bluuebunny/crossref_metadata_2025 huggingface dataset:
The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
Authors: Jiménez-Panizo Alba , Alegre-Martí Andrea , Fettweis Gregory , Abella Montserrat , Antón Rosa , Tettey Theophilus , Schiltz Louis R. , Johnson Thomas A , Nuñez-Barrios Israel , Font-Díaz Joan , Caelles Carme , Valledor Annabel F. , Pérez Paloma , Rojas Ana M. , Fernández-Recio Juan , Presman Diego M. , Hager Gordon L. , Fuentes-Prior Pablo , Estébanez-Perpiñá Eva
Published: October 2021

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in living cells. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work unveils likely pathophysiologically relevant quaternary assemblies of the nuclear receptor with important implications for glucocorticoid action and drug design.
A NYN domain protein directly interacts with DCP1 and is required for phyllotactic pattern in Arabidopsis
Authors: Schiaffini Marlene , Chicois Clara , Pouclet Aude , Chartier Tiphaine , Ubrig Elodie , Gobert Anthony , Zuber Hélène , Mutterer Jérôme , Chicher Johana , Kuhn Lauriane , Hammann Philippe , Gagliardi Dominique , Garcia Damien
Published: October 2021

In eukaryotes, general mRNA decay requires the decapping complex. The activity of this complex depends on its catalytic subunit, DCP2 and its interaction with decapping enhancers, including its main partner DCP1. Here, we report that in Arabidopsis, DCP1 also interacts with a NYN domain endoribonuclease, hence named DCP1-ASSOCIATED NYN ENDORIBONUCLEASE 1 (DNE1). Interestingly, we find DNE1 predominantly associated with DCP1 but not with DCP2 and reciprocally, suggesting the existence of two distinct protein complexes. We also show that the catalytic residues of DNE1 are required to repress the expression of mRNAs in planta upon transient expression. The overexpression of DNE1 in transgenic lines leads to growth defects and transcriptomic changes related to the one observed upon inactivation of the decapping complex. Finally, the combination of dne1 and dcp2 mutations, revealed a functional redundancy between DNE1 and DCP2 in controlling phyllotactic pattern formation in Arabidopsis. Our work identifies DNE1, a hitherto unknown DCP1 protein partner highly conserved in the plant kingdom and identifies its importance for developmental robustness.

One-sentence summary

DNE1, a NYN domain protein interacts with the decapping activator DCP1 and, together with DCP2, specify phyllotactic patterns in Arabidopsis.
Using conditional inference to quantify interaction effects of socio-demographic covariates of US COVID-19 vaccine hesitancy
Authors: Shen Ke , Kejriwal Mayank
Published: October 2021

COVID-19 vaccine hesitancy has become a major issue in the U.S. as vaccine supply has outstripped demand and vaccination rates slow down. At least one recent global survey has sought to study the covariates of vaccine acceptance, but an inferential model that makes simultaneous use of several socio-demographic variables has been lacking. In this article, we present such a model using US-based survey data collected by Gallup. Our study agrees with the global survey results in some respects, but is also found to exhibit significant differences. For example, women and people aged between 25-54 were found to be more vaccine hesitant. Our conditional inference tree model suggests that trust in government, age and ethnicity are the most important covariates for predicting vaccine hesitancy, and can interact in ways that make them useful for communication-based outreach, especially if conjoined with census data. In particular, we found that the most vaccine hesitant individuals were those who identified as Black Republicans with a high school (or lower) education and lower income levels, who were involuntarily unemployed and trusted in the Trump administration.
Dietary vitamin B12 regulates chemosensory receptor gene expression via the MEF2 transcription factor in Caenorhabditis elegans
Authors: McDonagh Aja , Crew Jeannette , van der Linden Alexander M.
Published: October 2021

Dynamic changes in chemoreceptor gene expression levels in sensory neurons is one strategy that an animal can use to modify their responses to dietary changes. However, the mechanisms underlying diet-dependent modulation of chemosensory gene expression are unclear. Here, we show that the expression of the srh-234 chemoreceptor gene localized in a single ADL sensory neuron type of C. elegans is downregulated when animals are fed a Comamonas bacterial diet, but not on an E. coli diet. Remarkably, this diet-modulated effect on srh-234 gene expression levels is dependent on the micronutrient vitamin B12 endogenously produced by Comamonas bacteria. Excess propionate and genetic perturbations in the canonical and shunt propionate breakdown pathways are able to override the repressing effects of vitamin B12 on srh-234 expression. The vitamin B12-mediated regulation of srh-234 expression levels in ADL requires the MEF-2 transcription factor, providing a potential mechanism by which dietary vitamin B12 may transcriptionally tune individual chemoreceptor genes in a single sensory neuron type, which in turn may change animal responses to biologically relevant chemicals in their diet.
Arabidopsis Apoplastic Fluid Contains sRNA- and Circular RNA-Protein Complexes that Are Located Outside Extracellular Vesicles
Authors: Zand Karimi Hana , Baldrich Patricia , Rutter Brian D. , Borniego Lucía , Zajt Kamil K. , Meyers Blake C. , Innes Roger W.
Published: October 2021

