bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulating 3D refractive index distributions of suspended cells
Authors: Borrelli Francesca , Pirone Daniele , Miccio Lisa , Memmolo Pasquale , Ferraro Pietro , Bianco Vittorio
Published: October 2024

The introduction of holo-tomographic flow cytometry has unlocked the possibility of imaging the 3D refractive index (RI) distribution of suspended cells while they flow and rotate in microfluidic streams. Similarly, approaches that optically trap and rotate the samples can image them in suspension conditions. Great effort has been spent in developing robust algorithms for the tomogram estimation, as well as denoising and 3D segmentation algorithms. However, the lack of a ground-truth dataset for suspended cells significantly hinders the development of image processing pipelines, limiting the advancement of the associated technology field. Here we propose a novel method for simulating 3D refractive index tomograms of suspended cells. We start with prior knowledge of the statistics of the 3D RI distribution and morphometry of various cell sub-compartments gathered from holo-tomographic flow cytometry experiments and combined with literature data to create realistic 3D distributions. Next, we introduce a simple method to obtain a simulation of the tomogram obtainable from each cell, which approximates the effects of the limited numerical aperture of the system, the speckle noise and the inversion algorithm itself. As a benchmark for the simulator, we created a shared dataset of RI tomograms with various levels of complexity, simulating yeast eukaryotic cells at different budding stages with various phenotypes of cytoplasmic vacuoles, and the presence of cytoplasmic vacuoles and lipid droplets in monocyte cells. We believe that this shared dataset and the simulation method will contribute to the development of a wide plethora of tomogram estimation and processing algorithms.
Representations of stimulus meaning in the hippocampus
Authors: Biane Jeremy S. , Ladow Max A. , Fan Austin , Choi Hye Sun , Zhou Lexi Zichen , Hassan Shazreh , Apodaca-Montano Daniel L. , Kwon Andrew O. , Bratsch-Prince Joshua X. , Kheirbek Mazen A.
Published: October 2024

The ability to discriminate and categorize the meaning of environmental stimuli and respond accordingly is essential for survival. The ventral hippocampus (vHPC) controls emotional and motivated behaviors in response to environmental cues and is hypothesized to do so in part by deciphering the positive or negative quality of these cues. Yet, what features of the environment are represented in the activity patterns of vCA1 neurons, and whether the positive or negative meaning of a stimulus is present at this stage, remains unclear. Here, using 2-photon calcium imaging across six different experimental paradigms, we consistently found that vCA1 ensembles encode the identity, sensory features, and intensity of learned and innately salient stimuli, but not their overall valence. These results offer a reappraisal of vCA1 function, wherein information corresponding to individual stimulus features and their behavioral saliency predominates, while valence-related information is attached elsewhere.
Genetic removal of Nlrp3 protects against sporadic and R345W Efemp1-induced basal laminar deposit formation
Authors: Ortega Antonio J. , Daniel Steffi , Renwick Marian , Kambhampati Pravallika , Thompson Krista N. , Collier Gracen E. , Baker Emily L. , Zaki Hasan , Hulleman John D.
Published: October 2024

Chronic, unresolved inflammation has long been speculated to serve as an initiating and propagating factor in numerous neurodegenerative diseases, including a leading cause of irreversible blindness in the elderly, age-related macular degeneration (AMD). Intracellular multiprotein complexes called inflammasomes in combination with activated caspases facilitate production of pro-inflammatory cytokines such as interleukin 1 beta. Specifically, the nucleotide-binding oligomerization (NOD)-like receptor protein 3 (NLRP3) has received heightened attention due to the wide range of stimuli to which it can respond and its potential involvement in AMD. In this study, we directly tested the role of Nlrp3 and its downstream effector, caspase 1 (Casp1) in mediating early AMD-like pathology (i.e., basal laminar deposits [BLamDs]) in wild-type (WT) mice and the Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) mouse model (p.R345W mutation in Efemp1). Compared to aged-matched controls, R345W+/+knockin mice demonstrated increased Muller cell gliosis, subretinal Iba-1+microglial cells, higher Nlrp3 immunoreactivity in the retina, as well as significant transcriptional upregulation of complement component 3, Nlrp3, pro-Il1b, pro-caspase-1, and tissue inhibitor of matrix metalloproteinase 3 in the retinal pigmented epithelium (RPE)/choroid. These findings were accompanied by an age-related increase in BLamD formation in the R345W+/+mice. Genetic elimination of either Nlrp3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+background, highlighting an important and underappreciated pathway that could affect ML/DHRD onset and progression. Moreover, Nlrp3 knockout reduced spontaneous, idiopathic BLamDs in WT mice, suggesting translatability of our findings not only to rare inherited retinal dystrophies, but also potentially to AMD itself.
Metabolic modeling of microbial communities in the chicken ceca reveals a landscape of competition and co-operation
Authors: Utkina Irina , Fan Yi , Willing Benjamin P. , Parkinson John
Published: October 2024

