bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal exposure to persistent organic pollutants and changes in infant growth and childhood growth trajectories
Authors: Cai Anran , Portengen Lützen , Govarts Eva , Martin Laura Rodriguez , Schoeters Greet , Legler Juliette , Vermeulen Roel , Lenters Virissa , Remy Sylvie
Published: September 2022

Background

Children are born with a burden of persistent organic pollutants (POPs) which may have endocrine disrupting properties and have been postulated to contribute to the rise in childhood obesity. The current evidence is equivocal, which may be because many studies investigate the effects at one time point during childhood. We assessed associations between prenatal exposure to POPs and growth during infancy and childhood.

Methods

We used data from two Belgian cohorts with cord blood measurements of five organochlorines [(dichlorodiphenyldichloroethylene (p,p’-DDE), hexachlorobenzene (HCB), polychlorinated biphenyls (PCB-138, -150, -180)] (N = 1,418) and two perfluoroalkyl substances [perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)] (N = 346). We assessed infant growth, defined as body mass index (BMI) z-score change between birth and 2 years, and childhood growth, characterized as BMI trajectory from birth to 8 years. To evaluate associations between POP exposures and infant growth, we applied a multi-pollutant approach, using penalized elastic net regression with stability selection, controlling for covariates. To evaluate associations with childhood growth, we used single-pollutant linear mixed models with random effects for child individual, parametrized using a natural cubic spline formulation.

Results

Prenatal exposures to p,p’-DDE and PCB-153 were selected in elastic net models for infant growth analysis, but the selections were unstable. No clear association between any of the exposures and longer-term childhood growth trajectories was observed. We did not find evidence of effect modification by child sex.

Conclusion

Our results suggest that prenatal exposure to PCB-153 and p,p’-DDE may affect infant growth in the first two years, with little evidence of more persistent effects.
GraMDTA: Multimodal Graph Neural Networks for Predicting Drug-Target Associations
Authors: Yella Jaswanth K. , Ghandikota Sudhir K. , Jegga Anil G.
Published: September 2022

Finding novel drug-target associations is vital for drug discovery. However, screening millions of small molecules for a select target protein is challenging. Several computational approaches have been developed in the past using Machine learning methods for computational drug-target association (DTA) prediction predominantly use structural data of drugs and proteins. Some of these approaches use knowledge graph networks and link prediction. To the best of our knowledge there have been no approaches that use both structural learning that offers molecular-based representations and knowledge graph-based learning which offers interaction-based representations for DTA discovery. Based on the premise that multimodal sources of information acting complimentarily could improve the robustness of DTA predictions, we developed GraMDTA, a multimodal graph neural network that learns both structural and knowledge graph representations utilizing multi-head attention to fuse the multimodal representations. We compare GraMDTA with other computational approaches for DTA prediction to demonstrate the power of multimodal fusion for discovery of DTA.
Coenzyme A governs proinflammatory macrophage metabolism
Authors: Timblin Greg. A. , Tharp Kevin. M. , ten Hoeve Johanna , Kantner Daniel S. , Baydemir Ilayda , Noel Eric A. , Khantwal Chandra , Singh Pankaj K. , Farahzad Joshua N. , Domínguez-Andrés Jorge , Vance Russell E. , Snyder Nathaniel W. , Weaver Valerie M.
Published: September 2022

Toll-like receptor (TLR)-dependent macrophage responses rely on acute increases in oxidative mitochondrial glucose metabolism that epigenetically support rapid proinflammatory transcriptional programming via histone acetylation. Subsequent suppression of oxidative metabolism restrains this metabolic-epigenetic support of proinflammatory gene transcription to enforce tolerance, an immunosuppressed state of innate immune memory. Identifying biology that promotes or counters these metabolic-epigenetic changes will inform therapeutic approaches to influence proinflammatory, antimicrobial, and immunosuppressed myeloid cellular states. Here, we demonstrate that Coenzyme A (CoA) is a “metabolic adjuvant”, as supplying exogenous CoA to macrophages both enhances the magnitude of TLR-driven proinflammatory and antimicrobial responses, and reverse tolerance, via promotion of oxidative metabolism. Extracellular CoA, which we isotopically trace to show its direct uptake by macrophages, works synergistically with tonic TLR signaling, which we demonstrate is a critical regulator of nutrient uptake, metabolism, histone acetylation, and gene expression in macrophages. Together, TLR signaling and exogenous CoA promote mitochondrial glucose oxidation, acetyl-CoA production, and TLR target gene-specific histone acetylation, enhancing metabolic-epigenetic support of proinflammatory transcriptional programming. Exogenous CoA unlocks tumor-associated macrophage (TAM)-dependent TLR agonist anti-tumor activity in anin vivobreast cancer model, and promotes macrophage restriction of the intracellular bacterial pathogenLegionella pneumophila in vitrovia anIrg1-dependent antimicrobial state of CoA-augmented itaconate biosynthesis. Our findings demonstrate direct acquisition of intact extracellular CoA, and the ability of this exogenously supplemented metabolic cofactor to augment a key oxidative metabolic-epigenetic pathway supporting proinflammatory and antimicrobial macrophage phenotypes. This may inform host-targeted metabolic adjuvant therapies to reverse myeloid immunosuppression.
Exercise performance is not improved in mice with skeletal muscle deletion of natriuretic peptide clearance receptor
Authors: Jia Brigitte , Hasse Alexander , Shi Fubiao , Collins Sheila
Published: September 2022

