bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Dose NSAIDs Efficacy in Orthopedic Applications
Authors: Oliva Francesco , Quaranta Marco , Cipollaro Lucio , Conti Valeria , De Bellis Emanuela , Filippelli Amelia , Maffulli Nicola
Published: August 2022

Non-steroidal anti-inflammatory drugs (NSAIDs) [cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors] and COXIBs (the COX-2 selective inhibitors) may induce several potentially severe and life-threatening issues especially in elderly patients. The use of low-dose NSAIDs is associated with lower risk of side effects compared to the standard dosage. Low-dose NSAIDs could minimize the side effects of these drugs while maintaining their clinical efficacy and effectiveness. The present study evaluates the effectiveness and safety of low-dose NSAIDs in musculoskeletal applications.
Association Between Immunoglobulin G4-Related Ophthalmic Disease and Nonlymphoid Malignancy Case Series and Comprehensive Review of the Literature
Authors: Hou Yanli , Su Qiang , Li Jing , Zhou Hang , Li Hongyang
Published: August 2022

Background:

Immunoglobulin G4-related disease (IgG4-RD) and immunoglobulin G4-related ophthalmic disease (IgG4-ROD) complicated with nonlymphoid malignancy (NL-malignancy) are rare. No exact relationship between IgG4-RD and NL-malignancies has been established yet, and there have been few reports of different types of IgG4-ROD and related malignancies.

Methods:

We retrospectively reviewed medical records of patients diagnosed with IgG4-RD and NL-malignancy, whichever occurred first, from January 2015 to March 2021. In addition, the literature on the relationship between IgG4-ROD and NL-malignancy was reviewed.

Results:

There were 115 patients diagnosed with IgG4-RD, and 10 patients were enrolled in the study with NL-malignancy. Three patients were diagnosed with IgG4-ROD. One patient reported a previous history of cancer, and the other 2 patients developed cancer at or after the diagnosis of IgG4-RD. The 3 patients' cancers were located in the lung, gastrointestinal tract, and thyroid.

Conclusions:

There may be potential malignancy occurrence during follow-up of IgG4-RD patients, especially among elderly patients. In addition, IgG4-RD could be a paraneoplastic syndrome at or before the diagnosis of malignancy.
Fully Personalised Degenerative Disease Modelling - A Duchenne Muscular Dystrophy Case Study
Authors: Baker Evan , Challenor Peter , Bamsey Ian , Muntoni Francesco , Manzur Adnan Y. , Tsaneva-Atanasova Krasimira
Published: August 2022

Predicting the trajectory of rare degenerative diseases can be extremely beneficial, especially when these predictions are personalised to be relevant for a specific patient. These predictions can help inform and advise patients, families, and clinicians about the next stages of treatment and care. Obtaining such predictions, however, can be challenging, especially when data is limited. In particular, it is important that these predictions do not rely too heavily on general trends from the wider afflicted population while not relying exclusively on the, potentially sparse, data from the patient in question. We present a case study, wherein a modelling framework is developed for predicting a patient’s long term trajectory, using a mix of data from the patient of concern and a database of previously observed patients. This framework directly accounts for the temporal structure of a patient’s trajectory, effortlessly handles a large amount of missing data, allows for a wide range of patient progression, and offers a robust quantification of the various uncertainties. We showcase this framework to an example involving Duchenne Muscular Dystrophy, where it provides promising results.
A magnetically actuated, optically sensed tensile testing method for mechanical characterisation of soft biological tissues
Authors: Rosalia Luca , Hallou Adrien , Cochrane Laurence , Savin Thierry
Published: August 2022

Mechanical properties of soft biological tissues play a key role in their normal physiology, contributing to their formation during development, maintenance and repair during adult homeostasis, and driving diseases such as cancer. Mechanics has been proposed to exert its effect by impacting cells fate decisions and cell behaviours including proliferation, differentiation and motility, amongst others. However, despite its critical relevance, a comprehensive analysis of the biomechanics of soft biological tissues is still lacking due to the limitations of the existing characterisation tools. In this article, we describe the development of a device for uniaxial tensile testing of small samples of epithelial and connective tissues, based on the closed-loop interaction between an electromagnetic force actuator and an optical strain sensor. First, we validate the device with synthetic elastomers of known mechanical properties and compare its performance with conventional tensile testing methods; then, we characterise the mechanical properties of the squamous epithelium of the mouse oesophagus along with its supporting connective tissue and underlying muscle in controlled environmental conditions. Through an analysis of strain-stress curves, we demonstrate that the whole oesophagus behaves as a trilayered composite material, whose overall mechanical response depends on the properties of each of its tissue layers. Overall, the proposed setup enables measurements of the mechanical properties of soft biological tissues with unprecedented reliability and precision, and offers an ideal platform for future instrument developments.
Sensing the Full Dynamics of the Human Hand with a Neural Interface and Deep Learning
Authors: Sîmpetru Raul C. , Arkudas Andreas , Braun Dominik I. , Osswald Marius , de Oliveira Daniela Souza , Eskofier Bjoern , Kinfe Thomas M. , Del Vecchio Alessandro
Published: August 2022

