bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimization of an unscented Kalman filter for an embedded platform
Authors: Graybill Philip P. , Gluckman Bruce J. , Kiani Mehdi
Published: January 2022

The unscented Kalman filter (UKF) is finding increased application in biological fields. While realizing a complex UKF system in a low-power embedded platform offers many potential benefits including wearability, it also poses significant design challenges. Here we present a method for optimizing a UKF system for realization in an embedded platform. The method seeks to minimize both computation time and error in UKF state reconstruction and forecasting. As a case study, we applied the method to a model for the rat sleep-wake regulatory system in which 432 variants of the UKF over six different variables are considered. The optimization method is divided into three stages that assess computation time, state forecast error, and state reconstruction error. We apply a cost function to variants that pass all three stages to identify a variant that computes 27 times faster than the reference variant and maintains required levels of state estimation and forecasting accuracy. We draw the following insights: 1) process noise provides leeway for simplifying the model and its integration in ways that speed computation time while maintaining state forecasting accuracy, 2) the assimilation of observed data during the UKF correction step provides leeway for simplifying the UKF structure in ways that speed computation time while maintaining state reconstruction accuracy, and 3) the optimization process can be accelerated by decoupling variables that directly impact the underlying model from variables that impact the UKF structure.

Author summary

Powerful statistical tools can be used to estimate unmeasured information in biological systems and predict the system’s future state. Translating these tools from a desktop computer to small, wearable or implantable platforms can unlock many benefits, but presents many design challenges, because tradeoffs between computational simplicity and system accuracy must be balanced. We present an approach to translating one such widely used statistical tool, the unscented Kalman filter, from a desktop computer to a miniature device. We demonstrate the approach with a case study centering on the neural circuits governing the mammalian sleep-wake cycle. By exploiting uncertainty in the biology being estimated and the corrective influence of biological measurements, we arrive at a design that is easily computable on the miniature device and maintains a high level of accuracy. We anticipate that our approach will aid others in designing such miniaturized systems for a broad range of applications.
PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance
Authors: Tabury Kevin , Monavarian Mehri , Listik Eduardo , Shelton Abigail K. , Choi Alex Seok , Quintens Roel , Arend Rebecca , Hempel Nadine , Miller C. Ryan , Györrfy Balázs , Mythreye Karthikeyan
Published: January 2022

Metastatic growth of ovarian cancer cells into the peritoneal cavity requires adaptation to various cellular stress factors to facilitate cell survival and growth. Here we demonstrate the role of PVT1, one such stress induced long non-coding RNA, in ovarian cancer growth and metastasis. PVT1 is an amplified and overexpressed lncRNA in ovarian cancer with strong predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by ovarian tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1 dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation modelsin vivo. We find that reducing PVT1 causes widespread transcriptome changes leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which directly impacts chemosensitivity. Together, these findings implicate PVT1 as a promising therapeutic target to suppress metastasis and avoid chemoresistance in ovarian cancer.

SUMMARY BLURB

PVT1 is a stress-responsive IncRNA regulated by YAP1, leading to increased ovarian cancer metastasis and chemoresistance, making PVT1 a promising therapeutic target.
Evolutionary adaptation to juvenile malnutrition impacts adult metabolism and impairs adult fitness inDrosophila
Authors: Erkosar Berra , Dupuis Cindy , Cavigliasso Fanny , Savary Loriane , Kremmer Laurent , Gallart-Ayala Hector , Ivanisevic Julijana , Kawecki Tadeusz J.
Published: January 2022

Juvenile undernutrition has lasting effects on adult metabolism of the affected individuals, but it is unclear how adult physiology is shaped over evolutionary time by natural selection driven by juvenile undernutrition. We combined RNAseq, targeted metabolomics and genomics to study the consequences of evolution under juvenile undernutrition for metabolism of reproductively active adult females ofDrosophila melanogaster. Compared to Control populations maintained on standard diet, Selected populations maintained for over 230 generations on a nutrient-poor larval diet evolved major changes in adult gene expression and metabolite abundance, in particular affecting amino-acid and purine metabolism. The evolved differences in adult gene expression and metabolite abundance between Selected and Control populations were positively correlated with the corresponding differences previously reported for Selected versus Control larvae. This implies that genetic variants affect both stages similarly. Even when well fed, the metabolic profile of Selected flies resembled that of flies subject to starvation. Finally, Selected flies had lower reproductive output than Controls even when both were raised under the conditions under which the Selected populations evolved. These results imply that evolutionary adaptation to juvenile undernutrition has large pleiotropic consequences for adult metabolism, and that they are costly rather than adaptive for adult fitness. Thus, juvenile and adult metabolism do not appear to evolve independently from each other even in a holometabolous species where the two life stages are separated by a complete metamorphosis.
HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation
Authors: Sathler Matheus F. , Doolittle Michael J. , Cockrell James A. , Nadalin India R. , Hofmann Franz , VandeWoude Sue , Kim Seonil
Published: January 2022

