bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of antibody-dependent enhancement in DENV-infected Wistar rats as a dengue murine model
Authors: Wihanto Laura , Tedyanto Cecilia Putri , Suwasanti Niluh , Sutandhio Silvia , Sucipto Teguh Hari
Published: May 2024

Preclinical studies for discovering and developing a drug for a disease involve utilizing animals as experimental subjects. The search for an effective and efficient murine model of dengue virus (DENV) infection is ongoing to support further scientific updates. This study aimed to explore the suitability of Wistar rats as a murine model for DENV infection. Twenty-four Wistar rats (male sex, 2-3 months old, 200-300 grams weight) were randomly divided into four groups (n=6 per group): control group (no infection), SC-Group (DENV-2 s.c.), IV-Group (DENV-2 i.v.), and ADE-Group (DENV-3 i.p. twice and DENV-2 i.v. once). Inactive 0.2 mL of 1011FFU/mL DENV-3 were injected on days -14 and -5. Active 0.2 mL of 5 x 108FFU/mL DENV-2 were injected on day 0. Rectal temperature was measured on day 0 until 6. NS1 antigen tests were carried out from the viral medium on days -14, -5, and 0 and from the blood serum samples on day 4. Hematological parameters (leukocytes, hemoglobin, hematocrits, and platelets) were analyzed on days 0, 4, and 6. Biochemical parameters (albumin, ALT, and AST) were analyzed on day 6. SC-Group showed significant increases in the temperature from day 0 to day 1 (p=0.028). IV-Group showed significant increases in the temperature from day 0 to day 1 (p=0.007), day 2 (p=0.002), and day 3 (p=0.006). There were significant temperature increases on day 1 (p=0.047), day 2 (p=0.009), and day 3 (p=0.001) compared to the control group. ADE-Group had a mortality rate of 33.3%, lusterless and ruffled hair coat, and several hemorrhagic manifestations. ADE-Group also showed significant increases in the temperature from day 0 to day 2 (p=0.043) and day 3 (p=0.038). There were significant temperature increases on day 1 (p=0.048), day 2 (p=0.002), day 3 (p=0.000), and day 4 (p=0.004) compared to the control group. Leukocytes in the ADE-Group showed significant decreases from day 0 to day 6 (p=0.021). ALT (p=0.033) and AST (p=0.011) of the ADE-Group also showed significant increases compared to the control group. DENV infection through an induction method adapted from the antibody-dependent enhancement mechanism shows the most severe clinical manifestations and laboratory findings compared to other induction methods in Wistar rats.
Volumetric mesoscopic electrophysiology: a new imaging modality for the non-human primate
Authors: Teichert Tobias , Papp László , Vincze Ferenc , Burns Nioka , Goodell Baldwin , Ahmed Zabir , Holmes Andrew , Gray Charles M , Chamanzar Maysam , Gurnsey Kate
Published: May 2024

The primate brain is a densely interconnected organ whose function is best understood by recording from the entire structure in parallel, rather than parts of it in sequence. However, available methods either have limited temporal resolution (functional magnetic resonance imaging), limited spatial resolution (macroscopic electroencephalography), or a limited field of view (microscopic electrophysiology). To address this need, we developed a volumetric, mesoscopic recording approach (MePhys) by tessellating the volume of a monkey hemisphere with 992 electrode contacts that were distributed across 62 chronically implanted multi-electrode shafts. We showcase the scientific promise of MePhys by describing the functional interactions of local field potentials between the more than 300,000 simultaneously recorded pairs of electrodes. We find that a subanesthetic dose of ketamine –believed to mimic certain aspects of psychosis– can create a pronounced state of functional disconnection and prevent the formation of stable large-scale intrinsic states. We conclude that MePhys provides a new and fundamentally distinct window into brain function whose unique profile of strengths and weaknesses complements existing approaches in synergistic ways.
Omicron-specific naive B cell maturation alleviates immune imprinting induced by SARS-CoV-2 inactivated vaccine
Authors: Yisimayi Ayijiang , Song Weiliang , Wang Jing , Jian Fanchong , Yu Yuanling , Chen Xiaosu , Xu Yanli , An Ran , Wang Yao , Wang Jing , Sun Haiyan , Wang Peng , Yu Lingling , Shao Fei , Jin Ronghua , Shen Zhongyang , Wang Youchun , Cao Yunlong
Published: May 2024

SARS-CoV-2 ancestral strain-induced immune imprinting poses great challenges to vaccine updates. Studies showed that repeated Omicron exposures could override immune imprinting induced by inactivated vaccines but not mRNA vaccines, a disparity yet to be understood. Here, we analyzed the underlying mechanism of immune imprinting alleviation in inactivated vaccine (CoronaVac) cohorts. We observed in CoronaVac-vaccinated individuals who experienced BA.5/BF.7 breakthrough infection (BTI), the proportion of Omicron-specific memory B cells (MBCs) substantially increased after an extended period post-Omicron BTI, with their antibodies displaying enhanced somatic hypermutation and neutralizing potency. Consequently, the neutralizing antibody epitope distribution encoded by MBCs post-BA.5/BF.7 BTI after prolonged maturation closely mirrors that in BA.5/BF.7-infected unvaccinated individuals. Together, these results indicate the activation and expansion of Omicron-specific naïve B cells generated by first-time Omicron exposure helped to alleviate CoronaVac-induced immune imprinting, and the absence of this process should have caused the persistent immune imprinting seen in mRNA vaccine recipients.

