bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibroblast Activation Protein–Targeted PET Imaging of Metastatic Castration-Resistant Prostate Cancer Compared With 68Ga-PSMA and 18F-FDG PET/CT
Authors: Isik Emine Goknur , Has-Simsek Duygu , Sanli Oner , Sanli Yasemin , Kuyumcu Serkan
Published: August 2021

Herein we present 2 mCRPC (metastatic castration-resistant prostate cancer) patients who underwent 68Ga-PSMA PET/CT for PSMA-targeted radioligand therapy eligibility. Prior studies have noted aggressive clinical behavior and poor prognosis associated with discordant FDG positivity and low PSMA expression. Accordingly, the patients also underwent 18F-FDG PET/CT, which revealed intratumoral heterogeneity. Therefore, an additional PET/CT targeting fibroblast activation proteins (FAPs) using 68Ga-FAPI-04 was performed to assess the potential for an FAP-targeted therapy. This report highlights the theranostic potential of FAP imaging in mCRPC, particularly in patients with heterogeneous tumor phenotypes.
Two Tumors, One Target
Authors: Rathke Hendrik , Fuxius Stefan , Giesel Frederik L. , Lindner Thomas , Debus Jürgen , Haberkorn Uwe , Kratochwil Clemens
Published: August 2021

We report a patient with breast cancer (BC) diagnosed in 2009 with metachronous lymph node, liver, and bone metastases. In 2017, colorectal cancer with peritoneal metastases was additionally diagnosed and treated with 8 cycles of capecitabine due to its antitumor activity against both malignancies. At progression of both diseases, FAPI PET/CT demonstrated positive tumor targeting in BC-related metastases and colorectal cancer–related metastases. The patient received an experimental therapy with 90Y-FAPI46. Although there was similar tracer uptake in the PET/CT, the radioligand therapy resulted in mixed response with disappearance of peritoneal metastases but minor efficacy treating the BC-related metastases.
Intratumoral Heterogeneity in a Patient With Metastatic Thymic Carcinoma on 18F-FDG, 68Ga-DOTATATE, and 68Ga-FAPI04 PET/CT
Authors: Isik Emine Göknur , Kuyumcu Serkan , Ozkan Zeynep Gözde , Has Simsek Duygu , Sanli Yasemin
Published: August 2021

Herein, we present a 72-year-old woman with metastatic thymic carcinoma, referred for salvage peptide receptor radionuclide therapy with 177Lu-DOTATATE after completing all treatment options according to current clinical practice and guidelines. However, the patient was not eligible for 177Lu-DOTATATE peptide receptor radionuclide therapy and underwent 68Ga-FAPI04 PET/CT to assess the potential for a FAP-targeted therapy.
Organizing Pneumonia With Intense 68Ga-FAPI Uptake Mimicking Lung Cancer on 68Ga-FAPI PET/CT
Authors: Tang Wenxin , Wu Junhao , Yang Songsong , Wang Qixin , Chen Yue
Published: August 2021

We report a case of organizing pneumonia, which revealed intense uptake on both 18F-FDG and 68Ga–FAPI (fibroblast activation protein inhibitor) PET/CT. Our findings indicate that organizing pneumonia should be taken into consideration when diagnosing a cancer-like pulmonary mass with intense 68Ga-FAPI uptake.
68Ga-FAPI PET/CT Detected Non–FDG-Avid Gastric Stromal Tumor
Authors: Qiu Lin , Lan Lianjun , Liu Hanxiang , Deng Jia , Chen Yue
Published: August 2021

We presented a case of 67-year-old man with epigastric discomfort and anorexia for more than 2 months. No abnormal 18F-FDG uptake was found throughout the gastrointestinal tract on 18F-FDG PET/CT. The patient was enrolled in the 68Ga-FAPI PET/CT clinical trial, and a 68Ga-FAPI PET/CT was performed to help detect primary lesion. This examination demonstrated a nodular thickening of the gastric wall with an increased 68Ga-FAPI uptake in the greater curvature of the stomach. Finally, the pathological result confirmed the diagnosis of gastric stromal tumor. This case highlights that 68Ga-FAPI PET/CT might outperform 18F-FDG PET/CT in helping identify gastrointestinal stromal tumors.
Interesting Manifestation of Autoimmune Encephalitis on FDG PET Scan
Authors: Doroudinia Abtin , Safarpour Lima Behnam , Bakhshayesh Karam Mehrdad , Ghadimi Niloufar , Yousefi Farhad
Published: August 2021