Previously, we have shown that apoplastic wash fluid purified from Arabidopsis leaves contains small RNAs (sRNAs). To investigate whether these sRNAs are encapsulated inside extracellular vesicles (EVs), we treated EVs isolated from Arabidopsis leaves with the protease trypsin and RNase A, which should degrade RNAs located outside EVs but not those located inside. These analyses revealed that apoplastic RNAs are mostly located outside EVs and are associated with proteins. Further analyses of these extracellular RNAs (exRNAs) revealed that they comprise both sRNAs and long non-coding RNAs (lncRNAs), including circular RNAs (circRNAs). We also found that exRNAs are highly enriched in the post-transcriptional modification N6-methyladenine (m6A). Consistent with this, we identified a putative m6A-binding protein in apoplastic wash fluid, GLYCINE-RICH RNA-BINDING PROTEIN 7 (GRP7), as well as the small RNA-binding protein ARGONAUTE2 (AGO2). These two proteins co-immunoprecipitated with each other, and with lncRNAs, including circRNAs. Mutation of GRP7 or AGO2 caused changes in both the sRNA and lncRNA content of apoplastic wash fluid, suggesting that these proteins contribute to the secretion and/or stabilization of exRNAs. We propose that these extravesicular RNAs mediate host-induced gene silencing, rather than RNA inside EVs.

One-sentence summary

The apoplast of Arabidopsis leaves contains diverse small and long-noncoding RNAs, including circular RNAs, that are bound to protein complexes and are located outside extracellular vesicles.
Stress-dependent cell stiffening by tardigrade tolerance proteins through reversible formation of cytoskeleton-like filamentous network and gel-transition
Authors: Tanaka Akihiro , Nakano Tomomi , Watanabe Kento , Masuda Kazutoshi , Honda Gen , Kamata Shuichi , Yasui Reitaro , Kozuka-Hata Hiroko , Watanabe Chiho , Chinen Takumi , Kitagawa Daiju , Sawai Satoshi , Oyama Masaaki , Yanagisawa Miho , Kunieda Takekazu
Published: October 2021

Tardigrades are able to tolerate almost complete dehydration by entering a reversible ametabolic state called anhydrobiosis and resume their animation upon rehydration. Dehydrated tardigrades are exceptionally stable and withstand various physical extremes. Although trehalose and late embryogenesis abundant (LEA) proteins have been extensively studied as potent protectants against dehydration in other anhydrobiotic organisms, tardigrades produce high amounts of tardigrade-unique protective proteins. Cytoplasmic-abundant heat-soluble (CAHS) proteins are uniquely invented in the lineage of eutardigrades, a major class of the phylum Tardigrada and are essential for their anhydrobiotic survival. However, the precise mechanisms of their action in this protective role are not fully understood. In the present study, we first postulated the presence of tolerance proteins that form protective condensates via phase separation in a stress-dependent manner and searched for tardigrade proteins that reversibly form condensates upon dehydration-like stress. Through comprehensive analysis, we identified 336 such proteins, collectively dubbed “Desolvataion-induced ReversiblY condensing Proteins (DRYPs)”. Unexpectedly, we rediscovered CAHS proteins as highly enriched in DRYPs, 3 of which were major components of DRYPs. We revealed that these CAHS proteins reversibly polymerize into many cytoskeleton-like filaments depending on hyperosmotic stress in cultured cells and undergo reversible gel-transition in vitro. CAHS filamentation increases cell stiffness to resist deformation and improves resistance to dehydration-like stress. The conserved putative helical C-terminal region is necessary and sufficient for filament formation by CAHS proteins, and mutations disrupting the secondary structure of this region impaired both the filament formation and the gel transition. On the basis of these results, we propose that CAHS proteins are novel cytoskeletal proteins that form filamentous networks and undergo gel-transition in a stress-dependent manner to provide on-demand physical stabilization of cell integrity against deformative forces during dehydration and also contribute to the exceptional physical stability in a dehydrated state.
Cockroaches adjust body and appendages to traverse cluttered large obstacles
Authors: Wang Yaqing , Othayoth Ratan , Li Chen
Published: October 2021