Highlights

Longitudinal MBC profiling of CoronaVac-vaccinated individuals following BA.5 BTI

Omicron-specific MBC proportion rises greatly after extended period post-BA.5 BTI

Omicron-specific naive B cell maturation reduces ancestral strain immune imprinting
Roles and mechanisms of leptomeningeal collaterals in human distal MCA territory ischemia
Authors: Zou Xiang , Mei Shuhao , Wu Zehan , Song Kun , Xu Yuhao , Hu Jie , Chen Liang , Mao Ying
Published: May 2024

Background

Leptomeningeal collaterals (LMCs) provided hemodynamic support and reperfusion during acute ischemic stroke (AIS). Although regulation details have been deeply acquired from animal models, human cortex may share limited hemodynamic patterns due to larger physical scale that needs further investigation.

Methods

We performed ‘sequential hierarchical blocking’ during awake craniotomy on fourteen human subjects to mimic AIS in middle cerebral artery (MCA) M4segment territory. Widefield microscope was applied to reveal microcirculation of LMCs. Relative flow rate (RFR) was measured to evaluate the impact of LMCs hierarchy on microcirculation maintenance. Single-cell sequencing and spatial transcriptomics were further performed to analyze the mechanism of different LMCs recruitment abilities.

Results

LMCs RFR decreased to 30.75% immediately (95% CI, 6.64 - 54.86%, P < 0.001), and about 80.25% RFR was finally recovered within 5 minutes (95% CI, 55.2 - 105.3%, P = 0.0034) during M4occlusion. For M5and pial branches occlusion, RFR decreased to 55.78% with no further recovery (95% CI, 22.50-89.05%, P = 0.014), and 4 in 11 subjects had no valid microcirculation. For subjects with better recruitment ability, the proportion of arteriole is much higher in leptomeninx (76 - 79% vs. 36 - 56%). There were more significant interaction pairs associated with key signaling pathways between arteriole and neuron/astrocyte (TGF-beta signaling pathway, ECM-receptor interaction)

Conclusions

Abundant LMCs supported hemodynamic stability during AIS in human subjects. The proportion of arteriole is much higher in leptomeninx for subjects with better recruitment ability. The Active neuron/astrocyte - arteriole interaction may improve LMCs recruitment.

GRAPH ABSTRACT
Innovating Urban Mosquito Control: Introducing Human-Controlled Breeding Sites as a Component of Integrated Mosquito Management (IMM)
Authors: Baigorria Guillermo A. , Romero Consuelo C.
Published: May 2024

This study introduces a novel method for mosquito control tailored specifically for urban and suburban areas, addressing their unique challenges. The concept of Human-Controlled Breeding Sites (HCBS) is presented as an innovative approach to reducing mosquito populations by providing controlled oviposition sites within households. The paper is structured into three main components. The first details the meticulous development of the HCBS method, the second explores the intricate development of the HCBS device, crucial for effective implementation of the HCBS approach. Finally, the experiment validating the HCBS methodology is described, offering insights into its practical application and efficacy in mosquito population control. Our proposal emphasizes the importance of considering mosquito needs, behavior and preferences in designing effective mosquito control strategies. Gravid mosquitoes must find a suitable place for oviposition, and HCBS provides an easy-access controlled environment for them to do so within households. Contrary to the commonly current recommendation to destroy all possible locations where mosquitoes can lay their eggs, the HCBS methodology provides an opportunity for gravid mosquitoes to oviposit their eggs without being deterred by chemical odors or dead larvae or pupae. It involves waiting for a timespan before effectively collecting and destroying the individuals in one concerted effort with zero impact on the environment and at minimal cost. Successful deposition of eggs by gravid mosquitoes into HCBS devices, followed by their destruction within the designated timeframe, validates the system’s efficacy in disrupting the mosquito life cycle. Moreover, our findings demonstrate the significant influence of color selection on HCBS effectiveness, with green HCBS devices being the preferred choice, although not an indispensable condition for oviposition. These integrated components offer a comprehensive understanding of the HCBS approach, effectively bridging the gap between methodological development, device design, and practical application. The findings underscore HCBS as a valuable addition to mosquito control strategies, with potential applications in diverse environments. Further research is essential to delve into and model the long-term effectiveness of HCBS, aiming to optimize its design for maximum efficacy and scalability. This includes studying its performance over extended periods and refining the design parameters to enhance its functionality and widespread applicability including the use of disaster risk management systems.
Food insecurity is associated with poor hypertension management in the Eastern Caribbean
Authors: Oladele Carol R. , Khandpur Neha , Galusha Deron , Nair Sanya , Hassan Saria , Martinez-Brockman Josefa , Nunez-Smith Marcella , Perez-Escamilla Rafael
Published: May 2024