We are presenting a 22-year-old man with intractable seizures. Autoimmune epilepsy, vasculitis, and paraneoplastic disorder were among initial differential diagnoses. His initial laboratory tests and toxicology screen were unremarkable. His initial brain MRI demonstrated generalized cortical atrophy. Features such as progressive encephalopathy, neuropsychiatric symptoms, personality change, and autonomic dysfunction were in favor of autoimmune encephalitis. Autoantibody evaluations including anti-NMDA receptor (NR1) IgG were negative in both serum and CSF samples. FDG PET scan demonstrated intense FDG uptake in the basal ganglia, more prominent in the caudate nuclei and putamina, which is one of the known autoimmune encephalitis imaging features.
Seeing the Invisible
Authors: Chuang Tzyy-Ling , Chen Yu-Ruei , Wang Yuh-Feng
Published: August 2021

A 76-year-old woman with uterine cervical cancer 20 years ago received right total hip replacement 3 months ago for right hip avascular necrosis without specific intraoperative finding. She reported persistent right hip pain after falling from bed. Pelvic x-ray showed right pubic ramus fracture. To evaluate prosthesis loosening, 99mTc-MDP 3-phase bone scan was arranged, showing diffusely and heterogeneously increased vascularity and tracer perfusion over the right hip, with intensely and heterogeneously increased metabolism in the right iliac bone and hip. SPECT/CT showed nearby swelling of calcified muscles. After debridement and synovectomy, the pathologic report showed chondroblastic osteosarcoma.
A Third Dose of SARS-CoV-2 Vaccine Increases Neutralizing Antibodies Against Variants of Concern in Solid Organ Transplant Recipients
Authors: Karaba Andrew H. , Zhu Xianming , Liang Tao , Wang Kristy H. , Rittenhouse Alex G. , Akinde Olivia , Eby Yolanda , Ruff Jessica E. , Blankson Joel N. , Abedon Aura T. , Alejo Jennifer L. , Cox Andrea L. , Bailey Justin R. , Thompson Elizabeth A. , Klein Sabra L. , Warren Daniel S. , Garonzik-Wang Jacqueline M. , Boyarsky Brian J. , Sitaras Ioannis , Pekosz Andrew , Segev Dorry L. , Tobian Aaron A.R. , Werbel William A.
Published: August 2021

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralizing activity. A third SARS-CoV-2 vaccine dose increased median anti-spike (1.6-fold) and receptor-binding domain (1.5-fold) IgG, as well as pseudoneutralization against VOCs (2.5-fold versus Delta). However, IgG and neutralization activity were significantly lower than healthy controls (p<0.001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination. Correlation with nAb was seen at anti-spike IgG >4 AU on the clinical assay and >10^4 AU on the research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.
International Completeness of Death Registration 2015-2019
Authors: Karlinsky Ariel
Published: August 2021

Death registration completeness, the share of deaths captured by countries’ vital registration systems, vary substantially across countries. Estimates of completeness, even recent ones, are outdated or contradictory for many countries. This paper presents the International Completeness of Death Registration (ICDR) dataset. ICDR contains the annual amount of deaths registered in 181 countries’ vital registration systems from 2015 to 2019. These counts allow derivation of the most up-to-date and consistent estimates of death registration completeness.
How big should this object be? Perceptual influences on viewing-size preferences
Authors: Chen (陳鴨嘉) Yi-Chia , Deza Arturo , Konkle Talia
Published: August 2021

When viewing objects depicted in a frame, observers prefer to view large objects like cars in larger sizes and smaller objects like cups in smaller sizes. That is, the visual size of an object that “looks best” is linked to its typical physical size in the world. Why is this the case? One intuitive possibility is that these preferences are driven by semantic knowledge: For example, when we recognize a sofa, we access our knowledge about its real-world size, and this influences what size we prefer to view the sofa within a frame. However, might visual processing play a role in this phenomenon—that is, do visual features that are related to big and small objects look better at big and small visual sizes, respectively, even when observers do not have explicit access to semantic knowledge about the objects? To test this possibility, we used “texform” images, which are synthesized versions of recognizable objects, which critically retain local perceptual texture and coarse contour information, but are no longer explicitly recognizable. To test for visual size preferences, we first used a size adjustment task, and the results were equivocal. However, clear results were obtained using a two-interval forced choice task, in which each texform was presented at the preferred visual size of its corresponding original image, and a visual size slightly bigger or smaller. Observers consistently selected the texform presented at the canonical visual size as the more aesthetically pleasing one. An additional control experiment ruled out alternative explanations related to size priming effects. These results suggest that the preferred visual size of an object depends not only on explicit knowledge of its real-world size, but also can be evoked by mid-level visual features that systematically covary with an object’s real-world size.