As the development of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) drastically improves the lifespan of individuals with HIV, many are now entering the prime age when Alzheimer’s disease (AD)-like symptoms begin to manifest. Hyperphosphorylated tau, a known AD pathological characteristic, has been prematurely increased in the brains of HIV-infected patients as early as in their 30s and is increased with age. This thus suggests that HIV infection may lead to accelerated AD phenotypes. However, whether HIV infection causes AD to develop more quickly in the brain is not yet fully determined. Interestingly, we have previously revealed that viral glycoproteins, HIV gp120 and feline immunodeficiency virus (FIV) gp95, induce neuronal hyperexcitation via cGMP-dependent kinase II (cGKII) activation in cultured hippocampal neurons. Here, we use cultured mouse cortical neurons to demonstrate that HIV gp120 and FIV gp95 are sufficient to increase cellular tau pathology, including intracellular tau hyperphosphorylation and tau release to the extracellular space. We further reveal that viral glycoprotein-induced cellular tau pathology requires cGKII activation. Together, HIV infection likely accelerates AD-related tau pathology via cGKII activation.
Evolution of a cis-acting SNP that controls Type VI Secretion in Vibrio cholerae
Authors: Ng Siu Lung , Kammann Sophia , Steinbach Gabi , Hoffmann Tobias , Yunker Peter J , Hammer Brian K.
Published: January 2022

Mutations in regulatory mechanisms that control gene expression contribute to phenotypic diversity and thus facilitate the adaptation of microbes and other organisms to new niches. Comparative genomics can be used to infer rewiring of regulatory architecture based on large effect mutations like loss or acquisition of transcription factors but may be insufficient to identify small changes in non-coding, intergenic DNA sequence of regulatory elements that drive phenotypic divergence. In human-derived Vibrio cholerae, the response to distinct chemical cues triggers production of multiple transcription factors that can regulate the Type VI Secretion System (T6), a broadly distributed weapon for interbacterial competition. However, to date, the signaling network remains poorly understood because no regulatory element has been identified for the major T6 locus. Here we identify a conserved cis-acting single nucleotide polymorphism (SNP) controlling T6 transcription and activity. Sequence alignment of the T6 regulatory region from diverse V. cholerae strains revealed conservation of the SNP that we rewired to interconvert V. cholerae T6 activity between chitin-inducible and constitutive states. This study supports a model of pathogen evolution through a non-coding cis-regulatory mutation and preexisting, active transcription factors that confers a different fitness advantage to tightly regulated strains inside a human host and unfettered strains adapted to environmental niches.

Importance

Organisms sense external cues with regulatory circuits that trigger the production of transcription factors, which bind specific DNA sequences at promoters (“cis” regulatory elements) to activate target genes. Mutations of transcription factors or their regulatory elements create phenotypic diversity, allowing exploitation of new niches. Waterborne pathogen Vibrio cholerae encodes the Type VI Secretion System “nanoweapon” to kill competitor cells when activated. Despite identification of several transcription factors, no regulatory element has been identified in the promoter of the major Type VI locus, to date. Combining phenotypic, genetic, and genomic analysis of diverse V. cholerae strains, we discovered a single nucleotide polymorphism in the Type VI promoter that switches its killing activity between a constitutive state beneficial outside hosts and an inducible state for constraint in a host. Our results support a role for non-coding DNA in adaptation of this pathogen.
Germline-soma Supply Mitochondria for mtDNA Inheritance in Mouse Oogenesis
Authors: Sha Hongying , Ye Zhao , Ye Zhen , Shi Sanbao , Pan Jianxin , Dong Xi , Zhao Yao
Published: January 2022

Maternal transmission paradigm of mtDNA remains controversial in mammalian oogenesis. Germline-soma-to-oocyte communication by numerous transzonal nanotubes (TZTs) reminds whether intercellular mitochondrial transfer is associated with maternal inheritance. Here, we found that mouse oocytes egocentrically receive mitochondria via TZTs, which projected from germline-soma, to achieve 105copies, instead ofde novosynthesis of mtDNA subpopulation in growing oocytes.De novoassembled TZTs amongst germline-soma and oocytes accumulated mtDNA amounts of the oocytesin vitro. However, mitochondrial supplement from germline-soma gradually diminished along with oocyte growth and was terminated by meiosis resumption, in line with a decrease in the proportion of germline-soma with thriving mtDNA replication and FSH capture capability. Thus, germline-soma-to-oocyte mitochondrial transfer is responsible for mammalian mtDNA inheritance as well as oogenesis and aging.