To traverse complex natural terrain, animals often transition between locomotor modes. It is well known that locomotor transitions can be induced by switching in neural control circuits or be driven by a need to minimize metabolic energetic cost. Recent work discovered that locomotor transitions in complex 3-D terrain cluttered with large obstacles can also emerge from physical interaction with the environment controlled by the nervous system. To traverse cluttered, stiff grass-like beams, the discoid cockroach often transitions from using a strenuous pitch mode to push across to using a less strenuous roll mode to maneuver through the gaps, during which a potential energy barrier must be overcome. Although previous robotic physical modeling demonstrated that kinetic energy fluctuation from body oscillation generated by leg propulsion can help overcome the barrier and facilitate this transition, the animal was observed to transition even when the barrier still exceeds kinetic energy fluctuation. Here, we further studied whether and how the cockroach makes active adjustments to facilitate this locomotor transition to traverse cluttered beams. We observed that the animal flexed its head and abdomen, reduced hind leg sprawl, and used both hind legs differentially during the pitch-to-roll transition, which were absent when running on a flat ground. Using a refined potential energy landscape with additional degrees of freedom modeling these adjustments, we found that head flexion did not substantially reduce the transition barrier, whereas the leg sprawl reduction did so dramatically. We discussed likely functions of the observed adjustments and suggested future directions.
Hemodynamics After Fontan Procedure are Determined by Patient Characteristics and Anastomosis Placement Not Graft Selection: a Patient-Specific Multiscale Computational Study
Authors: Kung Ethan , Baker Catriona , Corsini Chiara , Baretta Alessia , Biglino Giovanni , Arbia Gregory , Pant Sanjay , Marsden Alison , Taylor Andrew , Quail Michael , Vignon-Clementel Irene , Pennati Giancarlo , Migliavacca Francesco , Schievano Silvia , Hlavacek Anthony , Dorfman Adam , Hsia Tain-Yen , Figliola Richard ,   Modeling of Congenital Hearts Alliance (MOCHA)+ Investigators
Published: October 2021

Objectives

Patient-specific multiscale modeling simulates virtual surgeries of the Fontan procedure using three different graft options. Predictive modeling details post-operative outcomes that can help inform clinical decision support.

Methods

Six patients underwent preoperative cardiac magnetic resonance imaging and catheterization. Virtual surgery is carried out for each patient to test the resulting hemodynamics of three Fontan graft options: ECC, 9mm Y-graft, and 12mm Y-graft.

Results

1) one-way ANOVA p>0.998 in all systemic pressures and flows between graft options, 2) p=0.706 for hepatic flow distribution between graft options, 3) local power loss differences do not affect the systemic circulation, 4) anastomosis positioning modification of the same Y-graft in the same patient changed left PA hepatic distribution from 0.66 to 0.49

Conclusions

Systemic pressures and blood flow after the Fontan procedure are not affected by graft selection but are well influenced by patient pulmonary vascular impedance. The hepatic distribution can be affected by anastomosis placement.

Ultra-mini abstract

We present the first case series of patient-specific multiscale modeling of the Fontan procedure. Despite noticeable local power loss differences, graft selection does not affect systemic pressure and flow rates or other clinically relevant quantities. Anastomosis placement can affect hepatic distribution.
Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy
Authors: Takamatsu Shiro , Hamanishi Junzo , Brown JB , Yamaguchi Ken , Yamanoi Koji , Murakami Kosuke , Gotoh Osamu , Mori Seiichi , Mandai Masaki , Matsumura Noriomi
Published: October 2021

Higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. Systematic mutational signature analysis on all solid tumors in The Cancer Genome Atlas yielded eight distinct tumor genomic subtypes, which were characterized by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were construed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. Under this hypothesis, we developed a software to classify new tumors submitted to whole-exome sequencing. A pan-cancer dataset containing 973 cases treated with ICIs and clinical response was used for validation, where the classified tumor subtypes were significantly associated with ICI response, independent of cancer type and tumor mutational burden high or low status. The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.
Determination of utility of 3 minute and 6 minute walk tests in assessment of progression of mild COVID-19 infection at a tertiary hospital in North India
Authors: Goel Aastha , Chowdhury Souradeep , Ghosh Tamoghna , Singh Anupam , Kumar Arvind , Wig Naveet
Published: October 2021

Introduction

There have been 214 million confirmed cases of COVID-19 worldwide with a total death tally of 4.4 million. The current study aims to determine the predictive value of 3 minute and 6-minute walk tests in assessment of progression of mild COVID-19 infection at a tertiary care hospital in North India.

Methods

The study population consisted of adults (age more than 18 years) with a confirmed diagnosis of Covid-19 by RT-PCR on nasopharyngeal specimens. Patients with only mild illness were enrolled. After the patients were admitted to the isolation ward, the presenting history, comorbidity status, vital signs and laboratory parameters were recorded. The 3 and 6 minute walk test was performed daily from admission till discharge or progression of severity of COVID-19 and it was used to calculate BDS and NEWS2 scores.

