bluuebunny/crossref_metadata_2025 huggingface dataset:
The translocation mechanism of calcitriol throughHelicobacter pylorilipid membrane and influence on water permeability
Authors: Cao Zanxia , Zhao Liling , Chen Mingcui , Liu Lei
Published: March 2023

Helicobacter pyloriexhibits a unique membrane lipid composition, including dimyristoyl phosphatidylethanolamine (DMPE) and cholesterol, unlike other Gram-negative bacteria. Calcitriol has antimicrobial activity againstH. pylori, but cholesterol enhances antibiotics resistance inH. pylori. This study explored the changes in membrane structure and the molecular mechanisms of cholesterol/calcitriol translocation using well-tempered metadynamics (WT-MetaD) simulations and microsecond conventional molecular dynamics simulations. Our results showed that the average area per lipid and sterol tilt angles were slightly lower, while DP-P, DCG-CG, DAC-AC, and SCDwere higher in cholesterol membrane systems than in calcitriol membrane systems. Cholesterol membrane systems were more ordered than calcitriol-containing membranes. Calcitriol facilitated water transport across the membrane, while cholesterol had the opposite effect. The differing effects might result from the tail 25-hydroxyl group and a wider range of orientations of calcitriol in the DMPE/ dimyristoyl phosphatidylglycerol (DMPG) (3:1) membrane. Calcitriol moves across the bilayer center without changing its orientation along the membrane Z-axis, becomes parallel to the membrane surface at the membrane-water interface, and then rotates approximately 90º in this interface. The translocation mechanism of calcitriol is quite different from the flip-flop of cholesterol. Moreover, calcitriol crossed from one layer to another more easily than cholesterol, causing successive perturbations to the hydrophobic core and increasing water permeation. These results improve our understanding of the relationship between cholesterol/ calcitriol concentrations and the lipid bilayer structure and the role of lipid composition in water permeation.
Supervised learning of high-confidence phenotypic subpopulations from single-cell data
Authors: Ren Tao , Chen Canping , Danilov Alexey V. , Liu Susan , Guan Xiangnan , Du Shunyi , Wu Xiwei , Sherman Mara H. , Spellman Paul T. , Coussens Lisa M. , Adey Andrew C. , Mills Gordon B. , Wu Ling-Yun , Xia Zheng
Published: March 2023

Accurately identifying phenotype-relevant cell subsets from heterogeneous cell populations is crucial for delineating the underlying mechanisms driving biological or clinical phenotypes. Here, by deploying a learning with rejection strategy, we developed a novel supervised learning framework called PENCIL to identify subpopulations associated with categorical or continuous phenotypes from single-cell data. By embedding a feature selection function into this flexible framework, for the first time, we were able to select informative features and identify cell subpopulations simultaneously, which enables the accurate identification of phenotypic subpopulations otherwise missed by methods incapable of concurrent gene selection. Furthermore, the regression mode of PENCIL presents a novel ability for supervised phenotypic trajectory learning of subpopulations from single-cell data. We conducted comprehensive simulations to evaluate PENCIL’s versatility in simultaneous gene selection, subpopulation identification and phenotypic trajectory prediction. PENCIL is fast and scalable to analyze 1 million cells within 1 hour. Using the classification mode, PENCIL detected T-cell subpopulations associated with melanoma immunotherapy outcomes. Moreover, when applied to scRNA-seq of a mantle cell lymphoma patient with drug treatment across multiple time points, the regression mode of PENCIL revealed a transcriptional treatment response trajectory. Collectively, our work introduces a scalable and flexible infrastructure to accurately identify phenotype-associated subpopulations from single-cell data.
Artificially cultivated duckweed: a high-efficiency starch producer
Authors: Fang Yang , Guo Ling , Wang Songhu , Xiao Yao , Ding Yanqiang , Jin Yanling , Tian Xueping , Du Anping , Liao Zhihua , He Kaize , Chen Shuang , Zhao Yonggui , Tan Li , Yi Zhuolin , Che Yuqing , Chen Lanchai , Li Jinmeng , Zhao Leyi , Zhang Peng , Gu Zhengbiao , Zhang Fangyuan , Hong Yan , Zhang Qing , Zhao Hai
Published: March 2023