Natriuretic peptides (NP), including atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), play essential roles in regulating blood pressure, cardiovascular homeostasis, and systemic metabolism. One of the major metabolic effects of NP is manifested by their capacity to stimulate lipolysis and the thermogenesis gene program in adipocytes, however, their metabolic effect on skeletal muscle is much less appreciated. There are three NP receptors (NPR): NPRA, NPRB, and NPRC, and all three NPR genes are expressed in C2C12 myocytes. Treatment with either ANP, BNP, or CNP evokes the cGMP signaling process in C2C12 myocytes. We then generated a genetic model with Nprc gene deletion in skeletal muscle and tested whether enhancing NP signaling by preventing its clearance in skeletal muscle would improve exercise performance in mice. Under sedentary conditions, Nprc skeletal muscle knockout (MKO) mice showed comparable exercise performance to their floxed littermates in terms of maximal running velocity and total endurance running time. Eight weeks of voluntary running-wheel training in a young cohort increased exercise performance, but no significant differences were observed in MKO compared with control mice. Furthermore, 6-weeks of treadmill training in a relatively aged cohort also increased exercise performance compared with their baseline but did not result in an improvement in MKO mice compared with the controls. In summary, our study suggests that NP signaling is potentially important in myocytes but its function in skeletal muscle in vivo needs to be further studied in alternative physiological conditions or with new genetic mouse models.
A Comprehensive Enumeration of the Human Proteostasis Network. 1. Components of Translation, Protein Folding, and Organelle-Specific Systems
Authors:   The Proteostasis Consortium,   Overall coordination, Elsasser Suzanne , Elia Lisa P. , Morimoto Richard I. , Powers Evan T. ,   Harvard Medical School group (analysis), Finley Daniel ,   University of California, San Francisco and Gladstone Institutes group I (chaperones, analysis), Mockler Eric , Lima Leandro , Finkbeiner Steve ,   University of California, San Francisco group II (chaperones, analysis), Gestwicki Jason E. ,   Northwestern University group (chaperones, analysis), Stoeger Thomas , Cao Kedi ,   The Scripps Research Institute group (chaperones, endoplasmic reticulum proteostasis, mitochondrial proteostasis, analysis), Garza Dan , Kelly Jeffery W. ,   Stanford University group (chaperones, translation, mitochondrial proteostasis), Collier Miranda , Rainbolt T. Kelly , Taguwa Shuhei , Chou Ching-Chieh , Aviner Ranen , Barbosa Natália , Morales-Polanco Fabián , Masto Vincent B. , Frydman Judith
Published: September 2022

The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,500 genes that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology with direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. Here, we provide a curated list of 959 unique genes that comprise the protein synthesis machinery, chaperones, folding enzymes, systems for trafficking proteins into and out of organelles, and organelle-specific degradation systems. In subsequent manuscripts, we will delineate the human autophagy-lysosome pathway, the ubiquitin-proteasome system, and the proteostasis networks of model organisms.
PIP2 and Ca2+ regulation of TMEM16A currents in excised inside-out patches
Authors: Tembo Maiwase , Lara-Santos Crystal , Rosenbaum Joel C. , Carlson Anne E.
Published: September 2022

The Ca2+ activated Cl− channel formed by transmembrane member 16A (TMEM16A) is broadly expressed and regulates diverse processes. In addition to Ca2+, TMEM16A channels require the acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) to open. Like other channels regulated by PI(4,5)P2, TMEM16A-conducted currents recorded in excised patches slowly decay overtime. Here we assessed how intracellular Ca2+ alters the rate of this current rundown, using the channels endogenously expressed in oocytes from the African clawed frog, Xenopus laevis. We found that in excised, inside-out patches, the concentration of applied Ca2+ alters the rate of rundown, with high Ca2+ concentrations speeding rundown by activating membrane associated phospholipase C (PLC). Together, these results clarify our understanding of how Ca2+ regulates both TMEM16A directly, and targets PLC to regulate the membrane PI(4,5)P2 content.
Neuronal C-Reactive Protein Mediates Neuropathic Pain by Activating Nociceptive FcγRI-Coupled Signaling
Authors: Liu Fan , Su Si , Zhang Li , Fang Yehong , Cui Huan , Sun Jianru , Xie Yikuan , Ma Chao
Published: September 2022

Background

Neuropathic pain is difficult to treat in clinical practice, and the underlying mechanisms are insufficiently elucidated. Previous studies have demonstrated that Fcγ receptor I (FcγRI) is expressed in the neurons of the dorsal root ganglion (DRG) and may be involved in chronic pain.

Methods

Chronic constriction injury (CCI) was used to induce neuropathic pain in rats. Primary neuron-specificFcgr1conditional knockout (CKO) rats were established by crossing rats carrying aFcgr1loxP+/+with thePirtCRE+line. Behavioral and molecular studies were conducted to evaluate the differences between wild-type and CKO rats after CCI.

