bluuebunny/crossref_metadata_2025 huggingface dataset:
A Bayesian Approach to Hyperbolic Multi-Dimensional Scaling
Authors: Praturu Anoop , Sharpee Tatyana
Published: October 2022

Recent studies have increasingly demonstrated that hyperbolic geometry confers many advantages for analyzing hierarchical structure in complex systems. However, available embedding methods do not give a precise metric for determining the dimensionality of the data, and do not vary curvature. These parameters are important for obtaining accurate, low dimensional, continuous descriptions of the data. To address this we develop a Bayesian formulation of Multi-Dimensional Scaling for embedding data in hyperbolic spaces that can fit for the optimal values of geometric parameters such as curvature and dimension. We propose a novel model of embedding uncertainty within this Bayesian framework which improves both performance and interpretability of the model. Because the method allows for variable curvature, it can also correctly embed Euclidean data using zero curvature, thus subsuming traditional Euclidean MDS models. We demonstrate that only a small amount of data is needed to constrain the geometry in our model and that the model is robust against false minima when scaling to large datasets. We apply our model to real world datasets and uncover new insights into their hierarchical structure derived from our geometric embeddings.
Vocabulary relearning in aphasia is supported by hippocampal memory and cortical language systems
Authors: Gore Katherine R. , Woollams Anna M. , Lambon Ralph Matthew A.
Published: October 2022

Speech and language therapy can be an effective tool in improving language in post-stroke aphasia. Despite an increasing literature on the efficacy of language therapies, there is a dearth of evidence about the neurocognitive mechanisms that underpin language re-learning, including the mechanisms implicated in neurotypical learning. Neurotypical word acquisition fits within the idea of Complementary Learning Systems, whereby an episodic hippocampal system supports initial rapid and sparse learning, whilst longer-term consolidation and extraction of statistical regularities across items is underpinned by neocortical systems. Therapy may drive these neurotypical learning mechanisms, and efficacy outcome may depend on whether there is available spared tissue across these dual systems to support learning.

Here, for the first time, we utilised a reverse translation approach to explore these learning mechanisms in post-stroke aphasia, spanning a continuum of consolidation success. After three weeks of daily anomia treatment, 16 patients completed a functional magnetic resonance imaging protocol; a picture naming task which probed (i) premorbid vocabulary retained despite aphasia, (ii) newly re-learned treated items and (iii) untreated/unknown and therefore unconsolidated items. The treatment was successful, significantly improving patients’ naming accuracy and reaction time post-treatment. Consistent with the Complementary Learning Systems hypothesis, patients’ overall naming of treated items, like that of controls when learning new vocabulary, was associated with increased activation of both episodic and language regions. Patients with relatively preserved left hemisphere language regions, aligned with the control data in that hippocampal activity during naming of treated items was associated with lower accuracy and slower responses – demonstrating the shifting division of labour from hippocampally-dependent new learning towards cortical support for the efficiently-named consolidated items. In contrast, patients with greater damage to the left inferior frontal gyrus displayed the opposite pattern (greater hippocampal activity when naming treated items was associated with quicker responses), implying that their therapy-driven learning was still wholly hippocampally reliant.

Open access

For the purpose of open access, the UKRI-funded authors have applied a Creative Commons Attribution (CC-BY) licence to any Author Accepted Manuscript version arising from this submission.
Prefrontal norepinephrine represents a threat prediction error under uncertainty
Authors: Basu Aakash , Yang Jen-Hau , Yu Abigail , Glaeser-Khan Samira , Feng Jiesi , Krystal John H. , Li Yulong , Kaye Alfred P.
Published: October 2022

Animals must learn to predict varying threats in the environment to survive by enacting defensive behaviors. Dopamine is involved in the prediction of rewards, encoding a reward prediction error in a similar manner to temporal difference learning algorithm. However, the corresponding molecular and computational form of threat prediction errors is not as well-characterized, although norepinephrine and other neuromodulators and neuropeptides participate in fear learning. Here, we utilized fluorescent norepinephrine recordings over the course of fear learning in concert with reinforcement learning modeling to identify its role in the prediction of threat. By varying timing and sensory uncertainty in the formation of threat associations, we were able to define a precise computational role for norepinephrine in this process. Norepinephrine release approximates the strength of fear associations, and its temporal dynamics are compatible with a prediction error signal. Intriguingly, the release of norepinephrine is influenced by time and sensory feedback, serving as an antithesis of the classical reward prediction error role of dopamine. Thus, these results directly demonstrate a combined cognitive and affective role of norepinephrine in the prediction of threat, with implications for neuropsychiatric disorders such as anxiety and PTSD.
Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model
Authors: Parka Aleksandra , Degel Caroline , Dreyer Jakob , Richter Ulrike , Hall Benjamin , Bastlund Jesper F. , Laursen Bettina , Nedergaard Maiken , Sotty Florence , Botta Paolo
Published: October 2022