The increasing demand for starch has been a social struggle. We report a new technology that efficiently produces starch from duckweed. AlthoughLandoltia punctatahas a dramatic contraction of gene families, its starch content and productivity reached 72.2% (dry basis) and 10.4 g m-2d-1in 10 days, equivalent to a yield of 38.0 t ha-1y-1under nutrient limitation and CO2elevation treatment. Meanwhile, we also examined the mechanism of duckweed’s high starch accumulation. This is exhibited in the regulation of DNA methylation and transcription factors as well as the significantly up-regulated transcription levels and the increased enzyme activities of key genes in starch biosynthesis. Meantime, while nitrogen redistribution was enhanced, sucrose biosynthesis and transportation, and lignocellulose biosynthesis were all reduced. These alterations led to a reduction in lignocellulose and protein content and ultimately an increase in an accumulation of starch in the chloroplast. This work demonstrates duckweed’s potential of being a highly efficient starch producer.
A simple method to dramatically increaseC. elegansgermline microinjection efficiency
Authors: Gibney Theresa V. , Favichia Michelle , Latifi Laila , Medwig-Kinney Taylor N. , Matus David Q. , McIntyre Daniel C. , Arrigo Angelo B. , Branham Kendall R. , Bubrig Louis T. , Ghaddar Abbas , Jiranek Juliana A. , Liu Kendra E. , Marcucci Charles G. , Porter Robert J. , Pani Ariel M.
Published: March 2023

Genome manipulation methods inC. elegansrequire microinjecting DNA or ribonucleoprotein complexes into the microscopic core of the gonadal syncytium. These microinjections are technically demanding and represent a key bottleneck for all genome engineering and transgenic approaches inC. elegans. While there have been steady improvements in the ease and efficiency of genetic methods forC. elegansgenome manipulation, there have not been comparable advances in the physical process of microinjection. Here, we report a simple and inexpensive method for handling worms using a paintbrush during the injection process that nearly tripled average microinjection rates compared to traditional worm handling methods. We found that the paintbrush increased injection throughput by substantially increasing both injection speeds and post-injection survival rates. In addition to dramatically and universally increasing injection efficiency for experienced personnel, the paintbrush method also significantly improved the abilities of novice investigators to perform key steps in the microinjection process. We expect that this method will benefit theC. eleganscommunity by increasing the speed at which new strains can be generated and will also make microinjection-based approaches less challenging and more accessible to personnel and labs without extensive experience.
Coexistence of many species under a random competition-colonization trade-off
Authors: Miller Zachary R. , Clenet Maxime , Libera Katja Della , Massol François , Allesina Stefano
Published: March 2023

The competition-colonization trade-off is a well-studied coexistence mechanism for metacommunities. In this setting, it is believed that coexistence of all species requires their traits to satisfy restrictive conditions limiting their similarity. To investigate whether diverse metacommunities can assemble in a competition-colonization trade-off model, we study their assembly from a probabilistic perspective. From a pool of species with parameters (corresponding to traits) sampled at random, we compute the probability that any number of species coexist and characterize the set of species that emerges through assembly. Remarkably, almost exactly half of the species in a large pool typically coexist, with no saturation as the size of the pool grows, and with little dependence on the underlying distribution of traits. Through a mix of analytical results and simulations, we show that this unlimited niche packing emerges as assembly actively moves communities toward overdispersed configurations in niche space. Our findings also apply to a realistic assembly scenario where species invade one-at-a-time from a fixed regional pool. When diversity arises de novo in the metacommunity, richness still grows without bound, but more slowly. Together, our results suggest that the competition-colonization trade-off can support the robust emergence of diverse communities, even when coexistence of the full species pool is exceedingly unlikely.
Genetic structure and diversity ofrfblocus of pathogenic species of genusLeptospira
Authors: Ferreira L. C. A. , Ferreira Filho L. F. A. , Cosate M. R. V. , Sakamoto T.
Published: March 2023

Considered a globally important zoonotic bacterial disease, leptospirosis affects both humans and commercially important animals. It is transmitted through direct or indirect exposure to the urine of infected animals and is a major public health challenge in regions with heavy rainfall, floods, and poor socioeconomic conditions. The genusLeptospirahas 67 species, which can be grouped into pathogenic and saprophytic groups. Serological classification based on antigenic characteristics is important in epidemiology and clinical analysis but is laborious, requires infrastructure and specialized labor, and takes days to obtain results. In this study, we aimed to find genetic patterns associated with the serological classification ofLeptospirato propose molecular markers for classifyingLeptospirasamples at the serogroup level. For this, we used genomic data of 722 samples distributed in 67 species in public databases and compared the gene composition of theirrfblocus. Clustering analysis was able to group samples into five major classes that share similarities in both the serological and genetic composition of therfblocus. We also identified some syntenic blocks in the internal region of therfblocus and patterns of presence and absence of these blocks which can be used to determine the serogroup of a sample. Our findings can assist the development of molecular strategies for the serological identification ofLeptospirasamples, which could be more rapid and accurate than the current method.
Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC
Authors: Ding Shilei , Tolbert William D. , Zhu Huile , Lee Daniel , Higgins Tyler , Zhao Xuchen , Nguyen Dung , Sherburn Rebekah , Richard Jonathan , Lepage Gabrielle-Gendron , Medjahed Halima , Mohammadi Mohammadjavad , Abrams Cameron , Pazgier Marzena , Smith Amos B. , Finzi Andrés
Published: March 2023