Background

Limited evidence exists on the association between food insecurity (FI) and blood pressure control in the Caribbean despite the high burden of both. The objective of this study is to examine the relationship between FI and hypertension prevalence, awareness, and control in the Eastern Caribbean.

Methods and Findings

We conducted a cross-sectional analysis of baseline data (2013-2018) from the Eastern Caribbean Health Outcomes Research Network Cohort Study (n=2961). Food insecurity was measured using the Latin American and Caribbean Food Security Scale (ELCSA) and classified as 0=no FI, 1-6 mild/moderate FI, and 7-9 severe FI. Hypertension was defined by the Seventh Report of the Joint National Committee on Prevention. Logistic regression modeling was conducted to examine the relationship between FI and hypertension prevalence, awareness, and control, adjusting for age, sex, educational attainment, site, and usual source of care. Prevalence of FI was 28 percent among participants and was higher in Puerto Rico and Trinidad and Tobago compared to other sites. Seventeen percent of the participants experienced low, 6 percent moderate, and 4 percent experienced severe FI. Aggregate model results showed no association between FI and hypertension outcomes. Sex-stratified results showed moderate (OR=2.65, CI=1.25-5.65) and severe FI (OR=3.69, CI=1.20-11.31) were positively associated with lack of control among women.

Limitations of this study include the cross-sectional design, small sample size, and the average age of our cohort. Cross-sectional design precluded the ability to make inferences about temporality between FI and HTN prevalence and awareness. Small sample size precluded the ability to detect statistically significant differences despite strong odds ratios for model results like lack of control.

Conclusions

Findings align with prior evidence of greater FI prevalence among women and negative health impact. Nutrition policies are needed to reduce the overall FI burden in the Caribbean and increase access to affordable, nutritious foods.
Diurnal butterfly diversity in a human-modified landscape of the subtropical montane forest of NW Argentina
Authors: Guanuco Andrea del V. , Ordano Mariano , Pereyra Laura C. , Barrionuevo María José , Gonzalez Baffa Trasci Noelia V. , Vaira Marcos
Published: May 2024

The change and intensification in land-use is currently among the main causes of species declines and local extinctions around the world, therefore, forecasting changes in species diversity concerning habitat conditions may be crucial for conservation strategies. We explored the diurnal lepidopteran diversity in a modified landscape of subtropical montane forests of Jujuy, NW Argentina. We considered that degradation of the natural forest habitat would likely impact on resources crucial for butterflies, consequently altering both species richness and composition within these forests. We assessed and compared alpha diversity through Hill diversity profiles and beta diversity through the beta-diversity partitioning method. Additionally, we employed a multivariate permutational analysis of variance, and rank-abundance curves of butterfly species at different habitat types. Our results suggest that land-use changes diminish the number of forest-dependent species and increase species more tolerant to modified habitats and open areas. While alpha diversity did not decrease as land use changed, beta diversity showed significant changes in the butterfly species composition with a worrying reduction of forest-related species in altered habitats. Species composition became increasingly dominated by open area butterfly species resulting in biota homogenization, with possible consequences for ecosystem functioning and services of these forests. Further research on the mechanisms underlying the effects of human-induced habitat changes on forest butterfly diversity could help clarify which mitigation efforts are most likely to be successful for the conservation of butterflies of the subtropical montane forests.
Processing of auditory feedback in perisylvian and insular cortex
Authors: Kurteff Garret Lynn , Field Alyssa M. , Asghar Saman , Tyler-Kabara Elizabeth C. , Clarke Dave , Weiner Howard L. , Anderson Anne E. , Watrous Andrew J. , Buchanan Robert J. , Modur Pradeep N. , Hamilton Liberty S.
Published: May 2024

When we speak, we not only make movements with our mouth, lips, and tongue, but we also hear the sound of our own voice. Thus, speech production in the brain involves not only controlling the movements we make, but also auditory and sensory feedback. Auditory responses are typically suppressed during speech production compared to perception, but how this manifests across space and time is unclear. Here we recorded intracranial EEG in seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy who performed a reading/listening task to investigate how other auditory responses are modulated during speech production. We identified onset and sustained responses to speech in bilateral auditory cortex, with a selective suppression of onset responses during speech production. Onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production. Phonological feature tuning in these “onset suppression” electrodes remained stable between perception and production. Notably, the posterior insula responded at sentence onset for both perception and production, suggesting a role in multisensory integration during feedback control.
The complete genome of lettuce reveals centromere landscape and empowers breeding
Authors: Wang Ke , Jin Jingyun , Wang Jingxuan , Wang Xinrui , Sun Jie , Meng Dian , Wang Xiangfeng , Guo Li
Published: May 2024