Highlights

We prefer to view large objects like cars large, and small objects like cups small

Intuitively, such preferences may be driven by our knowledge of object sizes

We used unrecognizable texforms of objects that preserved mid-level visual features

Similar viewing size preferences can be revealed with these texforms

Such preferences thus arise not only from knowledge but also from visual processing
Measuring thousands of single vesicle leakage events reveals the mode of action of antimicrobial peptides
Authors: Nahas Kareem Al , Fletcher Marcus , Hammond Katharine , Nehls Christian , Cama Jehangir , Ryadnov Maxim G , Keyser Ulrich F
Published: August 2021

Host defense or antimicrobial peptides hold promise for providing new pipelines of effective antimicrobial agents. Their activity quantified against model phospholipid membranes is fundamental to a detailed understanding of their structure-activity relationships. However, existing characterization assays lack the resolution necessary to achieve this insight. Leveraging a highly parallelized microfluidic platform for trapping and studying thousands of giant unilamellar vesicles, we conducted quantitative long-term microscopy studies to monitor the membrane-disruptive activity of archetypal antimicrobial peptides with a high spatiotemporal resolution. We described the modes of action of these peptides via measurements of the disruption of the vesicle population under the conditions of continuous peptide dosing using a range of concentrations, and related the observed modes with the molecular activity mechanisms of these peptides. The study offers an effective approach for characterizing membrane-targeting antimicrobial agents in a standardized manner, and for assigning specific modes of action to the corresponding antimicrobial mechanisms.
Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice
Authors: Berghoff Stefan A. , Spieth Lena , Sun Ting , Hosang Leon , Depp Constanze , Sasmita Andrew O. , Vasileva Martina H. , Scholz Patricia , Zhao Yu , Krueger-Burg Dilja , Wichert Sven , Brown Euan R , Michael Kyriakos , Nave Klaus-Armin , Bonn Stefan , Odoardi Francesca , Rossner Moritz , Ischebeck Till , Edgar Julia M. , Saher Gesine
Published: August 2021

Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelinating lesions, astrocytes downregulate cholesterol synthesis and the cholesterol that is essential for remyelination has to originate from other cellular sources. Here, we show that repair following acute versus chronic demyelination involves distinct processes. In particular, we found that in chronic myelin disease, when recycling of lipids is often defective, de novo neuronal cholesterol synthesis is critical for regeneration. By gene expression profiling, genetic loss of function experiments and comprehensive phenotyping, we provide evidence that neurons increase cholesterol synthesis in chronic myelin disease models and MS patients. In mouse models, neuronal cholesterol facilitated remyelination specifically by triggering OPC proliferation. Our data contribute to the understanding of disease progression and have implications for therapeutic strategies in MS patients.
Robustness of trinucleosome compaction to A-tract mediated linker histone orientation
Authors: De Madhura , Würtz Martin , Müller Gabriele , Tóth Katalin , Wade Rebecca C.
Published: August 2021

Linker histones (LH) have been shown to preferentially bind to AT-rich DNA, particularly A-tracts, contiguous stretches of adenines. Using spFRET (single pair Förster/Fluorescence Resonance Energy Transfer), we recently found that the globular domain (gH) ofXenopus laevisH1.0b LH orients towards A-tracts on the linker-DNA (L-DNA) while binding on-dyad in LH:mononucleosome complexes. Here, we investigate the impact of this A-tract-mediated orientation of the gH on the compaction of higher-order structures by studying trinucleosomes as minimal models for chromatin. Two 600 bp DNA sequences were constructed, each containing three consecutive Widom 601 core sequences connected by about 40 bp L-DNA but differing in the positioning of A-tracts on either the outer or the inner L-DNAs flanking the first and third Widom 601 sequences. The two inner L-DNAs were fluorescently labelled at their midpoints. Trinucleosomes were reconstituted using the doubly labelled DNA, core histone octamers and H1.0b. SpFRET was performed for a range of NaCl concentrations to measure the compaction and whether gH orientations affected the stability of the trinucleosomes to salt-induced dissociation. While the LH compacted the trinucleosomes, the extent of compaction and the stability were similar for the two DNA sequences. Modeling constrained by the measured FRET efficiency suggests that the structures adopted by the trinucleosomes correspond to the standard zig-zagged two-helical start arrangement with the first and third nucleosomes stacked on top of each other. In this arrangement, the first and third LHs are insufficiently close to interact and affect compaction. Thus, despite differences in the positioning of the A-tracts in the sequences studied, LH binding compacts the corresponding trinucleosomes similarly.

Why it matters

The compaction and three-dimensional structure of chromatin affect the exposure of the DNA and thus regulate gene expression. Linker histone proteins bind to nucleosomes and thereby contribute to chromatin compaction. We here investigated whether the DNA A-tract-mediated orientation of a linker histone globular domain affects chromatin structure by using a trinucleosome as a minimal model for chromatin. Our observations suggest that the trinucleosome structure and compaction are robust against differences in linker histone globular domain orientations.

eTOC blurb

We investigate whether DNA sequences, such as adenine-tracts, and sequence-induced linker histone reorientation affect chromatin structure. Using trinucleosomes as model systems for chromatin, we demonstrate that the chromatin structure and compaction are robust to the studied DNA sequence differences and sequence-induced linker histone orientation.
Single-nucleus RNA-sequencing in pre-cellularizationDrosophila melanogasterembryos
Authors: Albright Ashley , Stadler Michael , Eisen Michael
Published: August 2021