Theories about the neural control of movement are largely based on movement-sensing devices that capture the dynamics of predefined anatomical landmarks. However, neuromuscular interfaces such as surface electromyography (sEMG) can potentially overcome the limitations of these technologies by directly sensing the motor commands transmitted to the muscles. This allows for the continuous, real-time prediction of kinematics and kinetics without being limited by the biological and physical constraints that affect motion-based technologies. In this work, we present a deep learning method that can decode and map the electrophysiological activity of the forearm muscles into movements of the human hand. We recorded the kinematics and kinetics of the human hand during a wide range of grasping and individual digit movements covering more than 20 degrees of freedom of the hand at slow (0.5 Hz) and fast (1.5 Hz) movement speeds in healthy participants. The input of the model consists of three-hundred EMG sensors placed only on the extrinsic hand muscles. We demonstrate that our neural network can accurately predict the kinematics and contact forces of the hand even during unseen movements and with simulated real-time resolution. By examining the latent space of the network, we find evidence that it has learned the underlying anatomical and neural features of the sEMG that drive all hand motor behaviours.
Changes in COVID-19-related mortality across key demographic and clinical subgroups: an observational cohort study using the OpenSAFELY platform on 18 million adults in England
Authors:   The OpenSAFELY Collaborative, Nab Linda , Parker Edward PK , Andrews Colm D , Hulme William J , Fisher Louis , Morley Jessica , Mehrkar Amir , MacKenna Brian , Inglesby Peter , Morton Caroline E , Bacon Sebastian CJ , Hickman George , Evans David , Ward Tom , Smith Rebecca M , Davey Simon , Dillingham Iain , Maude Steven , Butler-Cole Ben FC , O’Dwyer Thomas , Stables Catherine L , Bridges Lucy , Bates Christopher , Cockburn Jonathan , Parry John , Hester Frank , Harper Sam , Zheng Bang , Williamson Elizabeth J , Eggo Rosalind M , Evans Stephen , Goldacre Ben , Tomlinson Laurie A , Walker Alex J
Published: August 2022

Objectives

To quantify in absolute and relative terms how population-level COVID-19 death rates have changed in demographic and clinical subgroups.

Design

Retrospective cohort study on behalf of NHS England.

Setting

Linked primary care and death registry data from the OpenSAFELY-TPP platform, covering the first three pandemic waves in England (wave 1: March 23 to May 30, 2020; wave 2: September 7, 2020 to April 24, 2021; and wave 3, delta: May 28 to December 14, 2021).

Participants

In total, 18.7, 18.8, and 18.7 million adults were included for waves 1, 2, and 3 respectively.

Main outcome measures

COVID-19-related mortality based on linked death registry records.

Results

The crude absolute COVID-19-related death rate per 1,000 person-years decreased from 4.48 in wave 1 (95%CI 4.41;4.55), to 2.70 in wave 2 (95%CI 2.67;2.73), to 0.64 in wave 3 (95%CI 0.63;0.66). The absolute death rate decreased by 90% between waves 1 and 3 in patients aged 80+, but by only 20% in patients aged 18-39. This higher proportional reduction in age- and sex-standardised death rates was also seen for other groups, such as neurological disease, learning disability and severe mental illness. Conversely, standardised death rates in transplant recipients stayed constant across successive waves at 10 per 1,000 person-years. There was also only a small decrease in death rates between waves in people with kidney disease, haematological malignancies or conditions associated with immunosuppression. Consequently, the relative hazard of COVID-19-related death decreased over time for some variables (e.g. age), remained similar for some (e.g. sex, ethnicity), and increased for others (e.g. transplant).

Conclusions

COVID-19 death rates decreased over the first three pandemic waves. An especially large decrease was seen in older age groups and people with neurological disease, learning disability or severe mental illness. Some demographic inequalities in death rates persisted over time. Groups more likely to experience impaired vaccine effectiveness did not see the same benefit in COVID-19 mortality reduction.
Quantitative MRI and histopathology detect remyelination in inactive multiple sclerosis lesions
Authors: Wiggermann Vanessa , Endmayr Verena , Hernández-Torres Enedino , Höftberger Romana , Kasprian Gregor , Hametner Simon , Rauscher Alexander
Published: August 2022

Magnetic resonance imaging (MRI) of focal or diffuse myelin damage or remyelination may provide important insights into disease progression and potential treatment efficacy in multiple sclerosis (MS). We performed post-mortem MRI and histopathological myelin measurements in seven progressive MS cases to evaluate the ability of three myelin-sensitive MRI scans to distinguish different stages of MS pathology, particularly chronic demyelinated and remyelinated lesions.

At 3 Tesla, we acquired two different myelin water imaging (MWI) scans and magnetization transfer ratio (MTR) data. Histopathology included histochemical stainings for myelin phospholipids (LFB) and iron as well as immunohistochemistry for myelin proteolipid protein (PLP), CD68 (phagocytosing microglia/macrophages) and BCAS1 (remyelinating oligodendrocytes). Mixed-effects modelling determined which histopathological metric best predicted MWF and MTR in normal appearing and diffusely abnormal white matter, slowly expanding, inactive, remyelinated and ischemic lesions.

