bluuebunny/crossref_metadata_2025 huggingface dataset:
A method for morphological feature extraction based on variational auto-encoder : an application to mandible shape
Authors: Tsutsumi Masato , Saito Nen , Koyabu Daisuke , Furusawa Chikara
Published: May 2022

Shape analysis of biological data is crucial for investigating the morphological variations during development or evolution. However, conventional approaches for quantifying shapes are difficult as exemplified by the ambiguity in the landmark-based method in which anatomically prominent “landmarks” are manually annotated. In this study, a morphological regulated variational autoencoder (Morpho-VAE) is proposed that conducts image-based shape analysis using imaging processing through a deep-learning framework, thereby removing the need for defining landmarks. The proposed architecture comprises a VAE combined with a classifier module. This integration of unsupervised and supervised learning models (i.e., VAE and classifier modules) is designed to reduce dimensionality by focusing on the morphological features in which the differences between data with different labels are best distinguished. The proposed method is applied to the image dataset of the primate mandible to extract morphological features, which allow us to distinguish different families in a low dimensional latent space. Furthermore, the visualization analysis of decision-making of Morpho-VAE clarifies the area of the mandibular joint that is important for family-level classification. The generative nature of the proposed model is also demonstrated to complement a missing image segment based on the remaining structure. Therefore, the proposed method, which flexibly performs landmark-free feature extraction from complete and incomplete image data is a promising tool for analyzing morphological datasets in biology.

AUTHOR SUMMARY

Shape is the most intuitive visual characteristic; however, shape is generally difficult to measure using a small number of variables. Specifically, for biological data, shape is sometimes highly diverse as it has been acquired through a long evolutionary process, adaptation to environmental factors, etc., which limits the straightforward approach to shape measurement. Therefore, a systematic method for quantifying such a variety of shapes using a low-dimensional quantity is needed. To this end, we propose a novel method that extracts low-dimensional features to describe shapes from image data using machine learning. The proposed method is applied to the primate mandible image data to extract morphological features that reflect the characteristics of the groups to which the organisms belong and then those features are visualized. This method also reconstructs a missing image segment from an incomplete image based on the remaining structure. To summarize, this method is applicable to the shape analysis of various organisms and is a useful tool for analyzing a wide variety of image data, even those with a missing segment.
Extremely low level of genetic diversity in Gentiana yakushimensis, an endangered species in Yakushima Island, Japan
Authors: Ishii Naohiro I. , Hirota Shun K. , Tsunamoto Yoshihiro , Matsuo Ayumi , Abe Harue , Suyama Yoshihisa
Published: May 2022

Rare or endangered species largely contributing to global biodiversity are essential components of ecosystems. Because genetic diversity depends not only on apparent population size but also demographic processes, the conservation priority of endangered species based on population genetics needs to be assessed by comparison with common congeners and demographic events. In this study, we performed population genetic analysis for Gentiana yakushimensis Makino, a rare and endangered plant species with an isolated distribution on Yakushima Island, Japan. We performed comparison of genetic diversity with the congener (Gentiana triflora Pall. var. japonica (Kusn.) H.Hara), demographic inference, and bottleneck test based on genome-wide single nucleotide polymorphisms. The result was that G. yakushimensis had an extremely low genetic diversity level and a high inbreeding coefficient level compared to those of the congener. The population of G. yakushimensis was estimated to experience an expansion during the Last Glacial Maximum and a recent bottleneck by the demographic inference and the bottleneck test. Therefore, the low level of genetic diversity of this species might have resulted from the impact of the recent bottleneck and the long-term maintenance of a small population size. Due to the long lifespan of the genus Gentiana, the current level of genetic diversity probably does not reflect a large part of recent demographic events, which requires long-term monitoring of changes in genetic diversity to identify the time lag between the reduction in apparent population size and genetic diversity as a future outlook.
Gut microbiota of homing pigeons shows summer-winter variation under constant diet indicating a substantial effect of temperature
Authors: Dietz Maurine W. , Matson Kevin D. , Versteegh Maaike A. , van der Velde Marco , Parmentier Henk K. , Arts Joop. A.J. , Salles Joana F. , Tieleman B. Irene
Published: May 2022

Background

Gut microbiotas play a pivotal role in host physiology and behaviour, and may affect host life-history traits such as seasonal variation in host phenotypic state. Generally, seasonal gut microbiota variation is attributed to seasonal diet variation. However, seasonal temperature and day length variation may also drive gut microbiota variation. We investigated summer-winter differences in gut microbiota in 14 homing pigeons living outdoors under a constant diet by collecting cloacal swabs in both seasons during two years. Because temperature effects may be mediated by host metabolism, we determined basal metabolic rate (BMR) and body mass. Immune competence is influenced by day length and has a close relationship with gut microbiota, and it may thus be a link between day length and gut microbiota. Therefore, we measured seven innate immune indices. We expected gut microbiota to show summer-winter differences and gut microbiota to correlate with metabolism and immune indices.