Lettuce (Lactuca sativaL.) is a globally grown vegetable crop as the most popular salad ingredient. Lettuce breeding is crucial to enhancing yield, nutrition and disease resistance, but impeded by lacking a high-quality genome resource. In addition, the released genomes remain fragmented (with hundreds of gaps) and incomplete with omitting pivotal centromeres and telomeres. Here, we report a 2.59 Gb complete telomere-to-telomere (T2T) genome assembly for lettuce. T2T genome analysis revealed the unique genetic and epigenetic architectures of centromere repeats dominated by retrotransposons and satellites. The complete genome and annotation facilitate the identification of candidate disease resistance (NLR) genes induced during grey mold infection. The genomic resources, and biological insights into genetic and epigenetic landscape of centromeres not only advance lettuce research and breeding, but also propel the biology and evolution of centromeres across plant kingdom.
KBTBD4 Cancer Hotspot Mutations Drive Neomorphic Degradation of HDAC1/2 Corepressor Complexes
Authors: Xie Xiaowen , Zhang Olivia , Yeo Megan J.R. , Lee Ceejay , Harry Stefan A. , Paul Leena , Li Yiran , Payne N. Connor , Nam Eunju , Kwok Hui Si , Jiang Hanjie , Mao Haibin , Hadley Jennifer L. , Lin Hong , Batts Melissa , Gosavi Pallavi M. , D’Angiolella Vincenzo , Cole Philip A. , Mazitschek Ralph , Northcott Paul A. , Zheng Ning , Liau Brian B.
Published: May 2024

Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function1. As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB)2, the most common embryonal brain tumor in children, and pineoblastoma3. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST4. However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.
Regulatory T cells restrain skin inflammation by modulating peripheral neuron activation
Authors: Mendoza Alejandra , Bou-Puerto Regina , Giovanelli Paolo , Dikiy Stanislav , Andretta Emma , Rudensky Alexander
Published: May 2024

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we questioned whether regulatory T cells (Treg cells), a T cell subset that suppresses systemic and local inflammation, can modulate activation of peripheral neurons. Short-term ablation of Treg cells increased neuronal activation to noxious stimuli independently from immunosuppressive function. We find that a population of skin Treg cells is highly enriched for Penk expression, a precursor for endogenous opioid enkephalins. Acute depletion of Penk-expressing Treg cells, or cell-specific ablation of Penk in Treg cells increases neuronal activation in response to noxious stimuli and associated inflammation. Our study indicates that a population of Treg cells exhibits neuromodulatory activity to restrain inflammation.
Chromosomal domain formation by archaeal SMC, a roadblock protein, and DNA structure
Authors: Yamaura Kodai , Takemata Naomichi , Kariya Masashi , Ishino Sonoko , Yamauchi Masataka , Takada Shoji , Ishino Yoshizumi , Atomi Haruyuki
Published: May 2024

Structural maintenance of chromosomes (SMC) complexes fold genomes by extruding DNA loops. In eukaryotes, loop-extruding SMC complexes form topologically associating domains (TADs) by being stalled by roadblock proteins. It remains unclear whether a similar mechanism of domain formation exists in prokaryotes. Using high-resolution chromosome conformation capture sequencing, we show that an archaeal homolog of the bacterial Smc-ScpAB complex organizes the genome ofThermococcus kodakarensisinto TAD-like domains. We also find that TrmBL2, a nucleoid- associated protein that forms a stiff nucleoprotein filament, stalls theT. kodakarensisSMC complex and establishes a boundary at the site-specific recombination sitedif. TrmBL2 stalls the SMC complex at tens of additional non-boundary loci with lower efficiency. Intriguingly, the stalling efficiency is correlated with structural properties of underlying DNA sequences. Our study illuminates not only a eukaryotic-like mechanism of domain formation in archaea, but also an unforeseen role of intrinsic DNA structure in large-scale genome organization.
A Y chromosome-linked genome editor for efficient population suppression in the malaria vectorAnopheles gambiae
Authors: Tolosana Ignacio , Willis Katie , Burt Austin , Gribble Matthew , Nolan Tony , Crisanti Andrea , Bernardini Federica
Published: May 2024