The ability of HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1 infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engage the gp120 within the Phe43 cavity by targeting the highly-conserved Asp368Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination HIV-1-infected cells.
Human USP18 protects diverse cancer lineages from Type I Interferon independently of its canonical catalytic function
Authors: Jové Veronica , Wheeler Heather , Lee Chiachin Wilson , Healy David R. , Levine Kymberly , Ralph Erik C. , Yang Bing , Giddabasappa Anand , Loria Paula , Yamaguchi Masaya , Casimiro-Garcia Agustin , Kessler Benedikt M. , Pinto-Fernández Adán , Frattini Véronique , Wes Paul D. , Wang Feng
Published: March 2023

Precise temporal regulation of Type I interferon signaling is imperative to effectively fight infections and cancerous cells without triggering autoimmunity. The key negative regulator of Type I interferon signaling is ubiquitin-specific protease 18 (USP18). USP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and directly inhibits interferon receptor signaling through its scaffold role.USP18loss-of-function dramatically impacts autoimmune disease, viral susceptibility, and cancer cell survival. However, the relative contribution of catalytic versus scaffold function is unresolved and must be determined to design effective therapeutics targeting USP18. To precisely delineate individual contribution, we evaluated the functional impact of single amino acid mutations that disrupt catalytic or scaffold activity. Here we demonstrate catalytic activity does not contribute to cell autonomous Type I interferon sensitivity across multiple cancer cell lineages. Furthermore, introducing a patient-derived mutation that disrupts scaffold function is sufficient to inhibit cancer growth. These findings establish a fundamental mechanistic basis for USP18 therapeutic design across diseases.

OVERVIEW

USP18 is the key negative regulator of Type I interferon signaling in humans, mediating autoimmune disease, viral susceptibility, and cancer cell survival.

USP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and attenuates interferon receptor signaling through its scaffold role.

Delineating the contribution of each function is critical to resolve the mechanistic basis of interferon regulation and enable the development of therapeutics targeting USP18.

We demonstrate that cell intrinsic interferon sensitivity is not mediated by loss of catalytic activity. However, disruption of scaffold function by a patient-specific mutation inhibits cancer cell growth.

Furthermore, we discovered that canonical catalytic activity is surprisingly inefficient in human cells.

These results clarify a fundamental mechanism of immune regulation and cancer cell survival in humans.

Abstract Figure
MutationExplorer- a webserver for mutation of proteins and 3D visualization of energetic impacts
Authors: Philipp Michelle , Moth Christopher W. , Ristic Nikola , Tiemann Johanna K.S. , Seufert Florian , Panfilova Aleksandra , Meiler Jens , Hildebrand Peter W. , Stein Amelie , Wiegreffe Daniel , Staritzbichler René
Published: March 2023

Abstract

The possible effects of mutations on stability and function of a protein can only be understood in the context of protein 3D structure. The MutationExplorerwebserver maps sequence changes onto protein structures and allows users to study variation by inputting sequence changes. As the user enters variants, the 3D model evolves, and estimated changes in energy are highlighted. In addition to a basic per-residue input format, MutationExplorercan also upload an entire replacement sequence. Previously the purview of desktop applications, such an upload can back-mutate PDB structures to wildtype sequence in a single step. Another supported variation source is human single nucelotide polymorphisms (SNPs), genomic coordinates input in VCF format.

Structures are flexibly colorable, not only by energetic differences, but also by hydrophobicity, sequence conservation, or other biochemical profiling. Coloring by interface score reveals mutation impacts on binding surfaces.

MutationExplorerstrives for efficiency in user experience. For example, we have prepared 45,000 PDB depositions for instant retrieval and initial display. All modeling steps are performed by Rosetta. Visualizations leverage MDsrv/Mol*. MutationExploreris available at:http://proteinformatics.org/mutation_explorer/
High versatility to meet conservation targets for biodiversity and hydrological services at the Riviera Maya, Quintana Roo, Mexico
Authors: Aguilar-Sánchez Juan Alberto , Kolb Melanie
Published: March 2023