One-sentence summaries

The maternal mtDNA transmission accompanied by oogenesis is inseparable from germline-soma mitochondrial transport.
Bridging Transcriptome Regulation and Cellular Operational Efficiency with the Locality and Caching System Optimization Principles
Authors: Jiang Wen , Feliers Denis , Zheng W. Jim , Zhang Fangyuan , Wang Degeng
Published: January 2022

Gene expression is time-consuming and sequentially more so from bacteria to yeast to human, rendering human cells vulnerable to proteomic-response and operational latency. Computers once suffered such latency, imposed by much-slower information retrieval (hard-drive (HD) to memory to central-processing-unit (CPU)) than CPU execution. Optimization principles, namely, spatiotemporal-locality-principles that control specialized user-programs and caching that controls operating system (OS) kernel (the HD-CPU information flow channel), successfully mitigated the latency by gearing the memory towards near-future or high-priority CPU needs. We report evidence that the principles similarly act in cellular latency-mitigation via analogizing genome-mRNA-protein gene-expression to HD-memory-CPU information-retrieval, and transcriptome to memory. First, temporal-locality-principle is equivalent to mRNA stabilization-by-translation regulation and controls specialized cellular functions. Second, caching is equivalent to cytoplasmic mRNA sequestration. Highly sequestered mRNAs defy the locality-principle. In both cells and computers, caching controls the information channels; gene expression machinery and their regulators,i.e., the cellular channel (OS-kernel equivalent) that regulates arguably all cellular processes, are top sequestered mRNAs. Third, mRNA-caching contributes to the mRNA-protein expression discrepancy. Thus, locality and caching principles control specialized and core cellular functions, respectively, orchestrating transcriptome regulation and bridging it to cellular operational efficiency.
Development of a screening tool for pelvic floor dysfunction in female athletes: protocol of a Delphi consensus
Authors: Giagio Silvia , Turolla Andrea , Innocenti Tiziano , Salvioli Stefano , Gava Giulia , Pillastrini Paolo , Vecchiato Marco , Dakic Jodie , Frawley Helena Catherine , Bo Kari
Published: January 2022

Background/aim: Several epidemiological studies have found a high prevalence of Pelvic Floor Dysfunction (PFD) among female athletes. However, according to several authors, these data could even be underestimated, both in research and clinical practice. Screening for potential PFD is often delayed and risk factors are not often evaluated. As a consequence, withdrawal from sport, negative influence on performance, worsening symptoms and unrecognized diagnosis may occur.
The aim of our research is to develop a screening tool for pelvic floor dysfunction in female athletes useful for clinicians (musculoskeletal/sport physiotherapists, sports medicine physicians, team physicians) to guide referral to a PFD expert (e.g. pelvic floor/women's health physiotherapist, gynecologist, uro-gynecologist, urologist).
Methods: A 2-round modified Delphi study will be conducted to ascertain expert opinion on which combination of variables and risk factors should be included in the screening tool.
Conclusion: The implementation of the present screening tool into clinical practice may facilitate the referral to a PFD expert for further assessment of the pelvic floor and therefore, to identify potential dysfunction and, eventually, the related treatment pathway.
Deep Learning Based Long Term Mortality Prediction in the National Lung Screening Trial
Authors: Lu Yaozhi , Aslani Shahab , Emberton Mark , Alexander Daniel C. , Jacob Joseph
Published: January 2022

In this study, the long-term mortality in the National Lung Screening Trial (NLST) was investigated using a deep learning-based method. Binary classification of the non-lung-cancer mortality (i.e. cardiovascular and respiratory mortality) was performed using neural network models centered around a 3D-ResNet. The models were trained on a participant age, gender, and smoking history matched cohort. Utilising both the 3D CT scan and clinical information, the models can achieve an AUC of 0.73 which outperforms humans at cardiovascular mortality prediction. By interpreting the trained models with 3D saliency maps, we examined the features on the CT scans that correspond to the mortality signal. The saliency maps can potentially assist the clinicians’ and radiologists’ to identify regions of concern on the image that may indicate the need to adopt preventative healthcare management strategies to prolong the patients’ life expectancy.
Mosaic deletions in X-linked dystonia-parkinsonism influence repeat stability and disease onset
Authors: Trinh Joanne , Lüth Theresa , Schaake Susen , Laβ Joshua , Laabs Björn-Hergen , Schlüter Kathleen , Pozojevic Jelena , Tse Ronnie , Köenig Inke , Jamora Roland Dominic , Rosales Raymond L. , Brüggemann Norbert , Saranza Gerard , Diesta Cid Czarina E. , Kaiser Frank J. , Depienne Christel , Westenberger Ana , Klein Christine
Published: January 2022

Background

While multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO).

