bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutralizing antibodies to interferon alfa arising during peginterferon therapy of chronic hepatitis B in children and adults: Results from the HBRN Trials
Authors: Zahoor Muhammad Atif , Feld Joshua B. , Lin Hsing-Hua Sylvia , Mosa Alexander I. , Salimzadeh Loghman , Perrillo Robert P. , Chung Raymond T. , Schwarz Kathleen B. , Janssen Harry L.A. , Gehring Adam J. , Feld Jordan J.
Published: April 2024

Background & Aims:

Pegylated interferon-α (PegIFNα) is of limited utility during immunotolerant or immune active phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some patients receiving treatment are associated with limited/no virological responses. The study aimed to determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies.

Approach & Results:

Pre-treatment, on-treatment, and post-treatment sera from 61 immunotolerant trial participants on PegIFNα/entecavir therapy and 88 immune active trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by preincubation of sera±recombinant human IFNα added to Huh7 cells with the measurement of interferon-stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated. Preincubation of on-treatment serum from 26 immunotolerant (43%) and 13 immune active (15%) participants with recombinant-human IFNα markedly blunted ISG-induction in Huh7 cells. The degree of ISG inhibition correlated with IFNα antibody titer (p < 0.0001; r = 0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced quantitative HBsAg and qHBeAg declines (p < 0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults (p = 0.004) but nAbs in children had less impact on virological responses.

Conclusions:

The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for the optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.
Comparison of Scheimpflug Corneal Tomography and Anterior Segment Optical Coherence Tomography Measurements in Corneal Cystinosis: A Case Series
Authors: Vercauteren Leonie , Consejo Alejandra , De Vries Meindert Jan , Krolo Iva , Koppen Carina , Ní Dhubhghaill Sorcha
Published: April 2024

Purpose:

To report the clinical course and compare the utility of Scheimpflug tomography (ST) and anterior segment optical coherence tomography (AS-OCT) for central corneal thickness (CCT) and corneal densitometry (CD) assessment in patients with corneal crystals owing to nephropathic cystinosis.

Methods:

A retrospective chart analysis of three patients with nephropathic cystinosis and the presence of corneal cystine crystals in both eyes was performed. All patients underwent clinical examination and anterior segment photography, ST, and AS-OCT scans. Corneal densitometry was exported from built-in proprietary software for ST and from custom-made validated software for AS-OCT. Anterior segment optical coherence tomography images were rescaled to grayscale units from 0 (maximum transparency) to 100 (minimum transparency) to match built-in ST densitometry readings. Furthermore, the mean pixel intensity, representative of CD, was calculated from the pixels corresponding to the segmented cornea.

Results:

All three patients had pathognomonic cystine crystals deposits in the cornea and were treated with cysteamine medications that resulted in clinical improvement. The CCT measured using ST exhibited a range from 560 to 958 μm. Conversely, when assessed with AS-OCT, the CCT varied within the range of 548 to 610 μm. Both examinations could be performed, but in the more severe cases, AS-OCT showed far greater utility to estimate CD. In four of six eyes examined, ST showed disproportionate CCT values, compared with the AS-OCT, whereas reliable CD measurements were only available in AS-OCT.

Conclusion:

The AS-OCT could be considered a baseline ocular measurement in cystinosis and in the evaluation of disease progression and treatment efficacy.
Feasibility and Challenges of Interactive AI for Traditional Chinese Medicine: An Example of ChatGPT
Authors: KONG Qi , CHEN Liming , YAO Jingyi , DING Chao , YIN Peihao
Published: April 2024

ChatGPT, developed by OpenAI, is currently the largest language model with robust interactive capabilities. As a complementary alternative medicine (CAM), Traditional Chinese Medicine (TCM) represents an established medical system with a rich history and abundant clinical experience. TCM is an empirical medicine, the process of which is analogous to ChatGPT's learning and development model. In TCM, inquiry is a relatively objective way of traditional syndrome differentiation. Although various artificial intelligence systems related to TCM consultation exist, their interactive abilities remain limited. As such, we standardized the primary complaint and instructed ChatGPT to simulate a TCM practitioner, conducting three comprehensive inquiry tests. The results yielded unexpected conclusions, revealing that ChatGPT could simulate a TCM practitioner's inquiry with patients, confirming its potential in the field of TCM inquiry. However, current applications still pose certain limitations and risks. Hence, to integrate ChatGPT-like language models with traditional TCM AI to establish an associative mode that can facilitate TCM diagnosis and treatment with more convenience and standardization is crucial, yet at the same time, it should be treated very carefully.
Skeletal Muscle Mass Assessment in Pediatric Patients: Development of a Normative Equation and Assessment of Factors Associated With a Low Skeletal Muscle Mass in PICU Patients
Authors: Matsuoka Wakato , Mizuguchi Soichi , Kaku Noriyuki , Higashi Kanako , Tetsuhara Kenichi , Akahoshi Tomohiko , Ohga Shouichi
Published: April 2024

OBJECTIVES:

To develop an equation for defining a low skeletal muscle mass (SMM) in children and to investigate risk factors and outcomes associated with low SMM in critically ill pediatric patients.