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimer’s Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Spectral power analysis revealed a reduction of basal theta oscillations in rTg4510 mice. Enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol was further indicated by an increase in theta power and higher number of absence-like seizures in rTg4510 compared to control mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as a biomarker candidate in early stages of neurodegenerative tauopathies.
Divorce rate in birds increases with male promiscuity and migration distance
Authors: Chen Yiqing , Lin Xi , Song Zitan , Liu Yang
Published: October 2022

Socially monogamous animals may break up their partnership after one breeding season by a so-called ‘divorce’ behaviour. Divorce rate immensely varies across avian taxa that have a predominantly monogamous social mating system. Although a range of factors associated with divorce have been tested, there is not a consensus regarding the large-scale variation and relationships among associated factors. Moreover, the impact of sexual roles in divorce still needs further investigation. Here, we applied phylogenetic comparative methods to analyze one of the largest datasets ever compiled that included divorce rates from published case studies of 232 avian species from 25 orders and 61 families. We tested correlations between divorce rate and a group of factors that are closely related to pair bond strength: promiscuity of both sexes, migration distance, and adult mortality. Our results showed that only male promiscuity, but not female promiscuity, had a critical relationship with divorce rate. Furthermore, migration distance was positively correlated with divorce rate and indirectly affected divorce rate via male promiscuity. These findings indicated that divorce might not be simply explained as an adaptive strategy or neutral occurrence, but could be a mixed response to sexual conflict and stress from the ambient environment.
Human organoid model of PCH2a recapitulates brain region-specific pathology
Authors: Kagermeier Theresa , Hauser Stefan , Sarieva Kseniia , Laugwitz Lucia , Groeschel Samuel , Janzarik Wibke , Yentür Zeynep , Becker Katharina , Schöls Ludger , Krägeloh-Mann Ingeborg , Mayer Simone
Published: October 2022

Pontocerebellar hypoplasia type 2 a (PCH2a) is a rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is the hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. PCH2a results from a homozygous founder variant inTSEN54, which encodes a tRNA splicing endonuclease (TSEN) complex subunit. Despite the ubiquitous expression of the TSEN complex, the tissue-specific pathological mechanism of PCH2a remains unknown due to a lack of model system. In this study, we developed human models of PCH2a using brain region-specific organoids. We therefore obtained skin biopsies from three affected males with genetically confirmed PCH2a and derived induced pluripotent stem cells (iPSCs). Proliferation and cell death rates were not altered in PCH2a iPSCs. We subsequently differentiated cerebellar and neocortical organoids from control and PCH2a iPSCs. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. We observed milder growth deficits in neocortical PCH2a organoids. While PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we have generated a human model of PCH2a, which provides the foundation for deciphering brain region-specific disease mechanisms.
Is Kinesio taping effective for peripheral tissue perfusion in women with mild to moderate chronic venous insufficiency? A randomized controlled trial
Authors: Vieira Carvalho Maria Luiza , De Menezes Caceres Viviane , de Oliveira Nascimento Isabella , Costa Henrique Silveira , Schedit Figueiredo Pedro Henrique , Lima Vanessa Pereira , Monteiro Debora Pantuso , Pereira Danielle Aparecida Gomes
Published: October 2022

Objective

To evaluate the acute effect of Kinesio Taping® on peripheral tissue perfusion in women with chronic venous insufficiency (CVI).

Methods

This randomized, double-blind controlled trial included 59 women with mild to moderate CVI. They were randomized to a control group (n= 23; 54.08 ± 9.04 years) and Kinesio Taping® group (KT) (n= 36; 55.87 ± 9.97 years). Near-infrared spectroscopy was positioned in the medial gastrocnemius muscle for assessment of resting tissue perfusion 48 h after the first day of evaluation and after placement of the Kinesio Taping® tape. The evaluation also consisted of performing movements of the plethysmography examination. To verify the comparisons of pre- and post-Kinesio Taping® data, the variation delta was used for analysis. Mann–Whitney U test was performed an an alpha of 5% was considered statistically significant.

Results

There wasn’ st a significant difference between groups regarding the peripheral tissue perfusion evaluation variables Peripheral Oxygen Saturation Difference – DELTA_SPO2: (KT Group 3.21 (0.84–3.62); Control 2.21 (1.59–4.83), p = 0.219) and Difference in deoxygenate hemoglobin values – DELTA_HHB (units) KT Group -0.62 (−2.14–0.67); Control Group -0.07 (−2.15–2.62) p = 0.238). Despite the lack of statistical significance, the KT group had a 785.7% greater drop in HHB values than the control group.

Conclusions

Acute use of Kinesio Taping® in women with CVI did not significantly alter tissue perfusion of calf muscles. However, it was possible to observe percentage differences in venous retention to be considered from a clinical point of view.