With their ability to degrade dietary fibers to liberate otherwise unavailable substrates, members of the Bacteroidales exert a substantial influence on the microbiome of the lower intestine. Currently our knowledge of how this influence translates to the metabolic interactions that support community structure is limited. Here we applied constraints-based modeling to chicken cecal communities to investigate metabolic interactions in the presence and absence ofBacteroides. From metagenomic datasets previously generated from 33 chicken ceca, we constructed 237 metagenome-assembled genomes. Metabolic modeling of communities built from these genomes generated profiles of short chain fatty acids largely consistent with experimental assays and confirmed the role ofB. fragilisas a metabolic hub, central to the production of metabolites consumed by other taxa. In its absence, communities undergo significant functional reconfiguration, with metabolic roles typically fulfilled byB. fragilisassumed by multiple taxa. BeyondB. fragilis, we foundEscherichia coliandLactobacillus crispatusalso mediate influential metabolic roles that vary in the presence or absence ofB. fragilis. Compensatory adaptations adopted by the microbiome in the absence ofB. fragilisresulted in metabolic profiles previously associated with inflammatory bowel disease in humans, including energy deficiency, increased lactate production and altered amino acid metabolism. This work demonstrates the potential of chicken cecal microbiomes to investigate the complex metabolic interactions and key contributions that drive community dynamics.
Further characterization and engineering of a 11-amino acid motif for enhancing recombinant protein expression
Authors: Bi Jiawu , Tiong Elaine , Zhou Weibiao , Wong Fong Tian
Published: October 2024

Background

Recombinant protein production inEscherichia coli(E. coli) is a widely used system in both academic and industrial research owing to its low cost and wide availability of genetic tools. Despite its advantages, this system still struggles with soluble expression of recombinant proteins. To address this, various solubility-enhancing and yield-improving methods such as the addition of fusion tags have been developed. However, traditional tags such as small ubiquitin-related modifier (SUMO) and Glutathione S-transferase (GST) can interfere with protein folding or require removal post-translation, which adds complexity and cost to production. To circumvent these issues, smaller solubility tags (<10 kDa) are preferred. This study specifically focuses on an 11-amino acid solubility-enhancing tag (NT11) derived from the N-terminal domain of a duplicated carbonic anhydrase fromDunaliellaspecies.

Results

A comprehensive analysis was performed to improve the characteristics of the 11-amino acid tag. By investigating the alanine-scan library of NT11, we increased its activity and identified key residues for further development. Screening with the alanine mutant library consistently led to at least a two-fold improvement in protein yield for three different proteins. We also discovered that the NT11 tag is not limited to the N-terminal position and can function at either the N- or C-terminal of the protein, providing flexibility in designing protein expression constructs. With these new insights, we have successfully doubled the recombinant protein yields of valuable growth factors, such as fibroblast growth factor 2 (FGF2) and an originally low-yielding human epidermal growth factor (hEGF), inE. coli.