DESIGN:

Single-center retrospective pediatric cohorts, 2011–2018.

SETTING:

Tertiary Emergency and Critical Care Center of Kyushu University Hospital in Japan.

PATIENTS:

We studied two cohorts of pediatric patients 1–15 years old who underwent abdominal CT at the level of the third lumbar vertebra (L3). First a cohort of trauma patients presented to the emergency department in whom we developed an SMM regression equation. Second, a cohort of patients who had undergone abdominal CT within 3 days of PICU admission.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The equation for estimating normal SMM used sex, age, and weight. Low SMM was defined as less than 80% of normal. In the 112 patients in the PICU cohort, median (range) age was 68 (13–191) months, and 83 (74.1%) had underlying disease. There was low SMM in 54 patients (48.2%). Regarding associations, using odds ratio (OR) and 95% CI, we found that low dietary intake (OR 4.33 [95% CI, 1.37–13.70]; p = 0.013) and the presence of underlying disease (OR 7.44 [95% CI, 2.10–26.30]; p = 0.002) were independently associated with greater odds of low SMM. Low SMM, compared with normal SMM, was also associated with longer hospital stays (42.5 d vs. 20.5 d; p = 0.007; β, 1.59; 95% CI, 1.09–2.33; p = 0.016).

CONCLUSIONS:

In this retrospective PICU cohort from a single center in Japan, we found that low SMM at PICU admission was present in almost half the cases. Low SMM, as defined by being less than 80% of the normal, was associated with greater odds of low dietary intake and underlying chronic disease. Furthermore, low SMM was associated with longer hospital stays.
Tnfaip8 and Tipe2 Gene Deletion Ameliorates Immediate Proteoglycan Loss and Inflammatory Responses in the Injured Mouse Intervertebral Disc
Authors: Lu Jiawei , Tian Zuozhen , Shofer Frances S. , Qin Ling , Sun Honghong , Zhang Yejia
Published: April 2024

Objective

TNFAIP8 and TIPE2 belong to TNFa-induced protein 8 (TNFAIP8/TIPE) family. They control apoptosis and direct leukocyte migration. Nucleus pulposus cell loss is a hallmark of intervertebral disc degeneration in response to injury, and inflammation may cause pain. Here, we examined the effects of TNFAIP8/TIPE2 deficiency on the intervertebral discs in mice with these genes deleted.

Design

Tail intervertebral discs in Tnfaip8 or Tipe2 single and double knockout mice (Tnfaip8−/−
, Tipe2−/−
, and Tnfaip8/Tipe2 dko), and wild-type controls were injured. The spine motion segments were stained with safranin O to reveal proteoglycans. Macrophages were identified by immunostaining, and selected inflammatory marker and collagen gene expression was examined by Real Time PCR.

Results

The injured tail intervertebral discs of Tnfaip−/−
, Tipe2−/−
, and Tnfaip8/Tipe2 dko mice all displayed higher levels of proteoglycans than wild-type controls. Fewer macrophages were found in the injured intervertebral discs of Tipe2−/−
and Tnfaip8/Tipe2 dko mice than wild type. Il6, Adam8, and Col1 gene expression was downregulated in the injured intervertebral discs of Tnfip8/Tipe2 dko mice.

Conclusions

TNFAIP8 and TIPE2 loss of function ameliorated proteoglycan loss and inflammation in the injured intervertebral discs. They may serve as molecular targets to preserve disc structure and reduce inflammation.
Host Nuclear Genome Copy Number Variations Identify High-Risk Anal Precancers in People Living with HIV
Authors: Mutetwa Tinaye , Liu Yuxin , Silvera Richard , Evans Michelle , Yurich Michael , Tripodi Joseph , Leonard Issa , Houldsworth Jane , Gümüş Zeynep , Bowcock Anne M. , Sigel Keith , Gaisa Michael , Polak Paz
Published: April 2024

BACKGROUND:

People living with HIV (PLWH) have substantially increased incidence of anal precancer and cancer. There are very little data regarding genomic disturbances in anal precancers among PLWH. Here, we identified specific chromosomal variants in anal squamous intraepithelial lesions.

METHODS:

We collected 63 anal biopsy specimens (27 low-grade intraepithelial lesions [LSIL] and 36 high-grade intraepithelial lesions [HSIL]) from PLWH obtained as part of anal cancer screening in our NYC-based health system. Data on patient demographics, anal cytological and high-risk human papillomavirus (HR-HPV) diagnoses were collected. Specimens were tested for a panel of chromosomal alterations associated with HPV-induced oncogenesis using Fluorescence In-Situ Hybridization (FISH) and analyses compared the associations of these alterations with clinical characteristics.