Trial registration

Brazilian Registry of Clinical Trials (REBEC) RBR-9bhbrp.
Children’s visual acuity tests at home: A prospective repeated measures study
Authors: Osborne Daniel , Steele Aimee , Evans Megan , Ellis Helen , Pancholi Roshni , Harding Tomos , Dee Jessica , Leary Rachel , Bradshaw Jeremy , O’Flynn Elizabeth , Self Jay E
Published: October 2022

Background

Home visual acuity tests could ease pressure on ophthalmic services by facilitating remote review of a variety of patients. Home tests may have further utility in giving service users frequent updates of vision outcomes during therapy, identifying vision problems in an asymptomatic population, and engaging stakeholders in therapy.

The accuracy of home vision tests for children when completed without supervision from a professional is unknown.

Methods

Children attending outpatient clinics had their visual acuity measured 3 times in a randomised order at the same appointment. Once by a registered orthoptist as per standard clinical protocols, once by an orthoptist using a tablet-based visual acuity test (iSight Pro, Kay Pictures), and once by an unsupervised parent or carer using the tablet-based test.

Results

42 children were recruited to the study. The mean age was 5.6 years (range 3.3 to 9.3 years). Median measurements (interquartile range) for clinical standard, orthoptic-led and parent/carer-led iSight visual acuity measurements were 0.155 (0.18), 0.180 (0.26), and 0.300 (0.33) respectively.

The iSight app in the hands of parents/carers was significantly different from the standard of care measurements (P=0.009). In the hands of orthoptists, there was no significant difference between the iSight app and standard of care (P=0.551), nor was there significant difference between parents/carers using the app and orthoptists using the app (P=0.133).

Conclusion

This technique of unsupervised home visual acuity measures for children is not comparable to clinical measures and is unlikely to be valuable to clinical decision making and screening. Future work should focus on improving the technique through, for example, gamification of vision tests.

What is already known on this topic?

Children’s game visual acuity tests could improve things for hospital services and patients. The tablet-based tests are accurate when used by professionals to tests adults’ vision.

What this study adds

This study provides data about the accuracy of home tests when used by untrained parents or carers on their children.

How this study might affect research, practice, or policy

Current policy recommends apps home tests are not used to test children’s eyes for clinical decision-making purposes. Our data supports this policy and highlights the need for future research to focus on improving the tests.

Synopsis / precis (“At a glance”)

Visual acuity testing at home could improve patient care and reduce clinical visits, but data to show clinicians that they can rely upon the results in children are lacking. Our study shows the tests cannot be relied upon for clinical purposes. Improvements to the tests are required before they become useful and can be implemented into practice.
Molecular mechanisms associated with multiple sclerosis progression, severity and phenotype
Authors: Kosa Peter , Lumbard Keith , Wang Jing , Liang C. Jason , Masvekar Ruturaj , Kim Yujin , Varosanec Mihael , Jennings Lori , Bielekova Bibiana
Published: October 2022

While current treatments of multiple sclerosis (MS) effectively inhibit formation of focal lesions and relapses, most patients experience progression independent of relapse activity (PIRA). To understand PIRA, we analyzed nine prospectively acquired clinical and imaging outcomes in 176 relapsing-remitting and 215 progressive MS patients and 45 healthy volunteers, along with matched cellular and >5000 protein data in 1,042 cerebrospinal fluid (CSF) samples. Regressing out physiological aging and sex effects identified MS-related processes. Among these, compartmentalized inflammation and its effector mechanisms such as pyroptosis showed the strongest association with MS severity, irrespective of clinical categorization of patients. However, molecular processes affected localization of CNS injury: patients with predominant brain damage had proportionally higher neuroinflammation, while fibrosis and tissue hypoxia were linked to principal involvement of spinal cord. We did not identify inflammation-unrelated neurodegeneration; instead, CNS-related processes were beneficial, such as synaptogenesis. Machine learning-based CSF biomarker models predicted nine clinical and volumetric imaging outcomes in the independent cohort with accuracy exceeding published MS models.

These data show intra-individual diversity of putative disease mechanisms in MS and implicate processes related to compartmentalized neuroinflammation as leading candidate mechanisms of PIRA. Future drug development should include CNS-penetrant anti-inflammatory agents.
Epilepsy Classification using the International League Against Epilepsy (ILAE) 2017 classification, in resource limited setting
Authors: Alkhedir Hajatmena A M , MohamedSharif Abubaker A , Salih Mohammed Isra Bdraldein , Mohamed Inaam N
Published: October 2022

Objectives

The main aim of the study is to classify patients with epilepsy using ILAE classification 2017, and to test whether it can like Sudan.

Methods

This is a descriptive, prospective cross sectional study, conducted in two main pediatric epilepsy clinics in Khartoum State-Sudan.

Results

This study included 350 patients with a mean age of (8.4 ±4.7) years. Male to female ratio was 1.5:1. The mean age at the onset of seizure was (3.73 ±3.73) years. The mean duration of the illness was (4.71 ±3.91) years. ILAE Classification was applied and 251 (71.11%) had generalized onset seizures, 95 (27.7%) had focal onset and four (1.1%) had unknown seizure onset.