The ecosystem services (ES) framework has been proposed as an alternative to face the multiple challenges presented by biodiversity conservation, but the spatial conservation priorities of ES have been found to show low concordance levels with areas of high importance for biodiversity, which can lead to conflict during reserve design. To address this problem, the use of quantitative methods derived from systematic conservation planning has been proposed to identify spatial solutions that achieve the simultaneous representation of both elements in a spatially efficient manner. The aim of this study is to evaluate the differences between priority sites for biodiversity and hydrological ecosystem services (HES) using spatial prioritization models and to identify opportunities for co-benefits that allow an efficient conservation planning proposal, using as a case study the Riviera Maya, Mexico. The following hypothesis were tested by comparing models based on the prioritization algorithm Marxan: (1) Priority sites for biodiversity and HES are different, (2) HES priority sites adequately represent biodiversity conservation targets, and (3) integrating HES and biodiversity into one model is more efficient for representing conservation targets than combining the individual models for both elements. The results confirm: (1) Biodiversity and HES priority sites have different spatial patterns, sharing only 24% of priority sites, (2) HES priority sites achieve a high percentage (95%) of biodiversity conservation targets, showing that they can potentially be used for biodiversity representation, and (3) integrating HES and biodiversity into one model is more efficient to represent conservation targets than considering both elements individually (46% vs 66% of the study area). As there are no irreplaceable sites for biodiversity conservation, and less than 8% of the study area is covered by protected areas, there are clearly opportunities to align biodiversity and HES conservation actions at the Riviera Maya, Mexico. Despite the high context dependency of the spatial distribution of priority sites for biodiversity and HES, this study shows that the integration of conservation targets of both in the planning process can provide a solution to represent a high number of biodiversity and HES conservation targets.
A fast algorithm for 3D volume reconstruction from light field microscopy datasets
Authors: Taylor Jonathan M.
Published: March 2023

Light field microscopy can capture 3D volume datasets in a snapshot, making it a valuable tool for high-speed 3D imaging of dynamic biological events. However, subsequent computational reconstruction of the raw data into a human-interpretable 3D+time image is very time-consuming, limiting the technique’s utility as a routine imaging tool. Here we derive improved equations for 3D volume reconstruction from light field microscopy datasets, leading to dramatic speedups. We characterise our open-source Python implementation of these algorithms, and demonstrate real-world reconstruction speedups of more than an order of magnitude compared to established approaches. The scale of this performance improvement opens up new possibilities for studying large timelapse datasets in light field microscopy.
Stability of brain-behavior correlation patterns across measures of social support
Authors: Merritt Haily , Faskowitz Joshua , Gonzalez Marlen Z. , Betzel Richard F.
Published: March 2023

The social environment has a critical influence on human development, cognition, and health. By using network approaches to map and analyze the connectivity between all pairs of brain regions simultaneously, we can clarify how relationships between brain regions (e.g. connectivity) change as a function of social relationships. Here we apply multilayer modeling and modularity maximization–both established tools in network neuroscience–to jointly cluster patterns of brain-behavior associations for seven social support measures. Our analyses build on both neuroecological findings and network neuroscientific approaches. In particular we find that subcortical and control systems are especially sensitive to different constructs of perceived social support. Network nodes in these systems are highly flexible; their community affiliations, which reflect groups of nodes with similar patterns of brain behavior associations, differ across social support measures. The multilayer approach used here enables direct comparison of the roles of all regions of the brain across all social support measures included. Additionally, our application of multilayer modeling to patterns of brainbehavior correlations, as opposed to just functional connectivity, represents an innovation in how multilayer models are used in. More than that, it offers a generalizable technique for studying the stability brain-behavior correlations.
Multi-Scale Spiking Network Model of Human Cerebral Cortex
Authors: Pronold Jari , van Meegen Alexander , Vollenbröker Hannah , Shimoura Renan O. , Senden Mario , Hilgetag Claus C. , Bakker Rembrandt , van Albada Sacha J.
Published: March 2023

Although the structure of cortical networks provides the necessary substrate for their neuronal activity, the structure alone does not suffice to understand it. Leveraging the increasing availability of human data, we developed a multi-scale, spiking network model of human cortex to investigate the relationship between structure and dynamics. In this model, each area in one hemisphere of the Desikan-Killiany parcellation is represented by a 1 mm2column with a layered structure. The model aggregates data across multiple modalities, including electron microscopy, electrophysiology, morphological reconstructions, and DTI, into a coherent framework. It predicts activity on all scales from the single-neuron spiking activity to the area-level functional connectivity. We compared the model activity against human electrophysiological data and human resting-state fMRI data. This comparison reveals that the model can reproduce aspects of both spiking statistics and fMRI correlations if the cortico-cortical connections are sufficiently strong. Furthermore, we show that a single-spike perturbation propagates through the network within a time close to the limit imposed by the delays.
CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion
Authors: Zou Gengyi , Huang Yuanjian , Zhang Shengzhe , Ko Kyung-Pil , Kim Bongjun , Zhang Jie , Venkatesan Vishwa , Pizzi Melissa P. , Fan Yibo , Jun Sohee , Niu Na , Wang Huamin , Song Shumei , Ajani Jaffer A. , Park Jae-Il
Published: March 2023

This study investigates diffuse-type gastric adenocarcinoma (DGAC), a deadly and treatment-resistant cancer. It reveals that CDH1 inactivation occurs in a subset of DGAC patient tumors, leading to the identification of two distinct DGAC subtypes. The findings emphasize the importance of understanding DGAC’s molecular diversity for personalized medicine in patients with CDH1 inactivation.
Western diet dampens T regulatory cell function to fuel hepatic inflammation in nonalcoholic fatty liver disease
Authors: Chaudhary Sudrishti , Rai Ravi , Pal Pabitra B. , Tedesco Dana , Singhi Aatur D. , Monga Satdarshan P. , Grakoui Arash , Iyer Smita S. , Raeman Reben
Published: March 2023

Background and aims

The immunosuppressive T regulatory cells (Tregs) regulate immune responses and maintain immune homeostasis, yet their functions in nonalcoholic fatty liver disease (NAFLD) pathogenesis remains controversial.