Results

We first revealed that CCI activated neuronal FcγRI-related signaling in the DRG. CCI-induced neuropathic pain was alleviated in CKO rats. C-reactive protein (CRP) was increased in the DRG after nerve injury. Intraganglionic injection or overexpression of the recombinant CRP protein in the DRG evoked pain accompanied and activated neuronal FcγRI. CRP-evoked pain was significantly reduced in CKO rats. Furthermore, microinjection of native IgG into the DRG alleviated neuropathic pain and the activation of neuronal FcγRI-related signaling.

Conclusions

Our results indicate that the activation of neuronal CRP/FcγRI-related signaling plays an important role in the development of pain in CCI. Our findings may provide novel insights into the neuroimmune responses after peripheral nerve injury and might suggest potential therapeutic targets for neuropathic pain.
Single-cell multi-cohort dissection of the schizophrenia transcriptome
Authors: Ruzicka W. Brad , Mohammadi Shahin , Fullard John F. , Davila-Velderrain Jose , Subburaju Sivan , Tso Daniel Reed , Hourihan Makayla , Jiang Shan , Lee Hao-Chih , Bendl Jaroslav ,   PsychENCODE Consortium, Voloudakis Georgios , Haroutunian Vahram , Hoffman Gabriel E. , Roussos Panos , Kellis Manolis
Published: September 2022

Schizophrenia is a prevalent mental illness with a high societal burden, complex pathophysiology, and diverse genetic and environmental etiology. Its complexity, polygenicity, and heterogeneity have hindered mechanistic elucidation and the search for new therapeutics. We present a single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across two independent cohorts, one deeply profiling 48 subjects (361,996 cells), and the other broadly profiling 92 subjects (106,761 cells). We identified 25 cell types that we used to produce a high-resolution atlas of schizophrenia-altered genes and pathways. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Differentially expressed gene sets implicate a coherently expressed module of trans-acting regulatory factors involved in neurodevelopment and genetically associated with schizophrenia risk. Transcriptional alterations significantly overlapped with known genetic risk factors, suggesting convergence of rare and common genomic variants on reproducible neuronal population specific alterations in schizophrenia. The severity of transcriptional pathology segregated two populations of schizophrenia subjects in a manner consistent with the expression of specific transcriptional patterns marked by genes involved in synaptic function and chromatin dynamics. Our results provide a high-resolution single cell atlas linking transcriptomic changes within specific cell populations to etiological genetic risk factors, contextualizing established knowledge within the cytoarchitecture of the human cortex and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.
ACQuA: Arrhythmia Classification with Quasi-Attractors
Authors: Rudman William , Merullo Jack , Mercurio Laura , Eickhoff Carsten
Published: September 2022

In recent years, deep learning has redefined algorithms for detecting cardiac abnormalities. However, many state of the art algorithms still rely on calculating handcrafted features from a given heart signal that are then fed into shallow 1D convolutional networks or transformer architectures. We propose ACQuA (Anomaly Classification with Quasi Attractors), a task agnostic algorithm that can be used in a wide variety of cardiac settings, from classifying cardiac arrhythmias from ECG signals to detecting heart murmurs from PCG signals. Using theorems from dynamical analysis and topological data analysis, we create informative attractor images that 1) are human distinguishable and 2) can be used to train small, off the shelf deep neural networks for anomaly classification. In the George B. Moody 2022 Challenge, we receive an official score of 0.433 (263/305) for murmur classification and a score of 12616 (208/305) for outcome classification. Additionally, we evaluate our model on the CinC 2017 Challenge data that tasks practitioners to classify cardiac arrhythmias from ECG signals. On the CinC 2017 Challenge data, we improve upon the winning F1 scores by approximately 14% on the hidden validation data.
Federal Funding and Citation Metrics of Biomedical Research in the USA
Authors: Ioannidis John P.A. , Hozo Iztok , Djulbegovic Benjamin
Published: September 2022

Both citation and funding metrics converge in shaping current perceptions of academic success. We aimed to evaluate what proportion of the most-cited USA-based biomedical scientists are funded by biomedical federal agencies and whether funded scientists are more cited than not funded ones. We linked a Scopus-based database on top-cited researchers (n=75,316 USA-based) and the NIH RePORTER database of 33 biomedical federal agencies (n=204,603 grant records) with matching based on name and institution. The 40,887 USA-based top-cited scientists who were allocated to any of 69 scientific subfields highly related to biomedicine were considered in the main analysis. The proportion of USA-based top-cited biomedical scientists (based on career-long citation impact) who had received any federal funding from biomedical research agencies was 63% for any funding (1996-2022), 21% for recent funding (2015-2022), and 14% for current funding (2021-2022). Respective proportions were 65%, 31%, and 21%, when top-cited scientists based on recent single year impact were considered. There was large variability across scientific subfields. No subfield had more than 31% of its top-cited USA-based scientists (career-long impact) currently funded. Funded top-cited researchers were overall more cited than non-funded top-cited scientists, e.g. mean (median) 14,420 (8983) versus 8,445 (4613) (p<0.001) and a substantial difference remained (, after adjusting for subfield and years since first publication. Differences were more prominent in some specific biomedical subfields. Overall, biomedical federal funding has offered support to approximately two-thirds of the top-cited biomedical scientists at some point during the last quarter century, but only a small minority of top-cited scientists have current federal biomedical funding. The large unevenness across subfields needs to be addressed with ways that improve equity, efficiency, excellence, and translational potential.
RedRibbon: A new rank-rank hypergeometric overlap pipeline to compare gene and transcript expression signatures
Authors: Piron Anthony , Szymczak Florian , Alvelos Maria Inês , Defrance Matthieu , Lenaerts Tom , Eizirik Décio L. , Cnop Miriam
Published: September 2022