Results

Our study consisted of 50 patients with 34 (68%) males and the mean (SD) age of the patient population being 28.1 (6.4) years. The most common symptoms were fever, sore throat, and cough. All laboratory parameters were within normal ranges for all the patients. 96% recovered without progression, while only 4% of them progressed to moderate illness. Results of the 3 and 6 minutes walk tests, BDS and NEWS2 scores showed improvement over the course of hospital stay.

Conclusions

Although the walk tests and the scores improved over time, they failed to predict the disease progression.
Non-pharmaceutical interventions and vaccinating school children required to contain SARS-CoV-2 Delta variant outbreaks in Australia: a modelling analysis
Authors: Milne George J , Carrivick Julian , Whyatt David
Published: October 2021

Abstract
Background: In countries with high COVID-19 vaccination rates the SARS-CoV-2 Delta variant has resulted in rapidly increasing case numbers. This study evaluated the use of non-pharmaceutical interventions (NPIs) coupled with alternative COVID-19 vaccination strategies to determine feasible Delta mitigation strategies for Australia. We aimed to understanding the interplay between high vaccine coverage levels and NPI physical distancing activation, and to establish the benefit of adding children and adolescents to the vaccination program. Border closure has limited SARS-CoV-2 transmission in Australia, however slow vaccination uptake resulted in Delta outbreaks in the two largest cities, and may continue once international travel resumes.
Methods: An agent-based model was used to evaluate the potential reduction in the COVID-19 health burden resulting from alternative vaccination strategies. We assumed immunity was derived from vaccination with the BNT162b2 Pfizer BioNTech vaccine. Two age-specific vaccination strategies were evaluated, age 5 and above, and 12 and above, and the health burden determined under alternative coverages, with/without activation of NPIs. Age-specific infections generated by the model, together with recent UK data, permitted reductions in the health burden to be quantified.
Results: Cases, hospitalisations and deaths are shown to reduce by: i) increasing coverage to include children aged 5 to 11 years, ii) activating moderate NPI measures, and/or iii) increasing coverage levels above 80%. At 80% coverage, vaccinating ages 12 plus without NPIs is predicted to give 1,162 hospitalisations; adding ages 5 and above gives 1,073 cases per million population. Activating moderate NPIs reduces hospitalisations to 705. Alternatively, increasing coverage to 90% reduces this to 684. Combining all three measures is shown to reduce cases to 398, hospitalisations to 2 and deaths to zero.
Conclusions: Delta variant outbreaks may be successfully managed by an achievable 80% vaccine coverage rate and moderate NPI measures, allowing schools and many workplaces to remain open. This prevents use of hard lockdown measures, and consequential economic and societal damage. Activating moderate NPIs is shown to give a similar reduction in health burden as increasing coverage of ages 12 and above to 90%. If 90% coverage cannot be achieved, including children and adolescents in the vaccination program coupled with moderate NPIs appears necessary to contain future COVID-19 Delta transmission.
Actin capping protein regulates actomyosin contractility to maintain germline architecture in C. elegans
Authors: Ray Shinjini , Agarwal Priti , Zaidel-Bar Ronen
Published: October 2021

Actin dynamics play an important role in the morphogenesis of cells and tissues, yet the control of actin filament growth takes place at the molecular level. A challenge in the field is to link the molecular function of actin regulators with their physiological function. Here, we report the in vivo role of the actin capping protein CAP-1 in the C. elegans germline. We show that CAP-1 is associated with actomyosin structures in the cortex and rachis, where it keeps the level of contractility in check. A 60% reduction in the level of CAP-1 leads to a 2-fold increase in F-actin and non-muscle myosin II and only a 30% increase in Arp2/3. CAP-1 depletion leads to severe structural defects in the syncytial germline and oocytes, which can be rescued by reducing myosin activity. Thus, we uncover a physiological role for actin capping protein in maintaining C. elegans fertility by regulating the level of actomyosin contractility.
Multimodal Imaging Mass Spectrometry of Murine Gastrointestinal Tract with Retained Luminal Content Shows Molecular Localization Patterns
Authors: Guiberson Emma R. , Wexler Aaron G. , Good Christopher J. , Skaar Eric P. , Spraggins Jeffrey M. , Caprioli Richard M.
Published: October 2021