Both MWI measures correlated well with each other and histology across regions, reflecting the different stages of MS pathology. MTR data showed a considerable influence of components other than myelin and a strong dependency on tissue storage duration. Both MRI and histology revealed increased myelin densities in inactive compared with slowly expanding lesions. Chronic inactive lesions harboured single scattered myelin fibres indicative of low-level remyelination. Mixed-effects modelling showed that smaller differences between white matter areas were linked to PLP densities and only to a smaller extent confounded by iron.

MWI reflects differences in myelin lipids and proteins across all levels of myelin densities encountered in MS, including low-level remyelination in chronic inactive lesions.
cardiovascular safety of COVID-19 vaccines in real-world studies: a systematic review and meta-analysis
Authors: Chang Yafei , Lv Guoli , Liu Chao , Luo Bin , Huang Erwen
Published: August 2022

Aims

To assess the association between COVID-19 vaccines and the risk of major adverse cardiovascular events (MACE) in the real world and to provide a reliable evidence-based basis for the cardiovascular safety of COVID-19 vaccines.

Methods

We conducted a comprehensive search in databases from January 1, 2020 to June 15, 2022 for observational studies, that included reporting of MACE and COVID-19 vaccines were included. Random-effects or fixed-effects models were used to estimate the pooled incidence rate and risk ratio of MACE after vaccination. Meta-regression, subgroup analyses, publication bias, sensitivity analyses were performed to evaluate the process and quality of meta-analysis.

Results

The analyses included data from 43 studies reporting of 16,978 cases, 28,451 cases, and 96,269 cases of myocarditis, myocardial infarction, and cardiac arrhythmia, respectively. The overall incidence rate was 14.8 events per million persons of myocarditis, and 1.73 and 9.6 events per 10,000 persons of myocardial infarction and cardiac arrhythmia after COVID-19 vaccination, respectively. Overall and subgroup analyses showed the increased risks of myocarditis associated with second dose (RR, 2.09; 95%CI: 1.59-2.58), third dose (RR, 2.02; 95%CI: 1.40-2.91), mRNA-1273 (RR, 3.13; 95%CI: 2.11-4.14), or BNT162b2 (RR, 1.57; 95%CI: 1.30-1.85) vaccination. The risk ratios of myocarditis events were more frequently in males than in females (3.44, 2.61-4.54), in younger than in older (2.20, 1.06-4.55). No significant increase risk of myocardial infarction (RR, 0.96; 95%CI: 0.84-1.08) or cardiac arrhythmia (RR, 0.98; 95%CI: 0.84-1.12) events was observed following vaccination. The risk of cardiovascular events (myocarditis, RR, 8.53; myocardial infarction, RR, 2.59; cardiac arrhythmia, RR, 4.47) after SARS-CoV-2 infection was much higher than after vaccination.

Conclusion

Although there is a risk of cardiovascular events following vaccination, the risk was much lower than that following SARS-CoV-2 infection. The benefits of COVID-19 vaccination to the population outweigh the risks in terms of cardiovascular safety assessment.
Combination Venetoclax and Selinexor Effective in Relapsed Refractory Multiple Myeloma with Translocation t(11;14)
Authors: Nguyen Nina , Chaudhry Sana , Totiger Tulasigeri M. , Diaz Robert , Roberts Evan , Montoya Skye , Pardo Gabriel , Pardo Alejandro , Afaghani Jumana , Affer Maurizio , Jahn Jacob , Bradley Terrence , Maura Francesco , Kazandjian Dickran , Bilbao Daniel , Chapman Jennifer , Landgren Ola , Hoffman James , Taylor Justin
Published: August 2022

Patients with multiple myeloma bearing translocation t(11;14) have recently been shown to benefit from the apoptosis-inducing drug venetoclax; however, the drug lacks FDA approval in multiple myeloma thus far due to a potential safety signal in the overall patient population. Selinexor is an inhibitor of nuclear export that is FDA-approved for patients with multiple myeloma refractory multiple lines of therapy. Here, we report that in four patients with multiple myeloma with t(11;14), the concomitant administration of venetoclax and selinexor was safe and associated with disease response. Moreover, the combination was synergistic in t(11;14) multiple myeloma cell lines and caused decreased levels of Cyclin D1 (which is overexpressed due to the CCND1-IGH fusion) when given in combination as compared to single agents. These data suggest that the combination of venetoclax and selinexor is effective and t(11;14) may serve as a therapeutic marker for response and target for future clinical trials.
Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation
Authors: Lan Chenyang , Kim Juhyeong , Ulferts Svenja , Aprile-Garcia Fernando , Anandamurugan Abhinaya , Grosse Robert , Sawarkar Ritwick , Reinhardt Aleks , Hugel Thorsten
Published: August 2022