Genetic control – the deliberate introduction of genetic traits to control a pest or vector population – offers a powerful tool to augment conventional mosquito control tools that have been successful in reducing malaria burden but that are compromised by a range of operational challenges. Self-sustaining genetic control strategies have shown great potential in laboratory settings but hesitancy due to their invasive and persistent nature may delay their implementation. Here instead we describe a self-limiting strategy, designed to have geographically and/or temporally restricted effect, based on a Y chromosome-linked genome editor (YLE). The YLE comprises a CRISPR-Cas9 construct that is always inherited by males yet generates an autosomal dominant mutation that is transmitted to over 90% of the offspring and results in female-specific sterility. Males are unaffected. To our knowledge, our system represents the first engineering of the Y chromosome to generate a genetic control strain for mosquitoes. Mathematical modelling shows that this YLE technology is up to 8 times more efficient for population suppression than optimal versions of other self-limiting strategies.
CRISPR gene and transcriptome engineering (CRISPRgate) improves loss-of-function genetic screening approaches
Authors: Stadager Jannis , Bernardini Chiara , Hartmann Laura , May Henrik , Wiepcke Jessica , Kuban Monika , Najafova Zeynab , Johnsen Steven A. , Legewie Stefan , Traube Franziska R. , Jude Julian , Rathert Philipp
Published: May 2024

The CRISPR/Cas9 technology has revolutionized genotype-to-phenotype assignments through large-scale loss-of-function (LOF) screens. However, limitations like editing inefficiencies and unperturbed genes cause significant noise in data collection. To address this, we introduce CRISPR Gene and Transcriptome Engineering (CRISPRgate), which uses two specific sgRNAs to simultaneously repress and cleave the target gene within the same cell, increasing LOF efficiencies and reproducibility. CRISPRgate outperforms conventional CRISPRko, CRISPRi, or CRISPRoff systems in suppressing challenging targets and regulators of cell proliferation. Additionally, it efficiently suppresses modulators of EMT and impairs neuronal differentiation in a human iPSC model. In a multiplexed chromatin-focused phenotypic LOF screen, CRISPRgate exhibits improved depletion efficiency, reduced sgRNA performance variance, and accelerated gene depletion compared to individual CRISPRi or CRISPRko, ensuring consistency in phenotypic effects and identifying more significant gene hits. By combining CRISPRko and CRISPRi, CRISPRgate increases LOF rates without increasing genotoxic stress, facilitating library size reduction for advanced LOF screens.

Motivation

The CRISPR technology (CRISPRko/CRISPRi) enables the specific depletion of target genes with fewer off-target effects, facilitating precise investigations of gene function. Despite its benefits, CRISPR applications have limitations. Residual active protein expression mediated by in-frame DNA repair or alternative splicing1–8as well as strong epigenetic regulation and difficulties in sgRNA design to the transcription start site (TSS)9–12hinder the full potential of loss-of-function studies using CRISPRko or CRISPRi. We aimed to achieve robust target gene reduction in order to improve the reproducibility of the CRISPR technology by integrating the widely used CRISPRko and CRISPRi approaches into a single application.
The hippocampus supports interpolation into new states during category abstraction
Authors: Schäfer Theo A.J. , Thalmann Mirko , Schulz Eric , Doeller Christian F. , Theves Stephanie
Published: May 2024

The hippocampus forms concepts by integrating multi-feature relations into a unified representation. A common yet unconfirmed assumption is that such cognitive maps afford interpolations to never-experienced states. We approach this question as a category-learning problem in which prototypes are omitted from training but guide category-based decisions in a subsequent feature-inference task. Consistent with behavior, missing inferred stimulus features were represented at prototypical values in neocortex. This cortical completion effect correlated with hippocampal responses, which in turn reflected the distance between imagined prototypes and experienced exemplars. This was paralleled by a learning-dependent grid-like representation of the underlying conceptual space in entorhinal cortex. Our results suggest that abstracted prototypes correspond to interpolated central states in a cognitive map that guide cortical pattern completion during category-based decisions.
Compositional Shifts and Co-occurrence Patterns of Topsoil Bacteria and Micro-Eukaryotes Across a Permafrost Thaw Gradient in Alpine Meadows of the Qilian Mountains, China
Authors: Wang Zhu , Liu Yang , Wang Fang
Published: May 2024