Conclusion

The further characterisation and development of the NT11 tag have provided valuable insights into the optimization process for such small tags and expanded our understanding of its potential applications. The ability of NT11 tag to be positioned at different locations within the protein construct without compromising its effectiveness to enhance recombinant protein yields, makes it a valuable tool across a diverse range of proteins. Collectively, these findings have the potential to simplify and enhance the efficiency of recombinant protein production.
Functional characterization of luciferase in a brittle star indicates parallel evolution influenced by genomic availability of haloalkane dehalogenase
Authors: Lau Emily S , Majerova Marika , Hensley Nicholai M , Mukherjee Arnab , Vasina Michal , Pluskal Daniel , Damborsky Jiri , Prokop Zbynek , Delroisse Jérôme , Bayaert Wendy-Shirley , Parey Elise , Oliveri Paola , Marletaz Ferdinand , Marek Martin , Oakley Todd H
Published: October 2024

Determining why convergent traits use distinct versus shared genetic components is crucial for understanding how evolutionary processes generate and sustain biodiversity. However, the factors dictating the genetic underpinnings of convergent traits remain incompletely understood. Here, we use heterologous protein expression, biochemical assays, and phylogenetic analyses to confirm the origin of a luciferase gene from haloalkane dehalogenases in the brittle starAmphiura filiformis. Through database searches and gene tree analyses, we also show a complex pattern of presence and absence of haloalkane dehalogenases across organismal genomes. These results first confirm parallel evolution across a vast phylogenetic distance, because octocorals likeRenillaalso use luciferase derived from haloalkane dehalogenases. This parallel evolution is surprising, even though previously hypothesized, because many organisms that also use coelenterazine as the bioluminescence substrate evolved completely distinct luciferases. The inability to detect haloalkane dehalogenases in the genomes of several bioluminescent groups suggests that the distribution of this gene family influences its recruitment as a luciferase. Together, our findings highlight how biochemical function and genomic availability help determine whether distinct or shared genetic components are used during the convergent evolution of traits like bioluminescence.
Inflammation biomarkers and neurobehavioral performance in rural adolescents
Authors: Amdemicael Beemnet , Yang Kun , Chronister Briana N.C. , Mackey Caroline , Tu Xin , Gahagan Sheila , Martinez Danilo , Checkoway Harvey , Jacobs David R , Suarez-Torres Jose , Hong Suzi , Suarez-Lopez Jose R.
Published: October 2024

Background

Systemic inflammation has been associated with lower neurobehavioral performance in diverse populations, yet the evidence in adolescents remains lacking. Cytokines can alter neural network activity to induce neurocognitive changes. This work seeks to investigate the association between inflammation and neurobehavior in adolescents living in a rural region of Ecuador.

Methods

We examined 535 adolescents in rural communities of Ecuador (ESPINA study), 508 of which had neurobehavioral assessments (NEPSY-II) and circulating plasma levels of inflammatory markers (CRP, IL-6, TNF-⍺, sICAM-1, sVCAM-1, SAA, and sCD14). Associations between inflammatory biomarker concentrations and neurobehavioral scores were examined using adjusted bivariate semi-parametric models with generalized estimating equations. A partial least square regression approach was used to create composite variables from multiple inflammation biomarkers and model their association with cognitive outcomes.

Results

Higher sCD14 and TNF-α concentrations were significantly associated with lower social perception scores, by −0.47 units (95% CI: −0.80, −0.13) and −0.42 (−0.72, −0.12) for every 50% increase in inflammatory marker concentration, respectively. Similarly, every 50% increase in the inflammation summary score was associated with a significantly lower Social Perception score by −0.11 units (−0.19, −0.03). A unit increase in inflammatory composites of seven markers were associated with lower scores in language (−0.11 units, p=0.04), visuospatial processing (−0.15, p= 0.09), and social perception (−0.22, p=0.005) domains.

Conclusions

Higher levels of inflammation were associated with lower neurobehavioral performance in adolescents, especially with social perception. In addition, using a robust analytic method to examine an association between a composite inflammatory variable integrating seven markers led to additional findings, including the domains of language and visuospatial processing. A longitudinal follow-up of such investigations could unveil potential changes in inflammation-neurobehavior performance links through developmental stages and intervention opportunities.
Prospective validation of mean metacarpophalangeal joint extension as a measure of flexor compartment fibrotic inflammation in diabetes-related hand manifestations
Authors: Phatak Sanat , Jadhav Sarita , Wagh Rucha , Ladha Parth , Nalkande Rishi , Tope Rutvij , Balbudhe Harsh , Shah Rohan , Dhadge Smita , Goel Pranay , Ingram Jennifer L. , Yajnik Chittaranjan
Published: October 2024

