bluuebunny/crossref_metadata_2025 huggingface dataset:
Commonly prescribed medicines, core prescribing indicators, and prescription errors in a tertiary healthcare setting in Sri Lanka: a descriptive cross-sectional study
Authors: Ranasinghe Priyanga , Sri Ranganathan Shalini
Published: March 2024

Objectives

To describe the commonly prescribed medicines, WHO/INRUD core prescribing indicators, and prescription errors from a tertiary healthcare setting in Sri Lanka.

Methods

This study was conducted at clinics and wards in a group of tertiary hospitals from Colombo, Sri Lanka. A total of 1600 prescriptions (800 in-ward [IW] and 800 out-patient clinic [OP]) were analysed and evaluated against WHO/INRUD core prescribing indicators. Prescription errors and medication interactions were also analysed.

Key findings

Number of medicines per encounter on average was 4.2 ± 2.9 (median: 4.0; range: 1–18) (IW vs. OP: 5.0 ± 3.1 vs. 3.4 ± 2.1; P < 0.001). Overall, the percentage of prescriptions with an antibiotic was 25.9% (n = 415) (IW vs. OP: 45.0% vs. 6.9%, P < 0.001). Percentage of encounters with an injection was 20.4% (n = 326) (IW vs. OP: 36.9% vs. 3.9%, P < 0.001) and percentage of medicine prescribed by generic name was 90.7% (IW 92.9% vs. OP 87.3%, P < 0.001). Prescribing from the essential medicines list (EML) was 76.9% (IW 77.7% vs. OP 75.7%, P-NS). Among IW prescriptions details regarding allergies were not mentioned in 643 (80.4%), while in paediatric prescriptions weight was not specified in 242 (75.6%). At least a single abbreviation was used in 638 prescriptions (39.9%). One or more medication interactions were identified in 744 (46.5%) prescriptions (major: 86 [5.4%]).

Conclusions

We identified a relatively high number of average medicines per encounter, indicating a degree of polypharmacy. In addition, generic prescribing and usage of EML medicines are areas recommended for further improvement. Prescription errors were common, and several commission/omission errors had potential for preventable patient harm.
Coproducing a film resource for asylum seekers in the UK—A field reflection
Authors: Mäkelä Petra , Given-Wilson Zoe , Al Berkdar Kenan , Aljumma Zaina , Mostafanejad Rahman
Published: March 2024

In this field reflection, we critically explore our experiences of coproduction, as a group comprising people with lived experience of seeking asylum in the UK, and clinical academics. We collaboratively developed a film resource for people facing the challenges of the asylum system and for professionals who support them. We aim to (1) reflect on how this collaboration came about and how it led to both planned outputs and unanticipated outcomes, (2) identify a range of personal, organizational, and system factors that enabled or constrained our collaborations as researchers and asylum seekers or refugees in the UK, and (3) explore our own assumptions about ways of working together to enable partnership and equality of engagement. We reflect on our experiences in relation to four conditions of coproduction: combining knowledge and experience, commitment to the project and each other, flexibility in our ways of working together, and our valued achievements.
TWAIL, archives, and refugee law
Authors: Ramasubramanyam Jay
Published: March 2024

Critical scholars of refugee law and refugee studies have demonstrated the entrenched Eurocentricity and the ingrained hegemony that dominate the fields of study. Therefore, this article embarks on a methodological inquiry that intersperses Third-World Approaches to International Law (TWAIL) and archival research to the study of international refugee law, with specific focus on India. I base this article on the preconceived notion that TWAIL cannot be divorced from the inquiry into understanding alternate non-European notions of refugee protection. This article emphasizes TWAIL’s significance as a methodological tool, and explores India’s refugee hosting practices and resistance to Eurocentric international refugee law through archives. The article also contends that TWAIL and archival research in this context, are not just methodological innovations, but constitute deliberate disruptions in the field.
Comparative transcriptomics elucidates the cellular responses of an aeroterrestrial zygnematophyte to UV radiation
Authors: Busch Anna , Gerbracht Jennifer V , Davies Kevin , Hoecker Ute , Hess Sebastian
Published: March 2024

The zygnematophytes are the closest relatives of land plants and comprise several lineages that adapted to a life on land. Species of the genus Serritaenia form colorful, mucilaginous capsules, which surround the cells and block harmful solar radiation, one of the major terrestrial stressors. In eukaryotic algae, this ‘sunscreen mucilage’ represents a unique photoprotective strategy, whose induction and chemical background are unknown. We generated a de novo transcriptome of Serritaenia testaceovaginata and studied its gene regulation under moderate UV radiation (UVR) that triggers sunscreen mucilage under experimental conditions. UVR induced the repair of DNA and the photosynthetic apparatus as well as the synthesis of aromatic specialized metabolites. Specifically, we observed pronounced expressional changes in the production of aromatic amino acids, phenylpropanoid biosynthesis genes, potential cross-membrane transporters of phenolics, and extracellular, oxidative enzymes. Interestingly, the most up-regulated enzyme was a secreted class III peroxidase, whose embryophyte homologs are involved in apoplastic lignin formation. Overall, our findings reveal a conserved, plant-like UVR perception system (UVR8 and downstream factors) in zygnematophyte algae and point to a polyphenolic origin of the sunscreen pigment of Serritaenia, whose synthesis might be extracellular and oxidative, resembling that of plant lignins.
Asymmetry of the spectral lines of the coronal hole and quiet Sun in the transition region
Authors: Hosseini Razieh , Kayshap Pradeep , Alipour Nasibe , Safari Hossein
Published: March 2024