RESULTS:

Gains of 3q26, 5p15, 20q13 and cen7 were detected in 42%, 31%, 31%, and 19% of HSIL compared to 7%, 0%, 4%, and 0% of LSIL, respectively. Where at least one abnormality was seen, 89% had a 3q26 gain. In lesions with 5p15 gains, 20q13 gains co-occurred in 91% of cases, while cen7 gain only co-occurred with the other three alterations. Sensitivity and specificity of any alteration to predict HSIL was 47% (95% CI: 30-65%) and 93% (95% CI: 76%-99%) respectively.

CONCLUSIONS:

Genomic alterations seen in HPV-associated cancers may help distinguish anal LSIL from HSIL. 3q26 amplification may be an early component of anal carcinogenesis, preceding 5p16, 20q13 and/or chr7.

IMPACT:

We share insights on potential genomic biomarkers for discriminating high-risk anal precancers.
Early Open Extensive Suturectomy for the Severe Multisuture Synostosis
Authors: Yassaie Emily , Hennedige Anusha , Parks Christopher
Published: April 2024

Neonates born with severe multisuture synostosis can present as an emergency. The severe craniocerebral disproportion with or without underlying hydrocephalus and retruded midface can result in raised intracranial pressure and airway compromise within the first few days or weeks of life. This presents a challenging multidisciplinary condition. There is no international consensus on management. There are limited publications available describing the approach to treatment. In our unit, children who present in the neonatal period with severe multisuture synostosis are offered early open extensive suturectomy within the first few months of life. The goals are; reduction in raised intracranial pressure, improvement in head shape and bone formation, and avoidance of a ventriculoperitoneal shunt. This is performed as an adjunct, not a replacement of other traditional skull vault procedures. We describe the technique and postoperative care without the need for a helmet that leads to excellent skull-shape outcomes and avoidance of a ventriculoperitoneal shunt.
Modifying cellulose fibres with carbon dots: a promising approach for the development of antimicrobial fibres
Authors: Radha Remya , Makhlouf Zinb , Diab Rasha , Al-Sayah Mohammad H.
Published: April 2024

This study focuses on the development of antimicrobial fibres for use in medical and healthcare textile industries. Carbon dots (CDs) were designed with boronic acid groups for the attachment to cellulose fibres found in cotton textiles and to enhance their attachment to glycogens on bacterial surfaces. Boronic acid-based and curcumin-based CDs were prepared and characterized using various techniques, showing a nanoscale size and zeta potential values. The CDs inhibited the growth of both
Staphylococcus epidermidis
and
Escherichia coli
bacteria, with UV-activated CDs demonstrating improved antibacterial activity. The antimicrobial activity of the CDs was then tested, revealing strong adherence to cellulose paper fibres with no CD diffusion and potent inhibition of bacterial growth. Cytotoxicity assays on human cell lines showed no toxicity towards cells at concentrations of up to 100 µg ml
−1
but exhibited increased toxicity at concentrations exceeding 1000 µg ml
−1
. However, CD-modified cellulose paper fibres showed no toxicity against human cell lines, highlighting the antimicrobial properties of the CD-modified cellulose fibres are safe for human use. These findings show promising potential for applications in both industrial and clinical settings.
No evidence that a transmissible cancer has shifted from emergence to endemism in Tasmanian devils
Authors: Stammnitz Maximilian R. , Gori Kevin , Murchison Elizabeth P.
Published: April 2024

Tasmanian devils are endangered by a transmissible cancer known as Tasmanian devil facial tumour 1 (DFT1). A 2020 study by Patton
et al
. (
Science
370
, eabb9772 (doi:
10.1126/science.abb9772
)) used genome data from DFT1 tumours to produce a dated phylogenetic tree for this transmissible cancer lineage, and thence, using phylodynamics models, to estimate its epidemiological parameters and predict its future trajectory. It concluded that the effective reproduction number for DFT1 had declined to a value of one, and that the disease had shifted from emergence to endemism. We show that the study is based on erroneous mutation calls and flawed methodology, and that its conclusions cannot be substantiated.
Navigating the unknown: assessing anthropogenic threats to beaked whales, family Ziphiidae
Authors: Feyrer Laura J. , Stanistreet Joy E. , Moors-Murphy Hilary B.
Published: April 2024