The formation of biomolecular condensates underpins many cellular processes; however, our current understanding of condensate formation within cells is largely based on observing the final near-equilibrium condensate state. It is less clear how proteins behave before condensates form or at concentrations at which condensation does not occur in cells. Here, we use a combination of fluorescence microscopy and photobleaching analysis to quantify phase separation of negative elongation factor (NELF) in living and stressed cells. We use the recently reported system of stress-induced condensation of NELF in human nuclei as a model to study the behaviour of proteins before condensation. We find that pre-condensate heterogeneous clusters both grow and shrink and are not freely diffusing. Unexpectedly, we also find such small dynamic clusters in unstressed cells in which condensates do not form. We provide a categorisation of small and large clusters based on their dynamics and their response to p38 kinase inhibition. Overall, our data are best explained as non-classical nucleation with a flat free-energy landscape for clusters of a range of sizes and an inhibition of condensation.
Gene expression levels of the glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase platelet (PFKP) are good predictors of survival time, recurrence and risk of death in cervical cancer
Authors: Bolaños-Suárez Verónica , Alfaro Ana , Espinosa Ana María , Medina-Martínez Ingrid , Juárez Eligia , Villegas-Sepúlveda Nicolás , Gudiño-Zayas Marco , Gutiérrez-Castro América , Román-Bassaure Edgar , Salinas-Nieves María Eugenia , Bruno-Muñoz Sergio , Flores-Herrera Oscar , Berumen Jaime
Published: August 2022

Background

Up to 74% of patients with cervical cancer (CC) may experience recurrence after their treatment, and most of them are identified late when only the clinical parameters are used, which decreases their chances of recovery. Molecular markers can improve the prediction of clinical outcome and identify therapeutic targets in CC. Glycolysis is altered in 70% of CCs, so it could be a metabolic pathway in which molecular markers associated with the aggressiveness of CC can be identified.

Methods

The expression of 14 glycolytic genes was analyzed in 118 CC samples by microarrays, and only LDHA and PFKP were validated by qRT–PCR (n=58) and in second and third replicates by Western blotting (n=69) and immunohistochemistry (n=18).

Results

LDHA and PFKP were associated with poor overall survival [OS: LDHA HR=3.0 (95% CI= 1.1-8.2);p=2.9 × 10-2; PFKP HR=3.4 (95% CI= 1.1-10.5);p= 3.5 × 10-2] and disease-free survival [DFS: LDHA HR=2.7 (95% CI= 1.6-6.3);p=2.6 × 10-2] independent of FIGO clinical stage. The risk of death was greater when both biomarkers were overexpressed than when using only FIGO stage [HR =7 (95% CI 1.6-31.1,p=1.0 × 10-2) versus HR=8.1 (95% CI=2.6-26.1;p=4.3 × 10-4)] and increased exponentially as the expression of LDHA and PFKP increased.

Conclusions

LDHA and PFKP at the mRNA and protein levels were associated with poor overall survival, disease-free survival and increased risk of death of patients with CC regardless of FIGO stage. The measurement of expression of these two markers could be very useful to evaluate the clinical evolution and the risk of death from CC and to make better therapeutic decisions at the beginning of treatment.
The Parasite Intraerythrocytic Cycle and Human Circadian Cycle are Coupled During Malaria Infection
Authors: Motta Francis C. , McGoff Kevin , Moseley Robert C. , Cho Chun-Yi , Kelliher Christina M. , Smith Lauren M. , Ortiz Michael S. , Leman Adam R. , Campione Sophia A. , Devos Nicolas , Chaorattanakawee Suwanna , Uthaimongkol Nichaphat , Kuntawunginn Worachet , Thongpiam Chadin , Thamnurak Chatchadaporn , Arsanok Montri , Wojnarski Mariusz , Vanchayangkul Pattaraporn , Boonyalai Nonlawat , Smith Philip L. , Spring Michele , Jongsakul Krisada , Chuang Ilin , Harer John , Haase Steven B.
Published: August 2022

During infections with malaria parasitesP. vivax, patients exhibit rhythmic fevers every 48 hours. These fever cycles correspond with the time parasites take to traverse the Intraerythrocytic Cycle (IEC) and may be guided by a parasite-intrinsic clock. Different species ofPlasmodiahave cycle times that are multiples of 24 hours, suggesting they may be coordinated with the host circadian clock. We utilized anex vivoculture of whole blood from patients infected withP. vivaxto examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome. Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC were correlated across multiple patients, suggesting that the cycles are coupled. In mouse model systems, host-parasite cycle coupling appears to provide a selective advantage for the parasite. Thus, understanding how host and parasite cycles are coupled in humans could enable anti-malarial therapies that disrupt this coupling.
Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons
Authors: Knowles Sara J. , Holter Michael C. , Li Guohui , Bjorklund George R. , Rees Katherina P. , Martinez-Fuentes Johan S. , Nishimura Kenji J. , Afshari Ariana E. , Fry Noah , Stafford April M , Vogt Daniel , Mangone Marco , Anderson Trent , Newbern Jason M.
Published: August 2022

