bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychometric properties and observational data for COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) for post-COVID-19 syndrome
Authors: Kustura L , Bobek D , Poljičanin A , Pavelin S , Buljubašić Šoda M , Šoda J , Aksentijević J , Duka Glavor K , Narančić Knez N , Viali V , Cukrov A , Todorić Laidlaw I , Ipavec N , Vukorepa D , Stipica I , Bakrač K , Bošković B , Mastelić A , Režić Mužinić N , Markotić A , Đogaš Z , Dolić K , Rogić Vidaković M
Published: October 2023

Background

The recently developed modified COVID-19 (coronavirus of 2019) Yorkshire Rehabilitation Scale (C19-YRSm) captures comprehensive biopsychosocial components of WHO’s International Classification of Functioning, Disability, and Health related to the Long Covid or post-COVID syndrome. The scale response categories on C19-YRSm were done post hoc on data collected from the original version of C19-YRS.

Aim

To evaluate the C19-YRSm scale using reliability and validity measures.

Design

Prospective, observational study.

Methods

The study includes 369 patients (clinical group) and 426 subjects of the general population (control group) and captures their post-COVID-19 symptoms. In addition, the reliability of C19-YRSm was estimated by Cronbach’s alpha coefficients of internal consistency and inter-item correlations for subscales (‘Symptom severity, Functional disability, and Other symptoms’). Convergent validity was established using correlations between C19-YRSm and Fatigue Severity Scale (FSS). The incremental validity of C19-YRSm was measured by introducing a hierarchical regression model using the C19-YRSm ‘Overall health’ subscale and FSS as criterion variables.

Results

C19-YRSm subscales have excellent internal consistencies (Cronbach’s α value 0.81–0.96) and acceptable inter-item correlations (r value 0.23–0.79). Hereafter, the convergent validity of the C19-YRSm is good due to significant correlations between C19-YRSm subscales and FSS and C19-YRSm subscales. Finally, the hierarchical regression analysis supported consistent evidence for the incremental validity of the C19-YRSm subscales.

Conclusion

C19-YRSm is a reliable and valid self-assessment scale for the assessment of post-COVID-19 syndrome.
Advocating for Survival: Domestic Workers in the Necropolitical Regime of the Pandemic
Authors: Rosinska Anna , Pellerito Elizabeth
Published: September 2023

During the COVID-19 pandemic, advocating for basic protections became a matter of survival for domestic workers. With the onset of COVID-19, this largely female and immigrant workforce was expected to take on dangerous care duties with little protection against disease and death. We apply a necropolitical feminist analysis to expose the underlying logic of the deadly (virus) regime and to highlight how the movement counteracted that logic in the United States. Domestic worker organizations enacted a feminist model of collective care while also pushing for important changes within regulations designed to protect the economy above workers’ lives. The organizations representing domestic workers advanced their agendas of worker and immigrant rights, and the very value of care itself, while adapting their messaging to the prevailing rhetoric of limited relief measures in three stages, organized around three main narratives, centered on (essential) workers’ rights, public health, and a “healthy economy.”
Behavioural adjustments enable the colonization of subterranean environments
Authors: Lunghi Enrico , Mammola Stefano , Martínez Alejandro , Hesselberg Thomas
Published: October 2023

Specialized subterranean species are iconic examples of convergent evolution driven by environmental constraints, representing an ideal model system for eco-evolutionary studies. However, scientific research on the behavioural adaptations of subterranean organisms has lagged and is biased mostly towards a few model species. Through a systematic literature review, we aimed to assess quantitatively whether a congruent evolution of behavioural traits among subterranean species exists. We considered four types of behaviours (exploratory, feeding, social and anti-predator) and tested predictions about their occurrence among species with different degrees of adaptation to subterranean environments. We argue that these behaviours constitute the earliest adaptations to three main ecological factors characterizing subterranean habitats, namely the constant darkness, the limited food resources and the reduced predator pressure. Darkness selects for individuals that rely on non-visual cues to explore their surroundings, track food resources and locate potential sexual partners. The reduced availability of food promotes high foraging plasticity and deters species from adopting aggressive behaviours towards conspecifics. The reduced predator pressure allows species to abandon specific anti-predator behaviours and permits safer execution of their biological activities. Our analyses show that these four behaviours are likely to represent the result of an early convergent adaptation to the subterranean realm.
Phytophthora Root and Crown Rot of Lavender: New Host-Pathogen Relationships Involving Six Species of Phytophthora and Three Species of Lavandula
Authors: Dlugos Daniel M. , Bridges William C. , Jeffers Steven N.
Published: September 2023