Introduction

Hand conditions in diabetes, namely limited joint mobility (LJM), flexor tenosynovitis (FT), carpal tunnel syndrome (CTS), and Dupuytren disease (DD), share a common pathophysiological process involving pro-fibrotic inflammation in flexor structures. A unified, quantitative measure of disease severity across these conditions is lacking, limiting correlational research. We evaluated mean metacarpophalangeal (MCP) joint extension as a potential measure of severity.

Methods

We assessed 2405 adults, including individuals with type 1 diabetes (n=291), type 2 diabetes (n=877), prediabetes (n=326), and non-diabetic controls (n=911). MCP extension was calculated as the average maximum passive extension of the 2nd-5th fingers, measured with a protractor. Validity was determined by correlating MCP extension with physician-rated severity (convergent) and hand grip strength and the Duruoz Hand Index (DHI, both divergent). Inter-rater reliability was tested in 128 individuals, and sensitivity to change was evaluated in 143 participants over time and in 21 rheumatology patients with subacute noninfectious FT.

Results

Mean MCP extension was significantly lower in individuals with all hand conditions (42.4° LJM, 42.8° FT, 39.9° DD, 51.7° CTS) than in those without (58.6°, all p<0.05). MCP extension correlated with physician-rated severity (−0.5, p<0.01) and weakly with DHI (R2=0.03) and grip strength (R2=0.07). Inter-rater reliability was strong (ICC 0.72), and MCP extension demonstrated sensitivity to change, worsening over eight months (SRM -0.61) and improving after treatment in subacute FT (SRM 0.69).

Conclusion

Mean MCP extension is a valid, reliable, and responsive measure for assessing fibro-inflammatory hand conditions in diabetes, suitable for use in research studies.
Practices, perceptions, and ethical concerns of antimicrobial use among poultry farmers in Kiambu County, Kenya. One-Health context
Authors: Munene Ann , Majiwa Hamilton , Bukusi Elizabeth
Published: October 2024

Globally, the poultry sector is one of the primary animal protein sources for human consumption. The poultry sector enhances both food and economic security in Kenya. This has led to adaptations in the poultry sector to respond to the growing demand for animal protein. Practices such as antimicrobial use for disease management, growth promotion, and product improvement within the poultry industry have led to public health, environmental, and ethical concerns. A predominant poultry-producing region in Kenya, Kiambu County was chosen for this study. In-depth interviews (n=21) were conducted until saturation among both small- and large-scale poultry farmers of layers, broiler, and indigenous chicken breeds. The farmers revealed overuse and misuse of antimicrobials, use of antimicrobials for growth promotion and product improvement, and non-adherence to withdrawal periods. They also use poultry waste in other animal feeds and improperly dispose of antimicrobial dilutions. These practices are all likely to contribute to the development and spread of antimicrobial resistance (AMR), which is a global threat to human, animal, and environmental health. The lack of awareness of the potential harm caused by the practices and disregard of instructions, demonstrates the need for increased awareness among poultry farmers on rational use of antimicrobials in poultry farming. Poultry farmers’ ignorance and lack of adherence to regulations of antimicrobial use in poultry farming raises ethical concerns about the threat to human, animal, and environmental health. We conclude that a multifaceted One Health approach is required to evaluate the different ethical, social, and biological factors that contribute to the development and spread of antibiotic resistance arising from poultry production to safeguard public and environmental health.
Targeting the 3D genome by anthracyclines for chemotherapeutic effects
Authors: Tan Minkang , Sun Shengnan , Liu Yuchen , Perreault Andrea A. , Phanstiel Douglas H. , Dou Liping , Pang Baoxu
Published: October 2024