Methods

Mice were fed a normal diet (ND) or a western diet (WD) for 16 weeks to induce NAFLD. Diphtheria toxin injection to deplete Tregs in Foxp3DTRmice or Treg induction therapy in WT mice to augment Treg numbers was initiated at twelve and eight weeks, respectively. Liver tissues from mice and NASH human subjects were analyzed by histology, confocal imaging, and qRT-PCR.

Results

WD triggered accumulation of adaptive immune cells, including Tregs and effector T cells, within the liver parenchyma. This pattern was also observed in NASH patients, where an increase in intrahepatic Tregs was noted. In the absence of adaptive immune cells in Rag1 KO mice, WD promoted accumulation of intrahepatic neutrophils and macrophages and exacerbated hepatic inflammation and fibrosis. Similarly, targeted Treg depletion exacerbated WD-induced hepatic inflammation and fibrosis. In Treg-depleted mice, hepatic injury was associated with increased accumulation of neutrophils, macrophages, and activated T cells within the liver. Conversely, induction of Tregs using recombinant IL2/αIL2 mAb cocktail reduced hepatic steatosis, inflammation, and fibrosis in WD-fed mice. Analysis of intrahepatic Tregs from WD-fed mice revealed a phenotypic signature of impaired Treg function in NAFLD.Ex vivofunctional studies showed that glucose and palmitate, but not fructose, impaired the immunosuppressive ability of Treg cells.

Conclusions

Our findings indicate that the liver microenvironment in NAFLD impairs ability of Tregs to suppress effector immune cell activation, thus perpetuating chronic inflammation and driving NAFLD progression. These data suggest that targeted approaches aimed at restoring Treg function may represent a potential therapeutic strategy for treating NAFLD.

Lay summary

In this study, we elucidate the mechanisms contributing to the perpetuation of chronic hepatic inflammation in nonalcoholic fatty liver disease (NAFLD). We show that dietary sugar and fatty acids promote chronic hepatic inflammation in NAFLD by impairing immunosuppressive function of regulatory T cells. Finally, our preclinical data suggest that targeted approaches aimed at restoring T regulatory cell function have the potential to treat NAFLD.
TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy
Authors: Edwards George A. , Wood Caleb A. , Nguyen Quynh , Kim Peter J. , Gomez-Gutierrez Ruben , Park Kyung-Won , Zurhellen Cody , Al-Ramahi Ismael , Jankowsky Joanna L.
Published: March 2023

TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimer’s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation.
Poly(A) tail length regulation by mRNA deadenylases is critical for suppression of transposable elements
Authors: Wang Ling , Li Hui , Lei Zhen , Yan Mengxiao , Wang Yuqin , Zhao Jiamin , Wang Hongxia , Yang Jun , Cho Jungnam
Published: March 2023

Transposons are mobile genetic elements that can impair the host genome stability and integrity. In plants, suppression of transposons is thought to be mediated mainly by small RNAs; however, the role of RNA decay in posttranscriptional repression of transposons is unknown. Here we show that RNA deadenylation is critical for controlling transposons inArabidopsis. Previously, we demonstrated that transposon RNAs often harbor structural aberrancy owing to its inherently suboptimal codon usage and ribosome stalling. Such RNA aberrancy is monitored and resolved by RNA decay which is initiated by removal of poly(A) tail or deadenylation. The CCR4-NOT complex is a primary RNA deadenylase inArabidopsis, and we found that it is required for stable repression of transposons. Intriguingly, RNA deadenylation controls transposons that are not targeted by cytoplasmic secondary small RNAs, which implies a target-specific regulation of transposon by the host. Our study suggests a previously unknown mechanism for transposon repression mediated by RNA deadenylation and unveils a complex nature of the host’s strategy to maintain the genome integrity.
Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy
Authors: Cao Shijie , Maulloo Chitavi D. , Raczy Michal M. , Sabados Matthew , Slezak Anna J. , Nguyen Mindy , Solanki Ani , Wallace Rachel P. , Shim Ha-Na , Wilson D. Scott , Hubbell Jeffrey A.
Published: March 2023