Phytophthora root and crown rot has become a major threat to the lavender industry worldwide. Isolations from symptomatic plants between 2015 and 2019 revealed a number of potential causal agents in the United States. In this study, we tested nine species of Phytophthora and four species of Lavandula and used Koch’s Postulates to prove pathogenicity for six new host-pathogen relationships and confirm two pathogenic relationships for the first time in the United States. A total of 10 experiments were conducted with each consisting of two independent trials. Only host-pathogen combinations that occurred in the field were evaluated. All isolates used in these experiments were recovered from diseased lavender plants or, for one isolate, soil associated with a diseased plant sent to our lab or the Clemson University Plant and Pest Diagnostic Clinic for diagnosis. Experiments were conducted over 3 years, 2017 to 2019, in a research greenhouse under relatively uniform environmental conditions following a standard protocol. Plants were evaluated weekly for foliage symptom severity, and, at the end of each trial, plants were scored for final foliage symptom severity and root rot severity, area under the disease progress curve was calculated, fresh plant mass was weighed, and isolation of pathogens from roots was attempted. These studies successfully demonstrated for the first time pathogenicity of Phytophthora nicotianae, P. palmivora, and P. cinnamomi to hybrid lavender (Lavandula × intermedia), P. nicotianae to sweet lavender (L. heterophylla), and P. cryptogea and P. drechsleri to English lavender (L. angustifolia). In addition, a soil isolate of P. tropicalis was shown to be potentially pathogenic to L. × intermedia. Our results also documented for the first time in the United States pathogenicity of P. palmivora and P. citrophthora to L. angustifolia. We were not able to confirm pathogenicity for three host-pathogen relationships: P. megasperma on English lavender, P. cactorum on hybrid lavender, and P. nicotianae on Spanish lavender (L. stoechas). Results from this study expand the list of Phytophthora species causing root rot on lavender (Lavandula species) in the United States and elsewhere.
Exploring the role of epigenetic alterations and non-coding RNAs in melanoma pathogenesis and therapeutic strategies
Authors: Rubatto Marco , Borriello Silvia , Sciamarrelli Nadia , Pala Valentina , Tonella Luca , Ribero Simone , Quaglino Pietro
Published: October 2023

Melanoma is a rare but highly lethal type of skin cancer whose incidence is increasing globally. Melanoma is characterized by high resistance to therapy and relapse. Despite significant advances in the treatment of metastatic melanoma, many patients experience progression due to resistance mechanisms. Epigenetic changes, including alterations in chromatin remodeling, DNA methylation, histone modifications, and non-coding RNA rearrangements, contribute to neoplastic transformation, metastasis, and drug resistance in melanoma. This review summarizes current research on epigenetic mechanisms in melanoma and their therapeutic potential. Specifically, we discuss the role of histone acetylation and methylation in gene expression regulation and melanoma pathobiology, as well as the promising results of HDAC inhibitors and DNMT inhibitors in clinical trials. We also examine the dysregulation of non-coding RNA, particularly miRNAs, and their potential as targets for melanoma therapy. Finally, we highlight the challenges of epigenetic therapies, such as the complexity of epigenetic mechanisms combined with immunotherapies and the need for combination therapies to overcome drug resistance. In conclusion, epigenetic changes may be reversible, and the use of combination therapy between traditional therapies and epigenetically targeted drugs could be a viable solution to reverse the increasing number of patients who develop treatment resistance or even prevent it. While several clinical trials are underway, the complexity of these mechanisms presents a significant challenge to the development of effective therapies. Further research is needed to fully understand the role of epigenetic mechanisms in melanoma and to develop more effective and targeted therapies.
Effect of dehydroepiandrosterone therapy on cognitive performance among postmenopausal women: a systematic review of randomized clinical trial data
Authors: Sultana Farhana , Davis Susan R. , Islam Rakibul M.
Published: October 2023

Importance

Whether dehydroepiandrosterone (DHEA) supplementation improves cognitive performance in older women is uncertain. Nonetheless, DHEA supplements are readily available over the counter in several countries and are potentially being used to prevent cognitive decline and dementia.

Objective

This systematic review was conducted to evaluate the effect of exogenous DHEA on cognitive performance in postmenopausal women.

Evidence Review

Ovid MEDLINE, EMBASE, PsycINFO, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials databases were searched for studies of postmenopausal women until November 30, 2022. Eligible studies were required to be randomized clinical trials, be at least single blind, have a placebo or comparator arm and published in English. Risk of bias of the included studies was assessed by the revised Cochrane risk-of-bias tool.

Findings

Of the 15 articles retrieved for full-text review, four met the inclusion criteria. In all studies DHEA was administered as a 50-mg oral daily dose and all were double blind with an identical placebo. Three were placebo-controlled, crossover studies and one was a parallel-group clinical trial. The only positive outcome was limited to a 4-wk cross-over study in which DHEA statistically significantly enhanced five of six tests of visual-spatial performance compared with placebo in 24 cognitively normal postmenopausal women. Improvement in cognitive performance with DHEA treatment over placebo group was not seen in any other study. Heterogeneity of design and use of multiple measures of cognitive performance was a barrier to meta-analysis and between study comparisons. The studies were limited by high risk of bias in multiple domains.