Results

BMR, body mass, and two immune indices varied seasonally, other host factors did not. Gut microbiota showed differences between seasons and sexes, and correlated with metabolism and immune indices. The most abundant genus (Lachnoclostridium 12, 12%) and associated higher taxa, were more abundant in winter, though not significantly at the phylum level, Firmicutes. Bacteroidetes were more abundant in summer. The Firmicutes:Bacteroidetes ratio tended to be higher in winter. The KEGG ortholog functions for fatty acid biosynthesis and linoleic acid metabolism (PICRUSt2) had increased abundances in winter.

Conclusions

The gut microbiota of homing pigeons varied seasonally, even under a constant diet. The correlations between immune indices and gut microbiota did not involve consistently specific immune indices and included only one of the two immune indices that showed seasonal differences, suggesting that immune competence may be an unlikely link between day length and gut microbiota. The correlations between gut microbiota and metabolism indices, the higher Firmicutes:Bacteroidetes ratio in winter, and the resemblance of the summer-winter differences in gut microbiota with the general temperature effects on gut microbiota in the literature, suggest that temperature partly drove the summer-winter differences in gut microbiota in homing pigeons.
Increasing protein stability by inferring substitution effects from high-throughput experiments
Authors: Norrild Rasmus Krogh , Johansson Kristoffer Enøe , O’Shea Charlotte , Morth Jens Preben , Lindorff-Larsen Kresten , Winther Jakob Rahr
Published: May 2022

Protein stability is an important parameter in almost all protein-engineering efforts. Evaluating the effects of the many possible amino acid changes to guide such projects is a significant task, even with recent advances in experimental and computational approaches. Here, we apply a computational model, GMMA, to extract substitution effects from a cost-effective genetic screen of a randomly mutated protein library. Using a high mutation frequency, the method can map stability effects of even very stable proteins for which conventional selection systems have reached their limit. Thus, we screened a mutant library of a highly stable and optimised model protein using an in vivo genetic sensor for folding and assigned a stability effect to 374 of 912 possible single amino acid substitutions. Combining the top 9 substitutions increased the thermodynamic stability by almost 50% in a single engineering step. This illustrates the capability of the method, which is applicable to any screen for protein function.
A deeply conserved protease, acylamino acid-releasing enzyme (AARE), acts in ageing in Physcomitrella and Arabidopsis
Authors: Hoernstein Sebastian N.W. , Özdemir Buğra , van Gessel Nico , Miniera Alessandra A. , von Bieberstein Bruno Rogalla , Nilges Lars , Farinha Joana Schweikert , Komoll Ramona , Glauz Stella , Weckerle Tim , Scherzinger Friedrich , Rodriguez-Franco Marta , Müller-Schüssele Stefanie J. , Reski Ralf
Published: May 2022

Reactive oxygen species (ROS) are constant by-products of aerobic life. In excess, ROS lead to cytotoxic protein aggregates, which are a hallmark of ageing in animals and linked to age-related pathologies in humans. Acylamino acid-releasing enzymes (AARE) are bifunctional serine proteases, acting on oxidized proteins. AARE are found in all domains of life, albeit under different names, such as acylpeptide hydrolase (APEH/ACPH), acylaminoacyl peptidase (AAP), or oxidized protein hydrolase (OPH). In humans, AARE malfunction is associated with age-related pathologies, while their function in plants is less clear. Here, we provide a detailed analysis ofAAREgenes in the plant lineage and an in-depth analysis of AARE localization and function in the moss Physcomitrella and the angiosperm Arabidopsis.AAREloss-of-function mutants have not been described for any organism so far. We generated and analysed such mutants and describe a connection between AARE function, aggregation of oxidized proteins and plant ageing, including accelerated developmental progression and reduced life span. Our findings complement similar findings in animals and humans, and suggest a unified concept of ageing may exist in different life forms.
Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver
Authors: Sugino Kameron Y. , Mandala Ashok , Janssen Rachel C. , Gurung Sunam , Trammell MaJoi , Day Michael W. , Brush Richard S. , Papin James F. , Dyer David W. , Agbaga Martin-Paul , Friedman Jacob E. , Castillo-Castrejon Marisol , Jonscher Karen R. , Myers Dean A.
Published: May 2022