Soil microorganisms play a pivotal role in the biogeochemical cycles of alpine meadow ecosystems, especially in the context of permafrost thaw. However, the mechanisms driving microbial community responses to environmental changes, such as variations in active layer thickness (ALT) of permafrost, remain poorly understood. This study utilized next-generation sequencing to explore the composition and co-occurrence patterns of soil microbial communities, focusing on bacteria and micro-eukaryotes along a permafrost thaw gradient. Results showed a decline in bacterial alpha diversity with increasing permafrost thaw, while micro-eukaryotic diversity exhibited an opposite trend. Although changes in microbial community composition were observed in permafrost and seasonally frozen soils, these shifts were not statistically significant. Bacterial communities exhibited greater differentiation between frozen and seasonally frozen soils, a pattern not mirrored in eukaryotic communities. LEfSe analysis revealed a higher number of potential biomarkers in bacterial communities compared to micro-eukaryotes. Bacterial co-occurrence networks were more complex, with more nodes, edges, and positive linkages than those of micro-eukaryotes. Key factors such as soil texture, ALT, and bulk density significantly influenced bacterial community structures, particularly affecting the relative abundances of the Acidobacteria, Proteobacteria, and Actinobacteria phyla. In contrast, fungal communities (e.g.,Nucletmycea,Rhizaria,Chloroplastida, andDiscoseagroups) were more affected by electrical conductivity, vegetation coverage, and ALT. This study highlights the distinct responses of soil bacteria and micro-eukaryotes to permafrost thaw, offering insights into microbial community stability under global climate change.

Importance

This study sheds light on how permafrost thaw affects microbial life in the soil, with broader implications for understanding climate change impacts. As permafrost degrades, it alters the types and numbers of microbes in the soil. These microbes play essential roles in environmental processes, such as nutrient cycling and greenhouse gas emissions. By observing shifts from bacteria-dominated to fungi-dominated communities as permafrost thaws, the study highlights potential changes in these processes. Importantly, this research suggests that the stability of microbial networks decreases with permafrost degradation, potentially disrupting the delicate balance of these ecosystems. The findings not only deepen our understanding of microbial responses to changing climates but also support the development of strategies to monitor and potentially mitigate the effects of climate change on fragile high-altitude ecosystems.
Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM
Authors: Fernandez-Ramirez Maria del Carmen , Nguyen Binh A. , Singh Preeti , Afrin Shumaila , Evers Bret , Basset Parker , Wang Lanie , Pękała Maja , Ahmed Yasmin , Singh Virender , Canepa Jacob , Wosztyl Aleksandra , Li Yang , Saelices Lorena
Published: May 2024

ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing diverse clinical manifestations. Our laboratory aims to investigate a potential relationship between the different genotypes, organ of deposition, clinical phenotypes, and the structure of ATTR fibrils. Using cryo-electron microscopy, we have recently described how the neuropathic related mutations ATTRv-I84S and ATTRv-V122Δ can drive structural polymorphism inex vivofibrils. Here we question whether the mutation ATTRv-T60A, that commonly triggers cardiac and neuropathic symptoms, has a similar effect. To address this question, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, thyroid, kidney, and liver) from the same patient and from the heart of two additional patients. We have found a consistent conformation among all the fibril structures, acquiring the “closed-gate morphology” previously found in ATTRwt and others ATTRv related to cardiac or mixed manifestations. The closed-gate morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 act as a gate of the polar cavity. Our study indicates that ATTR-T60A fibrils present in peripheral organs adopt the same structural conformation in all patients, regardless of the organ of deposition.
A red algal polysaccharide influences the multicellular development of the choanoflagellateSalpingoeca rosetta
Authors: Perotti Olivia , Esparza Gabriel Viramontes , Booth David S.
Published: May 2024

We uncovered an interaction between a choanoflagellate and alga, in which porphyran, a polysaccharide produced by the red algaPorphyra umbilicalis, induces multicellular development in the choanoflagellateSalpingoeca rosetta. We first noticed this possible interaction when we tested the growth ofS. rosettain media that was steeped withP. umbilicalisas a nutritional source. Under those conditions,S. rosettaformed multicellular rosette colonies even in the absence of any bacterial species that can induce rosette development. In biochemical purifications, we identified porphyran, a extracellular polysaccharide produced by red algae, as the rosette inducing factor The response ofS. rosettato porphyran provides a biochemical insight for associations between choanoflagellates and algae that have been observed since the earliest descriptions of choanoflagellates. Moreover, this work provides complementary evidence to ecological and geochemical studies that show the profound impact algae have exerted on eukaryotes and their evolution, including a rise in algal productivity that coincided with the origin of animals, the closest living relatives of choanoflagellates.
RudS: Bacterial Desulfidase Responsible for tRNA 4-Thiouridine De-modification
Authors: Jamontas Rapolas , Laurynenas Audrius , Povilaityte Deimante , Meskys Rolandas , Aucynaite Agota
Published: May 2024

In this study, we present a comprehensive analysis of a widespread group of bacterial tRNA de-modifying enzymes, dubbed RudS, which consist of a TudS desulfidase fused to a domain of unknown function (DUF1722). RudS enzymes exhibit specific de-modification activity towards the 4-thiouridine modification (s4U) in tRNA molecules, as indicated by our experimental findings. Notably, heterologous overexpression of RudS genes in Escherichia coli leads to a significant reduction in tRNA 4-thiouridine content, highlighting the enzyme's role in tRNA s4U modification regulation. Through a combination of protein modeling, docking studies, and molecular dynamics simulations, we have identified amino acid residues involved in catalysis and tRNA binding. Experimental validation through targeted mutagenesis confirms the TudS domain as the catalytic core of RudS, with the DUF1722 domain facilitating tRNA binding in the anticodon region. Our results suggest a potential role for RudS tRNA modification eraser proteins in prokaryotic tRNA regulation pathways.
Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ
Authors: Shang Jinsai , Kojetin Douglas J.
Published: May 2024