The chromatins are folded into three-dimensional (3D) structures inside cells, which coordinates the regulation of gene transcription by the non-coding regulatory elements. Aberrant chromatin 3D folding has been shown in many diseases, such as acute myeloid leukemia (AML), and may contribute to tumorigenesis. The anthracycline topoisomerase II inhibitors can induce histone eviction and DNA damage. We performed genome-wide high-resolution mapping of the chemotherapeutic effects of various clinically used anthracycline drugs. ATAC-seq was used to profile the histone eviction effects of different anthracyclines. TOP2A ChIP-seq was used to profile the potential DNA damage regions. Integrated analyses show that different anthracyclines have distinct target selectivity on epigenomic regions, based on their respective ATAC-seq and ChIP-seq profiles. We identified the underlying molecular mechanism that unique anthracycline variants selectively target chromatin looping anchors via disrupting CTCF binding, suggesting an additional potential therapeutic effect on the 3D genome. We further performed Hi-C experiments, and data from K562 cells treated with the selective anthracycline drugs indicate that the 3D chromatin organization is disrupted. Furthermore, AML patients receiving anthracycline drugs showed altered chromatin structures around potential looping anchors, which linked to distinct clinical outcomes. Our data indicate that anthracyclines are potent and selective epigenomic targeting drugs and can target the 3D genome for anticancer therapy, which could be used for personalized medicine to treat tumors with aberrant 3D chromatin structures.
Spatial frequency channels mediate a visual metric for human spatial perception
Authors: Zhang Shijia , Mo Ce , Mo Lei , Fang Fang
Published: October 2024

An intriguing and ubiquitous phenomenon in vision is the perception of spatial property information (e.g. separation, size, shape etc.) that departs from the raw physical inputs yet conforms to the visual context. While it has been postulated that visual system employs an internal adaptable metric by which the signals conveying the spatial property information are scaled, it remains unknown whether and how such putative visual metric is represented in the brain. Here, we hypothesized the putative visual metric is mediated by the joint responses of differently-tuned spatial frequency (SF) channels, and investigated this idea by combining the use of psychophysics, fMRI-based population receptive field (pRF) mapping and computation modeling. We found that reweighting of spatial frequency (SF) channels, either by adaption or presentation of the corresponding SF background, led to systematic distortions of the perceived spatial property information. Moreover, the pRFs in V1 were more concentrated towards the fovea under the high SF stimulation regardless of their positions in the visual field. Importantly, both the perceptual distortions and the global-scale pRF displacement were functionally coupled with the changes in the population SF response induced by SF channel reweighting. Our findings revealed, for the first time, the neural apparatus signaling the putative visual metric that constrains spatial vision by establishing the comprehensive three-way connection between SF channel reweighting, pRF position displacement and perceptual distortions of spatial property information.
Small-molecule Activation of TFEB Alleviates Niemann-Pick Disease Type C via Promoting Lysosomal Exocytosis and Biogenesis
Authors: Du Kaili , Chen Hongyu , Pan Zhaonan , Zhao Mengli , Cheng Shixue , Luo Yu , Zhang Wenhe , Li Dan
Published: October 2024

Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists ie SFN as potential NPC therapeutic candidates.
Nrf2 orchestrates epigenetic regulations and serves as the master regulator of KLF4 expression and activity during arsenic-induced transformation
Authors: Wang Ziwei , Bi Zhuoyue , Bamrah Jessica , Qiu Yiran , Zhang Wenxuan , Ji Haoyan , Haley John D. , Thakur Chitra , Chen Fei
Published: October 2024

Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in cancer. Our previous study showed that arsenic-induced Nrf2 activation triggers metabolic reprogramming, leading to the formation of cancer stem-like cells. Here, we further demonstrated that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq analysis identified multiple Nrf2 binding peaks at the Klf4 gene locus, which overlap with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced both KLF4 expression and enhancer marker enrichment, accompanied by a global decrease in KLF4 binding across the genome. In wild-type (WT) cells, arsenic treatment increased KLF4 binding on genes involved in oncogenic pathways such as STAT3, SOX2, Nrf2, cell growth, Hedgehog, and EMT. We also found that KLF4 engages in a self-feedback loop in response to Nrf2 signaling. Lastly, our data showed that the co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancer hubs in the genome. These findings suggest that Nrf2’s oncogenic effects are, in part, mediated by Nrf2 dependent self-amplification of KLF4 expression and function. Thus, targeting both Nrf2 and KLF4 could be a promising therapeutic strategy for eliminating cancer stem-like cells.
Genetic compatibility and ecological connectivity drive the dissemination of antibiotic resistance genes
Authors: Lund David , Parras-Moltó Marcos , Inda-Díaz Juan S. , Ebmeyer Stefan , Larsson D.G. Joakim , Johnning Anna , Kristiansson Erik
Published: October 2024