Methods

Third-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches.

Results

An increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5×10-13) and AAO (r=0.34, p=9.5×10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers.

Conclusion

We present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.
Patients with Alzheimer’s disease have increased cellular amyloid uptake
Authors: Zaretsky Dmitry V. , Zaretskaia Maria V. , Molkov Yaroslav I. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2022

Amyloid plaques are the main signature of Alzheimer’s disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer’s Disease Neuroimaging Initiative cohort.

We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group.

Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.
Mid-level feature differences underlie early animacy and object size distinctions: Evidence from EEG decoding
Authors: Wang Ruosi , Janini Daniel , Konkle Talia
Published: January 2022

Responses to visually-presented objects along the cortical surface of the human brain have a large-scale organization reflecting the broad categorical divisions of animacy and object size. Mounting evidence indicates that this topographical organization is driven by differences between objects in mid-level perceptual features. With regard to the timing of neural responses, images of objects quickly evoke neural responses with decodable information about animacy and object size, but are mid-level features sufficient to evoke these rapid neural responses? Or is slower iterative neural processing required to untangle information about animacy and object size from mid-level features? To answer this question, we used electroencephalography (EEG) to measure human neural responses to images of objects and their texform counterparts – unrecognizable images which preserve some mid-level feature information about texture and coarse form. We found that texform images evoked neural responses with early decodable information about both animacy and real-world size, as early as responses evoked by original images. Further, successful cross-decoding indicates that both texform and original images evoke information about animacy and size through a common underlying neural basis. Broadly, these results indicate that the visual system contains a mid-level feature bank carrying linearly decodable information on animacy and size, which can be rapidly activated without requiring explicit recognition or protracted temporal processing.
Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction
Authors: Duttke Sascha H. , Montilla-Perez Patricia , Chang Max W. , Li Hairi , Chen Hao , Carrette Lieselot L. G. , de Guglielmo Giordano , George Olivier , Palmer Abraham A. , Benner Christopher , Telese Francesca
Published: January 2022

Substance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.
Multimodal cues displayed by submissive rats promote prosocial choices by dominants
Authors: Gachomba Michael Joe Munyua , Esteve-Agraz Joan , Caref Kevin , Maroto Aroa Sanz , Bortolozzo-Gleich Helena , Laplagne Diego Andrés , Márquez Cristina
Published: January 2022

Animals often display prosocial behaviours, performing actions that benefit others. Although prosociality is essential for social bonding and cooperation, we still know little about how animals integrate behavioural cues from those in need to make decisions that increase their wellbeing. To address this question, we used a two-choice task where rats can provide rewards to a conspecific in the absence of self-benefit, and interrogated which conditions promote prosociality by manipulating the social context of the interacting animals. While sex or degree of familiarity did not affect prosocial choices in rats, social hierarchy revealed to be a potent modulator, with dominant decision-makers showing faster emergence and higher levels of prosocial choices towards their submissive cage-mates. Leveraging quantitative analysis of multimodal social dynamics prior to choice, we identified that pairs with dominant decision-makers exhibited more proximal interactions. Interestingly, these closer interactions were driven by submissive animals that modulated their position and movement following their dominants and whose 50kHz vocalisation rate correlated with dominants’ prosociality. Moreover, Granger causality revealed stronger bidirectional influences in pairs with dominant focals and submissive recipients, indicating increased behavioural coordination. Finally, multivariate analysis highlighted body language as the main information dominants use on a trial-by-trial basis to learn that their actions have effects on others. Our results provide a refined understanding of the behavioural dynamics that rats use for action-selection upon perception of socially relevant cues and navigate social decision-making.
Improved biodiversity detection using a large-volume environmental DNA sampler with in situ filtration and implications for marine eDNA sampling strategies
Authors: Govindarajan Annette F. , McCartin Luke , Adams Allan , Allan Elizabeth , Belani Abhimanyu , Francolini Rene , Fujii Justin , Gomez-Ibañez Daniel , Kukulya Amy , Marin Fredrick , Tradd Kaitlyn , Yoerger Dana R. , McDermott Jill M. , Herrera Santiago
Published: January 2022