Significance

ILAE 2017 is the last updated classification for epilepsy and very few studies were done especially in resource-limited settings.
Clinical encounter heterogeneity and methods for resolving in networked EHR data: A study from N3C and RECOVER programs
Authors: Leese Peter , Anand Adit , Girvin Andrew , Manna Amin , Patel Saaya , Yoo Yun Jae , Wong Rachel , Haendel Melissa , Chute Christopher G , Bennett Tellen , Hajagos Janos , Pfaff Emily , Moffitt Richard
Published: October 2022

OBJECTIVE

Clinical encounter data are heterogeneous and vary greatly from institution to institution. These problems of variance affect interpretability and usability of clinical encounter data for analysis. These problems are magnified when multi-site electronic health record data are networked together. This paper presents a novel, generalizable method for resolving encounter heterogeneity for analysis by combining related atomic encounters into composite ‘macrovisits.’

MATERIALS AND METHODS

Encounters were composed of data from 75 partner sites harmonized to a common data model as part of the NIH Researching COVID to Enhance Recovery Initiative, a project of the National Covid Cohort Collaborative. Summary statistics were computed for overall and site-level data to assess issues and identify modifications. Two algorithms were developed to refine atomic encounters into cleaner, analyzable longitudinal clinical visits.

RESULTS

Atomic inpatient encounters data were found to be widely disparate between sites in terms of length-of-stay and numbers of OMOP CDM measurements per encounter. After aggregating encounters to macrovisits, length-of-stay (LOS) and measurement variance decreased. A subsequent algorithm to identify hospitalized macrovisits further reduced data variability.

DISCUSSION

Encounters are a complex and heterogeneous component of EHR data and native data issues are not addressed by existing methods. These types of complex and poorly studied issues contribute to the difficulty of deriving value from EHR data, and these types of foundational, large-scale explorations and developments are necessary to realize the full potential of modern real world data.

CONCLUSION

This paper presents method developments to manipulate and resolve EHR encounter data issues in a generalizable way as a foundation for future research and analysis.
Systems strengthening approach during antenatal care improves maternal nutrition and reduces childhood stunting in West Bengal, India
Authors: Mehta Kayur , Mukherjee Sreeparna Ghosh , Bhattacharjee Ipsita , Fate Kassandra , Kachwaha Shivani , Kant Aastha , Banerjee Meghendra , Shet Anita
Published: October 2022

Background

Early childhood growth failure including stunting is associated with suboptimal health and cognitive development outcomes. Despite progress, the prevalence of childhood stunting in India remains amongst the highest globally.

Objective

We aimed to evaluate the impact of a systems strengthening interventional package, including body-mass-index measurement at pregnancy registration, monthly weight monitoring, on-the-spot supplementary nutrition, iron-folic acid supplementation, and targeted dietary counselling provided to women during their antenatal care on childhood stunting.

Methods

This is a prospective follow-up comparison study. Women from three districts in West Bengal, India in their first trimester of pregnancy between May 2018 and May 2019 were enrolled into the study. Pregnancy, birth and infant characteristics were collected, and anthropometric indices measured. The relative risk of stunting in children in intervention and comparison groups were compared using generalized linear model to adjust for clustering effect.

Results

A total of 809 mother-child dyads (406 intervention; 403 comparison) were followed between May 2018 and May 2021. The median age of women in the intervention and comparison group was 23 (IQR 20-25) and 25 (IQR 24-27) years respectively. Median gestational weight gain was higher amongst women in the intervention group (9 vs. 8 kilograms, p=0.04). Low-birth-weight prevalence was 29.3% (119/406) and 32.0% (129/403) in the intervention and comparison group respectively. At 12-35 months of age, children born to women in the intervention group had significantly reduced risk of stunting (RR=0.58, 95% CI 0.45-0.75, p<0.001). The odds of stunting amongst children born with low birthweight to women in the comparison group were statistically significant [OR 2.44 (1.44-4.14)], unlike those amongst children born to women in the intervention group [1.19 (0.58-2.46)].

Conclusions

These results indicate that strengthening of routine antenatal care including targeted nutritional counselling to expectant mothers can have distal beneficial effects on childhood stunting beyond the immediate post-natal period.

Teaser Text

This article describes the impact of a systems strengthening approach during antenatal care that improved maternal nutrition and reduced childhood stunting in West Bengal, India.
“This guideline is not practical; it might be practical to specialists like you”: Doctors’ experiences of the Global Initiative for Asthma (GINA) guideline in Nigeria; A qualitative study
Authors: Ozoh Obianuju Beatrice , Dede Sandra Kelechi , Eze Joy Nkiru , Mortimer Kevin , Chinouya Martha
Published: October 2022

Background

The Global Initiative for Asthma (GINA) report sets out updated evidence-based strategy for asthma management. Little is known about how this report is perceived and implemented in low-income and middle-income countries (LMICs) like Nigeria. We explored the experiences of asthma management as informed by the current GINA guideline among doctors in Lagos, Nigeria.

Methods

Using a qualitative research approach, in-depth interviews were conducted among doctors in Lagos, Nigeria to explore their experiences of asthma management in the context of the current GINA report. The thematic framework approach was used for data analysis.