Conclusion and Relevance

Overall, this systematic review does not support a beneficial effect of DHEA therapy on cognitive performance in postmenopausal women.
Relationships between the vaginal microbiota and genitourinary syndrome of menopause symptoms in postmenopausal women: the Study of Women's Health Across the Nation
Authors: Waetjen L. Elaine , Crawford Sybil L. , Gajer Pawel , Brooks Maria M. , Gold Ellen B. , Reed Barbara D. , Hess Rachel , Ravel Jacques
Published: October 2023

Objective

To describe vaginal microbiota classified by community state types (CST) in a diverse cohort of postmenopausal women and evaluate relationships among genitourinary syndrome of menopause (GSM) symptoms (vaginal dryness, vulvovaginal irritation, sexual pain, dysuria, urinary urgency), CSTs, estrogen, vaginal maturation index (VMI), and vaginal pH.

Methods

In the Study of Women's Health Across the Nation, 1,320 women aged 60.4 to 72.5 years self-collected (2015-2017) vaginal samples analyzed for microbiota composition and structure (CSTs) using 16S rRNA gene amplicon sequencing, VMI, and pH. GSM symptoms were collected with self-administered questionnaires; interviewers elicited estrogen use and measured body mass index. Serum E2 and E1 were measured using high-performance liquid chromatography. We analyzed data using Pearson χ
2 tests, analysis of variance, Kruskal-Wallis tests, and binomial logistic regression.

Results

The most frequently occurring CST was low Lactobacillus species IV-C (49.8%); 36.4% of women had CSTs dominated by Lactobacillus species. More than half of the women with vaginal atrophy biomarkers (VMI <50 and pH >5) had CST IV-C0, whereas women using estrogen or with higher E1 and E2 levels had a higher prevalence of Lactobacillus crispatus–dominated CST I (P values < 0.001). Sexual pain was associated with atrophy biomarkers and independently associated with Streptococcus species–dominated CST IV-C1 (odds ratio, 2.26; 95% confidence intervals, 1.20-4.23). For all other GSM symptoms, we found no consistent associations with E1 or E2 levels, atrophy biomarkers, or any CST.

Conclusions

Although close relationships exist among estrogen, CSTs, VMI, and pH, sexual pain was the only GSM symptom associated with the structure of vaginal microbiota and atrophy biomarkers.
Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-cell Treated Patients
Authors: Panagiota Victoria , Kerschbaum Johanna Franziska , Penack Olaf , Stein Catarina M. , Arends Christopher M. , Koenecke Christian , Strzelecka Paulina M. , Kloos Arnold , Wiegand Laura , Lasch Alina , Altwasser Robert , Halik Adriane , Gabdoulline Razif , Thomson Julia , Weibl Konstantin , Franke Georg-Nikolaus , Berger Carolina , Hasenkamp Justin , Ayuk Francis , Na Il-Kang , Beutel Gernot , Keller Ulrich , Bullinger Lars , Wulf Gerald Georg , Kröger Nicolaus , Vucinic Vladan , Heuser Michael , Damm Frederik
Published: October 2023

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.
Comparison of Clinical, Economic, and Humanistic Outcomes Between Blood Collection Approaches: A Systematic Literature Review
Authors: Perry Cathy , Alsbrooks Kimberly , Mares Alicia , Hoerauf Klaus
Published: October 2023

Background:

A systematic literature review was performed to understand the prevalence, advantages, and disadvantages of blood collection using different approaches (direct venipuncture or vascular access devices), and interventions used to mitigate the disadvantages.

Methods:

The review included a broad range of study designs and outcomes. Database searches (Embase, MEDLINE, Cochrane library, and Centre for Reviews and Dissemination) were conducted in March 2021 and supplemented by hand searching.

Results:

One hundred forty-one publications were included. The data indicate that blood sampling from vascular access devices is common in emergency departments, trauma centers, and intensive care units. Studies showed that hemolysis and sample contamination place a considerable economic burden on hospitals. Significant cost savings could be made through enforcing strict aseptic technique, or using the initial specimen diversion technique.