Metabarcoding analysis of environmental DNA samples is a promising new tool for marine biodiversity and conservation. Typically, seawater samples are obtained using Niskin bottles and filtered to collect eDNA. However, standard sample volumes are small relative to the scale of the environment, conventional collection strategies are limited, and the filtration process is time consuming. To overcome these limitations, we developed a new large – volume eDNA sampler with in situ filtration, capable of taking up to 12 samples per deployment. We conducted three deployments of our sampler on the robotic vehicle Mesobot in the Flower Garden Banks National Marine Sanctuary in the northwestern Gulf of Mexico and collected samples from 20 to 400 m depth. We compared the large volume (∼40 – 60 liters) samples collected by Mesobot with small volume (∼2 liters) samples collected using the conventional CTD – mounted Niskin bottle approach. We sequenced the V9 region of 18S rRNA, which detects a broad range of invertebrate taxa, and found that while both methods detected biodiversity changes associated with depth, our large volume samples detected approximately 66% more taxa than the CTD small volume samples. We found that the fraction of the eDNA signal originating from metazoans relative to the total eDNA signal decreased with sampling depth, indicating that larger volume samples may be especially important for detecting metazoans in mesopelagic and deep ocean environments. We also noted substantial variability in biological replicates from both the large volume Mesobot and small volume CTD sample sets. Both of the sample sets also identified taxa that the other did not – although the number of unique taxa associated with the Mesobot samples was almost four times larger than those from the CTD samples. Large volume eDNA sampling with in situ filtration, particularly when coupled with robotic platforms, has great potential for marine biodiversity surveys, and we discuss practical methodological and sampling considerations for future applications.
Ancestral acetylcholine receptor β-subunit forms homopentamers that prime before opening spontaneously
Authors: Tessier Christian J. G. , Sturgeon R. Michel , Emlaw Johnathon R. , McCluskey Gregory D. , Pérez-Areales F. Javier , daCosta Corrie J. B.
Published: January 2022

Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from two α-subunits, and one each of the β-, δ-, and ε-subunits. To form functional channels, the subunits must assemble with one another in a precise stoichiometry and arrangement. Despite being different, the four subunits share a common ancestor that is presumed to have formed homopentamers. The extent to which the properties of the modern-day receptor result from its subunit complexity is unknown. Here we show that a reconstructed ancestral muscle-type β-subunit can form homopentameric ion channels. These homopentamers open spontaneously and display single-channel hallmarks of muscle-type acetylcholine receptor activity. Our findings demonstrate that signature features of muscle-type acetylcholine receptor function are independent of agonist, and do not necessitate the complex heteropentameric architecture of the modern-day receptor.
Estimating alpha, beta, and gamma diversity through deep learning
Authors: Andermann Tobias , Antonelli Alexandre , Barrett Russell L. , Silvestro Daniele
Published: January 2022

The reliable mapping of species richness is a crucial step for the identification of areas of high conservation priority, alongside other value considerations. This is commonly done by overlapping range maps of individual species, which requires dense availability of occurrence data or relies on assumptions about the presence of species in unsampled areas deemed suitable by environmental niche models. Here we present a deep learning approach that directly estimates species richness, skipping the step of estimating individual species ranges. We train a neural network model based on species lists from inventory plots, which provide ground truthing for supervised machine learning. The model learns to predict species richness based on spatially associated variables, including climatic and geographic predictors, as well as counts of available species records from online databases. We assess the empirical utility of our approach by producing independently verifiable maps of alpha, beta and gamma plant diversity at high spatial resolutions for Australia, a continent with highly contrasting diversity patterns. Our deep learning framework provides a powerful and flexible new approach for estimating biodiversity patterns.
Factor VII activating protease (FSAP) inhibits the outcome of ischemic stroke in mouse models
Authors: Kim Jeong Yeon , Manna Dipankar , Leergaard Trygve B. , Kanse Sandip M.
Published: January 2022