Motivation

High throughput omics technologies have generated a wealth of large protein, gene and transcript datasets that have exacerbated the need for new methods to analyse and compare big datasets. Rank-rank hypergeometric overlap is an important threshold-free method to combine and visualize two ranked lists of P-values or fold-changes, usually from differential gene expression analyses. Here, we introduce a new rank-rank hypergeometric overlap-based method aimed at both gene level and alternative splicing analyses at transcript or exon level, hitherto unreachable as transcript numbers are an order of magnitude larger than gene numbers.

Results

We tested the tool on synthetic and real datasets at gene and transcript levels to detect correlation and anti-correlation patterns and found it to be fast and accurate, even on very large datasets thanks to an evolutionary algorithm based minimal P-value search. The tool comes with a ready-to-use permutation scheme allowing the computation of adjusted P-values at low time cost. Additionally, the package is a drop-in replacement to previous packages as a compatibility mode is included, allowing to re-run older studies with close to no change to existing pipelines. RedRibbon holds the promise to accurately extricate detailed information from large analyses.

Availability

RNA-sequencing datasets are available through the Gene Expression Omnibus (GEO) portal with accession numbers GSE159984, GSE133218, GSE137136, GSE98485, GSE148058 and GSE108413. The C libraries and R package code are open to the community with a permissive licence (GPL3) and available for download from GitHub https://github.com/antpiron/ale, https://github.com/antpiron/cRedRibbon and https://github.com/antpiron/RedRibbon.

Contact

anthony.piron@ulb.be
Solid-State Single-Molecule Sensing with the Electronic Life-detection Instrument for Enceladus/Europa (ELIE)
Authors: Carr Christopher E. , Ramírez-Colón José L. , Duzdevich Daniel , Lee Sam , Taniguchi Masateru , Ohshiro Takahito , Komoto Yuki , Soderblom Jason M. , Zuber M. T.
Published: September 2022

Growing evidence of the potential habitability of Ocean Worlds across our Solar System is motivating the advancement of technologies capable of detecting life as we know it – sharing a common ancestry or common physicochemical origin to life on Earth – or don’t know it, representing a distinct genesis event of life quite different than our one known example. Here, we propose the Electronic Life-detection Instrument for Enceladus/Europa (ELIE), a solid-state single-molecule instrument payload that aims to search for life based on the detection of amino acids and informational polymers (IPs) at the parts per billion to trillion level. As a first proof-of- principle in a laboratory environment, we demonstrate single-molecule detection of the amino acid L-proline at a 10 µM concentration in a compact system. Based on ELIE’s solid-state quantum electronic tunneling sensing mechanism, we further propose the quantum property of the HOMO–LUMO gap (energy difference between a molecule’s highest energy occupied molecular orbital and lowest energy unoccupied molecular orbital) as a novel approach to measure amino acid complexity. Finally, we assess the potential of ELIE to discriminate between abiotically and biotically derived (-amino acids in order to reduce false positive risk for life detection. Nanogap technology can also be applied to the detection of nucleobases and short sequences of IPs such as, but not limited to, RNA and DNA. Future missions may utilize ELIE to target preserved biosignatures on the surface of Mars, extant life in its deep subsurface, or life or its biosignatures in the plume, surface, or subsurface of ice moons such as Enceladus or Europa.

One Sentence Summary:

A solid-state nanogap can determine the abundance distribution of amino acids, detect nucleic acids, and shows potential for detecting life as we know it and life as we don’t.
Habitat use differences mediate anthropogenic threat exposure in white sturgeon
Authors: Walter Jonathan A. , Singer Gabriel P. , Reuman Daniel C. , Colborne Scott F. , Sheppard Lawrence W. , O’Donnell Daniel R. , Coombs Nat , Johnston Myfanwy , Miller Emily A. , Steel Anna E. , Kelly John T. , Fangue Nann A. , Rypel Andrew L.
Published: September 2022

Understanding intraspecific variation in habitat use, particularly of long-lived fishes across multiple life history stages, is core to improved conservation management. Here, we present results from a synthesis of acoustic telemetry data for sub-adult and adult white sturgeon (Acipenser transmontanus) from 2010 to 2017 in the San Francisco Estuary and Sacramento River ecosystems. We focused primarily on uncovering spatial patterns of inferred habitat occupancy across life stages, and on linking habitat use to extant anthropogenic threats. We found substantial differences in habitat use across individuals and over time that was related to fish size classes defined relative to the slot limit (102-152 cm) used to regulate recreational fishing. However, differences in habitat use were not explained by fish sex or water year flow conditions. We also estimated indices of overall exposure for two major threats: capture by anglers and habitat modification. Fish of harvestable size were detected less often than others in areas where many are caught. Future monitoring and management of white sturgeon might benefit from examining multiple phases of white sturgeon life history. For example, additional tracking studies could improve our understanding of juvenile habitat use, adult survival rates, patterns of anadromy, and cross-basin habitat utilization.
Metabolic costs of walking and arm reaching in persons with mild multiple sclerosis
Authors: Courter Robert , Alvarez Enrique , Enoka Roger , Ahmed Alaa
Published: September 2022