The asymmetry of line profiles, i.e. the secondary component, is crucial to understanding the energy release of coronal holes (CH), quiet Sun (QS), and bright points (BPs). We investigate the asymmetry of Si iv 1393.75 Å of the transition-region (TR) line recorded by Interface Region Imaging Spectrograph (IRIS) and co-spatial-temporal Atmospheric Imaging Assembly (AIA) and Helioseismic and Magnetic Imager (HMI) data onboard Solar Dynamics Observatory (SDO) for three time series on 2015 April 26, 2014 July 24, and 2014 July 26. Most asymmetric profiles are in the complex magnetic field regions of the networks. The asymmetric profiles are fitted with both single and double Gaussian models. The mean value of Doppler velocity of the second component is almost zero (with a significant standard deviation) in QS/CH, which may indicate that the physical process to trigger the secondary Gaussian originates at the formation height of Si iv. While the mean Doppler velocity from secondary Gaussian in BPs is around +4.0 km s−1 (redshifted). The non-thermal velocities of the secondary Gaussian in all three regions are slightly higher than the single Gaussian. The statistical investigation leads to the prevalence of blueshifted secondary components in QS/CH. However, secondary Gaussian in the BPs redshifted, i.e. the BPs redshift behaviour could be interpreted due to the site of reconnection located above the formation height of the Si iv line. The peak intensity of the second component for all three regions is likely to follow a power law that is a signature of the small-scale flaring-like trigger mechanism.
The UV continuum slopes of early star-forming galaxies in JADES
Authors: Topping Michael W , Stark Daniel P , Endsley Ryan , Whitler Lily , Hainline Kevin , Johnson Benjamin D , Robertson Brant , Tacchella Sandro , Chen Zuyi , Alberts Stacey , Baker William M , Bunker Andrew J , Carniani Stefano , Charlot Stephane , Chevallard Jacopo , Curtis-Lake Emma , DeCoursey Christa , Egami Eiichi , Eisenstein Daniel J , Ji Zhiyuan , Maiolino Roberto , Williams Christina C , Willmer Christopher N A , Willott Chris , Witstok Joris
Published: March 2024

The power-law slope of the rest-ultraviolet (UV) continuum (fλ ∝ λβ) is a key metric of early star-forming galaxies, providing one of our only windows into the stellar populations and physical conditions of z ≳ 10 galaxies. Expanding upon previous studies with limited sample sizes, we leverage deep imaging from the JWST Advanced Deep Extragalactic Survey (JADES) to investigate the UV slopes of 179 z ≳ 9 galaxies with apparent magnitudes of mF200W ≃ 26–31, which display a median UV slope of β = −2.4. We compare to a statistical sample of z ≃ 5–9 galaxies, finding a shift towards bluer rest-UV colours at all $M_{\rm UV}$. The most UV-luminous z ≳ 9 galaxies are significantly bluer than their lower redshift counterparts, representing a dearth of moderately red galaxies within the first 500 Myr. At yet earlier times, the z ≳ 11 galaxy population exhibits very blue UV slopes, implying very low impact from dust attenuation. We identify a robust sample of 44 galaxies with β ≲ −2.8, which have spectral energy distributions requiring models of density-bounded H ii regions and median ionizing photon escape fractions of 0.51 to reproduce. Their rest-optical colours imply that this sample has weaker emission lines (median mF356W − mF444W = 0.19 mag) than typical galaxies (median mF356W − mF444W = 0.39 mag), consistent with the inferred escape fractions. This sample consists of relatively low stellar masses (median $\log (M/{\rm M}_{\odot })=7.5\pm 0.2$), and specific star formation rates (sSFRs; median $=79 \, \rm Gyr^{-1}$) nearly twice that of our full galaxy sample (median sSFRs $=44 \, \rm Gyr^{-1}$), suggesting these objects are more common among systems experiencing a recent upturn in star formation. We demonstrate that the shutoff of star formation provides an alternative solution for modelling of extremely blue UV colours, making distinct predictions for the rest-optical emission of these galaxies. Future spectroscopy will be required to distinguish between these physical pictures.
The abundance of core-collapsed subhaloes in SIDM: insights from structure formation in ΛCDM
Authors: Shah Neev , Adhikari Susmita
Published: March 2024