Results

Eleven doctors (five general practitioners (GPs) and six Family Physicians (FPs) took part. Four overarching themes were identified:

Knowledge of, and attitude towards the GINA strategy: Whilst most doctors were aware of the existence of the GINA report, there was limited knowledge about its content including current recommendations for mild asthma treatment.

Asthma diagnosis and treatment: There was limited access to lung function testing facilities and its role in asthma diagnosis was underappreciated.

Barriers to managing asthma according to GINA recommendations: These included complexity of the GINA report, unavailability and unaffordability of asthma medicines and poor patient adherence to medications, driven by socio-cultural factors.

Enablers of GINA-recommended asthma management: Improvement in asthma education for doctors and the general population and better access to diagnostic tests and medicines.

Conclusion

Whilst there was awareness of the existence of the GINA report, there was limited knowledge about its content and several barriers to its implementation were reported. Education about the GINA report, investment in diagnostic and treatment services and simplification of recommendations were identified as possible solutions.
A Scoping Review Protocol on Integration of mobile-linked POC diagnostics in community-based healthcare: User Experience
Authors: Nxele Siphesihle R. , Moetlhoa Boitumelo , Kgarosi Kabelo , Mashamba-Thompson Tivani
Published: October 2022

Background

Mobile-linked point-of-care diagnostics forms an integral part of diagnostic health services for efficient communication between patients and healthcare professionals despite geographical location and time of diagnosis. The efficiency of this technology lies in the user experience which means that the interaction of the user with the implemented technology needs to be simple, convenient, and consistent. Having a well-structured user experience of these devices in community-based healthcare will aid in sustainable implementation. Herein, we propose to conduct a literature search to systematically map out evidence based on mobile-linked POC diagnostics user experience at a community level in resource-limited settings.

Methodology

The proposed scoping review will be guided by the advanced Arksey and O’Malley methodological framework and further advanced by Levacet al. A comprehensive search will be conducted to find relevant published literature from the following electronic databases: Scopus, Web of Science, EBSCOhost (Medline, CINAHL, Africa-wide, Academic Search Complete). Grey literature will also be searched, including reports from government and international organizations such as World Health Organization (WHO), Foundation for Innovative New Diagnostics (FIND), and the Food and Drug Administration (FDA). Two independent reviewers will screen the relevant studies and the degree of the agreement will be determined by calculating Cohen’s kappa statistic. The quality of eligible data will also be appraised using the mixed method appraisal tool version 2018.

Discussion

We anticipate that the planned scoping review will present useful evidence to inform stakeholders on the integration of mobile-linked diagnostic devices in community-based healthcare which will guide further research on the subject.
Neural signatures of second language proficiency in narrative processing
Authors: Zhang Ruiqing , Wang Jing , Lin Hui , Turk-Browne Nicholas B. , Cai Qing
Published: October 2022

Making sense of speech in a second language relies on multiple abilities. Differences in brain activity related to proficiency in language tasks have often been attributed to processing demands. However, during naturalistic narrative comprehension, listeners at different proficiency levels may form different representations of the same speech. We hypothesized that the synchronization of these representations across people could thus be used to measure second-language proficiency. Using a searchlight shared response model, we found that highly proficient participants showed synchronization in regions similar to those of native speakers, including in the default mode network and in the lateral prefrontal cortex. In contrast, participants with low proficiency showed more synchronization in auditory cortex and word-level semantic processing areas in the temporal lobe. Moderate proficiency showed the greatest neural diversity, suggesting lower consistency in the source of this partial proficiency. Based on these synchronization differences, we were able to reliably classify the proficiency level or predict behavioral performance on an independent English test in held-out participants, suggesting the identified neural systems represented proficiency-sensitive information that was generalizable to other individuals. These findings suggest higher second-language proficiency leads to a more native-like neural processing of naturalistic language, including in systems beyond the cognitive control network or the core language network.

Highlights

Neural synchronization in second-language speech processing reflects proficiency.

High-proficiency individuals neurally resemble native speakers.

Low-proficiency individuals are synchronized in perceptual and word semantics areas.

Proficiency level can be predicted using neural synchronization signatures.
Disulfide stabilization reveals conserved dynamic features between SARS-CoV-1 and SARS-CoV-2 spikes
Authors: Zhang Xixi , Li Zimu , Zhang Yanjun , Liu Yutong , Wang Jingjing , Liu Banghui , Chen Qiuluan , Wang Qian , Fu Lutang , Wang Peiyi , Zhong Xiaolin , Jin Liang , Chen Ling , He Jun , Zhao Jincun , Xiong Xiaoli
Published: October 2022