Movement slowness is a common and disruptive symptom of multiple sclerosis (MS). A potential cause is that individuals with MS slow down to conserve energy as a behavioral adjustment to heightened metabolic costs of movement. To investigate this prospect, we measured the metabolic costs of both walking and seated arm reaching at five speeds in persons with mild MS (pwMS; n = 13; 46.0 ± 7.7yrs) and sex- and age-matched controls (HCs; n = 13; 45.8 ± 7.8yrs). Notably, the cohort of pwMS was highly mobile and no individuals required a cane or aid when walking. We found that the net metabolic power of walking was approximately 20% higher for pwMS across all speeds (p = 0.0185). In contrast, we found no differences in the gross costs of reaching between pwMS and HCs (p = 0.492). Collectively, our results suggest that abnormal slowness of movement in MS – particularly reaching – is not the consequence of heightened effort costs alone. Our findings are consistent with the possibility that demyelination of reward regions of the central nervous system in MS disrupt the dopamine-mediated impetus to move more quickly and thereby prompt slower movements.

NEW & NOTEWORTHY

Individuals with multiple sclerosis (MS) often move more slowly than those without the disease. A possible cause is that movements in MS are more energetically expensive and slowing is an adaptation to conserve metabolic resources. Here, we find that while walking is more costly for persons with MS, arm reaching movements are not. These results bring into question the driving force of movement slowness in MS and implicate other motor-related networks contributing to slowing.
Nicked tRNAs are stable reservoirs of tRNA halves in cells and biofluids
Authors: Costa Bruno , Calzi Marco Li , Castellano Mauricio , Blanco Valentina , Cuevasanta Ernesto , Litvan Irene , Ivanov Pavel , Witwer Kenneth , Cayota Alfonso , Tosar Juan Pablo
Published: September 2022

Nonvesicular extracellular RNAs (nv-exRNAs) constitute the majority of the extracellular RNAome, but little is known about their stability, function and potential use as disease biomarkers. Herein, we measured the stability of several naked RNAs when incubated in human serum, urine and cerebrospinal fluid (CSF). We identified extracellularly produced tRNA-derived small RNAs (tDRs) with half-lives of up to three hours in CSF. Contrary to widespread assumptions, these intrinsically stable small RNAs are full-length tRNAs containing broken phosphodiester bonds (i.e., nicked tRNAs). Standard molecular biology protocols, including phenol-based RNA extraction and heat, induce the artifactual denaturation of nicked tRNAs and the consequent in vitro production of tDRs. Broken bonds are roadblocks for reverse transcriptases, preventing amplification and/or sequencing of nicked tRNAs in their native state. To solve this, we performed enzymatic repair of nicked tRNAs purified under native conditions, harnessing the intrinsic activity of phage and bacterial tRNA repair systems. Enzymatic repair regenerated an RNase R-resistant tRNA-sized band in northern blot and enabled RT-PCR amplification of full-length tRNAs. We also separated nicked tRNAs from tDRs by chromatographic methods under native conditions, identifying nicked tRNAs inside stressed cells and in vesicle-depleted human biofluids. Dissociation of nicked tRNAs produces single-stranded tDRs that can be spontaneously taken up by human epithelial cells, positioning stable nv-exRNAs as potentially relevant players in intercellular communication pathways.
Mitochondrial bioenergetic dysfunction and cryptic splicing of stathmin-2 are neuropathological markers of disease duration in sporadic amyotrophic lateral sclerosis
Authors: Mehta Arpan R. , McDade Karina , Newton Judith , Ruepp Marc-David , Pal Suvankar , Chandran Siddharthan , Smith Colin , Selvaraj Bhuvaneish T.
Published: September 2022

A striking feature of sporadic amyotrophic lateral sclerosis (ALS) is the marked heterogeneity in disease duration; despite the stark median survival of three years from symptom onset, 10-20% of people with ALS survive longer than 10 years. An improved understanding of the mechanisms underpinning this is vital to revealing the biological basis of disease resilience. Accumulating experimental and pathological evidence implicates mitochondrial bioenergetic dysfunction and TDP-43 nuclear loss-of-function in the aetiopathogenesis of ALS. However, the relevance of these two molecular dysfunctions to disease duration and resilience in ALS is unknown. We curated a cohort of sporadic ALS cases comprising clinically linked autopsy samples to identify molecular neuropathological correlates of disease duration. We developed a novel dual BaseScope RNA in situ hybridisation probe that labels mitochondrial complex 1 transcript (MT-ND2) and truncated stathmin-2 (STMN2) transcripts to measure mitochondrial bioenergetic function and TDP-43 loss-of-function, respectively, in ventral horn neurons. We first show that there is dysfunctional mitochondrial bioenergetics in sporadic ALS. We observed reduced expression of MT-ND2 and increased expression of truncated STMN2 in ALS cases (N=20) compared to sex- and age-matched controls (N=10). We show that these findings correlate with ALS disease duration. Further mechanistic studies are needed to explore whether manipulation of STMN2 expression, by either suppressing cryptic splicing or overexpression, could modify disease duration.
Antibiotic Resistance associated with the COVID-19 Pandemic: A Rapid Systematic Review
Authors: Langford BJ , Soucy J-PR , Leung V , So M , Kwan ATH , Portnoff JS , Bertagnolio S , Raybardhan S , MacFadden D , Daneman N
Published: September 2022

Background

COVID-19 and antimicrobial resistance (AMR) are two intersecting global public health crises.