Maternal consumption of a high-fat, Western-style diet (WD) disrupts the maternal/infant microbiome and contributes to developmental programming of the immune system and nonalcoholic fatty liver disease (NAFLD) in the offspring. Epigenetic changes, including non-coding miRNAs in the fetus and/or placenta may also underlie this risk. We previously showed that obese nonhuman primates (NHP) fed a WD during pregnancy results in the loss of beneficial maternal gut microbes and dysregulation of cellular metabolism and mitochondrial dysfunction in the fetal liver, leading to a perturbed postnatal immune response with accelerated NAFLD in juvenile offspring. Here, we investigated associations between WD-induced maternal metabolic and microbiome changes, in the absence of obesity, and miRNA and gene expression changes in the placenta and fetal liver. After ∼8-11 months of maternal WD feeding (mWD), dams were similar in body weight but exhibited mild, systemic inflammation (elevated CRP and neutrophil count) and dyslipidemia (increased triglycerides and cholesterol) compared with dams fed a control diet. The maternal gut microbiome was mainly comprised ofLactobacillalesandClostridiales, with significantly decreased alpha diversity (P= 0.0163) in WD-fed dams but no community-wide differences (P= 0.26). At 0.9 gestation, mRNA expression ofIL6andTNFin mWD-exposed placentas trended higher, while increased triglycerides, expression of pro-inflammatoryCCR2, and histological evidence for fibrosis were found in mWD-exposed fetal livers. In the mWD-exposed fetus, hepatic expression levels of miR-204-5p and miR-145-3p were significantly downregulated, whereas in mWD-exposed placentas, miR-182-5p and miR-183-5p were significantly decreased. Notably, miR-1285-3p expression in the liver and miR-183-5p in the placenta were significantly associated with inflammation and lipid synthesis pathway genes, respectively.BlautiaandRuminococcuswere significantly associated with miR-122-5p in liver, whileCoriobacteriaceaandPrevotellaceawere strongly associated with miR-1285-3p in the placenta; both miRNAs are implicated in pathways mediating postnatal growth and obesity. Our findings demonstrate that mWD shifts the maternal microbiome, lipid metabolism, and inflammation prior to obesity and are associated with epigenetic changes in the placenta and fetal liver. These changes may underlie inflammation, oxidative stress, and fibrosis patterns that drive NAFLD and metabolic disease risk in the next generation.
Non-aging despite high mutation rate – genomic insights into the evolution ofHydra
Authors: Sahm Arne , Riege Konstantin , Groth Marco , Bens Martin , Kraus Johann , Fischer Martin , Kestler Hans , Englert Christoph , Schaible Ralf , Platzer Matthias , Hoffmann Steve
Published: May 2022

Hydrais a genus of freshwater polyps with remarkable regeneration abilities and a non-senescent phenotype under laboratory conditions. Thus, this animal is particularly interesting for aging research. Here, we gained insights intoHydra’srecent genetic evolution by genome sequencing of single cells and whole individuals. Despite its extreme longevity,Hydradoes not show a lower somatic mutation rate than humans or mice. While we identify biological processes that have evolved under positive selection in animals kept in optimal laboratory conditions for decades, we found no signs of strong negative selection during this tiny evolutionary window. Interestingly, we observe the opposite pattern for the preceding evolution in the wild over a longer time period. Moreover, we found evidence thatHydraevolution in captivity was accompanied and potentially accelerated by loss of heterozygosity. Processes under positive selection in captive animals include pathways associated withHydra’s simple nervous system, its nucleic acid metabolic process, cell migration, and hydrolase activity. Genes associated with organ regeneration, regulation of mRNA splicing, histone ubiquitination, and mitochondrial fusion were identified as highly conserved in the wild. Remarkably, several of the processes under strongest selection are closely related to those considered essential for the exapted, i. e. not brought about by natural selection, feature:Hydra’snon-aging.
Rap1 uses Canoe-dependent and Canoe-independent mechanisms to regulate apical contractility and allow embryonic morphogenesis without tissue disruption
Authors: Perez-Vale Kia Z. , Yow Kristi D. , Greene Melissa , Gurley Noah J. , Peifer Mark
Published: May 2022

Embryonic morphogenesis is powered by dramatic changes in cell shape and arrangement, driven by the cytoskeleton and its connections to adherens junctions. This requires robust linkage, allowing morphogenesis without disrupting tissue integrity. The small GTPase Rap1 is a key regulator of cell adhesion, controlling both cadherin-mediated and integrin-mediated processes. We have defined multiple roles in morphogenesis for one Rap1 effector, Canoe/Afadin, which ensures robust junction-cytoskeletal linkage. We now ask what mechanisms regulate Canoe and other junction-cytoskeletal linkers during Drosophila morphogenesis, defining roles for Rap1 and one of its guanine nucleotide exchange factor (GEF) regulators, Dizzy. Rap1 uses Canoe as one effector, regulating junctional planar polarity. However, Rap1 has additional roles in junctional protein localization and balanced apical constriction—in its absence, Bazooka/Par3 localization is fragmented, and cells next to mitotic cells apically constrict and invaginate, disrupting epidermal integrity. In contrast, the GEF Dizzy has phenotypes similar to but slightly less severe than Canoe loss, suggesting this GEF regulates Rap1 action via Canoe. Taken together, these data reveal that Rap1 is a crucial regulator of morphogenesis, likely acting in parallel via Canoe and other effectors, and that different Rap1 GEFs regulate distinct functions of Rap1.
Enhancer plasticity sustains oncogenic transformation and progression of B-Cell Acute Lymphoblastic leukemia
Authors: Corleone G , Sorino C , Caforio M , Di Giovenale S , De Nicola F , Bertaina V , Pitisci A , Cortile C , Locatelli F , Folgiero V , Fanciulli M
Published: May 2022