The dissemination of mobile antibiotic resistance genes (ARGs) via horizontal gene transfer is a significant threat to public health globally. The flow of ARGs into and between pathogens, however, remains poorly understood, limiting our ability to develop strategies for managing the antibiotic resistance crisis. Therefore, we aimed to identify genetic and ecological factors that are fundamental for successful horizontal ARG transfer. From the analysis of ∼1 million bacterial genomes and >20,000 metagenomes, we developed random forest models that could reliably predict horizontal ARG transfer between bacteria. Our results suggest that genetic incompatibility, measured as nucleotide composition dissimilarity, negatively influences the likelihood of transfer of ARGs between evolutionarily divergent bacteria. Conversely, environmental co-occurrence increased the likelihood, especially in humans and wastewater, in which several environment-specific dissemination patterns were observed. This study provides new ways to predict the spread of ARGs and provides new insights into the mechanisms governing this evolutionary process.
Aβ-targeting synNotch Receptor for Alzheimer’s Disease: Expanding Applications to Extracellular Protein Aggregates
Authors: Bergo Nicholas J. , Lee Suckwon , Siebrand Cynthia J. , Andersen Julie K. , Walton Chaska C.
Published: October 2024

The synthetic Notch receptor (synNotch) system is a versatile platform that induces gene transcription in response to extracellular signals. However, its application has been largely confined to membrane-bound targets due to specific activation requirements. Whether synNotch can also target extracellular protein aggregates, such as amyloid beta (Aβ) in Alzheimer’s disease (AD), is unclear. To address this, we engineered an Aβ-targeting synNotch receptor controlling the production of chimeric human-mouse versions of Lecanemab (Leqembi®) or Aducanumab (Aduhelm®), both FDA-approved antibodies for AD. We demonstrate that NIH 3T3 cells expressing this synNotch system detect and respond to extracellular Aβ aggregates by synthesizing and secreting Aducanumab or Lecanemab. These findings broaden the potential applications of synNotch, extending its targets beyond membrane-bound proteins to extracellular protein aggregates, providing obvious benefits to research in this scientific arena.
Are protected areas tracking threats to terrestrial biodiversity?
Authors: Pulido Chadid Katherine , Rahbek Carsten , Geldmann Jonas
Published: October 2024

1

Protected areas (PAs) are vital for nature conservation, yet evidence shows that pressure on biodiversity is increasing despite their global expansion. Using threat probability maps based on the IUCN Red List and PA data, we analyzed the relationship between PA coverage and the major threats—agriculture, hunting, logging, pollution, invasive species, and urbanization—affecting amphibians, birds, mammals, and reptiles. Our analysis includes data on 33,379 species and 255,848 protected sites. Our results reveal a potential disconnect between global PAs and threat tracking, often leaving high-threat areas insufficiently protected. Over half of the mapped area for amphibians and mammals faces high threat impact probability and insufficient PA cover. Amphibians face the highest proportion of high-simultaneous threats and lack sufficient cover. Areas facing a high probability of impact lacking sufficient PA cover also harbor the highest proportion of threatened species across all taxonomic groups. Our research provides crucial insights into the current state of terrestrial PAs concerning threats, highlighting areas requiring immediate attention and guiding strategic conservation planning.
An Extensive Atlas of Proteome and Phosphoproteome Turnover Across Mouse Tissues and Brain Regions
Authors: Li Wenxue , Dasgupta Abhijit , Yang Ka , Wang Shisheng , Hemandhar-Kumar Nisha , Yarbro Jay M. , Hu Zhenyi , Salovska Barbora , Fornasiero Eugenio F. , Peng Junmin , Liu Yansheng
Published: October 2024

Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications like phosphorylation, are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood. Here, we presentTurnover-PPT, a comprehensive resource mapping the abundance and lifetime of 11,000 proteins and 40,000 phosphosites across eight mouse tissues and various brain regions, using advanced proteomics and stable isotope labeling. We revealed tissue-specific short- and long-lived proteins, strong correlations between interacting protein lifetimes, and distinct impacts of phosphorylation on protein turnover. Notably, we discovered that peroxisomes are regulated by protein turnover across tissues, and that phosphorylation regulates the stability of neurodegeneration-related proteins, such as Tau and α-synuclein. Thus,Turnover-PPTprovides new fundamental insights into protein stability, tissue dynamic proteotypes, and the role of protein phosphorylation, and is accessible via an interactive web-based portal athttps://yslproteomics.shinyapps.io/tissuePPT.
A novel PhoPQ-potentiated mechanism of colistin resistance impairs membrane integrity inPseudomonas aeruginosa
Authors: Hsieh Yu-Ying Phoebe , O’Keefe Ian P. , Sun Wanting , Wang Zeqi , Yang Hyojik , Vu Linda M. , Ernst Robert K. , Dandekar Ajai A. , Malik Harmit S.
Published: October 2024

Polymicrobial communities are often recalcitrant to antibiotic treatment because interactions between different microbes can dramatically alter their responses and susceptibility to antimicrobials. However, the mechanisms of evolving antimicrobial resistance in such polymicrobial environments are poorly understood. We previously reported that Mg2+depletion caused by the fungusCandida albicanscan enablePseudomonas aeruginosato acquire significant resistance to colistin, a last-resort antibiotic targeting bacterial membrane. Here, we dissect the genetic and biochemical basis of this increased colistin resistance. We show thatP. aeruginosacells can acquire colistin resistance using three distinct evolutionary trajectories involving mutations in genes involved in lipid A biosynthesis, lipid A modifications that are dependent on low Mg2+, and a putative Mg2+transporter, PA4824. These mutations confer colistin resistance by altering acyl chains, hydroxylation, and aminoarabinose modification of lipid A moieties on the bacterial outer membrane. In all cases, enhanced colistin resistance initially depends on the low Mg2+-responsive PhoPQ pathway, which potentiates the evolution of resistance mutations and lipid A modifications that do not occur without Mg2+depletion. However, the PhoPQ pathway is not required to maintain high colistin resistance in all cases. In most cases, the genetic and biochemical changes associated with these novel forms of colistin resistance also impair bacterial membrane integrity, leading to fitness costs. Our findings provide molecular insights into how nutritional competition drives a novel antibiotic resistance mechanism and its ensuing fitness tradeoffs.
Fusobacterium necrophorumandFusobacterium variumare commensal members of the bovine reproductive microbiota and may colonize calf prenatally
Authors: Kilama Justine , Dahlen Carl R , Abbasi Mina , Shi Xiaorong , Nagaraja T. G. , Crouse Matthew S. , Cushman Robert A. , Snider Alexandria P. , McCarthy Kacie L. , Caton Joel S. , Amat Samat
Published: October 2024

Fusobacterium necrophorumis an important pathogen associated with several infectious diseases in cattle. However, recent sequencing-based studies have indicated thatF. necrophorumis positively associated with pregnancy in beef cows and thatFusobacteriumis the most abundant genus in the bull seminal microbiota, suggesting the potential role ofFusobacteriumin reproductive health and fertility. Here, we performed a comprehensive screening to 1) determine whetherFusobacterium necrophorum(subspeciesnecrophorum[FNN] andfunduliforme[FNF]), andFusobacterium varium(FV) are part of the commensal members of the reproductive microbiota in cattle; 2) to explore whether theseFusobacteriumspp. are colonized in calf prenatally. For this, we screened 11 different sample types including bovine and ram semen, bovine vaginal and uterine swabs, and bull fecal samples, as well as samples from 180- and 260-days old calf fetuses and their respective dams using both quantitative PCR (514 samples) and targeted culturing (499 samples). By qPCR, all the targetedFusobacteriumspp. were detected across all sample types, with FNF being the highly prevalent in the bull semen (66.7%) and maternal ruminal fluids (87.1%), which was confirmed by culturing. All the targetedFusobacteriumwere identified in vaginal and uterine (3.1%-9.4%) as well as placental caruncles, and fetal fluids, ruminal and meconium samples (2.7% - 26.3%) by qPCR and were not isolated by culture method. Overall, our results suggest thatF. necrophorumis a commensal member of healthy male reproductive microbiota, and that FNF, FNN and FV are present in bovine vagino-uterine microbiota, and calf intestine prenatally.
Commensal virome regulate intestinal nutrient sensing via Th17 cells
Authors: Lin Fengqing
Published: October 2024