The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. WhileErk1/2inactivation does not alter CIN number, we discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression inErk1/2mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.
Seasonal eDNA-based monitoring ofBatrachochytrium dendrobatidisand amphibian species in Norway
Authors: Ahmed Omneya , Andersson Johan , Martin-Sanchez Pedro M. , Eiler Alexander
Published: August 2022

Freshwaters represent the most threatened environments with regard to biodiversity loss and therefore there is a need for national monitoring programs to effectively document species distribution and evaluate potential risks for vulnerable species. The monitoring of species for effective management practices is, however, challenged by insufficient data acquisition when using traditional methods. Here we present the application of environmental DNA (eDNA) metabarcoding of amphibians in combination with quantitative PCR assays for an invasive pathogenic chytrid species (Batrachochytrium dendrobatidis-Bd), a potential threat to endemic and endangered amphibian species. Statistical comparison of amphibian species detection using either traditional or eDNA-based approaches showed weak correspondence. By tracking the distribution ofBdover three years, we concluded that the risk for amphibian extinction is low sinceBdwas only detected at five sites where multiple amphibians were present over the sampled years. Our results show that eDNA-based detection can be used for simultaneous monitoring of amphibian diversity and the presence of amphibian pathogens at the national level in order to assess potential species extinction risks and establish effective management practices. As such our study represents suggestions for a national monitoring program based on eDNA.
Representing experience over time: sustained sensory patterns and transient frontroparietal patterns
Authors: Vishne Gal , Gerber Edden M. , Knight Robert T. , Deouell Leon Y.
Published: August 2022

Instances of sustained stationary sensory input are ubiquitous. However, previous work focused almost exclusively on the transient onset responses. This presents a critical challenge for neural theories of consciousness, which should account for the full temporal extent of experience. Here we use intracranial recordings from human patients viewing diverse images in multiple durations. In sensory regions, we reveal that despite dramatic changes in activation magnitude, the distributed representation of categories and exemplars remains sustained and stable. In contrast, in frontoparietal regions we find transient content representation at stimulus onset. Our results highlight the connection between the anatomical and temporal correlates of experience. To the extent perception is sustained, it may rely on sensory representations, and to the extent it is discrete, centered on perceptual updating, it may rely on frontoparietal representations.
Nucleation and spreading rejuvenate polycomb domains every cell cycle
Authors: Veronezi Giovana M. B. , Ramachandran Srinivas
Published: August 2022

Gene repression by the polycomb pathway is essential for proper development in metazoans. Polycomb domains, characterized by trimethylation of histone H3 (H3K27me3), carry the memory of repression through successive cell divisions, and hence, need to be maintained to counter dilution during replication of parental H3K27me3 with unmodified nascent H3. Yet, how locus-specific H3K27me3 is maintained through replication is unknown. To understand H3K27me3 recovery post-replication, we first defined nucleation sites within each polycomb domain in mouse embryonic stem cells. Then, to track H3K27me3 dynamics in unperturbed cells during replication, we developed CUT&Flow, which maps H3K27me3 domains as a function of the cell cycle stage. Using CUT&Flow, we show that post-replication rejuvenation of polycomb domains occurs by nucleation and spreading, using the same nucleation sites used duringde novodomain formation. By using subunit-specific inhibitors of the PRC2 complex, we find that PRC2 need not rely on pre-existing H3K27me3 to target nucleation sites post-replication. The timing of nucleation relative to the cell cycle reflects the combination of replication timing and H3K27me3 deposition kinetics derived fromde novodomain formation. Thus, competition between H3K27me3 deposition and nucleosome turnover drives bothde novodomain formation and maintenance during every cell cycle.
Do Newly Born Orphan Proteins Resemble Never Born Proteins? A Study Using Three Deep Learning Algorithms
Authors: Liu Jing , Yuan Rongqing , Shao Wei , Wang Jitong , Silman Israel , Sussman Joel L.
Published: August 2022

‘Newly Born’proteins, devoid of detectable homology to any other proteins, known as orphan proteins, occur in a single species or within a taxonomically restricted gene family. They are generated by expression of novel Open Reading Frames, and appear throughout evolution. We were curious if the three recently developed programs for predicting protein structures, viz., AlphaFold2, RoseTTAFold, and ESMFold, might be of value for comparison of such ‘Newly Born’proteins to random polypeptides with amino acid content similar to that of native proteins, which have been called ‘Never Born’ proteins. The programs were used to compare the structures of two sets of ‘Never Born’proteins that had been expressed – Group 1, which had been shown experimentally to possess substantial secondary structure, and Group 3, which had been shown to be intrinsically disordered. Overall, the models generated were scored as being of low quality but revealed some general principles. Specifically, all four members of Group 1 were predicted to be compact by all three algorithms. The members of Group 3 were predicted to be very extended, as would be expected for intrinsically disordered proteins. The three programs were then used to predict the structures of three orphan proteins whose crystal structures had been solved, two of which display novel folds. Finally, they were used to predict the structures of seven orphan proteins with well-identified biological functions, whose 3D structures are not known. Two proteins, which were predicted to be disordered based on their sequences, are predicted by all three structure algorithms to be extended structures. The other five were predicted to be compact structures with two exceptions in the case of AlphaFold2. All three prediction algorithms make remarkably similar and high-quality predictions for one large protein, HCO_11565, from a nematode. It is conjectured that this is due to many homologs in the taxonomically restricted family of which it is a member and to the fact that theDaliserver revealed several non-related proteins with similar folds. Overall, orphan and taxonomically restricted proteins are often predicted to have compact 3D structures, sometimes with a novel fold that is a consequence of their novel sequences, which are associated with the appearance of new biological functions.
Confirming the Pro-longevity Effects of H3K4me3-deficient set-2 Mutants in Extending Lifespan in C. elegans
Authors: Silva-García Carlos G. , Mair William B.
Published: August 2022