This review comprehensively evaluates the impacts of anthropogenic threats on beaked whales (Ziphiidae)—a taxonomic group characterized by cryptic biology, deep dives and remote offshore habitat, which have challenged direct scientific observation. By synthesizing information published in peer-reviewed studies and grey literature, we identified available evidence of impacts across 14 threats for each Ziphiidae species. Threats were assessed based on their pathways of effects on individuals, revealing many gaps in scientific understanding of the risks faced by beaked whales. By applying a comprehensive taxon-level analysis, we found evidence that all beaked whale species are affected by multiple stressors, with climate change, entanglement and plastic pollution being the most common threats documented across beaked whale species. Threats assessed as having a serious impact on individuals included whaling, military sonar, entanglement, depredation, vessel strikes, plastics and oil spills. This review emphasizes the urgent need for targeted research to address a range of uncertainties, including cumulative and population-level impacts. Understanding the evidence and pathways of the effects of stressors on individuals can support future assessments, guide practical mitigation strategies and advance current understanding of anthropogenic impacts on rare and elusive marine species.
Individual variation in life-history timing: synchronous presence, asynchronous events and phenological compensation in a wild mammal
Authors: Beltran Roxanne S. , Lozano Raquel R. , Morris Patricia A. , Robinson Patrick W. , Holser Rachel R. , Keates Theresa R. , Favilla Arina B. , Kilpatrick A. Marm , Costa Daniel P.
Published: April 2024

Many animals and plants have species-typical annual cycles, but individuals vary in their timing of life-history events. Individual variation in fur replacement (moult) timing is poorly understood in mammals due to the challenge of repeated observations and longitudinal sampling. We examined factors that influence variation in moult duration and timing among elephant seals (
Mirounga angustirostris
). We quantified the onset and progression of fur loss in 1178 individuals. We found that an exceptionally rapid visible moult (7 days, the shortest of any mammals or birds), and a wide range of moult start dates (spanning 6–10× the event duration) facilitated high asynchrony across individuals (only 20% of individuals in the population moulting at the same time). Some of the variation was due to reproductive state, as reproductively mature females that skipped a breeding season moulted a week earlier than reproductive females. Moreover, individual variation in timing and duration within age-sex categories far outweighed (76–80%) variation among age-sex categories. Individuals arriving at the end of the moult season spent 50% less time on the beach, which allowed them to catch up in their annual cycles and reduce population-level variance during breeding. These findings underscore the importance of individual variation in annual cycles.
Mechanistic interactions as the origin of modularity in biological networks
Authors: Wechsler Daniel , Bascompte Jordi
Published: April 2024

Biological networks are often modular. Explanations for this peculiarity either assume an adaptive advantage of a modular design such as higher robustness, or attribute it to neutral factors such as constraints underlying network assembly. Interestingly, most insights on the origin of modularity stem from models in which interactions are either determined by highly simplistic mechanisms, or have no mechanistic basis at all. Yet, empirical knowledge suggests that biological interactions are often mediated by complex structural or behavioural traits. Here, we investigate the origins of modularity using a model in which interactions are determined by potentially complex traits. Specifically, we model system elements—such as the species in an ecosystem—as finite-state machines (FSMs), and determine their interactions by means of communication between the corresponding FSMs. Using this model, we show that modularity probably emerges for free. We further find that the more modular an interaction network is, the less complex are the traits that mediate the interactions. Altogether, our results suggest that the conditions for modularity to evolve may be much broader than previously thought.
Social and genetic connectivity despite ecological variation in a killer whale network
Authors: Jourdain Eve , Karoliussen Richard , Fordyce Martin Sarah L. , Langangen Øystein , Robeck Todd , Borgå Katrine , Ruus Anders , Foote Andrew D.
Published: April 2024

Philopatric kin-based societies encourage a narrow breadth of conservative behaviours owing to individuals primarily learning from close kin, promoting behavioural homogeneity. However, weaker social ties beyond kin, and across a behaviourally diverse social landscape, could be sufficient to induce variation and a greater ecological niche breadth. We investigated a network of 457 photo-identified killer whales from Norway (548 encounters in 2008–2021) with diet data available (46 mixed-diet individuals feeding on both fish and mammals, and 411 exclusive fish-eaters) to quantify patterns of association within and between diet groups, and to identify underlying correlates. We genotyped a subset of 106 whales to assess patterns of genetic differentiation. Our results suggested kinship as main driver of social bonds within and among cohesive social units, while diet was most likely a consequence reflective of cultural diffusion, rather than a driver. Flexible associations within and between ecologically diverse social units led to a highly connected network, reducing social and genetic differentiation between diet groups. Our study points to a role of social connectivity, in combination with individual behavioural variation, in influencing population ecology in killer whales.
Evaluating the impact of genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) on hospital infection prevention and control decisions
Authors: Blane Beth , Raven Kathy E. , Brown Nicholas M. , Harrison Ewan M. , Coll Francesc , Thaxter Rachel , Enoch David A. , Gouliouris Theodore , Leek Danielle , Girgis Sophia T. , Akram Asha , Matuszewska Marta , Rhodes Paul , Parkhill Julian , Peacock Sharon J.
Published: April 2024