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates gene expression programs in response to ligand binding. Endogenous lipids and synthetic ligands, including covalent antagonist inhibitors such as GW9662 and T0070907, are thought to compete for the orthosteric pocket in the ligand-binding domain (LBD). However, we previously showed that synthetic PPARγ ligands can cooperatively cobind with and reposition a bound endogenous orthosteric ligand to an alternate site, synergistically regulating PPARγ structure and function (Shang et al., 2018). Here, we reveal the structural mechanism of cobinding between a synthetic covalent antagonist inhibitor with other synthetic ligands. Biochemical and NMR data show that covalent antagonist inhibitors weaken—but do not prevent—the binding of other synthetic ligands via an allosteric mechanism rather than direct ligand clashing. The covalent ligands shift the LBD ensemble toward a transcriptionally repressive conformation, which structurally clashes with and reduces the orthosteric binding affinity of non-covalent synthetic ligands. Crystal structures reveal different non-covalent synthetic ligand-specific cobinding mechanisms ranging from alternate site binding to unexpectedly adopting an orthosteric binding mode by altering the covalent ligand binding pose. Our findings not only highlight the significant flexibility of the PPARγ orthosteric pocket and its ability to accommodate multiple ligands simultaneously, but also demonstrate that GW9662 and T0070907 should not be used as reliable chemical tools to inhibit the binding of other ligands to PPARγ.
Dual-Action Kinase Inhibitors Influence p38α MAP Kinase Dephosphorylation
Authors: Stadnicki Emily J , Ludewig Hannes , Kumar Ramasamy P , Wang Xicong , Qiao Youwei , Kern Dorothee , Bradshaw Niels
Published: May 2024

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase towards the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α MAP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we discovered three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are “dual-action” inhibitors that simultaneously block the active site and stimulate p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a new approach to achieving improved potency and specificity for therapeutic kinase inhibitors.
Rapid evolution of piRNA clusters in theDrosophila melanogasterovary
Authors: Srivastav Satyam P. , Feschotte Cédric , Clark Andrew G.
Published: May 2024

The piRNA pathway is a highly conserved mechanism to repress transposable element (TE) activity in the animal germline via a specialized class of small RNAs called piwi-interacting RNAs (piRNAs). piRNAs are produced from discrete genomic regions called piRNA clusters (piCs). Although the molecular processes by which piCs function are relatively well understood inDrosophila melanogaster, much less is known about the origin and evolution of piCs in this or any other species. To investigate piC origin and evolution, we use a population genomic approach to compare piC activity and sequence composition across eight geographically distant strains ofD. melanogasterwith high-quality long-read genome assemblies. We perform annotations of ovary piCs and genome-wide TE content in each strain. Our analysis uncovers extensive variation in piC activity across strains and signatures of rapid birth and death of piCs. Most TEs inferred to be recently active show an enrichment of insertions into old and large piCs, consistent with the previously proposed “trap” model of piC evolution. In contrast, a small subset of active LTR families is enriched for the formation of new piCs, suggesting that these TEs have higher proclivity to form piCs. Thus, our findings uncover processes leading to the origin of piCs. We propose that piC evolution begins with the emergence of piRNAs from individual insertions of a few select TE families prone to seed new piCs that subsequently expand by accretion of insertions from most other TE families during evolution to form larger “trap” clusters. Our study shows that TEs themselves are the major force driving the rapid evolution of piCs.
Is the effective potential effective for dynamics?
Authors: Herring Nathan , Cao Shuyang , Boyanovsky Daniel
Published: May 2024

We critically examine the applicability of the effective potential within dynamical situations and find, in short, that the answer is negative. An important caveat of the use of an effective potential in dynamical equations of motion is an explicit violation of energy conservation. An effective potential is introduced in a consistent quasistatic approximation, and its narrow regime of validity is discussed. Two ubiquitous instances in which even the adiabatic effective potential is not valid in dynamics are studied in detail: parametric amplification in the case of oscillating mean fields, and spinodal instabilities associated with spontaneous symmetry breaking. In both cases profuse particle production is directly linked to the failure of the effective potential to describe the dynamics. We introduce a consistent, renormalized, energy conserving dynamical framework that is amenable to numerical implementation. Energy conservation leads to the emergence of asymptotic highly excited, entangled stationary states from the dynamical evolution. As a corollary, decoherence via dephasing of the density matrix in the adiabatic basis is argued to lead to an emergent entropy, formally equivalent to the entanglement entropy. The results suggest novel characterization of asymptotic equilibrium states in terms of order parameter vs energy density.