Digestive diseases impact 62 million people a year in the United States. Despite the central role of the gut to human health, past imaging mass spectrometry (IMS) investigations into the gastrointestinal tract are incomplete. The gastrointestinal tract, including luminal content, harbors a complex mixture of microorganisms, host dietary content, and immune factors. Existing imaging approaches remove luminal content, and images focus on small regions of tissue. Here, we demonstrate the use of a workflow to collect multimodal imaging data for both intestinal tissue and luminal content. This workflow for matrix-assisted laser desorption/ionization imaging mass spectrometry retains luminal content and expands the amount of tissue imaged on one slide. Results comparing tissue and luminal content show unique molecular distributions using multimodal imaging modalities including protein, lipid, and elemental imaging. Leveraging this method to investigate intestinal tissue infected with Clostridioides difficile compared to control tissue shows clear differences in lipid abundance of various lipid classes in luminal content during infection. These data highlight the potential for this approach to detect unique biological and markers of infection in the gut.
Drug screening at single-organoid resolution via bioprinting and interferometry
Authors: Tebon Peyton J. , Wang Bowen , Markowitz Alexander L. , Davarifar Ardalan , Krawczuk Patrycja , Murray Graeme , Nguyen Huyen Thi Lam , Tavanaie Nasrin , Nguyen Thang L. , Boutros Paul C. , Teitell Michael A. , Soragni Alice
Published: October 2021

High-throughput drug screening is an established approach to investigate tumor biology and identify therapeutic leads. Traditional platforms for high-throughput screening use two-dimensional cultures of immortalized cell lines which do not accurately reflect the biology of human tumors. More clinically relevant model systems, such as three-dimensional tumor organoids, can be difficult to screen and scale. For example, manually seeded organoids coupled to destructive endpoint assays allow for the characterization of response to treatment, but do not capture the transitory changes and intra-sample heterogeneity underlying clinically observed resistance to therapy. We therefore developed a pipeline to generate bioprinted tumor organoids linked to label-free, real-time imaging via high-speed live cell interferometry (HSLCI) and machine learning-based quantitation of individual organoids. Bioprinting cells gives rise to 3D organoid structures that preserve tumor histology and gene expression. HSLCI imaging in tandem with machine learning-based image segmentation and organoid classification tools enables accurate, label-free parallel mass measurements for thousands of bioprinted organoids. We demonstrate that our method quantitatively identifies individual organoids as insensitive, transiently sensitive, or persistently sensitive to specific treatments. This opens new avenues for rapid, actionable therapeutic selection using automated tumor organoid screening.
Mechanistic Model of Replication Fork Progression in Yeast
Authors: Singh Ghanendra
Published: October 2021

Replication fork progression complex plays an essential role during DNA replication. It travels along with the DNA with a particular speed called replication fork speed. Faithful duplication of the genome requires strict control over replication fork speed. Both acceleration and pausing mechanisms of the replication fork complex are regulated at the molecular level. Based on the experimental evidence, DNA replicates faster in normal cells than cancer cells, whereas cancer cells duplicate themselves more quickly than normal cells. Then in principle, accelerating the replication fork complex in cancer cells beyond a specific threshold speed limit can cause DNA damage and plausibly kill them. A modular mathematical model is proposed to explain the dynamics of replication fork control during DNA replication using the underlying molecular mechanisms in yeast which can extend to the mammalian system in the future.
Quantifying Cellular Pluripotency and Pathway Robustness through Forman-Ricci Curvature
Authors: Murgas Kevin A. , Saucan Emil , Sandhu Romeil
Published: October 2021

In stem cell biology, cellular pluripotency describes the capacity of a given cell to differentiate into multiple cell types. From a statistical physics perspective, entropy provides a statistical measure of randomness and has been demonstrated as a way to quantitate pluripotency when considering biological gene networks. Furthermore, recent theoretical work has established a relationship between Ricci curvature (a geometric measure of “flatness”) and entropy (also related to robustness), which one can exploit to link the geometric quantity of curvature to the statistical quantity of entropy. Therefore, this study seeks to explore Ricci curvature in biological gene networks as a descriptor of pluripotency and robustness among gene pathways. Here, we investigate Forman-Ricci curvature, a combinatorial discretization of Ricci curvature, along with network entropy, to explore the relationship of the two quantities as they occur in gene networks. First, we demonstrate our approach on an experiment of stem cell gene expression data. As expected, we find Ricci curvature directly correlates with network entropy, suggesting Ricci curvature could serve as an indicator for cellular pluripotency much like entropy. Second, we measure Forman-Ricci curvature in a dataset of cancer and non-cancer cells from melanoma patients. We again find Ricci curvature is increased in the cancer state, reflecting increased pluripotency or “stemness”. Further, we locally examine curvature on the gene level to identify several genes and gene pathways with known relevance to melanoma. In turn, we conclude Forman-Ricci curvature provides valuable biological information related to pluripotency and pathway functionality. In particular, the advantages of this geometric approach are promising for extension to higher-order topological structures in order to represent more complex features of biological systems.
A critical assessment of the detailedAedes aegyptisimulation model Skeeter Buster 2 using field experiments of indoor insecticidal control in Iquitos, Peru
Authors: Gunning C.E. , Morrison A.C. , Okamoto K.W. , Scott T.W. , Astete H. , Vasquez G.M. , Gould F. , Lloyd A.L.
Published: October 2021