Dark matter haloes enter a phase of gravothermal core-collapse in the presence of self-interactions. This phase is expected to be subdominant given the long time-scales involved. However, it has been shown that collapse is accelerated in subhaloes in strong tidal environments. Cosmological simulations in ΛCDM give complete distributions of subhalo orbits and their profiles. We use these to estimate the fraction of the subhaloes in different host halo environments that are in the core-collapse phase. Our hosts range from the Large Magellanic cloud (LMC)-like hosts to clusters. We use fluid simulations of self-interacting dark matter (SIDM) to evolve subhaloes in their hosts, including the effect of tidal truncation at the time of pericentre crossing. We find, for parameters that allow the interaction cross-section to be high at dwarf scales, at least $10\%$ of all subhaloes are expected to have intrinsically collapsed within Hubble time up to the group mass host scales. This fraction increases significantly, becoming at least 20% when tidal interactions are considered. To identify these objects in observations, we find that we need to measure their densities at very small radial scales, where the subhaloes show a bimodal distribution of densities or we need to measure the slopes of their inner density profiles near the scale radius, which are much steeper than NFW slopes. Current measurements of central slopes of classical dwarfs do not show preference for being completely collapsed, however they are consistent with being cored or in a phase of transition between expansion and collapse.
Overlooked shell features: asymmetrical columellar folds in volutid gastropods
Authors: Vermeij Geerat J
Published: March 2024

Many gastropods have columellar folds, defined as continuous spiral ridges extending from the aperture to the shell interior on the adaxial side of the aperture. Despite their ubiquity, columellar folds have received little phylogenetic or functional study. In the vast majority of cases, columellar folds have a symmetrical profile, with the anterior (abapical) slope similar to the posterior (adapical) slope. Here I draw attention to the highly unusual phenomenon of asymmetry of columellar folds, where the anterior slope is markedly less inclined than the posterior slope of each fold. I have detected this condition in the volutid genera Scaphella Swainson, 1832; Cymbiola Swainson, 1831 and Lyrischapa Aldrich, 1911; as well as in the Palaeocene and Eocene genus Eovasum Douvillé, 1920. Following a review of Lyrischapa and Eovasum, I suggest that these two genera are closely related members of the volutid subfamily Indovolutinae, and that asymmetrical columellar folds have evolved three times in Volutidae. Although their function remains elusive, asymmetrical folds might prevent abapical displacement of the soft parts during rapid extension of the foot or feeding organs.
The zinc-finger protein Z4 cooperates with condensin II to regulate somatic chromosome pairing and 3D chromatin organization
Authors: Puerto Marta , Shukla Mamta , Bujosa Paula , Pérez-Roldán Juan , Torràs-Llort Mònica , Tamirisa Srividya , Carbonell Albert , Solé Carme , Puspo Joynob Akter , Cummings Christopher T , de Nadal Eulàlia , Posas Francesc , Azorín Fernando , Rowley M Jordan
Published: March 2024

Chromosome pairing constitutes an important level of genome organization, yet the mechanisms that regulate pairing in somatic cells and the impact on 3D chromatin organization are still poorly understood. Here, we address these questions in Drosophila, an organism with robust somatic pairing. In Drosophila, pairing preferentially occurs at loci consisting of numerous architectural protein binding sites (APBSs), suggesting a role of architectural proteins (APs) in pairing regulation. Amongst these, the anti-pairing function of the condensin II subunit CAP-H2 is well established. However, the factors that regulate CAP-H2 localization and action at APBSs remain largely unknown. Here, we identify two factors that control CAP-H2 occupancy at APBSs and, therefore, regulate pairing. We show that Z4, interacts with CAP-H2 and is required for its localization at APBSs. We also show that hyperosmotic cellular stress induces fast and reversible unpairing in a Z4/CAP-H2 dependent manner. Moreover, by combining the opposite effects of Z4 depletion and osmostress, we show that pairing correlates with the strength of intrachromosomal 3D interactions, such as active (A) compartment interactions, intragenic gene-loops, and polycomb (Pc)-mediated chromatin loops. Altogether, our results reveal new players in CAP-H2-mediated pairing regulation and the intimate interplay between inter-chromosomal and intra-chromosomal 3D interactions.
ARGLU1 enhances promoter-proximal pausing of RNA polymerase II and stimulates DNA damage repair
Authors: Bachus Scott , Akkerman Nikolas , Fulham Lauren , Graves Drayson , Helwer Rafe , Rempel Jordan , Pelka Peter
Published: March 2024

Arginine and glutamate rich 1 (ARGLU1) is a poorly understood cellular protein with functions in RNA splicing and transcription. Computational prediction suggests that ARGLU1 contains intrinsically disordered regions and lacks any known structural or functional domains. We used adenovirus Early protein 1A (E1A) to probe for critical regulators of important cellular pathways and identified ARGLU1 as a significant player in transcription and the DNA damage response pathway. Transcriptional effects induced by ARGLU1 occur via enhancement of promoter-proximal RNA polymerase II pausing, likely by inhibiting the interaction between JMJD6 and BRD4. When overexpressed, ARGLU1 increases the growth rate of cancer cells, while its knockdown leads to growth arrest. Significantly, overexpression of ARGLU1 increased cancer cell resistance to genotoxic drugs and promoted DNA damage repair. These results identify new roles for ARGLU1 in cancer cell survival and the DNA damage repair pathway, with potential clinical implications for chemotherapy resistance.
APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance
Authors: Wu Cheng-Kuei , Shiu Jia-Lin , Wu Chao-Liang , Hung Chi-Feng , Ho Yen-Chih , Chen Yen-Tzu , Tung Sheng-Yung , Yeh Cheng-Fa , Shen Che-Hung , Liaw Hungjiun , Su Wen-Pin
Published: March 2024

Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.
Stress guides in generic static mechanical metamaterials
Authors: Wang Aoxi , Chen Chang Qing
Published: March 2024

The confinement of waves within a waveguide can enable directional transmission of signals, which has found wide applications in communication, imaging, and signal isolation. Extending this concept to static systems, where material deformation is piled up along a spatial trajectory, remains elusive due to the sensitivity of localized deformation to structural defects and impurities. Here, we propose a general framework to characterize localized static deformation responses in two-dimensional generic static mechanical metamaterials, by exploiting the duality between space in static systems and time in one-dimensional non-reciprocal wave systems. An internal time-reverse symmetry is developed by the space-time duality. Upon breaking this symmetry, quasi-static load-induced deformation can be guided to travel along a designated path, thereby realizing a stress guide. A combination of time-reverse and inversion symmetries discloses the parity-time symmetry inherent in static systems, which can be leveraged to achieve directional deformation shielding. The tailorable stress guides can find applications in various scenarios, ranging from stress shielding and energy harvesting in structural tasks to information processing in mechanical computing devices.
Artificial intelligence capital and employment prospects
Authors: Drydakis Nick
Published: March 2024

There is limited research assessing how AI knowledge affects employment prospects. The present study defines the term ‘AI capital’ as a vector of knowledge, skills, and capabilities related to AI technologies, which could boost individuals’ productivity, employment, and earnings. Subsequently, the study reports the outcomes of a genuine correspondence test in England. It was found that university graduates with AI capital, obtained through an AI business module, experienced more invitations for job interviews than graduates without AI capital. Moreover, graduates with AI capital were invited to interviews for jobs that offered higher wages than those without AI capital. Furthermore, it was found that large firms exhibited a preference for job applicants with AI capital, resulting in increased interview invitations and opportunities for higher-paying positions. The outcomes hold for both men and women. The study concludes that AI capital might be rewarded in terms of employment prospects, especially in large firms.
Single-Cell Sequencing Illuminates Thymic Development: An Updated Framework for Understanding Thymic Epithelial Tumors
Authors: Nabel Christopher S , Ackman Jeanne B , Hung Yin P , Louissaint Abner , Riely Gregory J
Published: March 2024

Thymic epithelial tumors (TETs) are rare tumors for which treatment options are limited. The ongoing need for improved systemic therapies reflects a limited understanding of tumor biology as well as the normal thymus. The essential role of the thymus in adaptive immunity is largely effected by its epithelial compartment, which directs thymocyte (T-cell) differentiation and immunologic self-tolerance. With aging, the thymus undergoes involution whereby epithelial tissue is replaced by adipose and other connective tissue, decreasing immature T-cell production. Against this natural drive toward involution, a fraction of thymuses will instead undergo oncologic transformation, leading to the formation of TETs, including thymoma and thymic carcinoma. The rarity of these tumors restricts investigation of the mechanisms of tumorigenesis and development of rational treatment options. To this end, the development of technologies which allow deep molecular profiling of individual tumor cells permits a new window through which to view normal thymic development and contrast the malignant changes that result in oncogenic transformation. In this review, we describe the findings of recent illuminating studies on the diversity of cell types within the epithelial compartment through thymic differentiation and aging. We contextualize these findings around important unanswered questions regarding the spectrum of known somatic tumor alterations, cell of origin, and tumor heterogeneity. The perspectives informed by single-cell molecular profiling offer new approaches to clinical and basic investigation of thymic epithelial tumors, with the potential to accelerate development of improved therapeutic strategies to address ongoing unmet needs in these rare tumors.
Economic evaluation of a trial exploring the effects of a web-based support tool for parents of children with juvenile idiopathic arthritis
Authors: Flood Chris , Hirani Shashivadan P , Mulligan Kathleen , Taylor Jo , Harris Sally , Wedderburn Lucy R , Newman Stanton P
Published: March 2024

Objective

To explore the cost-effectiveness of a web-based support tool for parents of children with Juvenile idiopathic arthritis.

Methods

A multi-centred randomized controlled trial was conducted in paediatric rheumatology centres in England. The WebParC intervention consisted of online information about JIA and its treatment and a toolkit using cognitive-behavioural therapy principles to support parents manage their child’s JIA. An economic evaluation was performed alongside the trial involving 220 parents. The primary outcome was the self-report Pediatric Inventory for Parents measure of illness-related parenting stress, with two dimensions: difficulty and frequency. These measures along with costs were assessed post intervention at 4 and 12 months. Costs were calculated for healthcare usage using a UK NHS economic perspective. Data was collected and analysed on the impact of caring costs on families. Uncertainty around cost-effectiveness was explored using bootstrapping and cost-effectiveness acceptability curves.