Conclusions:

Hemolysis and sample contamination are far from inevitable in vascular access device-collected or venipuncture samples; both can be reduced through adherence to strict blood sampling protocols and utilization of the initial specimen diversion technique. Needle-free blood collection devices offer further hope for reducing hemolysis. No publication focused on the difficult venous access population; insertion success rates are likely to be lower (and the benefits of vascular access devices higher) in these patients.
Patient and Provider Decision Making About HIV Postexposure Prophylaxis Following Sexual Violence: A Qualitative Analysis
Authors: Anderson Jocelyn C. , Boakye Michelle D. S. , Draughon Moret Jessica
Published: October 2023

To explore patient and health care provider HIV postexposure prophylaxis (PEP) decision making following sexual assault, semistructured interviews regarding HIV PEP provision with 15 patients and 10 health care providers were conducted. A qualitative, descriptive, thematic analysis approach was used. Four themes were derived: (a) medical concerns; (b) emotional, trauma, and support factors; (c) daily medication management; and (d) ensuring access to HIV PEP. How participants described these themes and the importance placed on factors within each theme varied between the two groups. Altering provider communication so that HIV PEP discussions better align with patient decision-making factors (e.g., trauma and ability to take in information, how to manage side effects) could facilitate improvement in HIV PEP decision making following sexual assault for patients. High-level policy changes would improve HIV PEP access for sexual assault patients without necessitating the extraordinary efforts individual providers currently undertake.
Medium-term Outcomes in Pediatric Heart Transplant Recipients Managed Using a Steroid Avoidance Immune Suppression Protocol
Authors: Hartje-Dunn Christina , Blume Elizabeth D. , Bastardi Heather , Daly Kevin P. , Fynn-Thompson Francis , Gauvreau Kimberlee , Singh Tajinder P.
Published: October 2023

Background.

Short-term outcomes using steroid avoidance immune suppression are encouraging in pediatric heart transplant (HT) recipients at low risk of antibody-mediated rejection. We assessed medium-term outcomes in pediatric HT recipients initiated on a steroid avoidance protocol at our institution using surveillance biopsies.

Methods.

All primary HT recipients during 2006–2020 who did not have a donor-specific antibody were eligible for immune suppression consisting of 5-d Thymoglobulin/steroid induction followed by a tacrolimus-based, steroid-free regimen. We assessed freedom from graft failure (death or retransplant), acute rejection, posttransplant lymphoproliferative disease, and cardiac allograft vasculopathy.

Results.

Overall, 150 of 181 primary HT recipients were eligible for steroid avoidance regimen. Their median age was 8.7 y, 41% had congenital heart disease, 23% were sensitized, and 35% were on a mechanical support. The median follow-up was 6.1 y. Eleven patients (8%) were on maintenance steroids at discharge and 13% at 1 y. Graft survival was 94% at 1 y and 87% at 5 y. Freedom from rejection was 73% at 1 y and 64% at 5 y. Freedom from posttransplant lymphoproliferative disease was 96% at 1 y and 95% at 5 y. Freedom from moderate cardiac allograft vasculopathy was 94% at 5 y. Eight patients developed diabetes. Estimated glomerular filtration rate was <60 mL/min/1.73 m2 in 5% of the cohort at 5 y.

Conclusions.

Pediatric HT recipients at low risk of antibody-mediated rejection have excellent medium-term survival and relatively low incidence of posttransplant morbidities when managed using a steroid avoidance immune suppression protocol.
Public but ineffective: Fatality inquiries into childhood deaths in Alberta
Authors: Verbeke Mary-Claire , Mitchell Ian
Published: September 2023

Introduction

Child Death Review (CDR) processes are public efforts to review a child’s death to understand how and why children die, to improve child health and to prevent future deaths. In 2013, the Canadian Paediatric Society made specific recommendations to establish structured and comprehensive CDR systems in each province and territory. In Alberta, there is no comprehensive CDR process but there are some components. The most public and probably the most expensive component is the public fatality inquiry. A new notification policy adopted after in June 2017 appears to be of limited value for child death prevention.

Methods

We examined all Alberta fatality inquiry reports from January 1, 1995 to April 15, 2023 concerning children aged 0-17 years (n=133) to determine whether the fatality inquiry system might be effective in preventing future similar deaths.

Results

Recommendations made by judges in a fatality inquiry were not always followed by action, and hence inquiry recommendations have been largely ineffective. Fatality inquiry recommendations were sometimes untimely, and therefore had little chance of being effective. There is an increasing trend from 1995 (case 1) to 2023 (case 133) in the time taken to initiate a child fatality inquiry review.

Discussion and Conclusion

Information and recommendations from fatality inquiries into Alberta childhood deaths tend to be delayed and not followed by action. A comprehensive CDR process is required in Alberta. With system changes, public fatality inquiries could be an effective part of the child death prevention process.
Measuring Hemoglobin A1C with Frozen Packed Cell and Frozen Whole Blood Samples in an Epidemiologic Study: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Mukaz Debora Kamin , Tison Stephanie , Long D. Leann , Carson April P. , Hunt Kelly J. , Judd Suzanne E. , Cushman Mary
Published: September 2023

Introduction

Hemoglobin A1c (HbA1c) measurement in epidemiology studies could be increased if reliability of measurements in frozen stored samples was known. In the REasons for Geographic and Racial Differences in Stroke, a longitudinal study of 30,239 Black and White U.S. adults, we investigated reliability of HbA1c measurements for two types of samples stored at -80°C for up to 14 years.

