detection of the optic disc, definition of the region of interest surrounding the optic disc, automated segmentation of retinal arterioles and venules, and the engineering of digital biomarkers representing vasculature characteristics. To analyze the impact of demographic variables (age, sex) and clinical factors (disc size, primary open-angle glaucoma [POAG]), statistical analyses were performed using linear mixed-effects models.Main Outcome MeasuresThe primary outcomes measured were changes in the retinal vascular geometry. Special attention was given to evaluating the independent effects of age, sex, disc size, and POAG on the newly engineered microvasculature biomarkers.ResultsThe analysis revealed significant independent similarities in retinal vascular geometry alterations associated with both advanced age and POAG. These findings suggest a potential mechanism of accelerated vascular aging in patients with POAG.ConclusionsThis novel methodology allows for the comprehensive and quantitative analysis of retinal vasculature, facilitating the investigation of its correlations with specific diseases. By enabling the reproducible analysis of extensive datasets, this approach provides valuable insights into the state of retinal vascular health and its broader implications for cardiovascular and ocular health. The software developed through this research will be made publicly available upon publication, offering a critical tool for ongoing and future studies in retinal vasculature.
HIGHLY CITED ARTICLES IN EVOLUTIONARY PSYCHIATRY: ASSESSMENT WITH A QUALITY AND ERROR RATING SCALE
Authors: Beyer Chad , Robinson Chanel , Stein Dan J. 
Published: July 2024

ABSTRACTIntroductionEvolutionary psychiatry is a rapidly growing field that emphasizes the value of evolutionary explanations for traits that make individuals vulnerable to mental disorders. Some articles that apply evolutionary theory to psychiatric disorders make errors, such as viewing a disease as if it is an adaptation. We assessed the quantity of errors in the most widely cited articles on evolutionary psychiatry and its relationship to citation frequencyMethodsTwo reviewers searched PubMed, Web of Science, and Google Scholar on September 8, 2023, using specific search terms related to “evolution” and “psychiatry”, in order to find the most highly cited articles in the field. Based on the work of Nesse, we developed a measure for assessing the number of errors and overall quality in evolutionary psychiatry articles. We applied the measure to the 20 most highly cited articles, and calculated the correlations between article quality and number of errors with number of citations.ResultsTwenty highly cited articles, with a mean citation count of 758.95 and publication year range from 1964 to 2011, were rated. While the most highly cited articles had good quality on average, they also made important errors. There was no significant correlation of article quality or article errors and citation count.ConclusionHighly cited articles in evolutionary psychiatry demonstrated strengths but also exhibited weaknesses. The lack of a relationship of quality and error scores with citation rates suggests that other factors influence such citations. Future research should focus on achieving consensus on how best to assess the quality of evolutionary psychiatry articles and on what errors should be avoided.
Initial Treatment of Glaucoma with Selective Laser Trabeculoplasty: Economic Impact from the Perspective of the Brazilian Public Health System
Authors: Tavares Ivan M. , Hirai Flavio E. , Landim Diogo F. C. , Zucchi Paola 
Published: July 2024

AbstractObjectiveTo evaluate the economic impact on the Brazilian Public Health System (SUS) of the initial treatment of glaucoma in two scenarios: (1) the traditional continuous clinical treatment with hypotensive eye drops and (2) the single treatment with Selective Laser Trabeculoplasty.MethodsEconomic impact analysis was conducted in three scenarios, from the least to the most conservative, for the two initial treatment methods for open-angle glaucoma in a hypothetical cohort of 5,000 individuals. Projections were then made based on a prevalence of 3% of the Brazilian population in 2021.ResultsAll three scenarios analyzed showed a significantly lower economic impact for Selective Laser Trabeculoplasty on the Brazilian Public Health System over one to five years, with a favorable difference of more than 8 billion US dollars over five years when considering 3% of the Brazilian population over 40 years old in 2021.ConclusionThe economic impact on the Brazilian Public Health System was lower for Selective Laser Trabeculoplasty compared to the use of latanoprost and timolol maleate eye drops as the initial treatment for primary open-angle glaucoma in all scenarios studied over one and five-year periods.