Growing evidence report that non-genetic-driven events such as enhancer reprogramming promote neoplastic transformation and strongly contribute to the phenotypical heterogeneity of cancers as much as genetic variation. In this context, we investigated the role of enhancers in sustaining oncogenic transformation in B-Cell Acute Lymphoblastic leukemia in children (BCP-ALL), a type of cancer caused by the accumulation of lymphoid progenitor cells in the bone marrow and a leading cause of cancer-related mortality in children. Using next-generation sequencing (ATAC-seq), we built the most up-to-date map of chromatin accessibility in pediatric BCP-ALL. We observed that enhancer activity dynamically changes during cancer progression and represents principal phenomena underlying phenotypic–functional characteristics of BCP-ALL progression. BCP-ALL patients are dominated by a regulatory repertoire (N=∼11k) originally represented at diagnosis that shrinks under treatments and subsequently re-expands, driving the relapse. We then deployed a wide range of in-vivo, in-vitro assays, and in-silico analyses to demonstrate the impact of enhancer activity in determining the phenotypical complexity. CRISPR-Cas-9-mediated validation of selected productive enhancers demonstrated a high capability of these regions to control MYB and DCTD oncogenic activities. Taken together, these findings provide direct support to the notion that enhancer plasticity is a crucial determinant of the BCP-ALL phenotype.
The epigenomic landscape of single vascular cells reflects developmental origin and identifies disease risk loci
Authors: Weldy Chad S. , Cheng Paul P. , Guo Wenduo , Pedroza Albert J. , Dalal Alex R. , Worssam Matthew D. , Sharma Disha , Nguyen Trieu , Kundu Ramendra , Fischbein Michael P. , Quertermous Thomas
Published: May 2022

Rationale

Vascular beds have distinct susceptibility to atherosclerosis and aneurysm, yet the biological underpinnings of vascular bed specific disease risk are largely unknown. Vascular tissues have different developmental origins which may influence global chromatin accessibility. Understanding chromatin accessibility and gene expression profiles on single cell resolution is crucial to gain insight into vascular bed specific disease risk.

Objective

We aim to understand, at single cell resolution, the global chromatin accessibility and gene expression profiles across distinct vascular beds in the healthy adult mouse to provide insight into the potential mechanisms of vascular bed specific disease risk.

Methods and Results

We performed single cell chromatin accessibility (scATACseq) and gene expression profiling (scRNAseq) of healthy adult mouse vascular tissue from three vascular beds, 1) aortic root and ascending aorta, 2) brachiocephalic and carotid artery, and 3) descending thoracic aorta. By integrating datasets and comparing vascular beds within cell type, we identified thousands of differentially accessible chromatin peaks within smooth muscle cells, fibroblasts, and endothelial cells, demonstrating numerous enhancers to be vascular bed specific. We revealed an epigenetic ‘memory’ of embryonic origin with differential chromatin accessibility of key developmental transcription factors such asTbx20,Hand2,Gata4, andHoxbfamily members. Increased transcription factor motif accessibility in ascending fibroblasts compared to descending further highlights SMAD2/3 functions and suggests a differential susceptibility to TGFβ. By isolating primary adventitial fibroblasts from ascending and descending thoracic aorta from adult mice, we demonstrate ascending fibroblasts to have a distinctly higher transcriptional response to TGFβ compared to descending fibroblasts, highlighting that distinct chromatin accessibility between vascular beds is retained following primaryin vitroculture and influences responsiveness to disease relevant signaling.

Conclusions

This work supports a paradigm that the epigenomic and transcriptional landscapes of vascular cells are cell type and vascular bed specific and that differentially accessible regions are enriched for disease risk genes.
Serverless Prediction of Peptide Properties with Recurrent Neural Networks
Authors: Ansari Mehrad , White Andrew D.
Published: May 2022

We present three deep learning sequence prediction models for hemolysis, solubility, and resistance to non-specific interactions of peptides that achieve comparable results to the state-of-the-art models. Our sequence-based solubility predictor, MahLooL, outperforms the current state-of-art methods for short peptides. These models are implemented as a static website without the use of a dedicated server or cloud computing. Web-based models like this allow for accessible and effective reproducibility. Most existing approaches rely on third-party servers typically that require upkeep and maintenance. That trend leads to a relatively longer lifetime of web-based models. These predictive models do not require servers, require no installation of dependencies, and work on across a range of devices. The models are bidirectional recurrent neural networks. Thisserverlessprediction model is a demonstration of edge machine learning that removes the dependence on cloud providers. The code and models are accessible athttps://github.com/ur-whitelab/peptide-dashboard.
AI-guided screen identifies probucol-mediated mitophagy enhancement through modulation of lipid droplets
Authors: Moskal Natalia , Visanji Naomi P. , Gorbenko Olena , Narasimhan Vijay , Tyrrell Hannah , Nash Jess , Lewis Peter N. , McQuibban G. Angus
Published: May 2022