Genomic epidemiology enhances the ability to detect and refute methicillin-resistant Staphylococcus aureus (MRSA) outbreaks in healthcare settings, but its routine introduction requires further evidence of benefits for patients and resource utilization. We performed a 12 month prospective study at Cambridge University Hospitals NHS Foundation Trust in the UK to capture its impact on hospital infection prevention and control (IPC) decisions. MRSA-positive samples were identified via the hospital microbiology laboratory between November 2018 and November 2019. We included samples from in-patients, clinic out-patients, people reviewed in the Emergency Department and healthcare workers screened by Occupational Health. We sequenced the first MRSA isolate from 823 consecutive individuals, defined their pairwise genetic relatedness, and sought epidemiological links in the hospital and community. Genomic analysis of 823 MRSA isolates identified 72 genetic clusters of two or more isolates containing 339/823 (41 %) of the cases. Epidemiological links were identified between two or more cases for 190 (23 %) individuals in 34/72 clusters. Weekly genomic epidemiology updates were shared with the IPC team, culminating in 49 face-to-face meetings and 21 written communications. Seventeen clusters were identified that were consistent with hospital MRSA transmission, discussion of which led to additional IPC actions in 14 of these. Two outbreaks were also identified where transmission had occurred in the community prior to hospital presentation; these were escalated to relevant IPC teams. We identified 38 instances where two or more in-patients shared a ward location on overlapping dates but carried unrelated MRSA isolates (pseudo-outbreaks); research data led to de-escalation of investigations in six of these. Our findings provide further support for the routine use of genomic epidemiology to enhance and target IPC resources.
A Systematic Review of Military to Civilian Transition: The Role of Gender
Authors: Smith Alexandria , Rafferty Laura , Croak Bethany , Greenberg Neil , Khan Rafiyah , Langston Victoria , Sharp Marie-Louise , Stagg Anne , Fear Nicola , Stevelink Sharon
Published: April 2024

Background

The military-to-civilian transition can be a challenging period for many service members; however, recent research suggests that female ex-service personnel (veterans) confront additional complexities during reintegration into civilian life. This systematic review aimed to identify and synthesise findings across qualitative studies exploring the impact of gender on this transition process.

Methods

Peer-reviewed literature was drawn from a multi-database search, limited to qualitative studies. The studies included either female veterans or both male and female veterans aged 18 years or older who had previously served in the Armed Forces within the Five Eyes (FVEY) countries (Australia, Canada, New Zealand, the United Kingdom, and the United States). We used a Framework Analysis approach to guide the synthesis of the qualitative data. An assessment of study quality was conducted using the Joanna Briggs Institute (JBI) Qualitative Critical Appraisal Checklist for Qualitative Studies. The study protocol is registered with the Open Science Framework (osf.io/5stuj).

Results

In total, 10,113 articles were screened after the removal of duplicates, 161 underwent full-text review, with 19 meeting the eligibility criteria. The review identified eleven themes split across individual’s experience whilst serving and after transitioning out of the military service. Both male and female veterans discussed a period of acculturation when they joined service and adapted to military norms, culture and identity. Female veterans faced additional challenges at this stage centred on the conflict between feminine norms and the military masculine ideal. Upon leaving service both male and female veterans experienced a loss of military identity and purpose, and dissonance with civilian norms illustrating a military-civilian divide. For female veterans, adjustments and adaptations learned in the military clashed with civilian feminine norms and stereotypically male veteran culture. Female veterans also struggled with the legacies of gender inequality, discrimination, and sexual assault which affected their development of a female veteran identity and affected the provision of services designed to meet their needs as a female. Despite these challenges, female veterans’ expressed pride in their service and accomplishments.

Conclusions

Any effort to improve the military-to-civilian transition should take account of the legacy of gender discrimination, especially within the military service, and the potential mismatch between historical civilian female norms and the more traditionally masculine norms of military life.

Disclosures

This project was supported by a grant from the Forces in Mind Trust (FiMT) 2202. Full ethical clearance was granted by the Health Faculties Research Ethics Subcommittee, King’s College London. Project Reference: HR/DP-22/23-33303.
Enhancing transcriptome expression quantification through accurate assignment of long RNA sequencing reads with TranSigner
Authors: Ji Hyun Joo , Pertea Mihaela
Published: April 2024

Recently developed long–read RNA sequencing technologies promise to provide a more accurate and comprehensive view of transcriptomes compared to short-read sequencers, primarily due to their capability to achieve full–length sequencing of transcripts. However, realizing this potential requires computational tools tailored to process long reads, which exhibit a higher error rate than short reads. Existing methods for assembling and quantifying long–read data often disagree on expressed transcripts and their abundance levels, leading researchers to lack confidence in the transcriptomes produced using this data. One approach to address the uncertainties in transcriptome assembly and quantification is by assigning reads to transcripts, enabling a more detailed characterization of transcript support at the read level. Here, we introduce TranSigner, a versatile tool that assigns long reads to any input transcriptome. TranSigner consists of three consecutive modules performing: read alignment to the given transcripts, transcripts, computation of compatibility scores based on alignment scores and positions, and execution of an expectation–maximization algorithm to probabilistically assign read fractions to transcripts while estimating transcript abundances. Using simulated and experimental datasets from three well studied organisms — Homo Sapiens, Arabidopsis thaliana and Mus musculus — we demonstrate that TranSigner achieves higher accuracy in transcript abundance estimation and read assignment compared to existing tools.
Pathway-based similarity measurement to quantify transcriptomics similarity between human tissues and preclinical models
Authors: Parekh Paarth , Sherfey Jason , Alaybeyoglu Begum , Cirit Murat
Published: April 2024

Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among variousin vitroandin vivomodels. PBSM has potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance ofin vitromodels and supporting the development of more effective therapeutic interventions.
Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma
Authors: Akuma Mercy , Kim Minjun , Zhu Chenxuan , Wiljer Ella , Gaudreau-Lapierre Antoine , Patterson Leshan D. , Trinkle-Mulcahy Laura , Stanford William L. , Riazalhosseini Yasser , Russell Ryan C.
Published: April 2024

The von Hippel-Lindau (VHL) tumor suppressor is a component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by genetic aberrations is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss leads to constitutive stabilization of E3 ligase targets, including hypoxia inducible factor α (HIFα), in VHL-associated tumors. HIFα stabilization upon VHL loss promotes transactivation of hypoxia responsive genes, which contributes to ccRCC development. However, several HIF-independent VHL targets have also been implicated in the promotion of tumorigenesis. Using proximity labeling to identify proteasomal VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in an oxygen-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, the hyperstabilization of pRb in ccRCC promoted tumorigenesisin vitroand in mouse models. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.
Chromosome-level assembly ofCucumis sativus cv. ‘Tokiwa’ as a reference genome of Japanese cucumber
Authors: Seiko Takashi , Muto Chiaki , Shimomura Koichiro , Yano Ryoichi , Kawazu Yoichi , Sugiyama Mitsuhiro , Kato Kenji , Tomooka Norihiko , Naito Ken
Published: April 2024

Cucumber is one of the most important vegetables in the Japanese market. To facilitate genomics-based breeding, there is a demand for reference genome of Japanese cucumber. However, although cucumber genome is relatively small, its assembly is a challenging issue because of tandem repeats comprising ∼30% (∼100 Mbp) of the genome. To overcome, we deployed the Oxford nanopore sequencing that produces long reads with N50 length of >30 kbp. With this technology we achieved a chromosome-level assembly of cv ‘Tokiwa’, a founder line of Japanese cucumber represented with the elongated fruit shape and high-crisp texture. Compared to the existing cucumber genomes, the Tokiwa genome is 20% longer and annotated with 10% more genes. The assembly with nanopore long reads also resolved tandem repeats spanning >100 kbp, demonstrating its strength in overcoming repetitive sequences.
Changes in growth, lanthanide binding, and gene expression inPseudomonas alloputidaKT2440 in response to light and heavy lanthanides
Authors: Gorniak Linda , Bucka Sarah Luise , Nasr Bayan , Cao Jialan , Hellmann Steffen , Schäfer Thorsten , Westermann Martin , Bechwar Julia , Wegner Carl-Eric
Published: April 2024

Pseudomonas alloputidaKT2440 is a ubiquitous, soil-dwelling bacterium that metabolizes recalcitrant and volatile carbon sources. The latter are utilized by two redundant, Ca- and lanthanide (Ln)-dependent, pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ ADH), PedE and PedH, whose expression is regulated by Ln availability.P. alloputidaKT2440 is the best-studied, non-methylotroph in the context of Ln-utilization. We report the most comprehensive differential gene expression analysis, to date, for any Ln-utilizing microbe. Combined with microfluidic cultivation and single-cell elemental analysis, we studied the impact of light and heavy Ln when growingP. alloputidaKT2440 with 2-phenylethanol as the carbon and energy source. Light Ln (La, Ce, Nd) and a mixture of light and heavy Ln (La, Ce, Nd, Dy, Ho, Er, Yb) had a positive effect on growth, while supplementation with heavy Ln (Dy, Ho, Er, Yb) exerted fitness costs. These were likely a consequence of mismetallation and oxidative stress. Gene expression analysis showed that the Ln sensing and signaling machinery, the two-component system PedS2R2 and PedH, responds differently to (non-)utilizable Ln. We broadened the understanding of the Ln switch inP. alloputidaKT2440 and could show that it operates as a dimmer switch, modulating the pool of PQQ ADH dependent on Ln availability. Determined quantities of cell-associated Ln suggest a role for Ln beyond alcohol oxidation. The usability of Ln governs the response ofP. alloputidaKT2440 to different Ln elements.