Methods

Among 917 participants without diabetes, HbA1c was measured in 2017 in frozen packed cells from the first visit (2003-07) and in frozen whole blood samples from the second visit (2013-16). To study reliability, associations between HbA1c and glycemia-related characteristics were examined.

Results

Each 10mg/dL greater fasting glucose was associated with 0.08% (95%CI: 0.05-0.11%) greater HbA1c in frozen packed cells (visit 1) and 0.10% (95%CI: 0.08-0.12%) greater HbA1c in whole blood (visit 2). HbA1c was also similarly higher with both methods with increasing age, gender, systolic blood pressure, body mass index, high-density lipoprotein, triglycerides, C-reactive protein, and hemoglobin. Using both methods, ≤3.5% were classified with diabetes based on HbA1c ≥6.5%.

Conclusions

In REGARDS participants without diabetes, HbA1c measurement appeared reliable in frozen packed cells or whole blood under long-term storage, suggesting acceptability for study of the epidemiology of HbA1c.
Nanotope: A Graph Neural Network-Based Model for Nanobody paratope prediction
Authors: Meng Xiangpeng , Li Shangru , Li Rui , Huang Bingding , Wang Xin
Published: September 2023

Nanobodies are artificial antibodies derived from the immune system of camelid species, obtained through artificial processing and isolation of antigen-binding proteins. Their small molecular size and high specificity endow nanobodies with extensive potential applications in various fields. However, determining nanobody paratopes through experimental methods is both costly and time-consuming, while traditional computational approaches often lack sufficient accuracy. To enhance the prediction accuracy, we propose Nanotope, a structurebased model capable of efficiently and accurately predicting paratopes, utilizing graph neural networks and an antibody pretrained language model. Our approach primarily leverages sequence features obtained from the AntiBERTy antibody pretrained language model and three-dimensional spatial structure features of nanobodies as inputs. Employing one-dimensional convolution, EGConv graph convolution, and GATConv convolution, we predict the probability of nanobody paratopes with a much higher accuracy. Our method significantly improves the prediction of nanobody paratopes and requires only nanobody sequences and structural information, without the need for additional antigen information. Source code is freely available athttps://github.com/WangLabforComputationalBiology/Nanotope
Drug-bacterial membrane interactions: A Tale of two force fields
Authors: Basu Subhadip , Mandal Sandip , Maiti Prabal K.
Published: September 2023

Tuberculosis (TB), caused byMycobacterium tuberculosis(M.tb), a gram-positive bacteria, is known to infect and kill millions of people worldwide, specifically in poor and developing countries. M.tb has unique characteristics in terms of the presence of an extraordinarily thick cell wall structure, mainly composed of mycolic acid (MA) and arabinogalactan (AG). Between these components, mycolic acid is of particular interest because it exhibits extremely low permeability for most of the drug molecules, thus helping M.tb to survive against medical treatment. Hence, it is extremely useful to study the interactions between drug molecules and mycolic acids in order to better design potential TB medicine. On that premise, the present work aims to computationally model mycolic acid monolayer and probe its permeability against some first-line TB drugs, namely ethambutol, ethionamide, and isoniazid. It is a known fact that such modelling strongly depends on the interaction parameters used. The current study addresses this issue by employing two widely used force fields-GROMOS 54A7-ATB (hereafter GROMOS) united atom force fields and CHARMM36 (hereafter CHARMM) all-atom force fields to collate the drug-mycolic acid interplay. Our findings indicate that both force fields provide consistent results in terms of the mode of drug-monolayer interactions but significantly differ for the monolayer permeability. Mycolic acid monolayer generally exhibited a higher free energy barrier of crossing using CHARMM FF, while GROMOS parameters provide better stability of drug molecules on the monolayer surface, which can be attributed to the greater electrostatic potential at the monolayer-water interface. Both the force field parameters predicted the highest resistance against ethambutol, the most soluble molecule. However, significant differences can be recorded for the other two molecules with the change in the interaction parameter set. In summary, our study provides insight into the dependency ofin silicomodelling of membranes on force field parameters together with the guidelines to investigate the drug-membrane interactions consisting of non-standard lipids/fatty acids.
T cell receptor-centric perspective to multimodal single-cell data analysis
Authors: Mullan Kerry A. , Ha My , Valkiers Sebastiaan , de Vrij Nicky , Ogunjimi Benson , Laukens Kris , Meysman Pieter
Published: September 2023