Objective

We aim to describe the impact of the COVID-19 pandemic on AMR across healthcare settings.

Data Source

A search was conducted in December 2021 in World Health Organization’s COVID-19 Research Database with forward citation searching up to June 2022.

Study Eligibility

Studies evaluating the impact of COVID-19 on AMR in any population were included and influencing factors were extracted.

Methods

Pooling was done separately for Gram-negative and Gram-positive organisms. Random effects meta-analysis was performed.

Results

Of 6036 studies screened, 28 were included and 23 provided sufficient data for meta-analysis. The majority of studies focused on hospital settings (n=25, 89%). The COVID-19 pandemic was not associated with a change in the incidence density (IRR 0.99, 95% CI: 0.67 to 1.47) or proportion (RR 0.91, 95% CI: 0.55 to 1.49) of MRSA or VRE cases. A non-statistically significant increase was noted for resistant Gram-negatives (i.e., ESBL, CRE, MDR or carbapenem-resistant Pseudomonas or Acinetobacter species, IRR 1.64, 95% CI: 0.92 to 2.92; RR 1.08, 95% CI: 0.91 to 1.29). The absence of enhanced IPAC and/or ASP initiatives was associated with an increase in Gram-negative AMR (RR 1.11, 95%CI: 1.03 to 1.20), while studies that did report implementation of these initiatives noted no change in Gram-negative AMR (RR 0.80, 95%CI: 0.38 to 1.70). However, a test for subgroup differences showed no statistically significant difference between these groups (P=0.40)

Conclusion

The COVID-19 pandemic could play an important role in the emergence and transmission of AMR, particularly for Gram-negative organisms in hospital settings. There is considerable heterogeneity in both the AMR metrics utilized and the rate of resistance reported across studies. These findings reinforce the need for strengthened infection prevention, antimicrobial stewardship, and AMR surveillance in the context of the COVID-19 pandemic.

PROSPERO registration: CRD42022325831

This research was carried out as part of routine work, no funding was received Data collection template, data, and analytic code are available upon request.
Verbosity with retelling: narrative discourse production in temporal lobe epilepsy
Authors: D’Aprano Fiore , Malpas Charles B. , Roberts Stefanie E. , Saling Michael M.
Published: September 2022

The conversational language of individuals with temporal lobe epilepsy (TLE) is circumstantial. The micro- and macrolinguistic underpinnings of this disturbance in narrative discourse, and the role of epilepsy and cognitive variables warrants exploration. We examined the elicited narrative output of 15 surgically-naïve individuals with TLE and 14 healthy controls. To replicate and extend Field and colleagues’ (2000) work, participants were shown an eight-frame cartoon Cowboy Story from Joanette and colleagues (1986) and were asked to produce five immediately consecutive elicitations of the narrative. Following transcription and coding, detailed multi-level discourse analysis demonstrated a typical pattern of compression across repetitions in controls. They produce increasingly concise and coherent output, reflective of a refined mental representation of the narrative, while individuals with TLE fail to do so. The narratives produced by individuals with TLE do not compromise the essential story components, although they are less informative overall: producing fewer novel units, and introducing more content that is repetitive, extraneous, and does not progress the narrative. Their narratives are ultimately less fluent, less cohesive, and less coherent relative to controls. Change across trials suggests that there are significant group by trial interactions in sample length, spontaneous duration, and total statements, which are not explained by seizure burden, age, or lexical retrieval deficits among those with TLE. These findings replicate the pattern of findings previously identified by Field and colleagues (2000), with novel insights into the macrolinguistic disturbances that characterise their narrative discourse over sequential repetitions. These findings suggest that individuals with TLE do not benefit from repeated engagement with a narrative in the same way that neurologically normal individuals do. We conclude that disturbances to social cognition and ultimately pragmatics in TLE might underpin inefficiencies in their communication.
Cardiac Magnetic Resonance Findings of COVID-19 Vaccine Associated Myocarditis at Intermediate Follow Up: a Comparison to Classic Myocarditis and MIS-C Related Myocarditis
Authors: Dove Matthew L. , Slesnick Timothy C. , Oster Matthew E. , Hashemi Sassan , Patel Trisha , Wilson Hunter C.
Published: September 2022

Objective

To report intermediate cardiac magnetic resonance (CMR) findings of COVID-19 vaccine associated myocarditis (C-VAM) and compare to classic myocarditis (CM) and multisystem inflammatory syndrome in children (MIS-C).

Study Design

Retrospective cohort study including children diagnosed with C-VAM from 5/2021 through 12/2021 with early and intermediate CMR. Patients with CM and MIS-C with intermediate CMR were included for comparison.