The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. Knockdown or partial loss-of-function of SET-2, a member of the COMPASS complex, extends the lifespan of worms. However, recent observations suggested that full loss of SET-2 methyltransferase activity via deletion of its active site reduces lifespan, indicating the degree of COMPASS inhibition may be critical to its effects on aging. To further explore these inconsistencies, we examined set-2 longevity across a range of interventions from weak to full inhibition. Via CRISPR/Cas9 genome-editing, we made two new set-2 mutants, a new genocopy of the most commonly used set-2(ok952) allele for mild set-2 inhibition, and a full set-2 genomic deletion. We found that both new strains (partial and null) and RNAi show a lifespan extension in C. elegans fed HT115 E. coli. However, neither mutant was long-lived in C. elegans fed OP50-1 E. coli. These data confirm that the previous lifespan extension observed in set-2(ok952) mutants was indeed the result of set-2 inhibition (and not a secondary linked mutation generated in the original strain). These data also indicate that a diet-dependent mechanism might contribute to the regulation of lifespan under H3K4me3 deficiency and highlight how COMPASS-mediated longevity involves a complex interaction between chromatin state and environment.
Digital color-coded molecular barcoding reveals dysregulation of common FUS and FMRP targets in soma and neurites of ALS mutant motoneurons
Authors: Garone Maria Giovanna , Salerno Debora , Rosa Alessandro
Published: August 2022

Mutations in RNA binding proteins (RBPs) have been linked to the motor neuron disease amyotrophic lateral sclerosis (ALS). Extensive auto-regulation, cross-regulation, cooperation and competition mechanisms among RBPs are in place to ensure proper expression levels of common targets, often including other RBPs and their own transcripts. Moreover, several RBPs play a crucial role in the nervous system by localizing target RNAs in specific neuronal compartments. These include the RBPs FUS, FMRP and HuD. ALS mutations in a given RBP are predicted to produce a broad impact on such delicate equilibrium. Here we studied the effects of the severe FUS-P525L mutation on common FUS and FMRP targets. Expression profiling by digital color-coded molecular barcoding in cell bodies and neurites of human iPSC-derived motor neurons revealed altered levels of transcripts involved in cytoskeleton, neural projection and synapses. One of the common targets is HuD, which is upregulated because of the loss of FMRP binding to its 3’UTR due to mutant FUS competition. Notably, many genes are commonly altered upon FUS mutation or HuD overexpression, suggesting that a substantial part of the effects of mutant FUS on the motor neuron transcriptome could be due to HuD gain-of-function. Among altered transcripts we also identified other common FUS and FMRP targets, namely MAP1B, PTEN, and AP2B1, that are upregulated upon loss of FMRP binding on their 3’UTR in FUS-P525L motor neurons. This work demonstrates that the impairment of FMRP function by mutant FUS might alter the expression of several genes, including new possible biomarkers and therapeutic targets for ALS.
Coordinated cadherin functions sculpt respiratory motor circuit connectivity
Authors: Vagnozzi Alicia N. , Moore Matthew T. , Lin Minshan , Brozost Elyse M. , Ritesh KC , Agarwal Aambar , Schwarz Lindsay A. , Duan Xin , Zampieri Niccolò , Landmesser Lynn T. , Philippidou Polyxeni
Published: August 2022

Breathing, and the motor circuits that control it, are essential for life. At the core of respiratory circuits are Dbx1-derived interneurons, which generate the rhythm and pattern of breathing, and phrenic motor neurons (MNs), which provide the final motor output that drives diaphragm muscle contractions during inspiration. Despite their critical function, the principles that dictate how respiratory circuits assemble are unknown. Here we show that coordinated activity of a type I cadherin (N-cadherin) and type II cadherins (Cadherin-6, −9, and −10) is required in both MNs and Dbx1-derived neurons to generate robust respiratory motor output. Both MN- and Dbx1-specific cadherin inactivation during a critical developmental window results in perinatal lethality due to respiratory failure and a striking reduction in phrenic MN bursting activity. This combinatorial cadherin code is required to establish phrenic MN cell body and dendritic topography; surprisingly, however, cell body position appears to be dispensable for the targeting of phrenic MNs by descending respiratory inputs. Our findings demonstrate that type I and type II cadherins function cooperatively throughout the respiratory circuit to generate a robust breathing output and reveal novel strategies that drive the assembly of motor circuits.
Bayesian models for event-related potentials time-series and electrode correlations estimation
Authors: Busch-Moreno Simon , Fu Xiao , Roesch Etienne B.
Published: August 2022