The T-cell receptor (TCR) carries critical information regarding T-cell functionality. The TCR, despite its importance, is underutilized in single cell transcriptomics, with gene expression (GEx) features solely driving current analysis strategies. Here, we argue for a switch to a TCR-first approach, which would uncover unprecedented insights into T cell and TCR repertoire mechanics. To this end, we curated a large T-cell atlas from 12 prominent human studies, containing in total 500,000 T cells spanning multiple diseases, including melanoma, head-and-neck cancer, T-cell cancer, and lung transplantation. Herein, we identified severe limitations in cell-type annotation using unsupervised approaches and propose a more robust standard using a semi-supervised method or the TCR arrangement. We then showcase the utility of a TCR-first approach through application of the novel STEGO.R tool for the successful identification of hyperexpanded clones to reveal treatment-specific changes. Additionally, a meta-analysis based on neighbor enrichment revealed previously unknown public T-cell clusters with potential antigen-specific properties as well as highlighting additional common TCR arrangements. Therefore, this paradigm shift to a TCR-first with STEGO.R highlights T-cell features often overlooked by conventional GEx-focused methods, and enabled identification of T cell features that have the potential for improvements in immunotherapy and diagnostics.

One Sentence Summary

Revamping the interrogation strategies for single-cell data to be centered on T cell receptor (TCR) rather than the generic gene expression improved the capacity to find relevant disease specific TCR.

Key Points

The TCR-first approach captures dynamic T cell features, even within a clonal population.

A novel ∼500,000 T-cell atlas to enhance single cell analysis, especially for restricted populations.

Novel STEGO.R program and pipeline allows for consistent and reproducible interrogating of scTCR-seq with GEx.
Predicting rapid adaptation in time from adaptation in space: a 30-year field experiment in marine snails
Authors: Castillo Diego Garcia , Barton Nick , Faria Rui , Larsson Jenny , Stankowski Sean , Butlin Roger , Johannesson Kerstin , Westram Anja Marie
Published: September 2023

Predicting the outcomes of adaptation is a major goal of evolutionary biology. When temporal changes in the environment mirror spatial gradients, it opens up the potential for predicting the course of adaptive evolution over time based on patterns of spatial genetic and phenotypic variation. We assessed this approach in a 30-year transplant experiment in the marine snailLittorina saxatilis. In 1992, snails were transplanted from a predation-dominated environment to one dominated by wave action. Based on spatial patterns, we predicted transitions in shell size and morphology, allele frequencies at positions throughout the genome, and chromosomal rearrangement frequencies. Observed changes closely agreed with predictions. Hence, transformation can be both dramatic and rapid, and predicted from knowledge of the phenotypic and genetic variation among populations.
Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy
Authors: Li Mengshi , Robles-Planells Claudia , Liu Dijie , Graves Stephen A. , Vasquez-Martinez Gabriela , Mayoral-Andrade Gabriel , Lee Dongyoul , Rastogi Prerna , Marks Brenna M. , Sagastume Edwin A. , Weiss Robert M. , Linn-Peirano Sarah C. , Johnson Frances L. , Schultz Michael K. , Zepeda-Orozco Diana
Published: September 2023

Purpose

Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides’ renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLTs nephrotoxicity.

Methods

A bifunctional cyclic peptide, melanocortin ligand-1(MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers.

Results

Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary Neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings.

Conclusion

urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.
Anticipatory brain activity depends on the sensory modality of the expected stimulus: insights from single-trial analyses
Authors: Hoxha Isabelle , Chevallier Sylvain , Delorme Arnaud , Amorim Michel-Ange
Published: September 2023

Perceptual anticipation is known to impact the reaction time of decisions. While anticipatory patterns have been identified in human brain activity, the single-trial neural signature of anticipation remains unexplored. Similarly, past studies have underlined an effect of pre-stimulus alpha-band activity on reaction times. Still, it remains unknown whether this activity is stimulus-specific or rather acts as a general indicator of readiness. This study aimed to determine whether human participants expected a visual or an auditory stimulus at the single-trial level in both cued and uncued trials. We show that pre-stimulus brain activity entails information about the expected upcoming stimulus, and that the information content can be extracted from single-trial brain activity. Behavioral analyses helped uncover the link between correct anticipation and shifts in decision strategy, and additionally validated the classification of uncued trials. This understanding of single-trial stimulus-specific neural signatures of anticipation can significantly impact cognitive neuroscience, human-computer interaction, and neuroergonomics research, enabling the development of real-time systems capable of predicting and adapting to an individual’s anticipated stimuli, thereby enhancing task performance and user experience in diverse applications ranging from adaptive interfaces to clinical interventions.