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets and mitochondria. Conversely, lipid droplet expansion, which occurs following mitochondrial damage was suppressed by probucol and probucol-mediated mitophagy enhancement required lipid droplets. Probucol-mediated lipid droplet dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.
Targeting TACC3 represents a novel vulnerability in highly aggressive breast cancers with centrosome amplification
Authors: Saatci Ozge , Akbulut Ozge , Cetin Metin , Sikirzhytski Vitali , Sahin Ozgur
Published: May 2022

Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. However, there are no effective strategies targeting cancer cells with CA while sparing normal cells. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated that TACC3 forms distinct functional interactions in mitotic and non-mitotic cancer cells with CA to facilitate centrosome clustering (CC) and transcriptional repression of tumor suppressors, respectively. We showed, for the first time, that TACC3 interacts with the Kinesin Family Member C1 (KIFC1) via its TACC domain in mitotic cells with CA and inhibition of TACC3 blocks this interaction, leading to apoptosis via multipolar spindle formation and activation of spindle assembly checkpoint (SAC)/CDK1/p-Bcl2 axis. In interphase, TACC3 interacts with the members of the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus, and its inhibition causes p53-independent G1 arrest and apoptosis by blocking these interactions and activating the transcription of key tumor suppressors (e.g., p21, p16 and APAF1). Notably, inducing CA by chemical (cytochalasin D) or genomic (PLK4 overexpression or p53 loss) modulations renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by small molecule inhibitors or guide RNAs strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA. Altogether our results pave the way towards therapeutic targeting of TACC3 in highly aggressive cancers.
Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel
Authors: Li Jianlong , Sudiwala Sonia , Berthoin Lionel , May Alison J. , Mohabbat Seayar , Sinada Hanan , Gaylord Eliza A. , Pacheco Noel Cruz , Lombaert Isabelle M.A. , Jeon Oju , Alsberg Eben , Bahney Chelsea S. , Knox Sarah M.
Published: May 2022

Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here using the adult murine system, we demonstrate radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist, cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week post-radiation, with extensive acinar cell degeneration, dysfunction and cholinergic denervation occurring thereafter. However, we discovered that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline-alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at non-irradiated levels over the long-term (> 3 months). Thus, we reveal a novel regenerative approach for restoring epithelial organ structure and function that has significant implications for human patients.

Teaser

Novel application of an injectable neurogenic-based hydrogel for restoring the structure and function of radiation-damaged tissue.
Held out wings RNA binding activity in the cytoplasm during early spermatogenesis
Authors: Agapiou Michaela , Hopes Tayah , Hobor Fruzsina , Bretman Amanda , Edwards Thomas A. , Aspden Julie L.
Published: May 2022

Held out wings (HOW) is an RNA-binding protein essential for spermatogenesis in Drosophila melanogaster. HOW is a signal transduction and activation of RNA (STAR) protein, regulating post-transcriptional gene expression. The characteristics of RNA-binding by the conserved short cytoplasmic isoform, HOW(S), are unknown. In vivo RIP-seq identified 121 novel transcripts bound by HOW(S) in germ stem cells and spermatogonia, many with signal transduction functions. (A/G/U)CUAAC motifs were enriched in 3’-UTRs and GCG(A/U)G in 5’-UTRs. HOW binds with high-affinity to sites containing CUAAC motifs from lola and hipk mRNAs. This study provides new insight into STAR protein-RNA interactions and functions in spermatogenesis.
A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck
Authors: Juvkam Inga Solgård , Zlygosteva Olga , Arous Delmon , Galtung Hilde Kanli , Malinen Eirik , Søland Tine Merete , Edin Nina Jeppesen
Published: May 2022

Radiotherapy of head and neck cancer is known to cause both early and late-occurring toxicities. To better appraise normal tissue responses and their dependence on treatment parameters such as radiation field and type, as well as dose and fractionation scheme, a preclinical model with relevant endpoints is required. 12-week old female C57BL/6J mice were irradiated with 100 or 180 kV X-rays to total doses ranging from 30 to 85 Gy, given in 10 fractions over 5 days. The radiation field covered the oral cavity, swallowing structures, and salivary glands. Monte Carlo simulations were employed to estimate tissue dose distribution. The follow-up period was 35 days, in order to study the early radiation-induced effects. Baseline and post irradiation investigations included macroscopic and microscopic examinations of the skin, lips, salivary glands, and oral mucosa. Saliva sampling was performed to assess the salivary gland function following radiation exposure. A dose dependent radiation dermatitis in the skin was observed for doses above 30 Gy. Oral mucositis in the tongue appeared as ulcerations on the ventral surface of the tongue for doses of 75-85 Gy. The irradiated mice showed significantly reduced saliva production compared to controls. In summary, a preclinical model to investigate a broad panel of normal tissue responses following fractionated irradiation of the head and neck region was established. The optimal dose to study early radiation-induced effects was found to be around 75 Gy, as this was the highest tolerated dose that gave acute effects similar to what is observed in cancer patients.
Camera-based monitoring of Bogong moths in Alpine Australia reveals drivers of migratory behaviour
Authors: Wallace Jesse R A , Reber Therese , Khaldy Lana , Mathews-Hunter Benjamin , Green Ken , Dreyer David , Warrant Eric J
Published: May 2022