Results

There were 8 patients with C-VAM, 20 with CM, and 61 with MIS-C. Among those with C-VAM, CMR performed at median 3 days (IQR 3, 7) revealed 2/8 patients with left ventricular ejection fraction (LVEF)<55%, 7/7 patients with late gadolinium enhancement (LGE), and 5/8 patients with elevated native T1 values. Borderline T2 values suggestive of myocardial edema were present in 6/8. Follow-up CMRs performed at median 107 days (IQR 97, 177) showed normal ventricular systolic function, T1, and T2 values; 3/7 patients had LGE. At intermediate follow up the C-VAM group had a lower percentage of LVEF<55% compared to CM and MIS-C (0.0 vs 30.0 vs 6.6%, respectively, p=0.018) and an intermediate degree of LGE (42.9 vs 75.0 vs 3.3%, respectively, p<0.001). Pairwise comparisons showed fewer myocardial segments with LGE in the C-VAM group versus CM (4/119 vs 42/340, p=0.004) and more segments with LGE than MIS-C (4/119 vs 2/1020, p=0.0014).

Conclusion

Patients with C-VAM had no evidence of active inflammation or ventricular dysfunction on intermediate CMR although a minority had persistent LGE. Intermediate findings in C-VAM may be favorable compared to CM though LGE is more common compared to MIS-C.
Mucosal and systemic neutralizing antibodies to norovirus and rotavirus by oral immunization with recombinant rotavirus in infant mice
Authors: Kawagishi Takahiro , Sánchez-Tacuba Liliana , Feng Ningguo , Costantini Veronica P. , Tan Ming , Jiang Xi , Green Kim Y. , Vinjé Jan , Ding Siyuan , Greenberg Harry B.
Published: September 2022

Rotaviruses (RVs) preferentially replicate in the small intestine, frequently cause severe diarrheal disease, and following enteric infection generally induce variable levels of protective systemic and mucosal immune responses in humans and other animals. Rhesus rotavirus (RRV) is a simian RV that was previously used as a human RV vaccine and has been extensively studied in mice. Although RRV replicates poorly in the suckling mouse intestine, infection induces a robust and protective antibody response. The recent availability of plasmid-based RV reverse genetics systems has enabled the generation of recombinant RVs expressing foreign proteins. However, recombinant RVs have not yet been experimentally tested as potential vaccine vectors to immunize against other gastrointestinal pathogens in vivo. This is a missed opportunity because several live-attenuated RV vaccines are already widely administered to infants and young children worldwide. To explore the feasibility of using RV as a dual vaccine vector, we rescued a replication-competent recombinant RRV harboring bicistronic gene segment 7 that encodes both the native RV NSP3 protein and a human norovirus (HuNoV) VP1 protein from the predominant genotype GII.4 (rRRV-HuNoV-VP1). The rRRV-HuNoV-VP1 expressed HuNoV VP1 in infected cells in vitro and importantly, elicited both systemic and local antibody responses to HuNoV following oral infection of suckling mice. Serum IgG and fecal IgA from infected suckling mice bound to and neutralized both RV and HuNoV. These findings have encouraging practical implications for the design of RV-based next-generation multivalent enteric vaccines to target HuNoV and other human enteric pathogens while providing immunity to RV.

Significance statement

Mucosal immunity is a key component of protection against many pathogens. Robust and effective mucosal immune responses are generally induced following infection with a replication-competent pathogen at a mucosal surface. Several studies have attempted to develop viral vector-based enteric mucosal vaccines; however, the most advanced of these are still in clinical development. Here, we successfully induced systemic and mucosal antibody responses against both rotavirus and norovirus following inoculation of a recombinant rotavirus expressing the human norovirus major capsid protein. These responses are likely to correlate with protective immunity. Live-attenuated rotavirus vaccines have already proven safe and effective worldwide. These findings confirm the potential utility of using rotaviruses as a dual enteric vaccine platform for other important human enteric pathogens.
Opposite regulation of glycogen metabolism by cAMP produced in the cytosol and at the plasma membrane
Authors: Verhoeven Arthur J. , Bizerra Paulo F.V. , Gilglioni Eduardo H. , Go Simei , Li Hang Lam , Elferink Ronald P.J. Oude , Chang Jung-Chin
Published: September 2022

Cyclic AMP is produced in cells by two different types of adenylyl cyclases: at the plasma membrane by the transmembrane adenylyl cyclases (tmACs, ADCY1∼ADCY9) and in the cytosol by the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). By employing high-resolution extracellular flux analysis to study glycogen breakdown in real time, we show here thatcAMP regulates glycogen metabolism in opposite directions depending on its location of synthesis within cells. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we demonstrate that the non-canonical sAC-cAMP-Epac1 signalling suppresses glycogenolysis in a variety of cell types. Our findings demonstrate the importance of cAMP microdomain organization in glycogen metabolism and reveal a novel role of sAC in energy metabolism during glucose deprivation.
gUMI-BEAR, a modular, unsupervised population barcoding method to track variants and evolution at high resolution
Authors: Rezenman Shahar , Knafo Maor , Tsigalnitski Ivgeni , Barad Shiri , Jona Ghil , Levi Dikla , Dym Orly , Reich Ziv , Kapon Ruti
Published: September 2022