Results

The intervention arm showed improved average Pediatric Inventory for Parents scores for the dimensions of frequency and difficulty, of 1.5 and 3.6 respectively at 4 months and 0.35 and 0.39 at 12 months, representing improved PIP scores for the intervention arm. At both 4 and 12 month follow-up, the average total cost per case was higher in the control group when compared with the intervention arm with mean differences of £360 (95% CI £29.6 to £691) at 4 months and £203 (95% CI £16 to £390) at 12 months. The probability of the intervention being cost-effective ranged between 49% and 54%.

Conclusion

The WebParC intervention led to reductions in primary and secondary healthcare resource use and costs at 4 and 12 months. The intervention demonstrated particular savings for rheumatology services at both follow-ups. Future economies of scale could be realised by health providers with increased opportunities for cost-effectiveness over time.

Trial registration

ISRCTN, ISRCTN13159730.
Left Partisanship, Corporatism, and the Reorientation of the Knowledge Economy in Advanced Capitalist Societies
Authors: Huo Jingjing
Published: March 2024

While the progress of the knowledge economy is inexorable, this paper argues that partisan politics and labor market institutions can affect the direction in which the knowledge economy progresses. In particular, a combination of corporatist industrial relations systems and left partisanship tends to foster greater wage restraint, and such a wage outcome tends to encourage the greater adoption of communications technology than information-processing technology in the economy. This reorientation of the knowledge economy toward communications technology, in turn, has egalitarian distributive implications. In particular, the greater adoption of communications technology reduces wage inequality across the board in lower 90–10, 50–10, as well as 90–50 wage ratios. These arguments are tested using data across 15–21 OECD countries (1970–2015).
Saskatchewan law as a solution to the problem of informal wills in European countries?
Authors: Załucki Mariusz , Surtees Doug
Published: March 2024

This article is a presentation of the possible future of the law on the testamentary formalities, particularly in countries that adhere to very strict formal requirements. The authors present the positions of doctrine to date and conclude that the Canadian legislation in the province of Saskatchewan may offer a remedy to the problem of preparation of wills in contravention of the rules in the form of wills. In their opinion, the Canadian solution is a ready-made solution for many European legislators who would like to make their succession laws more flexible. The authors propose the wording of a provision that could be incorporated into the various legislations of European countries for this purpose.
Treatment of Acute Ischemic Stroke: The Last 30 Years of Trials and Tribulations
Authors: Jan Kalimullah , Chong Ji Y.
Published: March 2024

The landscape of acute ischemic stroke management has undergone a substantial transformation over the past 3 decades, mirroring our enhanced comprehension of the pathology and progress in diagnostic techniques, therapeutic interventions, and preventive measures. The 1990s marked a pivotal moment in stroke care with the integration of intravenous thrombolytics. However, the most significant paradigm shift in recent years has undoubtedly been the advent of endovascular thrombectomy. This article endeavors to deliver an exhaustive analysis of this revolutionary progression.
Quality of Life With Cochlear Implantation Using the CIQOL-35 at a Tertiary Urban Medical Center: Our Experience
Authors: Brooks Kaitlyn A. , Altartoor Khaled , Vivas Esther X.
Published: March 2024

Objective

Assessment of quality-of-life (QOL) outcomes after cochlear implantation (CI) using the Cochlear Implant Quality of Life-35 questionnaire (CIQOL-35).

Study Design

Retrospective cohort.

Setting

Single-institution tertiary care center.

Patients

Patients 18 years and older who have undergone CI and CIQOL-35 survey.

Interventions

Implementing CIQOL-35 from 2019 to 2022 to measure change in QOL after CI. Statistical analysis included nonparametric, univariate, and multivariate analyses. Significance was set at 0.05.

Main Outcome Measures

Differences in QOL among CI patients in each of the CIQOL-35 domains.

Results

Ninety-three patients (40 female, 53 male) aged 20 to 93 years (median 70 years) turned in 164 QOL surveys (68 preactivation, 96 postactivation). Postactivation median QOL was 5 to 15 points higher across all domains (p < 0.001). QOL score distributions among unilateral CI only, bilateral CI, and unilateral CI with contralateral hearing aid users were not statistically different (p > 0.05). Multivariate analysis identified that male sex (β = −2.0; 95% confidence interval, −3.9 to −0.1) was a negative predictor for environment scores and not being married (β = 2.0; 95% confidence interval, 0.02 to 4.0) was a positive predictor for entertainment scores. Median follow-up time was 13 months post-CI (interquartile range [IQR], 7.1–21.5 months).

Conclusions

CI patients experienced improved QOL postactivation among all QOL domains, whereas specific CI use pattern in regard to unilateral, bilateral, or bimodal did not affect QOL. Multivariate analysis identified marital status and sex as possible QOL predictors.
An Image Quality Transfer Technique for Localising Deep Brain Stimulation Targets
Authors: Zheng Ying-Qiu , Akram Harith , Li Zeju , Smith Stephen M , Jbabdi Saad
Published: March 2024