The Bogong moth Agrotis infusa is well known for its remarkable annual round-trip migration from its breeding grounds across eastern Australia to its aestivation sites in the Australian Alps, to which it provides an important annual influx of nutrients. Over recent years, we have benefited from a growing understanding of the navigational abilities of the Bogong moth. Meanwhile, the population of Bogong moths has been shrinking. Recently, the ecologically and culturally important Bogong moth was listed as endangered by the IUCN Red List, and the establishment of a program for long-term monitoring of its population has been identified as critical for its conservation. Here, we present the results of two years of monitoring of the Bogong moth population in the Australian Alps using a recently developed method for automated monitoring of flying insects, named Camfi. We found that the evening flights of Bogong moths occur throughout summer, and are modulated by daily weather factors. We present a simple heuristic model of the arrival to and departure from aestivation sites by Bogong moths, and confirm results obtained from fox-scat surveys which found that aestivating Bogong moths occupy higher elevations as the summer progresses. We also present the first recorded observations of the impact of bushfire smoke on aestivating Bogong moths. We observed a dramatic reduction in the size of a cluster of aestivating Bogong moths during the fire, and evidence of a large departure from the fire-affected area the day after the fire. Our results highlight the challenges of monitoring Bogong moths in the wild, and support the continued use of automated camera-based methods for that purpose.
Deep Learning-Based Parameter Estimation for Neurophysiological Models of Neuroimaging Data
Authors: Griffiths John David , Wang Zheng , Ather Syed Hussain , Momi Davide , Rich Scott , Diaconescu Andreea , McIntosh Anthony Randal , Shen Kelly
Published: May 2022

Abstract

Connectome-based neural mass modelling is the emerging computational neuroscience paradigm for simulating large-scale network dynamics observed in whole-brain activity measurements such as fMRI, M/EEG, and related techniques. Estimating physiological parameters by fitting these models to empirical data is challenging however, due to large network sizes, often physiologically detailed fast-timescale system equations, and the need for long (e.g. tens of minutes) simulation runs. Here we introduce a novel approach to connectome-based neural mass model parameter estimation by employing optimization tools developed for deep learning. We cast the system of differential equations representing both neural and haemodynamic activity dynamics as a deep neural network, implemented within a widely used machine learning programming environment (PyTorch). This allows us to use robust industry-standard optimization algorithms, automatic differentiation for computation of gradients, and other useful functionality. The approach is demonstrated using a connectome-based network with nodal dynamics specified by the two-state RWW mean-field neural mass model equations, which we use here as a model of fMRI-measured activity and correlation fluctuations. Additional optimization constraints are explored and prove fruitful, including restricting the model to domains of parameter space near a bifurcation point that yield metastable dynamics. Using these techniques, we first show robust recovery of physiological model parameters in synthetic data and then, as a proof-of-principle, apply the framework to modelling of empirical resting-state fMRI data from the Human Connectome Project database. For resting state activity, the system can be understood as a deep net that receives uncorrelated noise on its input layer, which is transformed into network-wide modelled functional connectivity on its output layer. This is consistent with the prevailing conception in theoretical neuroscience of resting-state functional connectivity patterns as an emergent phenomenon that is driven by (effectively) random activity fluctuations, which are then in turn spatiotemporally filtered by anatomical connectivity and local neural dynamics.
The role of the environment in transmission of antimicrobial resistance between humans and animals: a modelling study
Authors: Lepper Hannah C. , Woolhouse Mark E.J. , van Bunnik Bram A.D.
Published: May 2022

Background

Antimicrobial resistance can be transmitted between animals and humans both directly or indirectly, through transmission via the environment (such as fomites or sewage). However, there is a lack of understanding of, and quantitative evidence about, the contribution of the environment to AMR epidemiology. In this study we incorporate the transmission of resistance via the environment into a mathematical model to study the potential importance of this form of transmission for human resistance levels and any effects of the impact of interventions to reduce antibiotic consumption in animals.

Methods

We developed a compartmental model of human-animal AMR transmission with an additional environmental compartment. We compared the outcomes of this model under different human-animal-environment transmission scenarios, conducted a sensitivity analysis, and investigated the impact of curtailing antibiotic usage in animals on resistance levels in humans.

Results

Our findings suggest that human resistance levels are most sensitive to both parameters associated with the human compartment (rate of loss of resistance from humans) and parameters associated with the environmental compartment (rate of loss of resistance from the environment and the transmission rate from the environment to humans). The impact of curtailing antibiotic consumption in animals on long term prevalence of AMR in humans was weaker when environmental transmission was assumed to be high.