Recent developments on Bayesian inference and prediction for effects on event-related potentials (ERPs) stem from a wide variety of methods, including machine learning, multilevel models, and others. However, few of these approaches make use of clear estimates of the ERP voltage across time and across space (scalp). In the present article, via an iterative process, we propose Gaussian random walk (GRW) models that can estimate voltage uncertainty across time and also provide correlation matrices across electrodes. We apply these models to real ERP data from a P3b paradigm as an example. We discuss results in terms of past and current literature of both ERP estimation and electroencephalography analysis in general.
Mouse B2 SINE elements function as IFN-inducible enhancers
Authors: Horton Isabella , Kelly Conor J. , Simpson David M. , Chuong Edward B.
Published: August 2022

Regulatory networks underlying innate immunity continually face selective pressures to adapt to new and evolving pathogens. Transposable elements (TEs) can affect immune gene expression as a source of inducible regulatory elements, but the significance of these elements in facilitating evolutionary diversification of innate immunity remains largely unexplored. Here, we investigated the mouse epigenomic response to type II interferon (IFN) signaling and discovered that elements from a subfamily of B2 SINE (B2_Mm2) contain STAT1 binding sites and function as IFN-inducible enhancers. CRISPR deletion experiments in mouse cells demonstrated that a B2_Mm2 element has been co-opted as an IFN-inducible enhancer of Dicer1 and the nearby Serpina3f and Serpina3g genes. The rodent-specific B2 SINE family is highly abundant in the mouse genome and elements have been previously characterized to exhibit promoter, insulator, and non-coding RNA activity. Our work establishes a new role for B2 elements as inducible enhancer elements that influence mouse immunity and exemplifies how lineage-specific TEs can facilitate evolutionary divergence of innate immune regulatory networks.
Antagonist tendon vibration dampens estimates of persistent inward currents in motor units of the human lower limb
Authors: Pearcey Gregory E P , Khurram Obaid U , Beauchamp James A , Negro Francesco , Heckman Charles J
Published: August 2022

We can readily measure motoneuron discharge patterns in humans due to the one-to-one spike relation between motoneuron and muscle fiber action potentials, which allows us to make inferences about motor commands. Persistent inward currents (PICs), which provide gain control of motoneuronal output, are facilitated by monoaminergic input from the brainstem. This monoaminergic input is greatly diffuse, but resulting PICs are highly sensitive to inhibitory inputs. Antagonist muscle stretch, and thus Ia input from the antagonist decreases PIC magnitudes in the decerebrate cat. In the present study, we explored whether estimates of PICs are altered with vibratory input to antagonist muscles in humans. MUs of the tibialis anterior (TA), soleus (SOL), and medial gastrocnemius (MG) were discriminated using high-density surface electromyography and convolutive blind source separation. We estimated PICs using the paired MU analysis technique, which quantifies discharge rate hysteresis (ΔF) by comparing the discharge rate of a lower-threshold MU at the onset and offset of a higher-threshold MU. Participants performed isometric plantarflexion and dorsiflexion contractions to a peak of 30% of maximal voluntary contraction, with 10 s ascending and descending phases. In half of the trials, we applied vibration to the antagonist tendon and found that ΔF in agonist MUs decreased in the presence of vibration. These findings suggest that inhibition from the antagonist muscle, most likely Ia reciprocal inhibition, can reduce discharge rate hysteresis. This provides insights about non-invasive methods potentially capable of dampening PICs in hyperexcitable motoneurons, which are manifest in some neurological impairments.

KEY POINTS

Persistent inward currents in motoneurons amplify synaptic inputs and thus have a major impact on motor unit firing patterns.

We show that sustained vibration to the antagonist tendon reduces estimates of persistent inward currents (ΔF) of the contracting muscle in both the plantarflexors and dorsiflexors.

These findings provide evidence for the important role of sensory input in the control of persistent inward currents in the human.

Reciprocal inhibition may help refine neuromodulatory commands to tailor motor unit activation to diverse movement patterns and specific tasks, and loss of inhibition may exacerbate symptoms of neurological impairment.
Fast, accurate local ancestry inference with FLARE
Authors: Browning Sharon R. , Waples Ryan K. , Browning Brian L.
Published: August 2022

Local ancestry is the source ancestry at each point in the genome of an admixed individual. Inferred local ancestry is used for admixture mapping and population genetic analyses. We present FLARE (Fast Local Ancestry Estimation), a new method for local ancestry inference. FLARE achieves high accuracy through the use of an extended Li and Stephens model, and it achieves exceptional computational performance through incorporation of computational techniques developed for genotype imputation. Memory requirements are reduced through on-the-fly compression of reference haplotypes and stored checkpoints. Computation time is reduced through the use of composite reference haplotypes. These techniques allow FLARE to scale to data sets with hundreds of thousands of sequenced individuals and to provide superior accuracy on large-scale data. FLARE is freely available at https://github.com/browning-lab/flare.
Acquirement of the autonomic nervous system modulation evaluated by heart rate variability in medaka (Oryzias latipes)
Authors: Watanabe-Asaka Tomomi , Niihori Maki , Igarashi Kento , Oda Shoji , Iwasaki Ken-ichi , Katada Yoshihiko , Yamashita Toshikazu , Sonobe Hiroki , Terada Masahiro , Baba Shoji A. , Mitani Hiroshi , Mukai Chiaki
Published: August 2022