Our current understanding of the regulation of gene expression in the earlyDrosophila melanogasterembryo comes from observations of a few genes at a time, as within situhybridizations, or observation of gene expression levels without regards to patterning, as with RNA-sequencing. Single-nucleus RNA-sequencing however, has the potential to provide new insights into the regulation of gene expression for many genes at once while simultaneously retaining information regarding the position of each nucleus prior to dissociation based on patterned gene expression. In order to establish the practicality of single-nucleus RNA sequencing in the context of a real biological question, here we look at the difference in gene expression between control and an insulator protein, dCTCF, maternal null embryos during zygotic genome activation at nuclear cycle 14. We find that early embryonic nuclei can be grouped into distinct clusters according to gene expression. From both virtual and publishedin situhybridizations, we also find that these clusters correspond to spatial regions of the embryo. Lastly, we present multiple examples of differential gene expression between control and maternal CTCF null nuclei in one or more clusters, but not in bulk when grouping expression across all nuclei. These results highlight the potential for single-nucleus RNA-sequencing to reveal new insights into the regulation of gene expression in the earlyDrosophila melanogasterembryo.
Screening of cell-virus, cell-cell, gene-gene cross-talks among kingdoms of life at single cell resolution
Authors: Chen Dongsheng , Ou Zhihua , Zhu Jiacheng , Ding Peiwen , Wang Haoyu , Luo Lihua , Ding Xiangning , Lan Tianming , Wu Weiying , Yuan Yuting , Wu Wendi , Qiu Jiaying , Zhu Yixin , Jia Yi , Wei Yanan , Qin Qiuyu , Li Runchu , Sun Chengcheng , Zhao Wandong , Lv Zhiyuan , Pu Mingyi , Yang Shangchen , Chang Ashley , Wei Xiaofeng , Chen Fengzhen , Yang Tao , Wei Zhenyong , Yang Fan , Li Yuejiao , Hua Yan , Liu Huan
Published: August 2021

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) issued a significant and urgent threat to global health. The exact animal origin of SARS-CoV-2 remains obscure and understanding its host range is vital for preventing interspecies transmission. Previously, we have assessed the target cell profiles of SARS-CoV-2 in pets, livestock, poultry and wild animals. Herein, we expand this investigation to a wider range of animal species and viruses to provide a comprehensive source for large-scale screening of potential virus hosts. Single cell atlas for several mammalian species (alpaca, hamster, hedgehog, chinchilla etc.), as well as comparative atlas for lung, brain and peripheral blood mononuclear cells (PBMC) for various lineages of animals were constructed, from which we systemically analyzed the virus entry factors for 113 viruses over 20 species from mammalians, birds, reptiles, amphibians and invertebrates. Conserved cellular connectomes and regulomes were also identified, revealing the fundamental cell-cell and gene-gene cross-talks between these species. Overall, our study could help identify the potential host range and tissue tropism of SARS-CoV-2 and a diverse set of viruses and reveal the host-virus co-evolution footprints.
Nrf2 is a central regulator of the metabolic landscape in macrophages and finetunes their inflammatory response
Authors: Ryan Dylan G. , Knatko Elena V. , Casey Alva , Hukelmann Jens L. , Brenes Alejandro J. , Naidu Sharadha Dayalan , Higgins Maureen , Tronci Laura , Nikitopoulou Efterpi , O’Neill Luke A.J. , Frezza Christian , Lamond Angus I. , Abramov Andrey Y. , Cantrell Doreen A. , Murphy Michael P. , Dinkova-Kostova Albena T.
Published: August 2021

To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator the Kelch-like ECH associated protein 1 (Keap1). Here, we used high-resolution mass-spectrometry to characterize the proteomes of macrophages with genetically altered Nrf2 status. Our analysis revealed significant differences among the genotypes in cellular metabolism and redox homeostasis, which we validated with respirometry and metabolomics, as well as in anti-viral immune pathways and the cell cycle. Nrf2 status significantly affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity observed. Of note, Nrf2 activation was found to promote mitochondrial fusion in inflammatory macrophages. The Keap1 inhibitor, 4-octyl itaconate (4-OI), a derivative of the mitochondrial immunometabolite itaconate, remodeled the inflammatory macrophage proteome, increasing redox and suppressing anti-viral immune effectors in a Nrf2-dependent manner. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.