Novelty and Significance

With a focus on uncovering single-trial neural signatures of anticipation, this study aims to explore the specificity of pre-stimulus brain activity to expected visual or auditory stimuli in both cued and uncued trials, i.e. whether participants are informed about the upcoming stimulus or not. Our research seeks to contribute to the fundamental understanding of human cognition by elucidating the informational content embedded in anticipatory brain patterns. The insights gained hold promise in advancing fields like cognitive neuroscience and human-computer interaction, paving the way for innovative applications in adaptive interface design, real-time systems, and personalized interventions.
Nuclear corepressors NCOR1 and NCOR2 entrain thymocyte signaling, selection, and emigration
Authors: David Natalie A. , Lee Robin D. , LaRue Rebecca S. , Joo Sookyong , Farrar Michael A.
Published: September 2023

T cell development proceeds via discrete stages that require both gene induction and gene repression. Transcription factors direct gene repression by associating with corepressor complexes containing chromatin-remodeling enzymes; the corepressors NCOR1 and NCOR2 recruit histone deacetylases to these complexes to silence transcription of target genes. Earlier work identified the importance of NCOR1 in promoting the survival of positively-selected thymocytes. Here, we used flow cytometry and single-cell RNA sequencing to identify a broader role for NCOR1 and NCOR2 in regulating thymocyte development. UsingCd4-cremice, we found that conditional deletion of NCOR2 had no effect on thymocyte development, whereas conditional deletion of NCOR1 had a modest effect. In contrast,Cd4-crexNcor1f/fxNcor2f/fmice exhibited a significant block in thymocyte development at the DP to SP transition. Combined NCOR1/2 deletion resulted in increased signaling through the T cell receptor, ultimately resulting in elevated BIM expression and increased negative selection. The NF-κB, NUR77, and MAPK signaling pathways were also upregulated in the absence of NCOR1/2, contributing to altered CD4/CD8 lineage commitment, TCR rearrangement, and thymocyte emigration. Taken together, our data identify multiple critical roles for the combined action of NCOR1 and NCOR2 over the course of thymocyte development.
Auditory attention detection in cocktail-party: A microstate study
Authors: Roushan Hossein , Bakhshalipour Gavgani Sahar , Geravanchizadeh Masoud
Published: September 2023

Healthy human brain can easily attend to one auditory stimulus and filter out the other stimuli, described in the terms of “selective auditory attention” or referred to as the cocktail party phenomenon. This paper proposes a new real-time mapping-based selective auditory attention detection (SAAD) system using only EEG signals. In the proposed system, several quasi-stable maps, called EEG microstates, are extracted. After the optimization of the microstates topographies, the temporal dynamics of the microstates are used for the classification of auditory attention direction. The evaluation results obtained in different listening conditions (i.e., dichotic and spatial hearing) show that the use of an integrated set of 6 microstate topographies best describes the data and provides better classification performance. Due to the nature of EEG microstates in reflecting the fundamentals of brain information processing, this study provides an appropriate way of reaching the underlying mechanism of selective attention. The proposed system based on microstates can effectively detect the attention direction in dynamic scenarios, where the listener’s attention might be switched in seconds, making the model suitable for real-time applications. Furthermore, the proposed auditory attention detection system is advantageous in the sense that the detection of attention is performed without using speech signals.
Improvement of cell growth in green algaeChlamydomonas reinhardtiithrough co-cultivation with yeastSaccharomyces cerevisiae
Authors: Karitani Yukino , Yamada Ryosuke , Matsumoto Takuya , Ogino Hiroyasu
Published: September 2023

Biological fixation methods have attracted considerable attention because they can be applied for the fixation of dilute CO2in the atmosphere. Co-cultivation of certain microalgae with heterotrophic microorganisms can increase the growth potential of microalgae under dilute CO2conditions. The objective of this study was to determine the culture conditions under which the growth potential of green algaeChlamydomonas reinhardtiiis enhanced by co-culturing with the yeastSaccharomyces cerevisiae, and to identify the cause of the enhanced growth potential using transcriptome analysis. WhenC. reinhardtiiandS. cerevisiaewere co-cultured with an initial green algae to yeast inoculum ratio of 1:3, the cell concentration ofC. reinhardtiireached 133 × 105cells/mL on day 18 of culture, which was 1.5 times higher than that of the monoculture. Transcriptome analysis revealed that the expression levels of 363 green algae and 815 yeast genes were altered through co-cultivation. These include genes responsible for ammonium transport and CO2enrichment mechanism in green algae and the genes responsible for glycolysis and stress responses in yeast. In conclusion, we identified the culture condition suitable for the co-cultivation ofC. reinhardtiiandS. cerevisiae. In addition, we discuss the cause of the increased growth potential ofC. reinhardtiibased on transcriptome analysis data. Although further studies are needed to elucidate the full impact of microbial interactions inC. reinhardtiiandS. cerevisiaeco-cultures, the findings of this study represent an important first step toward achieving this goal.
Test-retest reliability of MEG functional brain connectivity related to language processing
Authors: Ala-Salomäki Heidi , van Vliet Marijn , Kujala Jan , Roine Timo , Liljeström Mia , Salmelin Riitta
Published: September 2023