Small teleosts have recently been established as models of human diseases. However, measuring heart rate by electrocardiography is highly invasive for small fish. The physiological nature and function of vertebrate autonomic nervous system (ANS) modulation of the heart has traditionally been investigated in larvae with an incompletely developed ANS or in anesthetized adults, whose ANS activity may possibly be disturbed under anesthesia. Here, we defined the frequency characteristics of heart rate variability (HRV) modulated by the ANS from observations of heart movement in high-speed movie images and changes in ANS regulation under environmental stimulation in unanesthetized adult medaka (Oryzias latipes), a small teleost.

The HRV was significantly reduced by atropine (1 mM) in the 0.25 – 0.65 Hz and by propranolol (100 μM) at 0.65–1.25 Hz range, suggesting that HRV in adult medaka is modulated by both the parasympathetic and sympathetic nervous systems within these frequency ranges. Such modulations of HRV by the ANS were remarkably suppressed in anesthetized adult medaka. Continuous exposure to light suppressed HRV only in the 0.25 – 0.65 Hz range, indicating parasympathetic withdrawal. The power of HRV increased along developmental processes. These results suggest that ANS modulation of the heart in adult medaka is frequency-dependent phenomenon, and that the impact of long-term environmental stimuli on ANS activities can be precisely evaluated in unanesthetized adult fish using this method.
Enhancing the spectral range of plant and bacterial Light-Harvesting pigment-protein complexes with various synthetic chromophores incorporated into lipid vesicles
Authors: Hancock Ashley M. , Swainsbury David J. K. , Meredith Sophie A. , Morigaki Kenichi , Hunter C. Neil , Adams Peter G.
Published: August 2022

The Light-Harvesting (LH) pigment-protein complexes found in photosynthetic organisms have the role of absorbing solar energy with high efficiency and transferring it to reaction centre complexes. LH complexes contain a suite of pigments that each absorb light at specific wavelengths, however, the natural combinations of pigments within any one protein complex do not cover the full range of solar radiation. Here, we provide an in-depth comparison of the relative effectiveness of five different organic “dye” molecules (Texas Red, ATTO, Cy7, Dil, DiR) for enhancing the absorption range of two different LH membrane protein complexes (the major LHCII from plants and LH2 from purple phototrophic bacteria). Proteoliposomes were self-assembled from defined mixtures of lipids, proteins and dye molecules and their optical properties were quantified by absorption and fluorescence spectroscopy. Both lipid-linked dyes and alternative lipophilic dyes were found to be effective excitation energy donors to LH protein complexes, without the need for direct chemical or generic modification of the proteins. The Förster theory parameters (e.g., spectral overlap) were compared between each donor-acceptor combination and found to be good predictors of an effective dye-protein combination. At the highest dye-to-protein ratios tested (over 20:1), the effective absorption strength integrated over the full spectral range was increased to ~180% of its natural level for both LH complexes. Lipophilic dyes could be inserted into pre-formed membranes although their effectiveness was found to depend upon favourable physicochemical interactions. Finally, we demonstrated that these dyes can also be effective at increasing the spectral range of surface-supported models of photosynthetic membranes, using fluorescence microscopy. The results of this work provide insight into the utility of self-assembled lipid membranes and the great flexibility of LH complexes for interacting with different dyes.
Assessing the importance of demographic risk factors across two waves of SARS-CoV-2 using fine-scale case data
Authors: Wood A.J. , Sanchez A.R. , Bessell P.R. , Wightman R. , Kao R.R.
Published: August 2022

For the long term control of an infectious disease such as COVID-19, it is crucial to identify the most likely individuals to become infected and the role that differences in demographic characteristics play in the observed patterns of infection. As high-volume surveillance winds down, testing data from earlier periods are invaluable for studying risk factors for infection in detail. Observed changes in time during these periods may then inform how stable the pattern will be in the long term.

To this end we analyse the distribution of cases of COVID-19 across Scotland in 2021, where the location (census areas of order 500–1,000 residents) and reporting date of cases are known. We consider over 450,000 individually recorded cases, in two infection waves triggered by different lineages: B.1.1.529 (“Omicron”) and B.1.617.2 (“Delta”). We use random forests, informed by measures of geography, demography, testing and vaccination. We show that the distributions are only adequately explained when considering multiple explanatory variables, implying that case heterogeneity arose from a combination of individual behaviour, immunity, and testing frequency.

Despite differences in virus lineage, time of year, and interventions in place, we find the risk factors remained broadly consistent between the two waves. Many of the observed smaller differences could be reasonably explained by changes in control measures.