Graphical abstract

Highlights

First high-resolution proteome of macrophages with genetically altered Nrf2 status

Nrf2 is key regulator of macrophage redox and intermediary metabolism

Nrf2 finetunes the inflammatory response suppressing anti-viral immune and cytokine effectors, whilst promoting T cell activation factors

Nrf2 regulates mitochondrial adaptation in inflammatory macrophages promoting the formation of a fused network

4-octyl itaconate (4-OI) suppresses anti-viral immune effectors in inflammatory macrophages in a Nrf2-dependent manner
“Playing mysterious”: occurrence of Bio-duck calls in Brazil reveals a complex acoustic behaviour for the Antarctic minke whale (Balaenoptera bonaerensis)
Authors: Rossi-Santos Marcos R. , Filun Diego , Soares-Filho William , Paro Alexandre D. , Wedekin Leonardo L.
Published: August 2021

Acoustic methods can provide important data on the occurrence and distribution of migratory species. Information about Antarctic Minke whale (Balaenoptera bonaerensis) occurrence in the winter breeding grounds is scarce, mostly limited to old records from whaling stations before 1960’s international moratory, such as Costinha Station in Northeastern Brazil (6° S / 34° W). This work describes the occurrence of the Antarctic minke whale (AMW) through Bio-duck acoustic detections in the Santos Basin, South-Southeastern Brazil (22° and 28° S / 42° and 48° W), registered between November 12 and December 19, 2015. AMW calls were detected for 12 days. We detected and classified 9 different Bio-duck calls in Brazilian coast waters, evidencing a high diverse acoustic behaviour for the minke whale breeding ground. This is the first study to describe the acoustic diversity of AMW vocalizations in lower latitudes, constituting important information to the conservation and management of cetaceans and their habitat. Therefore, our study presents the foremost acoustic evidence of the Antarctic minke whale in Brazil, utilizing high technological passive acoustic methods, such as autonomous underwater vehicle (SeaGlider) sampling.
Microtubule-associated proteins promote microtubule generation in the absence of γ-tubulin in human colon cancer cells
Authors: Tsuchiya Kenta , Goshima Gohta
Published: August 2021

γ-Tubulin complex acts as the predominant microtubule (MT) nucleator that initiates MT formation and is therefore an essential factor for cell proliferation. Nonetheless, cellular MTs are formed after experimental depletion of the γ-tubulin complex, suggesting that cells possess other factors that drive MT nucleation. Here, by combining gene knockout, auxin-inducible degron, RNA interference, MT depolymerisation/regrowth assay, and live microscopy, we identified four microtubule-associated proteins (MAPs), ch-TOG, CLASP1, CAMSAPs, and TPX2, which are involved in γ-tubulin-independent MT generation in human colon cancer cells. In the mitotic MT regrowth assay, nucleated MTs organised non-centriolar MT organising centres (ncMTOCs) in the absence of γ-tubulin. Depletion of CLASP1 or TPX2 substantially delayed ncMTOC formation, suggesting that they promote MT nucleation in the absence of γ-tubulin. In contrast, depletion of CAMSAPs or ch-TOG did not affect the timing of ncMTOC appearance. CLASP1 also accelerates γ-tubulin-independent MT regrowth during interphase. Thus, MT generation can be promoted by MAPs without the γ-tubulin template.
Phase-locking patterns underlying effective communication in exact firing rate models of neural networks
Authors: Reyner-Parra David , Huguet Gemma
Published: August 2021

Macroscopic oscillations in the brain have been observed to be involved in many cognitive tasks but their role is not completely understood. One of the suggested functions of the oscillations is to dynamically modulate communication between neural circuits. The Communication Through Coherence (CTC) theory establishes that oscillations reflect rhythmic changes in excitability of the neuronal populations. Thus, populations need to be properly phase-locked so that input volleys arrive at the peaks of excitability of the receiving population to communicate effectively. Here, we present a modeling study to explore synchronization between neuronal circuits connected with unidirectional projections. We consider an Excitatory-Inhibitory (E-I) network of quadratic integrate-and-fire neurons modeling a Pyramidal-Interneuronal Network Gamma (PING) rhythm. The network receives an external periodic input from either one or two sources, simulating the inputs from other oscillating neural groups. We use recently developed mean-field models which provide an exact description of the macroscopic activity of the spiking network. This low-dimensional mean field model allows us to use tools from bifurcation theory to identify the phase-locked states between the input and the target population as a function of the amplitude, frequency and coherence of the inputs. We identify the conditions for optimal phaselocking and selective communication. We find that inputs with high coherence can entrain the network for a wider range of frequencies. Besides, faster oscillatory inputs than the intrinsic network gamma cycle show more effective communication than inputs with similar frequency. Our analysis further shows that the entrainment of the network by inputs with higher frequency is more robust to distractors, thus giving them an advantage to entrain the network. Finally, we show that pulsatile inputs can switch between attended inputs in selective attention.