The importance of mosquitoes in human pathogen transmission has motivated major research efforts into mosquito biology in pursuit of more effective vector control measures.Aedes aegyptiis a particular concern in tropical urban areas, where it is the primary vector of numerous flaviviruses, including the yellow fever, Zika, and dengue viruses. With an anthropophilic habit,Ae. aegyptiprefers houses, human blood meals, and ovipositioning in water-filled containers. We hypothesized that this relatively simple ecological niche should allow us to predict the impacts of insecticidal control measures on mosquito populations. To do this, we use Skeeter Buster 2 (SB2), a stochastic, spatially explicit, mechanistic model ofAe. aegyptipopulation biology. SB2 builds on Skeeter Buster, which reproduced equilibrium dynamics ofAe. aegyptiin Iquitos, Peru. Our goal was to predict the response of mosquito populations to perturbations by indoor insecticidal spraying and widespread destructive insect surveys.

To evaluate SB2, we conducted two field experiments in Iquitos, Peru: a smaller pilot study in 2013 (S-2013) followed by a larger experiment in 2014 (L-2014). Here, we compare model predictions with (pre-viously reported) empirical results from these experiments. In both simulated and empirical populations, repeated spraying yielded substantial yet temporary reductions in adult densities. The proportional effects of spraying were broadly comparable between simulated and empirical results, but we found noteworthy differences. In particular, SB2 consistently over-estimated the proportion of nulliparous females and the proportion of containers holding immature mosquitoes. We also observed less temporal variation in simulated surveys of adult abundance relative to corresponding empirical observations. Our results indicate the presence of ecological heterogeneities or sampling processes not effectively represented by SB2. Although additional empirical research could further improve the accuracy and precision of SB2, our results under-score the importance of non-linear dynamics in the response ofAe. aegyptipopulations to perturbations, and suggest general limits to the fine-grained predictability of its population dynamics over space and time.
Role of the Topoisomerase IIα Chromatin Tether domain in Nucleosome Binding & Chromosome Segregation
Authors: Sundararajan Sanjana , Park Hyewon , Kawano Shinji , Johansson Marnie , Saito-Fujita Tomoko , Saitoh Noriko , Arnaoutov Alexei , Dasso Mary , Clarke Duncan J. , Azuma Yoshiaki
Published: October 2021

Due to the intrinsic nature of DNA replication, replicated genomes retain catenated genomic loci that must be resolved to ensure faithful segregation of sister chromatids in mitosis. Type II DNA Topoisomerase (TopoII) decatenates the catenated genomic DNA through its unique Strand Passage Reaction (SPR). Loss of SPR activity results in anaphase chromosome bridges and formation of Polo-like Kinase Interacting Checkpoint Helicase (PICH)-coated ultra-fine DNA bridges (UFBs) whose timely resolution is required to prevent micronuclei formation. Vertebrates have two TopoII isoforms– TopoIIα and TopoIIβ, that share a conserved catalytic core. However, the essential mitotic function of TopoIIα cannot be compensated by TopoIIβ, due to differences in their catalytically inert C-terminal domains (CTDs). Using genome-edited human cells, we show that specific binding of TopoIIα to methylated histone, tri-methylated H3K27 (H3K27me3), via its Chromatin Tether (ChT) domain within the CTD contributes critically to avoid anaphase UFB formation. Reducing H3K27 methylation prior to mitosis increases UFBs, revealing a requirement for proper establishment of H3K27me3 after DNA replication to facilitate TopoIIα-ChT dependent UFB prevention. We propose that interaction of the TopoIIα-ChT with H3K27me3 is a key factor that ensures the complete resolution of catenated loci to permit faithful chromosome segregation in human cells.