The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We have developed a tolerance-inducing vaccine technology that utilizes glycosylation-modified antigens to induce antigen-specific non-responsiveness. The glycosylation-modified antigens were administered intravenously (i.v.) or subcutaneously (s.c.) and were found to traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow’s milk allergy, treatment with glycosylation-modified β- lactoglobulin (BLG) was effective in preventing the onset of allergy. In addition, s.c. administration of glycosylation-modified BLG showed superior safety and potential in treating existing allergies in combination with an anti-CD20 co-therapy. This platform may provide an antigen-specific immunomodulatory strategy to prevent and treat food allergies.
Developmental exposure to polychlorinated biphenyls prevents recovery from noise-induced hearing loss and disrupts the functional organization of the inferior colliculus
Authors: Ibrahim Baher A. , Louie Jeremy , Shinagawa Yoshitaka , Xiao Gang , Asilador Alexander R. , Sable Helen J. K. , Schantz Susan L. , Llano Daniel A.
Published: March 2023

Exposure to combinations of environmental toxins is growing in prevalence, and therefore understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins – polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise – interact to produce dysfunction in central auditory processing. PCBs are well-established to impose negative developmental impacts on hearing. However, it is not known if developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 minutes of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.

Significance statement

Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.
Atomistic molecular simulations of Aβ-Zn conformational ensembles
Authors: Aduriz-Arrizabalaga Julen , Lopez Xabier , De Sancho David
Published: March 2023

The amyloid-forming Aβpeptide is able to interact with metal cations to form very stable complexes that influence fibril formation and contribute to the onset of Alzheimer’s disease. Multiple structures of peptides derived from Aβin complex with different metals have been resolved experimentally to provide an atomic-level description of the metal-protein interactions. However, Aβis intrinsically disordered, and hence more amenable to an ensemble description. Molecular dynamics simulations can now reach the timescales needed to generate ensembles for this type of complexes. However, this requires accurate force fields both for the protein and the protein-metal interactions. Here we use state-of-the-art methods to generate force field parameters for the Zn(II) cations in a set of Aβcomplexes and combine them with the Amber99SB⋆-ILDN optimized force field. Upon comparison of NMR experiments with the simulation results, further optimized with a Bayesian/Maximum entropy approach, we provide an accurate description of the molecular ensembles for most Aβ-metal complexes. We find that the resulting conformational ensembles are more heterogeneous than the NMR models deposited in the Protein Data Bank.
Forecasting dynamics of a recolonizing wolf population under different management strategies
Authors: Petracca Lisanne S. , Gardner Beth , Maletzke Benjamin T. , Converse Sarah J.
Published: March 2023

Species recovery can be influenced by a wide variety of factors, such that predicting the spatiotemporal dynamics of recovering species can be exceedingly difficult. These predictions, however, are valuable for decision makers tasked with managing species and determining their legal status. We applied a novel spatially explicit projection model to estimate population viability of gray wolves (Canis lupus) from 2021-2070 in Washington State, USA, where wolves have been naturally recolonizing since the establishment of the first resident pack in 2008. Using this model, we predicted the effects of 12 scenarios of interest relating to management actions (e.g., lethal removals, translocation, harvest) and system uncertainties (e.g., immigration from out of state, disease) on the probability of meeting Washington’s wolf recovery goals, along with other metrics related to population status. Population recovery was defined under Washington’s Wolf Conservation and Management Plan as four breeding pairs in each of three recovery regions and three additional breeding pairs anywhere in the state. The baseline, translocation, and 50% immigration scenarios indicated a high (>60%) probability of wolf recovery in Washington over the next 50 years, but scenarios related to harvest mortality (removal of 5% of the population every six months), increased lethal removals (removal of 30% of the population every four years), and cessation of immigration from out of state resulted in low probabilities (0.07, 0.12, and 0.12, respectively) of meeting recovery goals across all years (2021-2070). All but one management scenarios exhibited a geometric mean of population growth that was ≥1, indicating long-term population stability or growth, depending on the scenario. Our results suggest that wolves will continue to recolonize Washington and that recovery goals will be met so long as harvest and lethal removals are not at unsustainable levels and adjacent populations support immigration into Washington.
JUMP Cell Painting dataset: morphological impact of 136,000 chemical and genetic perturbations
Authors: Chandrasekaran Srinivas Niranj , Ackerman Jeanelle , Alix Eric , Ando D. Michael , Arevalo John , Bennion Melissa , Boisseau Nicolas , Borowa Adriana , Boyd Justin D. , Brino Laurent , Byrne Patrick J. , Ceulemans Hugo , Ch’ng Carolyn , Cimini Beth A. , Clevert Djork-Arne , Deflaux Nicole , Doench John G , Dorval Thierry , Doyonnas Regis , Dragone Vincenza , Engkvist Ola , Faloon Patrick W. , Fritchman Briana , Fuchs Florian , Garg Sakshi , Gilbert Tamara J. , Glazer David , Gnutt David , Goodale Amy , Grignard Jeremy , Guenther Judith , Han Yu , Hanifehlou Zahra , Hariharan Santosh , Hernandez Desiree , Horman Shane R , Hormel Gisela , Huntley Michael , Icke Ilknur , Iida Makiyo , Jacob Christina B. , Jaensch Steffen , Khetan Jawahar , Kost-Alimova Maria , Krawiec Tomasz , Kuhn Daniel , Lardeau Charles-Hugues , Lembke Amanda , Lin Francis , Little Kevin D. , Lofstrom Kenneth R. , Lotfi Sofia , Logan David J. , Luo Yi , Madoux Franck , Marin Zapata Paula A. , Marion Brittany A. , Martin Glynn , McCarthy Nicola Jane , Mervin Lewis , Miller Lisa , Mohamed Haseeb , Monteverde Tiziana , Mouchet Elizabeth , Nicke Barbara , Ogier Arnaud , Ong Anne-Laure , Osterland Marc , Otrocka Magdalena , Peeters Pieter J. , Pilling James , Prechtl Stefan , Qian Chen , Rataj Krzysztof , Root David E , Sakata Sylvie K. , Scrace Simon , Shimizu Hajime , Simon David , Sommer Peter , Spruiell Craig , Sumia Iffat , Swalley Susanne E , Terauchi Hiroki , Thibaudeau Amandine , Unruh Amy , Van de Waeter Jelle , Van Dyck Michiel , van Staden Carlo , Warchoł Michał , Weisbart Erin , Weiss Amélie , Wiest-Daessle Nicolas , Williams Guy , Yu Shan , Zapiec Bolek , Żyła Marek , Singh Shantanu , Carpenter Anne E.
Published: March 2023

Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community has lacked a large, public reference set of data from chemical and genetic perturbations. Here we present data generated by the Joint Undertaking for Morphological Profiling (JUMP)-Cell Painting Consortium, a collaboration between 10 pharmaceutical companies, six supporting technology companies, and two non-profit partners. When completed, the dataset will contain images and profiles from the Cell Painting assay for over 116,750 unique compounds, over-expression of 12,602 genes, and knockout of 7,975 genes using CRISPR-Cas9, all in human osteosarcoma cells (U2OS). The dataset is estimated to be 115 TB in size and capturing 1.6 billion cells and their single-cell profiles. File quality control and upload is underway and will be completed over the coming months at the Cell Painting Gallery:https://registry.opendata.aws/cellpainting-gallery. A portal to visualize a subset of the data is available athttps://phenaid.ardigen.com/jumpcpexplorer/.
Fast centromeric repeat turnover provides a glimpse into satellite DNA evolution in Nothobranchius annual killifishes
Authors: Volenikova Anna , Luksikova Karolina , Mora Pablo , Pavlica Tomas , Altmanova Marie , Stundlova Jana , Pelikanova Sarka , Simanovsky Sergey A. , Jankasek Marek , Reichard Martin , Nguyen Petr , Sember Alexandr
Published: March 2023

Satellite DNA (satDNA) is rapidly evolving class of tandem repeats with some motifs being involved in centromere organization and function. Rapid co-evolution of centromeric satDNA and associated proteins has been mostly attributed to the so-called centromere drive. To identify repeats associated with centromeric regions and test for the role of meiotic drive in their evolution, we investigated satDNA across Southern and Coastal clades of African annual killifishes of the genus Nothobranchius. C-banding showed expansion of (peri)centromeric heterochromatin regions in the Southern-clade killifishes. Molecular cytogenetic and bioinformatic analyses further revealed that two previously identified satellites, Nfu-SatA and Nfu-SatB, are associated with centromeres only in one lineage of the Southern clade. Nfu-SatB was, however, detected outside centromeres also in other members of the Coastal clade, which is consistent with the "library" hypothesis of satDNA evolution. We also identified a novel satDNA, Cl-36, associated with (peri)centromeres in N. foerschi, N. guentheri and N. rubripinnis from the Coastal clade. Our findings could be explained by centromere drive shaping karyotype change and centromeric repeat turnover in Nothobranchius species with possible reversal of spindle polarity within the Southern clade.
Three Species of Axenic Mosquito Larvae Recruit a Shared Core of Bacteria in a Common Garden Experiment
Authors: Hyde Josephine , Brackney Doug E , Steven Blaire
Published: March 2023