Conclusions

This study highlights that environment-human sharing of resistance can influence the epidemiology of resistant bacterial infections in humans and reduce the impact of interventions that curtail antibiotic consumption in animals. More data on the types and dynamics of resistance in the environment and frequency of human-environment transmission is crucial to understanding the population dynamics of antibiotic resistance.
Top-down control of flight by a non-canonical cortico-amygdala pathway
Authors: Borkar Chandrashekhar D. , Stelly Claire E. , Fu Xin , Dorofeikova Maria , Le Quan-Son Eric , Vutukuri Rithvik , Vo Catherine , Walker Alex , Basavanhalli Samhita , Duong Anh , Bean Erin , Resendez Alexis , Parker Jones G. , Tasker Jeffrey G. , Fadok Jonathan P.
Published: May 2022

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as posttraumatic stress and panic disorder.1Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation to the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping,in-vivocalcium imaging, functional manipulations, and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus. Using a behavioural paradigm that elicits both freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP projections target distinct medial CeA neuronal populations projecting to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.
Mechanism of Mg2+ Mediated Encapsulation of an Anionic Cognate Ligand in a Bacterial Riboswitch
Authors: Kumar Sunil , Reddy Govardhan
Published: May 2022

Riboswitches in bacteria regulate gene expression and are targets for antibiotic development. The fluoride riboswitch is essential for bacteria’s survival as it is critical to maintaining the F− ion concentration below the toxic level. The anionic cognate ligand, F− ion, is encapsulated by three Mg2+ ions in a trigonal pyramidal arrangement bound to the ligand-binding domain (LBD) of the riboswitch. The assembly mechanism of this intriguing LBD structure and its role in transcription initiation are not clear. Computer simulations using both coarse-grained and all-atom RNA models show that F− and Mg2+ binding to the LBD are essential to stabilize the LBD structure and tertiary stacking interactions. We propose that the first two Mg2+ ions sequentially bind to the LBD through water-mediated outer-shell coordination. The first bound Mg2+ should undergo a transition to a direct inner shell interaction through dehydration to strengthen its interaction with LBD before the binding of the second Mg2+ ion. The binding of the third Mg2+ and F− to the LBD occurs in two modes. In the first mode, the third Mg2+ binds first to the LBD, followed by F− binding. In the second mode, Mg2+ and F− form a water-mediated ion pair and bind to the LBD simultaneously, which we propose to be the efficient binding mode. We show that the linchpin hydrogen bonds involved in the antiterminator helix formation and transcription initiation are stable only after F− binding. The intermediates populated during riboswitch folding and cognate-ligand binding are potential targets for discovering new antibiotics.
The evolutionary potential of the influenza A virus hemagglutinin is highly constrained by intersegment epistasis
Authors: Liu Tongyu , Wang Yiquan , Tan Timothy J C , Wu Nicholas C , Brooke Christopher B
Published: May 2022

The ongoing antigenic evolution of the influenza A virus (IAV) hemagglutinin (HA) gene limits efforts to effectively control the spread of the virus in the human population through vaccination. The factors that influence and constrain the evolutionary potential of the HA gene remain poorly understood. Efforts to understand the mechanisms that govern HA antigenic evolution typically examine the HA gene in isolation and ignore the importance of balancing HA receptor-binding activities with the receptor-destroying activities of the viral neuraminidase (NA) for maintaining viral fitness. We hypothesized that the need to maintain functional balance with NA significantly constrains the evolutionary potential of the HA gene. We used deep mutational scanning to show that variation in NA activity significantly reshapes the HA fitness landscape by modulating the overall mutational robustness of the HA protein. Consistent with this, we observe that different NA backgrounds support the emergence of distinct repertoires of HA escape variants under neutralizing antibody pressure. Our results reveal a critical role for intersegment epistatic interactions in shaping the evolutionary potential of the HA gene.
Crystal structure and Hirshfeld analysis of (1aS,3aR,4aS,5aR)-15-acetoxylinden-7(11),8-trieno-12,8-lactone
Authors: Lu Qiang-Qiang , Shi Xin-Wei , Zhou Ya-Fu , Cui Xin-Ai , Wang Hong
Published: May 2022