Summary Statement

Genomic catenations originating from the DNA replication process must be resolved by DNA Topoisomerase II (TopoII) to permit sister chromatid disjunction. The results show that specific recognition of methylated histone containing chromatin by TopoII is critical for complete resolution of the genome.
Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments
Authors: Mundi Prabhjot S. , Dela Cruz Filemon S. , Grunn Adina , Diolaiti Daniel , Mauguen Audrey , Rainey Allison R. , Guillan Kristina C. , Siddiquee Armaan , You Daoqi , Realubit Ronald , Karan Charles , Ortiz Michael V. , Accordino Melissa , Mistretta Suzanne , Brogan Frances , Bruce Jeffrey N. , Caescu Cristina I. , Carvajal Richard , Crew Katherine , Decastro Guarionex , Heaney Mark , Henick Brian , Hershman Dawn , Hou June , Iwamoto Fabio , Jurcic Joseph , Kiran Ravi P. , Kluger Michael , Kreisl Teri , Lamanna Nicole , Lassman Andrew , Lim Emerson , Manji Gulam A. , McKhann Guy , McKiernan James , Neugut Alfred , Olive Kenneth , Rosenblat Todd , Schwartz Gary K. , Shu Catherine , Sisti Michael , Tergas Ana , Vattakalam Reena , Welch Mary , Wenske Sven , Wright Jason D. , Hibshoosh Hanina , Kalinsky Kevin , Aburi Mahalaxmi , Sims Peter A. , Alvarez Mariano J. , Kung Andrew L. , Califano Andrea
Published: October 2021

Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors—from patients with distinct malignancies who had progressed on multiple lines of therapy—and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91 %, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.
Allometric scaling of RNA abundance from genes to communities
Authors: Lopez Mark Louie D. , Lin Ya-ying , Schneider Stephan Q. , Machida Ryuji J.
Published: October 2021

The metabolic theory of ecology (MTE) and growth rate hypothesis (GRH) help explain the mechanistic basis of size (allometry) and temperature dependence on growth rate and whole-body-RNA content in organisms. However, testing RNA allometric scaling with next-generation sequencing is yet to be done. Here, we validated the assumptions of GRH and MTE on messenger RNA and ribosome abundance using mock community metatranscriptome analysis. Our findings highlight that fast-growing smaller species harbor greater RNA abundance per mass of tissue compared with species having larger body sizes and slower growth rates, where allometric slopes for genomic and gene-level RNA abundance range from –⅓ to −1. We found that genome size and body size impose significant constraints in interspecific RNA abundance scaling, while the assumed temperature dependence appeared to be weak. Lastly, allometric scaling integration in community-level models may extend the use of metatranscriptomics as a reliable tool for estimating ecosystem processes.
COVID-19 aerosol transmission simulation-based risk analysis for in-person learning
Authors: Swanson Tessa , Guikema Seth , Bagian James , Schemanske Christopher , Payne Claire
Published: October 2021

As educational institutions begin a school year following a year and a half of disruption from the COVID-19 pandemic, risk analysis can help to support decision-making for resuming in-person instructional operation by providing estiamtes of the relative risk reduction due to different interventions. In particular, a simulation-based risk analysis approach enables scenario evaluation and comparison to guide decision making and action prioritization under uncertainty. We develop a simulation model to characterize the risks and uncertainties associated with infections resulting from aerosol exposure in in-person classes. We demonstrate this approach by applying it to model a semester of courses in a real college with approximately 11,000 students embedded within a larger university. To have practical impact, risk cannot focus on only infections as the end point of interest, we estimate the risks of infection, hospitalizations, and deaths of students and faculty in the college. We incorporate uncertainties in disease transmission, the impact of policies such as masking and facility interventions, and variables outside of the college’s control such as population-level disease and immunity prevalence. We show in our example application that universal use of masks that block 40% of aerosols and the installation of near-ceiling, fan-mounted UVC systems both have the potential to lead to substantial risk reductions and that these effects can be modeled at the individual room level. These results exemplify how such simulation-based risk analysis can inform decision making and prioritization under great uncertainty.
Impairment of CSF Egress through the Cribriform Plate plays an Apical role in Alzheimer’s disease Etiology
Authors: Zaragoza Ricardo , Miulli Daniel , Kashyap Samir , Carson Tyler A , Obenaus Andre , Siddiqi Javed , Ethell Douglas W
Published: October 2021

Cerebrospinal fluid (CSF) clears the brain’s interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer’s disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment. Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb—directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli’s vault to a bony manifold within the olfactory fossa’s back wall, connecting with large apertures in between. We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer’s disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seen AD pathology. We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95y). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer’s disease years before a clinical presentation of cognitive impairment. This study provides a new perspective of the cribriform plate as a critical regulator of CSF egress and brain homeostasis.
Covariate clustering: women with breast cancer in southwestern Paraná, Brazil
Authors: Romeiro Neyva M. L. , Panis Carolina , dos Santos Mara C.T. , Rech Daniel , Natti Paulo L. , Cirilo Eliandro R.
Published: October 2021