SARS-CoV-2 spike protein (S) is structurally dynamic and has been observed by cryo-EM to adopt a variety of prefusion conformations that can be categorized as locked, closed and open. The locked conformations feature tightly packed trimers with structural elements incompatible with RBD in “up” position. For SARS-CoV-2 S, it has been shown that the locked conformations are transient under neutral pH. Probably due to their transience, locked conformations remain largely uncharacterized for SARS-CoV-1 S. Intriguingly, locked conformations were the only conformations captured for S proteins of bat and pangolin origin SARS-related coronaviruses. In this study, we introduced x1, x2, and x3 disulfides into SARS-CoV-1 S. Some of these disulfides have been shown to preserve rare locked conformations when introduced to SARS-CoV-2 S. Introduction of these disulfides allowed us to image a variety of locked and other rare conformations for SARS-CoV-1 S by cryo-EM. We identified bound cofactors and structural features that are associated with SARS-CoV-1 S locked conformations. We compare newly determined structures to other available spike structures of Sarbecoviruses to identify conserved features and discuss their possible functions.
Music and Speech Elicit Similar Subcortical Responses in Human Listeners
Authors: Shan Tong , Cappelloni Madeline S. , Maddox Ross K.
Published: October 2022

Music and speech are two sounds that are unique to human beings and encountered in daily life. Both are transformed by the auditory pathway from an initial acoustical encoding to higher level cognition. Most studies of speech and music processing are focused on the cortex, and the subcortical response to natural, polyphonic music is essentially unstudied. This study was aimed to compare the subcortical encoding of music and speech using the auditory brainstem response (ABR). While several methods have recently been developed to derive the ABR to continuous speech, they are either not applicable to music or give poor results. In this study, we explored deriving the ABR through deconvolution using three regressors: 1) the half-wave rectified stimulus waveform, 2) the modeled inner hair cell potential, and 3) the auditory nerve model firing rate (ANM), where the latter two were generated from a computational auditory periphery model. We found the ANM regressor yields robust and interpretable ABR waveforms to diverse genres of music and multiple types of speech. We then used the ANM-derived ABRs to compare the subcortical responses to music and speech and found that they are highly similar in morphology. We further investigated cortical responses using the same deconvolution method, and found the responses there were also quite similar, which was unexpected based on previous studies. We conclude that when using our proposed deconvolution regressor that accounts for acoustical differences’ nonlinear effects on peripheral encoding, the derived brainstem and cortical responses to music and speech are highly correlated.
SARS-CoV-2 multi-antigen protein microarray for detailed characterization of antibody responses in COVID-19 patients
Authors: Celikgil Alev , Massimi Aldo B. , Nakouzi Antonio , Herrera Natalia G. , Morano Nicholas C. , Lee James H. , Yoon Hyun ah , Garforth Scott J. , Almo Steven C.
Published: October 2022

Antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target multiple epitopes on different domains of the spike protein, and other SARS-CoV-2 proteins. We developed a SARS-CoV-2 multi-antigen protein microarray with the nucleocapsid, spike and its domains (S1, S2), and variants with single (D614G, E484K, N501Y) or double substitutions (N501Y/Deletion69/70), allowing a more detailed high-throughput analysis of the antibody repertoire following infection. The assay was demonstrated to be reliable and comparable to ELISA. We analyzed antibodies from 18 COVID-19 patients and 12 recovered convalescent donors. S IgG level was higher than N IgG in most of the COVID-19 patients, receptor-binding domain of S1 showed high reactivity, but no antibodies were detected against heptad repeat domain 2 of S2. Furthermore, antibodies were detected against S variants with single and double substitutions in COVID-19 patients who were infected with SARS-CoV-2 early in the pandemic. Here we demonstrated that SARS-CoV-2 multi-antigen protein microarray is a powerful tool for detailed characterization of antibody responses, with potential utility in understanding the disease progress and assessing current vaccines and therapies against evolving SARS-CoV-2.
Intuitive movement-based prosthesis control enables arm amputees to reach naturally in virtual reality
Authors: Segas Effie , Mick Sébastien , Leconte Vincent , Dubois Océane , Klotz Rémi , Cattaert Daniel , de Rugy Aymar
Published: October 2022

Impressive progress is being made in bionic limbs design and control. Yet, controlling the numerous joints of a prosthetic arm necessary to place the hand at a correct position and orientation to grasp objects remains challenging. Here, we designed an intuitive, movement-based prosthesis control that leverages natural arm coordination to predict distal joints missing to people with transhumeral limb loss based on proximal residual limb motion and knowledge of the movement goal. This control was validated on 29 participants, including 7 with above-elbow limb loss, who picked and placed bottles in a wide range of locations in virtual reality, with median success rates over 99% and movement times identical to those of natural movements. This control also enabled 15 participants, including 3 with limb difference, to reach and grasp real objects with a robotic arm operated according to the same principle. Remarkably, this was achieved without any prior training, indicating that this control is intuitive and instantaneously usable. It could be used for phantom limb pain management in virtual reality, or to augment reaching capabilities of invasive neural interfaces usually more focused on hand and grasp control.
Mito-SiPE: A sequence-independent, PCR-free mitochondrial DNA enrichment method for ultra-deep sequencing that minimises amplification and alignment artefacts for the analysis of mitochondrial heteroplasmy/variation
Authors: Walsh Darren J , Bernard David J , Pangilinan Faith , Esposito Madison , Harold Denise , Parle-McDermott Anne , Brody Lawrence C
Published: October 2022

Background

Deep sequencing is often used to measure somatic variation in the mitochondrial genome. Selective enrichment methods, such as PCR amplification or probe hybridization/capture are commonly used. These methods can introduce bias and are prone to contamination by nuclear-mitochondrial sequences (NUMTs); elements that can introduce artefacts into analyses such as an assessment of mitochondrial heteroplasmy.