Author summary

Oscillations are ubiquitous in the brain and are involved in several cognitive tasks but their role is not completely understood. The Communication Through Coherence theory proposes that background oscillations in the brain regulate the information flow between neural populations. The oscillators that are properly phase-locked so that inputs arrive at the peaks of excitability of the receiving population communicate effectively. In this paper, we study the emerging phase-locking patterns of a network generating PING oscillations under external periodic forcing, simulating the oscillatory input from other neural groups. We identify the conditions for optimal phase-locking and selective communication. Namely, we find that inputs with higher frequency and coherence have an adavantage to entrain the network and we quantify how robust are to distractors. Furthermore, we show how selective attention can be implemented by means of phase locking and we show that pulsatile inputs can switch between attended inputs.
An approximate stochastic optimal control framework to simulate nonlinear neuro-musculoskeletal models in the presence of noise
Authors: Van Wouwe Tom , Ting Lena H. , De Groote Friedl
Published: August 2021

Optimal control simulations have shown that both musculoskeletal dynamics and physiological noise are important determinants of movement. However, due to the limited efficiency of available computational tools, deterministic simulations of movement focus on accurately modelling the musculoskeletal system while neglecting physiological noise, and stochastic simulations account for noise while simplifying the dynamics. We took advantage of recent approaches where stochastic optimal control problems are approximated using deterministic optimal control problems, which can be solved efficiently using direct collocation. We were thus able to extend predictions of stochastic optimal control as a theory of motor coordination to include muscle coordination and movement patterns emerging from non-linear musculoskeletal dynamics. In stochastic optimal control simulations of human standing balance, we demonstrated that the inclusion of muscle dynamics can predict muscle co-contraction as minimal effort strategy that complements sensorimotor feedback control in the presence of sensory noise. In simulations of reaching, we demonstrated that nonlinear multi-segment musculoskeletal dynamics enables complex perturbed and unperturbed reach trajectories under a variety of task conditions to be predicted. In both behaviors, we demonstrated how interactions between task constraint, sensory noise, and the intrinsic properties of muscle influence optimal muscle coordination patterns, including muscle co-contraction, and the resulting movement trajectories. Our approach enables a true minimum effort solution to be identified as task constraints, such as movement accuracy, can be explicitly imposed, rather than being approximated using penalty terms in the cost function. Our approximate stochastic optimal control framework predicts complex features, not captured by previous simulation approaches, providing a generalizable and valuable tool to study how musculoskeletal dynamics and physiological noise may alter neural control of movement in both healthy and pathological movements.
Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma
Authors: Lozano Anthony , Souche François-Régis , Ramirez Christel , Vegna Serena , Desandré Guillaume , Riviere Anaïs , Dardalhon Valérie , El Aabidine Amal Zine , Fort Philippe , Akkari Leila , Hibner Urszula , Grégoire Damien
Published: August 2021

Quantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to metastatic tumours, despite the evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumoral microenvironment at the two locations suggests that fast metastatic growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and highlights potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.
Autophagy coordinates chondrocyte development and early joint formation in zebrafish
Authors: Moss Joanna J. , Wirth Martina , Tooze Sharon A. , Lane Jon D. , Hammond Chrissy L.
Published: August 2021

Autophagy is a catabolic process responsible for the removal of waste and damaged cellular components by lysosomal degradation. It plays a key role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for cartilage cell (chondrocyte) development and survival, and for the formation of cartilage. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders such as osteoarthritis and osteoporosis. To test the requirement for autophagy during skeletal development in zebrafish, we generated an atg13 CRISPR knockout zebrafish line. This line showed a complete loss of atg13 expression, and restricted autophagic activity in vivo. In the absence of autophagy, chondrocyte maturation was accelerated, with chondrocytes exhibiting signs of premature hypertrophy. Focussing on the jaw element, autophagy disruption affected joint articulation causing restricted mouth opening. This gross behavioural phenotype corresponded with a failure to thrive, and death in homozygote atg13 nulls within 17 days. Taken together, our results are consistent with autophagy contributing to the timely regulation of chondrocyte maturation and for extracellular matrix formation.
Response of Posidonia oceanica (L.) Delile and its associated N2 fixers to different combinations of temperature and light levels
Authors: García-Márquez Manuela Gertrudis , Fernández-Juárez Víctor , Rodríguez-Castañeda José Carlos , Agawin Nona S. R.
Published: August 2021