In this study we describe the generation of two new species of axenic mosquito,Aedes albopictusandAedes triseriatus.Along withAedes aegypti, axenic larvae of these three species were exposed to an environmental water source to document the assembly of the microbiome in a common garden experiment. Additionally, the larvae were reared either individually or combinatorially with the other species to characterize the effects of co-rearing on the composition of the microbiome. We found that the microbiome of the larvae was composed of a relatively low diversity collection of bacteria from the colonizing water. The abundance of bacteria in the water was a poor predictor for their abundance in the larvae, suggesting the larval microbiome is made up of a subset of relatively rare aquatic bacteria. We found eleven bacterial 16S rRNA gene amplicon sequence variants (ASVs) that were conserved amongst>90% of the mosquitoes sampled, including two found in 100% of the larvae, pointing to a conserved core of bacteria capable of colonizing all three species of mosquito. Yet, the abundance of these ASVs varied widely between larvae suggesting individuals harbored largely unique microbiome structures, even if they overlapped in membership. Finally, larvae reared in a tripartite mix of the host species consistently showed a convergence in the structure of their microbiome, indicating that multi-species interactions between hosts potentially lead to shifts in the composition of their respective microbiomes.

IMPORTANCE

This study is the first report of the axenic (free of external microbes) rearing of two species of mosquito,Aedes albopictusandAedes triseriatus. With our previous report of axenicAedes aegypti, brings the number of axenic species to three. We designed a method to perform a common garden experiment to characterize the bacteria the three species of axenic larvae assemble from their surroundings. Furthermore, species could be reared in isolation or in multi-species combinations to assess how host species interactions influence the composition of the microbiome. We found all three species recruited a common core of bacteria from their rearing water, with a large contingent of rare and sporadically detected bacteria. Finally, we also show that co-rearing of mosquito larvae leads to a coalescence in the composition of their microbiome, indicating that host species interactions potentially influence the composition of the microbiome.
Seventy Years of Mortality Transition in India: 1950-2021
Authors: Chaurasia Aalok Ranjan
Published: March 2023

Mortality in India remains high by international standards. This paper analyses mortality transition in India during the 70 years since 1950 based on the annual estimates of age-specific probabilities of death prepared by the United Nations Population Division for the period 1950-2021. The analysis reveals that characterisation of mortality transition is sensitive to the summary index of mortality used. Mortality transition in India based on the geometric mean of the age-specific probabilities of death is found to be different from that based on the life expectancy at birth. The transition in mortality based on the geometric mean of age-specific probabilities of death accelerated during 2008-2019 but decelerated when based on the life expectancy at birth. The reason is that mortality transition in younger ages has been faster than mortality transition in older ages. The analysis also reveals that there were around 4.3 excess deaths associated with the COVID-19 epidemic in the country leading to a loss of around 3.7 years in the life expectancy at birth between 2019 and 2021.
High-resolution functional description of vaginal microbiomes in health and disease
Authors: Holm Johanna B. , France Michael T. , Gajer Pawel , Ma Bing , Brotman Rebecca M. , Shardell Michelle , Forney Larry , Ravel Jacques
Published: March 2023

Background

ALactobacillus-dominated vaginal microbiome provides the first line of defense against numerous adverse genital tract health outcomes. However, there is limited understanding of the mechanisms by which the vaginal microbiome modulates protection, as prior work mostly described its composition through morphologic assessment and marker gene sequencing methods that do not capture functional information. To address this limitation, we developed metagenomic community state types (mgCSTs) which uses metagenomic sequences to describe and define vaginal microbiomes based on both composition and function.

Results

MgCSTs are categories of microbiomes classified using taxonomy and the functional potential encoded in their metagenomes. MgCSTs reflect unique combinations of metagenomic subspecies (mgSs), which are assemblages of bacterial strains of the same species, within a microbiome. We demonstrate that mgCSTs are associated with demographics such as age and race, as well as vaginal pH and Gram stain assessment of vaginal smears. Importantly, these associations varied between mgCSTs predominated by the same bacterial species. A subset of mgCSTs, including three of the six predominated byGardnerellamgSs, as well as a mgSs ofL. iners, were associated with a greater likelihood of Amsel bacterial vaginosis diagnosis. ThisL. inersmgSs, among other functional features, encoded enhanced genetic capabilities for epithelial cell attachment that could facilitate cytotoxin-mediated cell lysis. Finally, we report a mgSs and mgCST classifier as an easily applied, standardized method for use by the microbiome research community.

Conclusions

MgCSTs are a novel and easily implemented approach to reducing the dimension of complex metagenomic datasets, while maintaining their functional uniqueness. MgCSTs enable investigation of multiple strains of the same species and the functional diversity in that species. Future investigations of functional diversity may be key to unraveling the pathways by which the vaginal microbiome modulates protection to the genital tract. Importantly, our findings support the hypothesis that functional differences between vaginal microbiomes, including those that may look compositionally similar, are critical considerations in vaginal health. Ultimately, mgCSTs may lead to novel hypotheses concerning the role of the vaginal microbiome in promoting health and disease, and identify targets for novel prognostic, diagnostic, and therapeutic strategies to improve women’s genital health.