Results

Here, we demonstrate a method to obtain ultra-deep (>80,000X) sequencing coverage of the mitochondrial genome by selectively purifying the intact organelle itself using differential centrifugation and alkaline lysis. We applied this approach to seven different mouse tissues. Isolation of mitochondria yields a preparation of highly enriched mtDNA. We compared this method to the commonly used PCR-based method. Mito-SiPE avoids false-heteroplasmy calls that occur when long-range PCR amplification is used for mtDNA enrichment.

Discussion

We have described a modified version of a long-established protocol for purifying mtDNA and have quantified the increased level of mitochondrial DNA post-enrichment in 7 different mouse tissues. This method will enable researchers to identify changes in low-frequency heteroplasmy without introducing PCR biases or NUMT contamination that are falsely identified as heteroplasmy when long-range PCR is used.
Probing the diabetes and colorectal cancer relationship using gene – environment interaction analyses
Authors: Dimou Niki , Kim Andre E. , Flanagan Orlagh , Murphy Neil , Diez-Obrero Virginia , Shcherbina Anna , Aglago Elom K , Bouras Emmanouil , Campbell Peter T , Casey Graham , Gallinger Steven , Gruber Stephen B , Jenkins Mark A , Lin Yi , Moreno Victor , Ruiz-Narvaez Edward , Stern Mariana C , Tian Yu , Tsilidis Kostas K , Arndt Volker , Barry Elizabeth L , Baurley James W , Berndt Sonja I , Bézieau Stéphane , Bien Stephanie A , Bishop D Timothy , Brenner Hermann , Budiarto Arif , Carreras-Torres Robert , Cenggoro Tjeng Wawan , Chan Andrew T , Chang-Claude Jenny , Chanock Stephen J , Chen Xuechen , Conti David V , Dampier Christopher H , Devall Matthew , Drew David , Figueiredo Jane C , Giles Graham G , Gsur Andrea , Harrison Tabitha A , Hidaka Akihisa , Hoffmeister Michael , Huyghe Jeroen R , Jordahl Kristina , Kawaguchi Eric , Keku Temitope O , Larsson Susanna C , Marchand Loic Le , Lewinger Juan Pablo , Li Li , Mahesworo Bharuno , Morrison John , Newcomb Polly A , Newton Christina C , Obon-Santacana Mireia , Ose Jennifer , Pai Rish K , Palmer Julie R , Papadimitrou Nick , Pardamean Bens , Peoples Anita R , Pharoah Paul D P , Platz Elizabeth A , Potter John D , Rennert Gad , Scacheri Peter C , Schoen Robert E , Su Yu-Ru , Tangen Catherine M , Thibodeau Stephen N , Thomas Duncan C , Ulrich Cornelia , Um Caroline Y , van Duijnhoven Franzel JB , Visvanathan Kala , Vodicka Pavel , Vodickova Ludmila , White Emily , Wolk Alicja , Woods Michael O , Qu Conghui , Kundaje Anshul , Hsu Li , Gauderman W. James , Gunter Marc J , Peters Ulrike
Published: October 2022

Diabetes is an established risk factor for colorectal cancer; however, the mechanisms underlying this relationship are not fully understood and the role of genetic variation is unclear. We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes and joint testing of Gxdiabetes, G-colorectal cancer association and/or G-diabetes correlation (2,3-degrees of freedom joint tests; d.f.). Based on the joint tests, variant rs3802177 inSLC30A8(p-value3-d.f.:5.46×10−11; regulates phosphorylation of the insulin receptor and phosphatidylinositol-3 kinase activity) and rs9526201 inLRCH1(p-value2-d.f.:7.84×10−09; regulates T cell migration and Natural Killer Cell cytotoxicity) were associated with colorectal cancer. These results suggest that variation in genes related to insulin signalling and immune function may modify the association of diabetes with colorectal cancer and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Left ventricular mass and global wall thickness – prognostic utility and characterization of left ventricular hypertrophy
Authors: Lundin Magnus , Heiberg Einar , Nordlund David , Gyllenhammar Tom , Steding-Ehrenborg Katarina , Engblom Henrik , Carlsson Marcus , Atar Dan , van der Pals Jesper , Erlinge David , Borgquist Rasmus , Khoshnood Ardavan , Ekelund Ulf , Nickander Jannike , Themudo Raquel , Nordin Sabrina , Kozor Rebecca , Bhuva Anish N , Moon James C , Maret Eva , Caidahl Kenneth , Sigfridsson Andreas , Sörensson Peder , Schelbert Erik B , Arheden Håkan , Ugander Martin
Published: October 2022

AIMS

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, which is associated with morbidity and mortality. Several measures related to LV wall thickness exist, with uncertain relative prognostic strength. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy.