Factor VII activating protease (FSAP) is a circulating serine protease, and individuals with the Marburg I (MI) single nucleotide polymorphism (SNP), which results in an inactive enzyme, have an increased risk of stroke. The outcome of ischemic stroke is more marked in FSAP-deficient mice compared to their wild-type (WT) counterparts. Plasma FSAP levels are raised in patients as well as mice after stroke. In vitro, FSAP promotes fibrinolysis by cleavage of fibrinogen, activates protease-activated receptors and decreases the cellular cytotoxicity of histones. Since these are desirable properties in stroke treatment, we tested the effect of recombinant serine protease domain of FSAP (FSAP-SPD) on ischemic stroke in mice. A combination of tissue plasminogen activator (tPA) and FSAP-SPD enhanced clot lysis, improved microvascular perfusion and neurological outcome and reduced infarct volumes in a mouse model of thromboembolic stroke. In the tail bleeding model FSAP-SPD treatment provoked a faster clotting time indicating that it has a pro-coagulant effect that is described before. FSAP-SPD improved stroke outcome and diminished the negative effects of co-treatment with tPA in the transient middle cerebral artery occlusion model. The inactive MI-isoform of FSAP did not have any effects in either model. In mice with FSAP deficiency there were minor differences in the outcomes of stroke but the treatment with FSAP-SPD was equally effective. Thus, FSAP represents a promising novel therapeutic strategy in the treatment of ischemic stroke that requires further evaluation.
Multiple horizontal acquisitions of plant genes in the whitefly Bemisia tabaci
Authors: Gilbert Clément , Maumus Florian
Published: January 2022

The extent to which horizontal gene transfer (HGT) has shaped eukaryote evolution remains an open question. Two recent studies reported four plant-like genes acquired through two HGT events by the whitefly Bemisia tabaci, a major agricultural pest (Lapadula et al. 2020; Xia et al. 2021). Here, we uncovered a total of 49 plant-like genes deriving from at least 24 independent HGT events in the genome of the MEAM1 whitefly. Orthologs of these genes are present in three cryptic B. tabaci species, they are phylogenetically nested within plant sequences, and expressed and under purifying selection. The predicted functions of these genes suggest that most of them are involved in plant-insect interactions. Thus, substantial plant-to-insect HGT may have facilitated the evolution of B. tabaci towards adaptation to a large host spectrum. Our study shows that eukaryote-to-eukaryote HGT may be relatively common in some lineages and it provides new candidate genes that may be targeted to improve current control strategies against whiteflies.
Rare Genetic Variants Correlate with Better Processing Speed
Authors: Song Zeyuan , Gurinovich Anastasia , Nygaard Marianne , Mengel-From Jonas , Andersen Stacy , Cosentino Stephanie , Schupfs Nicole , Lee Joseph , Zmuda Joseph , Ukraintseva Svetlana , Arbeev Konstantin , Christensen Kaare , Perls Thomas , Sebastiani Paola
Published: January 2022

We conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from two Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5×10−8). Among these, 18 variants had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059 on chromosome 3, which were replicated in the combined Danish twin cohort. These SNPs are located in/near two genes, THRB and RARB, that belonged to thyroid hormone receptors family that may influence speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these two genes are associated with processing speed.
SNP-level FST outperforms window statistics for detecting soft sweeps in local adaptation
Authors: da Silva Ribeiro Tiago , Galván José A. , Pool John E.
Published: January 2022

Local adaptation can lead to elevated genetic differentiation at the targeted genetic variant and nearby sites. Selective sweeps come in different forms, and depending on the initial and final frequencies of a favored variant, very different patterns of genetic variation may be produced. If local selection favors an existing variant that had already recombined onto multiple genetic backgrounds, then the width of elevated genetic differentiation (high FST) may be too narrow to detect using a typical windowed genome scan, even if the targeted variant becomes highly differentiated. We therefore used a simulation approach to investigate the power of SNP-level FST (specifically, the maximum SNP FST value within a window) to detect diverse scenarios of local adaptation, and compared it against whole-window FST and the Comparative Haplotype Identity statistic. We found that SNP FST had superior power to detect complete or mostly complete soft sweeps, but lesser power than window-wide statistics to detect partial hard sweeps. To investigate the relative enrichment and nature of SNP FST outliers from real data, we applied the two FST statistics to a panel of Drosophila melanogaster populations. We found that SNP FST had a genome-wide enrichment of outliers compared to demographic expectations, and though it yielded a lesser enrichment than window FST, it detected mostly unique outlier genes and functional categories. Our results suggest that SNP FST is highly complementary to typical window-based approaches for detecting local adaptation, and merits inclusion in future genome scans and methodologies.