The number of studies examining changes in functional connectivity of the human brain is increasing rapidly. In this magnetoencephalography (MEG) study, we examined the reliability of dynamic connectivity related to language processing in a picture naming test-retest paradigm, using data collected from the same participants on two separate days. We determined the connections that were reliable across both days and also examined the behavioral, functional, and structural properties underlying this reliability. A particularly salient finding among a rich set of results was a reliable pattern of beta connectivity increase in the left motor and frontal regions (0–400 ms and 400–800 ms after stimulus onset) and gamma connectivity decrease in the bilateral motor regions (800–1200 ms) which we suggest to represent the motor preparation of speech production. Furthermore, the reliable connections tended to be more frequently associated with the behavioral performance than the non-reliable ones. Finally, the reliable connections were also linked to stronger functional connectivity, as well as to stronger structural connectivity and shorter structural path length, as determined through diffusion MRI (magnetic resonance imaging). Overall, this study defines reliable language-related functional connectivity and introduces practices that may increase reliability.

AUTHOR SUMMARY

Research applying connectivity metrics in neuroimaging has increased rapidly during recent years. Hence, the focus has also been to define the best methods for increasing the reliability of connectivity estimation. This study determined reliable functional connectivity from MEG data related to language processing. Moreover, we defined what makes a connection reliable by studying the behavioral, functional, and structural properties underlying the reliable connections.
Is there a spinal tap responder in progressive supranuclear palsy?: The first prospective study
Authors: Ohara Masahiro , Hattori Takaaki , Chen Qingmeng , Shimano Kaoru , Hirata Kosei , Matsui Mie , Yokota Takanori
Published: September 2023

Objective

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap.

Methods

Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined “tap responders” as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of tap responders in patients with PSP to patients with iNPH and controls.

Results

The ratio of tap responders in patients with PSP was significantly higher than that in control patients, but not different from patients with iNPH. The ratio of sham tap responders was significantly higher in PSP patients than that in control patients, but not that in patients with iNPH. Notably, one patient with PSP responded to the spinal tap beyond the effect of sham spinal tap, and even to the shunt operation.

Interpretation

This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP and iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.
Exploration of the potential of high resolution and contrast 7 Tesla MR brain imaging in neonates
Authors: Bridgen Philippa , Tomi-Tricott Raphael , Uus Alena , Cromb Daniel , Quirke Megan , Almalbis Jennifer , Bonse Beya , De la Fuente Botella Miguel , Maggioni Alessandra , Di Cio Pierluigi , Cawley Paul , Casella Chiara , Dokumaci Ayse Sila , Thomson Alice R , Willers Moore Jucha , Bridglal Devi , Saravia Joao , Finck Thomas , Price Anthony N , Pickles Elisabeth , Cordero-Grande Lucilio , Egloff Alexia , O’Muircheartaigh Jonathan , Counsell Serena J , Giles Sharon L , Deprez Maria , De Vita Enrico , Rutherford Mary A , Edwards A David , Hajnal Joseph V , Malik Shaihan J , Arichi Tomoki
Published: October 2023

BACKGROUND

Ultra-high field MR imaging offers marked gains in signal-to-noise ratio, spatial resolution, and contrast which translate to improved sensitivity for pathology and anatomy. These benefits are particularly relevant for the neonatal brain, as it is rapidly developing and sensitive to injury. However, experience of imaging neonates at 7T has been limited due to regulatory, safety, and practical considerations.

PURPOSE

To establish a program for safely acquiring high resolution and contrast brain images from neonates on a 7T system.

STUDY TYPE

Prospective case series.

POPULATION

Images were safely acquired from 35 neonates on 44 occasions (median age 39+6 postmenstrual weeks, range 33+4 to 52+6; median body weight 2.93kg, range 1.57to 5.3kg) over a median of 49 mins 30 sec.

FIELD STRENGTH/SEQUENCE

7T, acquired sequences included T2 weighted (TSE), Actual Flip angle Imaging, functional MRI (BOLD EPI), susceptibility weighted imaging, and MR spectroscopy (STEAM).

ASSESSMENT

Peripheral body temperature, physiological measures (heart rate, oxygen saturations). Review of acquired images by Neonatal Neuroradiologists for visual identification of anatomy and pathology, and by radiographer and researcher for assessment of image quality.

STATISTICAL TESTS

Two tailed paired t-test, P<0.05 was considered statistically significant.

RESULTS

There was no significant difference between temperature before and after scanning (p=0.76). Image quality assessment compared favourably to state-of-the-art 3T acquisitions. Anatomical imaging demonstrated excellent sensitivity to structures which are typically hard to visualise at lower field strengths including the hippocampus, cerebellum, and vasculature. The potential of 7T imaging is highlighted using contrast mechanisms which are enhanced at ultra-high field including susceptibility weighted imaging, functional MRI, and MR spectroscopy.

DATA CONCLUSION

We demonstrate safety and feasibility of imaging vulnerable neonates at ultra-high field. Our preliminary imaging suggests ultra-high field has untapped potential to provide important new insights into brain development and pathological processes during this critical phase of early life.