Ocean warming and water turbidity are threats for the persistence of seagrass meadows and their effects on the productivity of seagrasses and the functioning of their associated microorganisms have not been studied extensively. The purpose of this study was to assess the effects of different light levels and temperatures on Posidonia oceanica, the endemic seagrass species in the Mediterranean Sea, and their N2 fixing community, which contributes importantly to the nitrogen requirements and high productivity of the plants. Aquarium experiments were conducted in winter when the plants are more vulnerable to changes in temperature, subjecting them to short-term exposures to ambient (15.5 °C) and elevated temperatures (ambient+5.5 °C) and at limited (13 μmol photons m-2 s-1) and saturating light conditions (124 μmol photons m-2 s-1). Primary production, chlorophyll content, reactive oxygen species production, polyphenols content, the nifH gene expression, N2 fixation and alkaline phosphatase activities were measured in different plant tissues. Plants incubated at ambient temperature and high light exhibited enhanced total chlorophyll production and significantly higher gross and net primary production, which were approximately two-fold compared to the rest of the treatments. The oxidative stress analyses revealed increased production of reactive oxygen species in young leaves incubated at ambient temperature and saturating light, while the polyphenols content in top leaves was considerably higher under elevated temperatures. In contrast, N2 fixation and alkaline phosphatase rates were significantly higher under elevated temperature and low light levels. The presence of the N2 fixing phylotypes UCYN-A, -B and -C was detected through genetic analyses, with UCYN-B demonstrating the highest nifH gene transcription levels at elevated temperatures. These findings emphasize the significant role of irradiance on the productivity of P. oceanica and the temperature dependence of the N2 fixation process in winter.
Engineering Bacillus subtilis for the formation of a durable living biocomposite material
Authors: Kang Sun-Young , Pokhrel Anaya , Bratsch Sara , Benson Joey J. , Seo Seung-Oh , Quin Maureen B. , Aksan Alptekin , Schmidt-Dannert Claudia
Published: August 2021

Engineered living materials (ELMs) are a fast-growing area of research that combine approaches in synthetic biology and material science. Here, we engineer B. subtilis to become a living component of a silica material composed of self-assembling protein scaffolds for functionalization and cross-linking of cells. B. subtilis was engineered to display SpyTags on polar flagella for cell attachment and cross-linking of SpyCatcher modified secreted scaffolds. Through deletion of the autolysis LytC, endospore limited B. subtilis cells become a structural component of the material with spores for long-term storage of genetic programming. Known silica biomineralization peptides were screened and scaffolds designed for silica polymerization to fabricate biocomposite materials with enhanced mechanical properties. We show that the resulting ELM can be regenerated from a piece of silica material and that new functions can be readily incorporated by co-cultivation of engineered B. subtilis strains. We believe that this work will serve as a framework for the future design of resilient ELMs as functional, self-healing materials for use as responsive coatings and plasters.
Gpnmb inhibits oligodendrocyte differentiation of adult neural stem cells by amplifying TGFβ1 signaling
Authors: Radecki Daniel Z. , Wang Albert R. , Johnson Abigail S. , Overman Christian A. , Thatcher Madison M. , Iyer Gopal , Samanta Jayshree
Published: August 2021

Gli1 expressing neural stem cells, in the subventricular zone of the adult mammalian brain, respond to demyelination injury by differentiating into oligodendrocytes. We have identified Gpnmb as a novel regulator of oligodendrogenesis in Gli1 neural stem cells, whose expression is induced by TGFβ1 signaling via Gli1, in response to a demyelinating injury. Upregulation of Gpnmb further activates the TGFβ1 pathway by increasing the expression of the TGFβ1 binding receptor subunit, TGFβR2. Thus the TGFβ1→Gli1→Gpnmb→TGFβR2 signaling pathway forms a feed forward loop for sustained activation of TGFβ1 signaling in Gli1 neural stem cells, resulting in inhibition of their differentiation into mature oligodendrocytes following demyelination.
Severe inbreeding and gene loss in the historical and extant population of the critically endangered Devils Hole pupfish
Authors: Tian David , Turner Bruce J. , Martin Christopher H.
Published: August 2021

Small populations with limited geographic distributions are predicted to be threatened by inbreeding and lack of genetic diversity, both of which may negatively impact fitness and exacerbate population decline. One of the most extreme natural examples is the Devils Hole pupfish (Cyprinodon diabolis), an iconic and critically endangered species with the smallest known habitat range of any vertebrate. This imperiled species has experienced severe declines in population size over the last thirty years and suffered major, repeated bottlenecks in 2007 and 2013, when the population sunk to 38 and 35 individuals, respectively. Here we sequenced contemporary and historical genomes of Devils Hole and neighboring Death Valley and Ash Meadows desert pupfishes to examine the genomic consequences of small population size. We found extreme inbreeding (FROH = 0.71 - 0.82) and increased genetic load in the Devils Hole pupfish. We also document unique fixed loss-of-function (LOF) alleles and deletions in genes associated with sperm motility, stress, and hypoxia within the extant Devils Hole pupfish population that likely reduce fitness. Comparisons between contemporary samples (2008 – 2012) and a genome sequenced from a 1980 formalin-fixed museum specimen suggest that inbreeding has increased 6% as the population has declined, but that many putatively deleterious variants have been segregating in the population since at least 1980. This includes a fixed early stop codon in cfap43 (n = 8/8 samples), which is associated with sperm flagellum defects and causes infertility in humans and mice. Out of ninety-four unique deletions, fifteen were detected within 2 kb of annotated genes. Five have roles in physiological responses to hypoxia and mitochondrial activity, such as redd1 (n = 7/7 samples), suggesting impaired hypoxia tolerance in this species despite the low oxygen concentrations of Devils Hole. We thus document one of the most extreme inbreeding events in a natural population and a set of candidate deleterious variants to inform management and potential genetic rescue in this conservation icon.
Using Oxford Nanopore Technology direct RNA sequencing to identify depurination events induced by ricin and other ribosome inactivating proteins
Authors: Ryan Yan , Harrison Abbie , Trivett Hannah , Hartley Catherine , David Jonathan , Clark Graeme , Hiscox Julian A.
Published: August 2021