The ventral intermediate nucleus of the thalamus (Vim) is a well-established surgical target in functional neurosurgery for the treatment of tremor. As the structure lacks intrinsic contrast on conventional MRI sequences, targeting the Vim has predominantly relied on standardised Vim atlases which can fail to account for individual anatomical variability. To overcome this limitation, recent studies define the Vim using its structural connectivity profile generated via tractography. Although successful in accounting for individual variability, these connectivity-based methods are sensitive to variations in image acquisition and processing, and require high-quality diffusion imaging protocols which are usually not available in clinical settings. Here we propose a novel transfer learning approach to accurately target the Vim particularly on clinical-quality data. The approach transfers anatomical information from publicly-available high-quality datasets to a wide range of white matter connectivity features in low-quality data to augment inference on the Vim. We demonstrate that the approach can robustly and reliably identify Vim even with compromised data quality and is generalisable to datasets acquired with different protocols, outperforming previous surgical targeting methods. The approach is not limited to targeting Vim and can be adapted to other deep brain structures.
The remarkable similarity in the serum proteome between type 2 diabetics and controls
Authors: Mosedale David E. , Sharp Tilly , de Graff Adam , Grainger David J.
Published: March 2024

Type 2 diabetes mellitus (T2DM) is a rapidly increasing threat to global health, which brings with it a demand for better treatments. This study aimed to identify differences in the proteome of patients with T2DM to identify new targets for therapeutic intervention. We used a highly reproducible bottom-up proteomics protocol to investigate differences in protein, peptide and post-translational modifications between subjects with T2DM and matched controls in an untargeted manner. The serum proteome was remarkably similar at the protein level with no differences between the subject groups across 175 proteins and five orders of magnitude. Strong associations were found, however, between fasting serum glucose levels and glycations of abundant serum proteins, including sites on apolipoprotein A1, apolipoprotein A2 and α2- macroglobulin. We also investigated proteome differences associated with BMI, and found all three components of the ternary complex (IGF-binding protein complex acid-labile subunit (ALS), IGF-binding protein 3 (IGFBP-3) and IGF-2) were strongly negatively associated with BMI. The results show the power of a proteomics protocol optimised for precision rather than depth of coverage, which here has identified strong correlations between physiological measurements and very low abundance post-translational modifications. In T2DM any differences in the serum proteome are very small, and likely a consequence rather than a cause of hyperglycaemia.

Article highlights

Our goal was to use high-precision label-free bottom-up LC-MS/MS proteomics to investigate differences in the proteome of patients with T2DM and controls, and potentially identify novel targets for future research.

The serum proteome is remarkably similar in patients with T2DM and controls, with the only major difference being glycations of abundant serum proteins

All three components of the ternary complex (comprised of ALS, IGFBP-3 and IGF-2) were strongly negatively associated with BMI.

The results highlight the power of a proteomics study designed with three key features at its core: a proteomics protocol optimised for precision rather than depth of coverage; an open bioinformatics approach investigating proteins, peptides and PTMs without prior assumptions about which features are important; and analysis of individual subject samples so that results take into account person-to-person variability
Combining Top-Down and Bottom-Up: An Open Microfluidic Microtumor Model for Investigating Tumor Cell-ECM Interaction and Anti-Metastasis
Authors: Li Chao , Li Jiayi , Argall-Knapp Zach , Hendrikse Nathan W. , Farooqui Mehtab A. , Raykowski Bella , King Anna , Nong Serratt
Published: March 2024

Using a combined top-down (i.e., operator-directed) and bottom-up (i.e., cell-directed) strategy, we present an Under-oil Open Microfluidic System (UOMS)-based microtumor model for investigating tumor cell migration and anti-metastasis drug test. Compared to the mainstream closed microfluidics-based microtumor models, the UOMS microtumor model features: i) micrometer-scale lateral resolution of surface patterning with open microfluidic design for flexible spatiotemporal sample manipulation (i.e., top-down); ii) self-organized extracellular matrix (ECM) structures and tumor cell-ECM spontaneous remodeling (i.e., bottom-up); and iii) free physical access to the samples on a device with minimized system disturbance. The UOMS microtumor model is used to test an anti-metastasis drug (incyclinide, aka CMT-3) with a triple negative breast cancer cell line (MDA-MB-231). Thein vitroresults show a suppression of tumor cell migration and ECM remodeling echoing with thein vivomice metastasis results.
Evaluation ofOctopus mayaenzyme activity of the digestive gland and gastric juice
Authors: Pineda-Suazo Daisy , Escobedo-Hinojosa Wendy , Canseco Lenin E. Fabian , Gallardo Pedro , Ojeda Cintia Moguel , Caamal-Monsreal Claudia , Sánchez-Arteaga Ariadna , Rosas Carlos
Published: March 2024

Background

As the demand forOctopus mayagrows, sustainable farming practices become essential to prevent overexploitation. Thus, its farming development can be a sustainable alternative to traditional fishing. Understanding the digestive dynamics is essential for devising optimal dietary formulations in aquaculture, particularly the role of enzymes like cathepsins and others. Despite the progress in understanding cephalopod digestion, little is known about the specific functioning of the digestive enzymes responsible for breaking down protein substrates. This knowledge gap underscores the need for further research to ensureO. mayapopulation sustainable management.