Significance statement

Studies that use genetic variation to search for genes evolving under population-specific natural selection tend to analyze data at the level of genomic windows that may each contain hundreds of variable sites. However, some models of natural selection (e.g. favoring an existing genetic variant) may result in genetic signals of local adaptation that are too narrow to be detected by such approaches. Here we use both simulations and empirical data analysis to show that searching for a site-specific signal of elevated genetic differentiation can find instances of local adaptation that other approaches miss, and therefore the integration of this signal into future studies may significantly improve our understanding of adaptive evolution and its genetic targets.
Heterosynaptic NMDA Receptor Plasticity in Hippocampal Dentate Granule Cells
Authors: Rodenas-Ruano Alma , Nasrallah Kaoutsar , Lutzu Stefano , Castillo Maryann , Castillo Pablo E.
Published: January 2022

The dentate gyrus is a key relay station that controls information transfer from the entorhinal cortex to the hippocampus proper. This process heavily relies on dendritic integration by dentate granule cells (GCs) of excitatory synaptic inputs from medial and lateral entorhinal cortex via medial and lateral perforant paths (MPP and LPP, respectively). N-methyl-D-aspartate receptors (NMDARs) can contribute significantly to the integrative properties of neurons. While early studies reported that excitatory inputs from entorhinal cortex onto GCs can undergo activity-dependent long-term plasticity of NMDAR-mediated transmission, the input-specificity of this plasticity along the dendritic axis remains unknown. Here, we examined the NMDAR plasticity rules at MPP-GC and LPP-GC synapses using physiologically relevant patterns of stimulation in acute rat hippocampal slices. We found that MPP-GC, but not LPP-GC synapses, expressed homosynaptic NMDAR-LTP. In addition, induction of NMDAR-LTP at MPP-GC synapses heterosynaptically potentiated distal LPP-GC NMDAR plasticity. The same stimulation protocol induced homosynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-LTP at MPP-GC but heterosynaptic AMPAR-LTD at distal LPP synapses, demonstrating that NMDAR and AMPAR are governed by different plasticity rules. Remarkably, heterosynaptic but not homosynaptic NMDAR-LTP required Ca2+ release from intracellular, ryanodine-dependent Ca2+ stores. Lastly, the induction and maintenance of both homo- and heterosynaptic NMDAR-LTP were blocked by GluN2D antagonism, suggesting the recruitment of GluN2D-containing receptors to the synapse. Our findings uncover a mechanism by which distinct inputs to the dentate gyrus may interact functionally and contribute to hippocampal-dependent memory formation.

Significance Statement

NMDARs are key players in synaptic plasticity. In addition to their classical role as coincidence detectors and triggers of AMPAR plasticity, there is compelling evidence that NMDARs can undergo activity-dependent plasticity independent of AMPAR plasticity. However, whether NMDAR-plasticity is expressed heterosynaptically remains unclear. Here, in the dentate gyrus of the hippocampus, we show that the induction of burst timing-dependent LTP of NMDAR-mediated transmission at proximal medial perforant path synapses is accompanied by heterosynaptic NMDAR-LTP at lateral perforant path synapses. These findings provide the first evidence for heterosynaptic NMDAR plasticity, which may have important consequences on the dendritic integration of functionally distinct excitatory inputs by dentate granule cells.
Parent-Child Autonomic Synchrony During Vicarious Extinction Learning in Pediatric PTSD
Authors: George Grace C. , Heyn Sara A. , Konishi Shuka , Marin Marie-France , Herringa Ryan J.
Published: January 2022

Children learn about threat and safety in their environment in part from their caregivers, a process which may be disrupted in child psychopathology. This transmission may be seen through biological measures like peripheral nervous system outputs such as skin conductance (SCR). Fear learning deficits have been observed in fear-related disorders like PTSD but have received little study in terms of parent-child learning transmission. We used a vicarious fear extinction paradigm to examine whether biological synchrony (SCR and heart rate variability [HRV]) is a potential mechanism by which children learn safety cues from their parents. In this pilot study, 16 dyads (PTSD n=11, typically developing [TD] n=5) underwent a vicarious fear extinction paradigm. We used cross-recurrence quantification analysis (CRQA) to assess SCR and HRV synchrony between parent-child dyads. We then used a linear model to examine group differences between PTSD dyads and TD dyads. For SCR, a significant group difference (p=.037) indicated that TD dyads had higher SCR synchrony compared to PTSD dyads. For HRV, there were no group differences between PTSD and TD dyads (p=.325). In exploratory analyses, increased synchrony was related to an overall decreased autonomic reactivity during recall of fear (p=0.032). These results suggest that SCR synchrony, but not HRV, may be a potential mechanism that allows for fear and safety learning in youth. While these data are preliminary, they provide novel insights on how disruptions in vicarious extinction learning may contribute to fear-related disorders in youth. Furthermore, this study suggests novel approaches to studying dyadic trauma-focused therapies which critically rely on parental coaching to model appropriate fear responses to help their child to recover from trauma.