Cellular lineage tracking provides a means to observe population makeup at the clonal level, allowing exploration of heterogeneity, evolutionary and developmental processes and individual clones’ relative fitness. It has thus contributed significantly to understanding microbial evolution, organ differentiation and cancer heterogeneity, among others. Its use, however, is limited because existing methods are highly specific, expensive, labour-intensive, and, critically, do not allow the repetition of experiments. To address these issues, we developed gUMI-BEAR (genomic Unique Molecular Identifier Barcoded Enriched Associated Regions), a modular, cost-effective method for tracking populations at high resolution. We first demonstrate the system’s application and resolution by applying it to track tens of thousands ofSaccharomyces cerevisiaelineages growing together under varying environmental conditions applied across multiple generations, revealing fitness differences and lineage-specific adaptations. Then, we demonstrate how gUMI-BEAR can be used to perform parallel screening of a huge number of randomly generated variants of theHsp82gene. We further show how our method allows isolation of variants, even if their frequency in the population is low, thus enabling unsupervised identification of modifications that lead to a behaviour of interest.
Synthetic genotype networks
Authors: Santos-Moreno Javier , Tasiudi Eve , Kusumawardhani Hadiastri , Stelling Joerg , Schaerli Yolanda
Published: September 2022

Genotype networks are sets of genotypes connected by small mutational changes that share the same phenotype. They facilitate evolutionary innovation by enabling the exploration of different neighborhoods in genotype space. Genotype networks, first suggested by theoretical models, have been empirically confirmed for proteins and RNAs. Comparative studies also support their existence for gene regulatory networks (GRNs), but direct experimental evidence is lacking. Here, we report the construction of three interconnected genotype networks of synthetic GRNs producing three distinct gene expression phenotypes inEscherichia coli. These genotype networks, composed of over twenty different synthetic GRNs, provide robustness in face of mutations while enabling transitions to innovative phenotypes. Through realistic mathematical modeling, we quantify robustness and evolvability for the complete genotype-phenotype map and link these features mechanistically to GRN motifs. Our work thereby exemplifies how GRN evolution along genotype networks might be driving evolutionary innovation.
IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion
Authors: Klein Steffen , Golani Gonen , Lolicato Fabio , Lahr Carmen , Beyer Daniel , Herrmann Alexia , Wachsmuth-Melm Moritz , Reddmann Nina , Brecht Romy , Hosseinzadeh Mehdi , Kolovou Androniki , Makroczyova Jana , Peterl Sarah , Schorb Martin , Schwab Yannick , Brügger Britta , Nickel Walter , Schwarz Ulrich S. , Chlanda Petr
Published: September 2022

Interferon-induced transmembrane protein 3 (IFITM3) inhibits the entry of numerous viruses through undefined molecular mechanisms. IFITM3 localizes in the endosomal-lysosomal system and specifically impacts virus fusion with target cell membranes. We found that IFITM3 induces local lipid sorting, resulting in an increased concentration of lipids disfavoring viral fusion at the hemifusion site. This increases the energy barrier for fusion pore formation and the hemifusion dwell time, promoting viral degradation in lysosomes.In situcryo-electron tomography captured IFITM3-mediated arrest of influenza A virus membrane fusion. Observation of hemifusion diaphragms between viral particles and late endosomal membranes confirmed hemifusion stabilization as a molecular mechanism of IFITM3. The presence of the influenza fusion protein hemagglutinin in post-fusion conformation close to hemifusion sites further indicated that IFITM3 does not interfere with the viral fusion machinery. Collectively, these findings show that IFITM3 induces lipid sorting to stabilize hemifusion and prevent virus entry into target cells.
Outsourcing Memory Through Niche Construction
Authors: Lee Edward D. , Flack Jessica C. , Krakauer David C.
Published: September 2022

Adaptation to changing environments is a universal feature of life and can involve the organism modifying itself in response to the environment as well as actively modifying the environment to control selection pressures. The latter case couples the organism to environment. Then, how quickly should the organism change in response to the environment? We formulate this question in terms of how memory duration scales with environmental rate of change when there are trade-offs in remembering vs. forgetting. We derive a universal scaling law for optimal memory duration, taking into account memory precision as well as two components of environmental volatility, bias and stability. We find sublinear scaling with any amount of environmental volatility. We use a memory complexity measure to explore the strategic conditions (game dynamics) favoring actively reducing environmental volatility—outsourcing memory through niche construction—over investing in neural tissue. We predict stabilizing niche construction will evolve when neural tissue is costly, the environment is variable, and it is beneficial to be able to encode a rich repertoire of environmental states.

Significance Statement

All organisms must adapt to changing environments, but adaptation can modify the environment itself. We solve a version of this problem in terms of how long organisms remember. Shorter memory should be better for variable environments and longer for slow changing ones, but environmental variability depends on feedback. Surprisingly, we find the same mathematical law in both cases, revealing how much shorter memory should be relative to the environmental timescale. We consider how this depends on memory complexity and metabolic costs in populations, allowing us to predict a general set of conditions for when organism will outsource memory to the environment: when maintaining a brain is costly, the environment fluctuates quickly, and organisms inhabit a complex environment.