Methods and Results

Dietary formulations are identified for cephalopods by characterizingO. mayadigestive enzymes present in the digestive gland and gastric juice. The present investigation revealed that acidic proteases showed a peak activity at higher temperatures than alkaline proteases. Inhibitors confirmed the presence of H, L, and D cathepsins. Noteworthy is a lower activation energy of alkaline enzymes compared to acidic, ones highlighting an intriguing aspect ofO. maya’sdigestive physiology.

Conclusion

Overall, this research provides valuable insights intoO. mayadigestive enzyme functions representing a significant advancement in formulating diets crucial for octopus successful farming that may help to fully understand its physiology.
NEST: Spatially-mapped cell-cell communication patterns using a deep learning-based attention mechanism
Authors: Zohora Fatema Tuz , Flores-Figueroa Eugenia , Li Joshua , Paliwal Deisha , Notta Faiyaz , Schwartz Gregory W.
Published: March 2024

Dysregulation of communication between cells mediates complex diseases such as cancer and diabetes. However, detecting cell-cell communication (CCC) at scale remains one of the greatest challenges in transcriptomics. While gene expression measured with single-cell RNA sequencing and spatial transcriptomics reinvigorated computational approaches to detecting CCC, most existing methods exhibit high false positive rates, do not integrate spatial proximity of ligand-receptor interactions, and cannot detect CCC between individual cells. We overcome these challenges by presentingNEST (NEural network on Spatial Transcriptomics), which uses a graph attention network paired with an unsupervised contrastive learning approach to decipher patterns of communication while retaining the strength of each signal. We introduce new synthetic benchmarking experiments which demonstrate how NEST outperforms existing tools and detects biologically-relevant CCC along with directionality and confidence across spot- and cell-based technologies measuring several different tissues and diseases. In our applications, NEST identifies T-cell homing signals in human lymph nodes, aggressive cancer CCC in lung adenocarcinoma, and discovers new patterns of communication that act as relay networks in pancreatic cancer. Beyond two-dimensional data, we also highlight NEST’s ability to detect CCC in three-dimensional spatial transcriptomic data.
Plant species richness and the root economics space drive soil fungal communities
Authors: Hennecke Justus , Bassi Leonardo , Albracht Cynthia , Amyntas Angelos , Bergmann Joana , Eisenhauer Nico , Fox Aaron , Heimbold Lea , Heintz-Buschart Anna , Kuyper Thomas W. , Lange Markus , Alves de Souza Yuri Pinheiro , Rai Akanksha , Solbach Marcel Dominik , Mommer Liesje , Weigelt Alexandra
Published: March 2024

Trait-based approaches have been increasingly used to relate plants to soil microbial communities. However, the plant organs mediating this plant-microbe interaction – the roots – have been largely overlooked. The recent discovery of the root economics space offers a predictive framework for the structure of soil microbial communities, and specifically soil-borne fungal communities. Applying this novel approach, our study in a grassland plant diversity experiment reveals distinct root trait strategies at the level of the plant community. In addition to significant effects of plant species richness, we show that both axes of the root economics space – the collaboration and conservation gradient – are strong drivers of the composition of the different guilds of soil fungi, including saprotrophic, plant pathogenic, and mycorrhizal fungi. Our results illustrate that the root economics space and plant species richness jointly determine the effects of plants on fungal communities and their potential role in plant health and ecosystem functioning.
Paradigm shift in biomarker translation: a pipeline to generate clinical grade biomarker candidates from DIA-MS discovery
Authors: Fu Qin , Vegesna Manasa , Sundararaman Niveda , Damoc Eugen , Arrey Tabiwang N. , Pashkova Anna , Mengesha Emebet , Debbas Philip , Joung Sandy , Li Dalin , Cheng Susan , Braun Jonathan , McGovern Dermot P.B. , Murray Christopher , Xuan Yue , Eyk Jennifer E. Van
Published: March 2024

Clinical biomarker development has been stymied by inaccurate protein quantification from mass spectrometry (MS) discovery data and a prolonged validation process. To mitigate these issues, we created the Targeted Extraction Assessment of Quantification (TEAQ) software package. This innovative tool uses the discovery cohort analysis to select precursors, peptides, and proteins that adhere to established targeted assay criteria. TEAQ was applied to Data-Independent Acquisition MS data from plasma samples acquired on an Orbitrap™ Astral™ MS. Identified precursors were evaluated for linearity, specificity, repeatability, reproducibility, and intra-protein correlation from 11-point loading curves under three throughputs, to develop a resource for clinical-grade targeted assays. From a clinical cohort of individuals with inflammatory bowel disease (n=492), TEAQ successfully identified 1116 signature peptides for 327 quantifiable proteins from 1180 identified proteins. Embedding stringent selection criteria adaptable to targeted assay development into the analysis of discovery data will streamline the transition to validation and clinical studies.
A humanized knock-inCol6a1mouse recapitulates a deep-intronic splice-activating variant
Authors: Bolduc Véronique , Guirguis Fady , Lubben Berit , Trank Lindsey , Silverstein Sarah , Brull Astrid , Nalls Matthew , Cheng Jun , Garrett Lisa , Bönnemann Carsten G.
Published: March 2024