Importance

The Ln switch, the inverse regulation of Ca- and Ln-dependent PQQ ADH dependent on Ln availability in organisms featuring both, is central to our understanding of Ln utilization. Although the preference of bacteria for light Ln is well known, the effect of different Ln, light and heavy, on growth and gene expression has rarely been studied. We provide evidence for a dimmer switch-like regulation of Ca- and Ln-dependent PQQ ADH inP. alloputidaKT2440, and could show that the response to (non-)utilizable Ln differs depending on the element. Ln commonly co-occur in nature. Our findings underline that Ln-utilizing microbes must be able to discriminate between Ln to use them effectively. Considering the prevalence of Ln-dependent proteins in many microbial taxa, more work addressing Ln sensing and signaling is needed. Ln availability likely necessitates different adaptations regarding Ln utilization.
Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists
Authors: Nilson Ashley N , Felsing Daniel E , Wang Pingyuan , Jain Manish , Zhou Jia , Allen John
Published: April 2024

The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective non-catechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and non-catechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, non-catechol agonists display G protein biased signaling at the D1R and have reduced or absent Beta-arrestin recruitment. A notable exception was compound (Cmpd) 19, a non-catechol agonist with full efficacy at both D1R-G protein or D1R Beta-arrestin pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R Beta-arrestin activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The Beta-arrestin super agonist, A-77636, showed significantly increased D1R endocytosis. Moreover, Beta-arrestin recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.
Validation of a urine- based proteomics test to predict clinically significant prostate cancer: complementing MRI pathway
Authors: Frantzi Maria , Morillo Ana Cristina , Lendinez Guillermo , Blanca-Pedregosa Ana , Ruiz Daniel Lopez , Parada Jose , Heidegger Isabel , Culig Zoran , Mavrogeorgis Emmanouil , Beltran Antonio Lopez , Mora-Ortiz Marina , Carrasco-Valiente Julia , Mischak Harald , Medina Rafael A , Hernandez Juan Pablo Campos , Gómez Enrique Gómez
Published: April 2024

Purpose

Prostate cancer (PCa) is the most frequently diagnosed cancer in men. One major clinical need is to accurately predict clinically significant PCa (csPCa). A proteomics based 19-biomarker model (19-BM) was previously developed using Capillary Electrophoresis-Mass Spectrometry (CE-MS) and validated in 1000 patients at risk for PCa. Here, our objective was to validate 19-BM in a multicentre prospective cohort of 101 biopsy-naive patients using current diagnostic pathways.

Materials and Methods

Urine samples from 101 PCa patients were analysed through CE-MS. All patients underwent MRI using a 3-T system. The 19-BM score was estimated via a support vector machine-based software (MosaCluster; v1.7.0), employing previously established cut-off criterion of -0.07. Previously developed diagnostic nomograms were calculated along with MRI.

Results

Independent validation of the 19-BM yielded a sensitivity of 77% and specificity of 85% (AUC:0.81). This performance surpasses that of PSA (AUC:0.56), and PSA density (AUC:0.69). For PI-RADS≤ 3 patients, the 19-BM showed a sensitivity of 86% and specificity of 88%. Integrating the 19-BM with MRI resulted in significantly better accuracy (AUC:0.90) compared to the individual investigations alone (AUC19BM=0.81; p=0.004 and AUCMRI:0.79; p=0.001). Examining the decision curve analysis, the 19-BM with MRI surpassed other approaches for the prevailing risk interval from 30% cut-off.

Conclusions

19-BM exhibited favourable reproducibility for prediction of csPCa. In PI-RADS≤3 patients the 19-BM correctly classified 88% of the patients with insignificant PCa at the cost of one csPCa patient that was missed. Utilising 19-BM test could prove valuable complementing MRI and reducing the need for unnecessary biopsies.
Propionylpromazine: Unveiling a Novel Inhibitory Agent AgainstMycobacterium tuberculosis
Authors: Suresh U. , Punnam M. , Kartick C. , Sugunan A. P.
Published: April 2024

The emergence of multidrug-resistantmycobacterium tuberculosispresents a significant hurdle, as it shows resistance to existing standard therapies, underscoring the critical need for novel antibacterial agents. This study presents propionylpromazine as a promising compound with potent activity againstM. tuberculosis. Our research indicates that propionylproma zine effectively curtails the proliferation ofM. tuberculosisH37Rv. Importantly, propionylpromazine has shown the capability to impede the growth ofM. tuberculosiswithin macrophages without causing detrimental effects. These findings endorse the potential of propionylpromazine to be further developed as a clinical drug for the effective treatment ofM. tuberculosisinfections.
DNA methylation differences between the female and male X chromosomes in human brain
Authors: Morgan Robert , Loh Eddie , Singh Devika , Mendizabal Isabel , Yi Soojin
Published: April 2024