Published by the American Physical Society
2024
Holographic RG from an exact RG: Locality and general coordinate invariance in the bulk
Authors: Dharanipragada Pavan , Sathiapalan B.
Published: May 2024

In earlier papers it was shown that the correct kinetic term for scalar, vector gauge field and the spin two field in AdSD+1 space is obtained starting from the exact renormalization group (ERG) equation for a CFTD perturbed by scalar composite, conserved vector current, and conserved traceless energy momentum tensor respectively. In this paper interactions are studied, and it is shown that a flipped version of the Polchinski ERG equation that evolves toward the UV can be written down and is useful for making contact with the usual AdS/CFT prescriptions for correlation function calculations. The scalar-scalar-spin-2 interaction in the bulk is derived from the ERG equation in the large N semiclassical approximation. It is also shown that after mapping to AdS the interaction is local on a scale of the bare cutoff rather than the moving cutoff (which would have corresponded to the anti–de Sitter scale). The map to AdSD+1 plays a crucial role in this locality. The local nature of the coupling ensures that this interaction term in the bulk action is obtained by gauge fixing a general coordinate invariant scalar kinetic term in the bulk action. A wave function renormalization of the scalar field is found to be required for a mutually consistent map of the two fields to AdSD+1.

Published by the American Physical Society
2024
Maximum power of coupled-qubit Otto engines
Authors: Gao Jingyi , Hatano Naomichi
Published: May 2024

We put forward four schemes of a coupled-qubit quantum Otto machine, a generalization of the single-qubit quantum Otto machine, based on work and heat transfer between an internal system consisting of a coupled pair of qubits and an external environment consisting of two heat baths and two work storages. The four schemes of our model are defined by the positions of attaching the heat baths, which play a key role in the power of the coupled-qubit engine. First, for the single-qubit heat engine, we find a maximum-power relation, and the fact that its efficiency at the maximum power is equal to the Otto efficiency, which is greater than the Curzon-Ahlborn efficiency. Second, we compare the coupled-qubit engines to the single-qubit engine from the point of view of achieving the maximum power based on the same energy-level change for work production and find that the coupling between the two qubits can lead to greater powers but the system efficiency at the maximum power is lower than the single-qubit system's efficiency and the Curzon-Ahlborn efficiency.

Published by the American Physical Society
2024
Features of the crystal structure and surface of superprotonic conductor caesium hydrogen sulfate phosphate
Authors: Makarova Irina P. , Isakova Natalia N. , Kalyukanov Andrey I. , Gainutdinov Radmir V. , Tolstikhina Alla L. , Komornikov Vladimir A.
Published: May 2024

The crystal structure of superprotonic conductor caesium hydrogen sulfate phosphate [Cs4(HSO4)3(H2PO4)] have been analyzed using neutron diffraction methods. Additionally, its structure and surface layers have been investigated using atomic force microscopy. From the diffraction data obtained, Fourier syntheses of neutron scattering densities were calculated, and the localization of hydrogen atoms and the parameters of three types of hydrogen bonds in the crystal structure were accurately determined. Correlation of surface characteristics of samples obtained by atomic force microscopy with their crystal structure is shown.
Knowledge management–performance nexus: Mediating effect of motivation and innovation
Authors: Ştefan Simona Cătălina , Popa Ion , Olariu Ana Alexandra , Popa Ştefan Cătălin , Popa Cătălina-Florentina
Published: May 2024

Purpose

The current study has a two-fold purpose. Firstly, it aims to analyze the extent to which knowledge management (KM) affects the performance of individuals (task and contextual) on the one hand and that of organizations (product or service, perceived and financial) on the other hand. Secondly, it proposes to investigate the mediating effect of motivation and innovation in the relationship between KM and individual and organizational performance.

Design/methodology/approach

Partial least squares structural equation modeling (PLS-SEM) was employed in this study, with mediation analysis performed using advanced PLS-SEM techniques. A total of 1,284 respondents from organizations in both the public and private sectors were included in the sample.

Findings

The findings emphasize that KM has a more significant direct effect on individual performance compared to organizational performance. Concurrently, in terms of indirect influence, it is found that KM, through motivation and innovation, has a positive and significant effect on both individual and organizational performances, with a higher influence on the organizational one.

Originality/value

The originality of the work can be noted in designing two different structural models to represent the proposed relationships at the individual and organizational levels. These findings could provide organizational decision makers with empirical evidence, helping them (1) internalize the significance of the KM process in organizations as well as its subsequent effects on individual and organizational performance and (2) identify factors that mediate variable relationships.