Antisense therapeutics such as splice-modulating antisense oligonucleotides (ASOs) are promising tools to treat diseases caused by splice-altering intronic variants. However, their testing in animal models is hampered by the generally poor sequence conservation of the intervening sequences between human and other species. Here we aimed to model in the mouse a recurrent, deep-intronic, splice-activating,COL6A1variant, associated with a severe form of Collagen VI-related muscular dystrophies (COL6-RDs), for the purpose of testing human-ready antisense therapeuticsin vivo. The variant, c.930+189C>T, creates a donor splice site and inserts a 72-nt-long pseudoexon, which, when translated, acts in a dominant-negative manner, but which can be skipped with ASOs. We created a unique humanized mouse allele (designated as “h”), in which a 1.9 kb of the mouse genomic region encoding the amino-terminus (N-) of the triple helical (TH) domain of collagen α1(VI) was swapped for the human orthologous sequence. In addition, we also created an allele that carries the c.930+189C>T variant on the same humanized knock-in sequence (designated as “h+189T”). We show that in both models, the human exons are spliced seamlessly with the mouse exons to generate a chimeric mouse-human collagen α1(VI) protein. In homozygousCol6a1h+189T/h+189Tmice, the pseudoexon is expressed at levels comparable to those observed in heterozygous patients’ muscle biopsies. WhileCol6a1h/hmice do not show any phenotype compared to wild-type animals,Col6a1h/h+189TandCol6a1h+189T/h+189Tmice have smaller muscle masses and display grip strength deficits detectable as early as 4 weeks of age. The pathogenic h+189T humanized knock-in mouse allele thus recapitulates the pathogenic splicing defects seen in patients’ biopsies and allows testing of human-ready precision antisense therapeutics aimed at skipping the pseudoexon. Given that theCOL6A1N-TH region is a hot-spot for COL6-RD variants, the humanized knock-in mouse model can be utilized as a template to introduce otherCOL6A1pathogenic variants. This unique humanized mouse model thus represents a valuable tool for the development of antisense therapeutics for COL6-RDs.
Reconstructing the dynamics of past coral endosymbiotic algae communities using coral ancient DNA (coraDNA)
Authors: Rey Olivier , Dissard Delphine , Toulza Eve , Guinebert Thomas , Saccas Mathilde , Allienne Jean-François , Butsher John , Zoubir Mourad BenSalah , Iwankow G. , Tougard Christelle , Vidal-Dupiol Jérémie
Published: March 2024

Most scleractinian corals are drastically threatened due to global changes but some colonies are intriguingly resistant to heat stress. Coral thermal tolerance partly relies on genomic determinism among the cnidarian compartment but also on the physiology of their associated symbiotic algae (Symbiodiniaceae). In fact, some corals can shift and/or shuffle their associated Symbiodiniaceae communities to temporally cope with heat stress. So far coral adjustments of their endosymbiotic algae were mainly observed at short-term evolutionary time scales and we lack a general vision of coral holobiont evolution at broader timescales. We here combined the use of ancient DNA from a coral core and a metabarcoding approach, to retrace past Symbiodiniaceae communities associated with a living colony ofPorites lobatafrom New Caledonia over the last century. We were able to extract ancient DNA along the coral core at 19 time points dating back to the 1870’s. Overall, we detected 13 OTUs, nine of which were affiliated to the SymbiodiniaceaeCladocopiumclade, one toAzadinium spinosum(Dinophycae); one to the hostP. lobata, the two other OTUs remained unidentified. One OTU was largely predominant and was ubiquitous over all samples. The number of OTUs was marginally correlated to the total number of sequences per sample but not to the age of thecoraDNA sample. We found a generally stable core microbiota associated withP. lobata, although drastic change in community composition was observed in coraDNA samples corresponding to an extreme hot winter temperature event. More generally, this study paves the way for further investigations on the evolutionary dynamics of coral holobionts at the colony level over large temporal scales.
MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats
Authors: Luo Longhua , Wang Zixin , Tong Xuxian , Xiong Tenxian , Chen Minggen , Liu Xiang , Peng Cong , Sun Xiang
Published: March 2024

Erectile dysfunction (ED) is a male sexual dysfunction with a gradually increasing prevalence, and current treatments are ineffective. This study aims to find a safer and more effective treatment for erectile dysfunction. Bone marrow-derived mesenchymal stem cells (BM-MSCs) treated with VEGFA. The expression of endothelial markers vWF, VE-cadherin and eNOS were determined by overexpressing MALAT1 and CDC42, respectively. The results showed that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs and the expression of endothelial marker-related proteins. Moreover, MALAT1 induced differentiation of BM-MCs to ECs through the CDC42/PAK1/Paxillin pathway was explored by transfecting si-MALAT1 and overexpressing CDC42 as well as PAK1 in the BM-MSCs. Next, miR-206 was overexpressed within BM-MCs to determine CDC42 expression. The binding sites of MALAT1, miR-206 and CDC42 were reported using luciferase. it was found that the MALAT1 competes with CDC42 3’-UTR for binding miR-206, which in turn is involved in differentiating BM-MSCs to ECs. Finally, DMED rat modeling success was demonstrated by APO experiments. MALAT1 overexpression-modified BM-MSCs had significant therapeutic effects in DMED rats.