Depurination is a frequent modification to both DNA and RNA, in DNA causing point mutations through misincorporation, in RNA, disabling ribosomes and halting protein synthesis. Some modifications of nucleic acids can be determined by direct sequencing using Oxford Nanopore Technologies (ONT). However, the identification of modifications is often limited by noise and their variety and number. Ricin is a toxin which enters cells and depurinates an adenine base in the sarcin-ricin loop of the large ribosomal subunit. This leaves only a ribose backbone, thus inhibiting protein translation. In humans, biological threat agents and ribosome inactivating proteins, such as ricin and saporin, depurinate base 4605 on the 28S rRNA providing a single defined target to try and identify. We postulated that the depurination event could be detected using ONT direct RNA sequencing through a change in charge in the ricin loop. A software tool was developed, RIPpore, that quantified the adenine modification from direct RNA sequencing data of ribosomal RNA purified from respiratory epithelial cells exposed to ricin. This provided a novel method of directly identifying ricin exposure and a basis for ONT’s utility in detecting lesions in nucleic acids caused by depurination events.
Analysis of Mouse Vocal Communication (AMVOC): A deep, unsupervised method for rapid detection, analysis, and classification of ultrasonic vocalizations
Authors: Stoumpou Vasiliki , Vargas César D. M. , Schade Peter F. , Giannakopoulos Theodoros , Jarvis Erich D.
Published: August 2021

Some aspects of the neural mechanisms underlying mouse ultrasonic vocalizations (USVs) are a useful model for the neurobiology of human speech and speech-related disorders. Much of the research on vocalizations and USVs is limited to offline methods and supervised classification of USVs, hindering the discovery of new types of vocalizations and the study of real-time free behavior. To address these issues, we developed AMVOC (Analysis of Mouse VOcal Communication) as a free, open-source software to analyze and detect USVs in both online and offline modes. When compared to hand-annotated ground-truth USV data, AMVOC’s detection functionality (both offline and online) has high accuracy, and outperforms leading methods in noisy conditions, thus allowing for broader experimental use. AMVOC also includes the implementation of an unsupervised deep learning approach that facilitates discovery and analysis of USV data by clustering USVs using latent features extracted by a convolutional autoencoder and isimplemented in a graphical user interface (GUI), also enabling user’s evaluation. These results can be used to explore the vocal repertoire space of the analyzed vocalizations. In this way, AMVOC will facilitate vocal analyses in a broader range of experimental conditions and allow users to develop previously inaccessible experimental designs for the study of mouse vocal behavior.
Novel murine models of post-implantation and midgestional malaria-induced preterm birth
Authors: Andrew Alicer K. , Cooper Caitlin A. , Moore Julie M.
Published: August 2021

Despite major advances made in malaria treatment and control over recent decades, the development of new models for studying disease pathogenesis remains a vital part of malaria research efforts. The study of malaria infection during pregnancy is particularly reliant on mouse models, as a means of circumventing many challenges and costs associated with pregnancy studies in endemic human populations. Here, we introduce three novel murine models that will further our understanding of how post-implantation and midgestional malaria infection affects pregnancy outcomes. When C57BL/6J (B6) mice are infected with Plasmodium chabaudi chabaudi AS on either embryonic day (E) 6.5, 8.5, or 10.5, preterm birth occurs in all animals by E16.5, E17.5, or E18.5 respectively, with no evidence of intrauterine growth restriction. We found that the time to delivery, placental inflammatory and antioxidant transcript upregulation, and the relationships between parasitemia and transcript expression prior to preterm birth are different based on the embryonic day of infection. On the day before preterm delivery, E6.5 infected mice did not experience significant upregulation of the inflammatory or antioxidant gene transcripts examined; however, parasitemia correlated positively with Il1β, Cox1, and Hmox1 placental transcript abundance. E8.5 infected mice had elevated transcripts for Ifnγ, Tnf, Il10, Cox1, Cox2, Sod1, Sod2, Cat, and Nrf2, while Sod3 was the only transcript that correlated with parasitemia. Finally, E10.5 infected mice had elevated transcripts for Ifnγ only, with a tendency for Tnf transcripts to correlate with parasitemia. Tumor necrosis factor deficient (TNF-/-) and TNF receptor 1 deficient (TNFR1-/-) mice infected on E8.5 experienced preterm birth at the same time as B6 controls. Further characterization of these models is necessary to discover new and/or existing mechanism(s) or trigger(s) responsible for malaria-driven preterm birth that is determined by gestational age upon maternal infection, parasite-host dynamics, or both.