The mechanisms of X chromosome inactivation suggest fundamental epigenetic differences between the female and male X chromosomes. However, DNA methylation studies often exclude the X chromosomes. In addition, many previous studies relied on techniques that examine non-randomly selected subsets of positions such as array-based methods, rather than assessing the whole X chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Here we addressed this gap of knowledge by studying X chromosome DNA methylation using 89 whole genome bisulfite sequencing (WGBS) maps from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that DNA methylation of the female X chromosomes is globally reduced (hypomethylated) across the entire chromosome compared to the male X chromosomes and autosomes. On the other hand, the majority of X-linked promoters were more highly methylated (hypermethylated) in females compared to males, consistent with the role of DNA methylation in X chromosome inactivation and dosage compensation. Remarkably, hypermethylation of female X promoters was limited to a group of previously lowly methylated promoters. The other group of highly methylated promoters were both hyper- and hypo- methylated in females with no obvious association with gene expression. Therefore, X chromosome inactivation by DNA methylation was exclusive to a subset of promoters with distinctive epigenetic feature. Apart from this group of promoters, differentially methylated regions in the female and male X chromosomes were dominated by female hypomethylation. Our study furthers the understanding of X-chromosome dosage regulation by DNA methylation on the chromosomal level as well as on individual gene level.
Elastic and anelastic behavior associated with magnetic ordering in the skyrmion host
Cu2OSeO3
Authors: Adachi Kanta , Wilhelm Heribert , Schmidt Marcus P. , Carpenter Michael A.
Published: April 2024

Magnetic ordering in Cu2OSeO3 occurs without any detectable changes in the lattice symmetry but involves significant coupling with strain. The strain coupling effects in Cu2OSeO3 have been investigated with a focus on the skyrmion lattice by examining elastic and anelastic properties. Resonant ultrasound spectroscopy has been used to measure these properties of a Cu2OSeO3 single crystal as a function of temperature and magnetic field. On heating, the skyrmion phase has been characterized by slightly softer elasticity compared to the helical phase. However, there were no obvious anomalies in elastic and anelastic properties associated with the boundary of the stability field of the skyrmion lattice. Evolution of elastic properties with magnetic field, passing through the stability field of the skyrmion lattice, showed a characteristic pattern of a glassy state, where an equilibrium state is never reached. These imply that coupling of the skyrmions with strain is extremely weak in Cu2OSeO3, leading to glassy or liquidlike behavior of skyrmions. Three Debye-like loss peaks were observed near ∼40, ∼50, and ∼60K. The relaxation mechanism for the 40 K loss peak has been found to have a single relaxation time. Overlapping acoustic loss peaks in the temperature interval ∼50–62K suggest that the magnetic transitions with variable temperature in this temperature range involve freezing of some dynamic aspect(s) of the magnetic structure with an activation energy of ∼0.1–0.15 eV.

Published by the American Physical Society
2024
Equilibrium Dynamics of Infinite-Range Quantum Spin Glasses in a Field
Authors: Tikhanovskaya Maria , Sachdev Subir , Samajdar Rhine
Published: April 2024

We determine the low-energy spectrum and Parisi replica-symmetry-breaking function for the spin-glass phase of the quantum Ising model with infinite-range random exchange interactions and transverse and longitudinal (h) fields. We show that, for all h, the spin-glass state has full replica symmetry breaking and the local spin spectrum is gapless, with a spectral density that vanishes linearly with frequency. These results are obtained using an action functional—argued to yield exact results at low frequencies—that expands in powers of a spin-glass order parameter, which is bilocal in time, and a matrix in replica space. We also present the exact solution of the infinite-range spherical quantum p-rotor model at nonzero h: here, the spin-glass state has one-step replica symmetry breaking and gaplessness only appears after imposition of an additional marginal stability condition. Possible connections to experiments on random arrays of trapped Rydberg atoms are noted.

Published by the American Physical Society
2024
Linking solid-state phenomena via energy differences in `archetype crystal structures'
Authors: Dittrich B. , Connor L. E. , Fabbiani F. P. A. , Piechon P.
Published: April 2024

Categorization underlies understanding. Conceptualizing solid-state structures of organic molecules with `archetype crystal structures' bridges established categories of disorder, polymorphism and solid solutions and is herein extended to special position and high-Z′ structures. The concept was developed in the context of disorder modelling [Dittrich, B. (2021). IUCrJ, 8, 305–318] and relies on adding quantum chemical energy differences between disorder components to other criteria as an explanation as to why disorder – and disappearing disorder – occurs in an average structure. Part of the concept is that disorder, as probed by diffraction, affects entire molecules, rather than just the parts of a molecule with differing conformations, and the finding that an R·T energy difference between disorder archetypes is usually not exceeded. An illustrative example combining disorder and special positions is the crystal structure of oestradiol hemihydrate analysed here, where its space-group/subgroup relationship is required to explain its disorder of hydrogen-bonded hydrogen atoms. In addition, we show how high-Z′ structures can also be analysed energetically and understood via archetypes: high-Z′ structures occur when an energy gain from combining different rather than overall alike conformations in a crystal significantly exceeds R·T, and this finding is discussed in the context of earlier explanations in the literature. Twinning is not related to archetype structures since it involves macroscopic domains of the same crystal structure. Archetype crystal structures are distinguished from crystal structure prediction trial structures in that an experimental reference structure is required for them. Categorization into archetype structures also has practical relevance, leading to a new practice of disorder modelling in experimental least-squares refinement alluded to in the above-mentioned publication.