Significance Statement

This study provides evidence that biological synchrony is a potential mechanism through which youth learn threat and safety cues through their parents. We found that youth with PTSD have lower synchrony with their caregiver, and that synchrony was related to decreased overall autonomic reactivity, suggesting that synchrony may be indicative of overall safety learning. Further, decreased synchrony during fear extinction may potentially underlie the etiology of fear related disorders such as PTSD. These novel approaches may improve our understanding of dyadic trauma-focused therapies which critically rely on parental coaching to model appropriate fear responses to help their child to recover from trauma.
Climate change impacts on the abiotic degradation of acyl-homoserine lactones in the fluctuating conditions of marine biofilms
Authors: Roggatz Christina C. , Parsons Daniel R.
Published: January 2022

Marine biofilms are functional communities that shape habitats by providing a range of structural and functional services integral to coastal ecosystems. Impacts of climate change on biological aspects of such communities are increasingly studied, but impacts on the chemicals that mediate key interactions of biofilm organisms have largely been overlooked. Acyl-homoserine lactones (AHLs), crucial bacterial signals within biofilms, are known to degrade through pH and temperature-dependent hydrolysis. However, the impact of climate change on AHLs and thus on biofilm form and function is presently unknown. This study investigates the impact of changes in pH and temperature on the hydrolysis rate, half-life time and quantitative abundance of different AHLs on daily and seasonal timescales for current conditions and future climate change scenarios.

We established the mathematical relationships between pH, hydrolysis rates/ half-life times and temperature, which revealed that natural daily pH-driven changes within biofilms cause the greatest fluctuations in AHL concentration (up to 9-fold). Season-dependant temperature enhanced or reduced the observed daily dynamics, leading to higher winter and lower summer concentrations and caused a shift in timing of the highest and lowest AHL concentration by up to two hours. Simulated future conditions based on climate change projections caused an overall reduction of AHL degradation and led to higher AHL concentrations persisting for longer across both the daily and seasonal cycles.

This study provides valuable quantitative insights into the theoretical natural dynamics of AHL concentrations. We highlight critical knowledge gaps on the scale of abiotic daily and seasonal fluctuations affecting estuarine and coastal biofilms and on the biofilms’ buffering capacity. Detailed experimental studies of daily and seasonal dynamics of AHL concentrations and assessment of the potential implications for a suite of more complex interactions are required. Substantial fluctuations like those we show in this study, particularly with regards to concentration and timing, will likely have far reaching implications for fundamental ecosystem processes and important ecosystem services such as larval settlement and coastal sediment stabilisation.
Maternally transferred monoclonal antibodies protect neonatal mice from herpes simplex virus-induced mortality and morbidity
Authors: Backes Iara M. , Byrd Brook K. , Patel Chaya D. , Taylor Sean A. , Garland Callaghan R. , MacDonald Scott W. , Balazs Alejandro B. , Davis Scott C. , Ackerman Margaret E. , Leib David A.
Published: January 2022

Neonatal herpes simplex virus (HSV) infections often result in significant mortality and neurological morbidity despite antiviral drug therapy. Maternally-transferred HSV-specific antibodies reduce the risk of clinically-overt neonatal HSV (nHSV), but this observation has not been translationally applied. Using a neonatal mouse model, we tested the hypothesis that passive transfer of HSV-specific human monoclonal antibodies (mAbs) can prevent mortality and morbidity associated with nHSV. The mAbs were expressedin vivoby vectored immunoprophylaxis, or administeredin vivofollowing recombinant expressionin vitro. Through these maternally-derived routes or through direct administration to pups, diverse mAbs to HSV glycoprotein D protected against neonatal HSV-1 and HSV-2 infection. Usingin vivobioluminescent imaging, both pre- and post-exposure mAb treatment significantly reduced viral load. Administration of mAb also reduced nHSV-induced behavioral morbidity, as measured by anxiety-like behavior. Together these studies support the notion that HSV-specific mAb-based therapies may prevent or improve HSV infection outcomes in neonates.

Graphical Abstract

Different antibody sources were used to maternally-transfer or directly administer HSV-specific mAbs to mouse pups. Neonatal mice were challenged with wild type or bioluminescent virus before or after mAb acquisition. Following infection, pups were assessed for survival, virus-induced bioluminescence and anxiety-like behavior as a measure of neurological morbidity. Efficacy was time and mAb dependent. Notably, all HSV-specific mAbs prevented nHSV-associated mortality.