METHODS AND RESULTS

Subjects having undergone CMR were studied (cardiac patients, n=2543; healthy volunteers, n=100). A new measure, global wall thickness (GT, GTI if indexed to body surface area), and related measures, including mass/volume and mass/volume2/3, were calculated. GT was accurately calculated from LV mass and LV end-diastolic volume. Among patients with follow-up (n=1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12–1.20], p<0.001), followed by GTI (HR 1.14[1.09–1.19], p<0.001). Among patients with normal mass, volume, systolic function and absence of scar (n=326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35–1.94], p<0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, or concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p<0.05 for all).

CONCLUSIONS

LV mass is highly prognostic when mass is elevated (advanced disease), but global wall thickness is easily and accurately calculated, and adds value and discrimination amongst those with normal mass (early disease). The combination of these two measures can be used to characterize hypertrophy.
Three-dimensional cranial ultrasound and functional near infrared spectroscopy for bedside monitoring of intraventricular hemorrhage in preterm neonates
Authors: Kebaya Lilian M N , Stubbs Kevin , Lo Marcus , Al-Saoud Sarah , Karat Bradley , St Lawrence Keith , de Ribaupierre Sandrine , Duerden Emma G.
Published: October 2022

Germinal Matrix-Intraventricular hemorrhage (GMH-IVH) remains a significant cause of adverse neurodevelopment in preterm infants. Current management relies on 2-dimensional cranial ultrasound (2D cUS) ventricular measurements. Reliable biomarkers are needed to aid in the early detection of posthemorrhagic ventricular dilatation (PHVD) and subsequent neurodevelopment. In a prospective cohort study, we incorporated 3-dimensional (3D) cUS and functional infrared spectroscopy (fNIRS) to monitor neonates with GMH-IVH. Preterm neonates (<32 weeks’ gestation) were enrolled following a GMH-IVH diagnosis. Neonates underwent sequential measurements: 3D cUS images were manually segmented using in-house software, and the ventricle volumes (VV) were extracted. Multichannel fNIRS data were acquired using a high-density system, and spontaneous functional connectivity (sFC) was calculated. Of the 30 neonates enrolled in the study, 21 (70%) had grade I-II and 12 (40%) grade III-IV GMH-IVH, and 23 neonates (77%) underwent surgical interventions to divert cerebrospinal fluid (CSF). Infants with severe GMH-IVH who underwent CSF diversion had larger VV and significantly decreased sFC (p<0.001). Our findings of increased VV and reduced sFC suggest that regional disruptions of ventricular size may impact the development of the underlying grey matter. Hence, 3D cUS and fNIRS are promising bedside tools for monitoring the progression of GMH-IVH in preterm neonates.
Parental COVID-19 vaccine hesitancy and vaccine uptake among children and adolescents in the US: Findings from a prospective national cohort
Authors: Rane Madhura S. , Robertson McKaylee , Westmoreland Drew , Zimba Rebecca , Kulkarni Sarah G. , Shen Yanhan , Berry Amanda , Chang Mindy , You William , Grov Christian , Nash Denis ,   the CHASING COVID Cohort Team
Published: October 2022

Objectives

Our aim was to measure COVID-19 vaccine uptake among children aged 5-17 years old via parents participating in the CHASING COVID Cohort and identify sociodemographic factors associated with it.

Methods

In this longitudinal study, parents of school-aged children were asked about their own vaccination status and that of their children at three time points between June 2021-January 2022, along with reasons for vaccinating immediately or delaying vaccinations for their children. Multivariable log binomial models were used to identify correlates of vaccine uptake among children.

Results

Of the 1,583 children aged 5-17 years, 64.9% were vaccinated. Over 40% of parents of 5-11 year old children who intended to delay vaccinating their child in June 2021 had still not vaccinated them by January 2022, including 30% of the parents who were vaccinated. After adjusting for measured confounders, parents’ vaccination status was associated with higher likelihood of children’s vaccine uptake (age-specific adjusted odds ratios [aORs]: aOR16-173.7, 95% CI 2.3, 5.9, aOR12-153.7, 95% CI 2.6, 5.3; aOR5-1110.6, 95% CI 5.4, 20.9). Parents’ education (aOR16-171.4, 95% CI 1.1, 1.8, aOR12-151.5, 95% CI 1.2, 1.9; aOR5-112.1, 95% CI 1.5, 2.9) and worry about others getting infected (aOR5-111.4, 95% CI 1.1, 1.6) were also associated with higher vaccine uptake among children. A higher proportion of parents of 5-11 year olds (vs. 12-17 year olds) had concerns about vaccine safety and effectiveness.

Conclusion

To increase vaccination coverage among young children, vaccination campaigns should focus on both vaccinated and unvaccinated parents and messaging should be specific to the child’s age.