Due to the high incidence and aggressiveness of breast cancer, the understanding of specific factors associated with the profile of the disease is necessary. In this context, the aim of the study was to analyze data from 155 patients with breast cancer, attended at a reference hospital for Oncology of the Unified Health System (SUS), in the period 2015-2020, in the southwest region of Paraná, Brazil. Using multivariate statistical analysis, sample data were divided into three clusters. The heterogeneity between clusters was obtained by Ward’s method. The clinical and pathological variables obtained from the patients’ medical records were: presence of intratumoral emboli, presence of lymph nodes, menopausal status, molecular subtype of breast cancer, histological grade, TNM staging of the disease, tumor size (cm), age at diagnosis (years), weight (kg), height (m2) and body mass index (BMI) (kg/m2). From the data of the total sample, it is observed that 70% of the patients were in menopause at diagnosis, 31.5% had tumors containing emboli, and 41% had positive lymph nodes. The prevalence of Luminal subtype B tumors, intermediate histological grade, and TNM staging II was verified. Furthermore, the prevalence of the disease was higher in women aged over 50 years, representing 66% of cases. The BMI of the patients ranged from 17.63 kg/m2to 51.26 kg/m2, with 26.45% of the patients with a BMI below 25 kg/m2, 40.65% with a BMI between 25 kg/m2and 30 kg/m2and 32.9% with BMI above 30 kg/m2. Cluster analysis, using the spatial distribution of patients, showed that the region of Vale do Iguaçu was the region with the worst averages for clinical-pathological variables, while the region of Vale do Marrecas had the highest number of breast cancer cases.
A randomized placebo-controlled clinical trial of Nicotinamide Riboside and Pterostilbene supplementation in experimental muscle injury in elderly subjects
Authors: Jensen Jonas Brorson , Dollerup Ole L. , Møller Andreas B. , Billeskov Tine B. , Dalbram Emilie , Chubanava Sabina , Dellinger Ryan W. , Trost Kajetan , Moritz Thomas , Ringgaard Steffen , Møller Niels , Treebak Jonas T. , Farup Jean , Jessen Niels
Published: October 2021

Background

Maintenance and regeneration of functional skeletal muscle are dependent on a sufficient pool of muscle stem cells (MuSCs). During ageing there is a functional decline in this cellular pool which influences the regenerative capacity of skeletal muscle. Preclinical evidence have suggested that Nicotinamide Riboside (NR) and Pterostilbene (PT) can improve muscle regeneration e.g. by increasing MuSC function. The objective of the present study was to investigate if NRPT supplementation promotes skeletal muscle regeneration after muscle injury in elderly humans by improved recruitment of MuSCs.

Methods

In a randomized, double-blinded, placebo-controlled trial, 32 elderly men and women (55-80 yr) received daily supplementation with either NRPT (1000 mg NR + 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, a skeletal muscle injury was applied in the vastus lateralis part of the quadriceps femoris muscle by electrically induced eccentric muscle work in a dynamometer. Skeletal muscle biopsies were obtained pre, 2h, 2, 8, and 30 days post injury. The main outcome of the study was change in MuSC content 8 days post injury.

Results

31 enrolled subjects completed the entire protocol. The muscle work induced a substantial skeletal muscle injury in the study participants and was associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content increased by 107% 8 days post injury (p= 0.0002) but with no effect of NRPT supplementation (p=0.58 for supplementation effect). MuSC proliferation and cell size revealed a large demand for recruitment post injury but was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, internal nuclei and embryonic Myosin Heavy Chain showed no effect of NRPT supplementation.

Conclusion

Daily supplementation with 1000 mg NR + 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly subjects.
A randomized, double-blind phase I clinical trial of two recombinant dimeric RBD COVID-19 vaccine candidates: safety, reactogenicity and immunogenicity
Authors: Pérez-Rodríguez Sonia , de la Caridad Rodríguez-González Meiby , Ochoa-Azze Rolando , Climent-Ruiz Yanet , González-Delgado Carlos Alberto , Paredes-Moreno Beatriz , Valenzuela-Silva Carmen , Rodríguez-Noda Laura , Perez-Nicado Rocmira , González-Mugica Raúl , Martínez-Pérez Marisel , Sánchez-Ramírez Belinda , Hernández-García Tays , Díaz-Machado Alina , Tamayo-Rodríguez Maura , Martín-Trujillo Alis , Rubino-Moreno Jorman , Suárez-Batista Anamary , Dubed-Echevarría Marta , Pérez-Guevara María Teresa , Amoroto-Roig Mayté , Chappi-Estévez Yanet , Bergado-Báez Gretchen , Pi-Estopiñán Franciscary , Chen Guang-Wu , Valdés-Balbín Yuri , García-Rivera Dagmar , Vérez-Bencomo Vicente
Published: October 2021

Background

The Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase 1 clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD).

Methods

We performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 mcg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 mcg d-RBD (three doses); 3) FINLAY-FR-1A-25 mcg d-RDB (three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or of FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction.

Results

Most adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules.

Conclusions

Vaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant.

Trial registry

https://rpcec.sld.cu/en/trials/RPCEC00000338-En