The structure of the title compound, C17H20O4 [systematic name: (1aS,3aR,4aS,5aR)-15-(acetoxy)linden-7(11),8-trieno-12,8-lactone or (4aR,5S,5aR,6aS,6bR)-5-(acetoxymethyl)-4a,5,5a,6,6a,6b-hexahydro-3,6b-dimethylcyclopropa[2,3]indeno[5,6-b]furan-2(4H)-one, ent-chloranthalactone C], a natural product isolated from the whole plant Chloranthus japonicus Sieb., is a typical lindenane-type sesquiterpenoid. The molecule comprises a bicyclo[3.1.0]hexane ring (A/B system) bearing an acetoxymethyl (C-4) group, a bicyclo[4.3.0]nonane ring (B/C system) containing a double bond (C-8/9) and a chiral quaternary carbon (C-10), and a 7(11)-en-12,8-olide structural moiety on the cyclohexan-8-ene (C ring). In the tetracyclic skeleton, the 1,3-cyclopropane ring has a β-configuration, and atoms H-5 and H3-14 have α- and β-orientations, respectively. In the crystal, the molecules are assembled into a two-dimensional network by weak O...H/H...O interactions. Hirshfeld surface analysis illustrates that the greatest contributions are from H...H (55.2%), O...H/H...O (34.6%) and C...H/H...C (8.9%) contacts.
Crystal structure of 2-amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(naphthalen-2-yl)-5-oxo-4H-chromene-3-carbonitrile
Authors: Hebishy Ali M. S. , Elgemeie Galal H. , Ali Rasha A. E. , Jones Peter G.
Published: May 2022

In the title compound, C22H20N2O2, both six-membered rings of the fused heterocyclic system display envelope conformations; the two carbon atoms bearing the methyl groups and the naphthyl substituent both lie outside the planes of the other atoms of each ring. In the crystal, the amino group forms hydrogen bonds of the types N—H...O=C and N—H...N[triple-bond]C, leading to the formation of a double layer structure propagating parallel to the bc plane. Weak C—H...O and C—H...π interactions may reinforce the layers.
(Phenyliodosyl)benzene tosylate dihydrate
Authors: Smith Timothy J. , Koser Gerald , Chen Yi , Zeller Matthias , Iacino Rocco , Selzer Nichole
Published: May 2022

The structure of the title salt (systematic name: oxodiphenyl-λ5-iodanylium 4-methylbenzenesulfonate dihydrate), C12H10IO+·C7H7O3S−·2H2O, at 150 K, has monoclinic (P21/c) symmetry. The molecular structure features an angular (phenyliodosyl)benzene cation, the geometry of which was hitherto undescribed in the literature: in the cation, both I—C bonds are approximately normal to the I=O bond, forming a C—I—C angle of 95.36 (4)°. The crystal structure displays O—H...O, O—H...I and O—H...S hydrogen bonding.
Finite element analysis of lateral response of lightweight foamed concrete-filled cold-formed steel walls
Authors: Alabbadi Ghadeer , Allouzi Rabab
Published: May 2022

Purpose

The purpose of this study is to improve the lateral capacity of Cold-Formed Steel (CFS) frame walls filled with lightweight foamed concrete (LFC) and supported with straw boards by introducing structural foamed concrete and/or bracing.

Design/methodology/approach

Finite element models are developed and calibrated based on previous experimental work. Then, these models are extended to conduct a parametric study to quantify the effect of filling CFS walls and structural LFC and the effect of supporting CFS walls with bracing.

Findings

Results of the study conclude that the finite element analysis can be used to simulate and analyze the lateral capacity of CFS walls effectively since the maximum deviation between calibrated and experimental results is 10%. The structural LFC usage in CFS walls improves the lateral capacity considerably by (25–75) % depending on the wall properties. Besides, the application of lateral bracing does not always have a positive effect on the lateral performance of these walls.

Originality/value

Although CFS walls are preferred due to it is light in weight, low in cost, easy to install and recyclable, low seismic performance, buckling vulnerability, poor thermal insulation and sound insulation properties, low lateral stiffness, and low shear strength limit their use. This study proposes the use of structural foamed concrete and a different bracing method than what is available in the literature. This can overcome the drawbacks of the CFS walls alone which can permit the usage of such walls in mid-rise buildings and other applications.
A branch-and-price algorithm for robust parallel batch scheduling problem with uncertain size
Authors: Wang Ting , Shao Xiaoling , Yan Xue
Published: May 2022

Purpose

In intelligent scheduling, parallel batch processing can reasonably allocate production resources and reduce the production cost per unit product. Hence, the research on a parallel batch scheduling problem (PBSP) with uncertain job size is of great significance to realize the flexibility of product production and mass customization of personalized products.

Design/methodology/approach

The authors propose a robust formulation in which the job size is defined by budget constrained support. For obtaining the robust solution of the robust PBSP, the authors propose an exact algorithm based on branch-and-price framework, where the pricing subproblem can be reduced to a robust shortest path problem with resource constraints. The robust subproblem is transformed into a deterministic mixed integer programming by duality. A series of deterministic shortest path problems with resource constraints is derived from the programming for which the authors design an efficient label-setting algorithm with a strong dominance rule.

Findings

The authors test the performance of the proposed algorithm on the extension of benchmark instances in literature and compare the infeasible rate of robust and deterministic solutions in simulated scenarios. The authors' results show the efficiency of the authors' algorithm and importance of incorporating uncertainties in the problem.

Originality/value

This work is the first to study the PBSP with uncertain size. To solve this problem, the authors design an efficient exact algorithm based on Dantzig–Wolfe decomposition. This can not only enrich the intelligent manufacturing theory related to parallel batch scheduling but also provide ideas for relevant enterprises to solve problems.