Our study explores the influence of gut virome on nutrient sensing via T cells in the small intestine. We discovered that the gut virome can independently affect the digestion and absorption of carbohydrates in the small intestine, and this effect is contingent upon T cell surveillance. Additionally, our research reveals heterogeneous responses elicited by virome components across different small intestinal cell types. Stimulation of intestinal epithelial cells is dependent on intact viral particles, while the stimulation of T cells and antigen-presenting cells relies on viral capsids. In the normal murine gut, the virome stimulates antigen-presenting cells to recruit T cells and induce IL22 expression. These findings are significant for developing therapeutic and nutritional strategies targeting metabolic diseases, underscoring the importance of incorporating the gut virome as a key element in interventions.
Illumination mediates a switch in both active sensing and control in weakly electric fish
Authors: Yeh Huanying , Yang Yu , Biswas Debojyoti , Cowan Noah J.
Published: October 2024

To execute sensory-guided behavior, the nervous system must manage uncertainty within multiple streams of information. There are two highly nonlinear mechanisms for achieving this: 1) sensory reweighting, aninternal neural computationwhich places more emphasis on sensory information that exhibits the least uncertainty, e.g. in a Bayesian framework, and 2) active sensing, anovert behaviorthat seeks to improve the quality of sensory information before it enters the nervous system. Here we show that animals solve both of these nonlinear problems concurrently. We studied how the weakly electric glass knifefishEigenmannia virescensalters its movement dynamics under parametric manipulations of illumination. We hypothesized a concomitant switch in both overt active sensing and internal multisensory reweighting. To test this, we varied illumination levels from 0.1 to 210 lx as fish tracked a moving refuge. We discovered that in a neighborhood of a critical threshold (on the order of 1 to 10 lx), small increases in illumination led to dramatic changes in both active sensing and multisensory control, specifically in 1) steep reductions in fish head and tail movements and 2) decreased refuge tracking phase lag. Outside of this threshold, large changes in illumination only caused small changes in active sensing and control. A control-theoretic model that dynamically modulates the weights of vision and electrosense due to illumination changes corroborates our findings. These findings underscore the complex, multipartite, nonlinear nature of locomotor control and the remarkable ability of the nervous system to execute multiple parallel strategies for managing sensory uncertainty.
Mindfulness training impacts brain network dynamics linked to stress response in young adolescents
Authors: Gaviria Julian , Celen Zeynep , Smith Mariana Magnus , Peek Lucas , Brosset Soraya , Vuilleumier Patrik , Van De Ville Dimitri , Merglen Arnaud , Klauser Paul , Piguet Camille
Published: October 2024

Mindfulness-based interventions (MBI) may lead to lower levels of psychological distress, including depression, anxiety, and stress in adolescents. Past research has advanced the discovery of neural architecture recruited by MBI. However, the brain mechanisms through which mindfulness exerts more resilient responses to social stressors in teens remain unclear. Here, we examined how MBI modulates changes in brain network dynamics following social stress with different affective valence (i.e., neutral, negative, and positive). For this aim, we carried out a longitudinal randomized controlled trial in which non-clinical adolescents underwent MBI for 8 weeks. They completed a psychosocial stress task before and following MBI. Functional magnetic resonance imaging (fMRI) and self-reported measurements of psychological distress were collected in both measurement points (i.e., “pre” and “post” MBI). We computed co-activation patterns on fMRI data to characterize dynamic functional connectivity within whole-brain networks. The results depicted how MBI modulates transient co-activation changes in dorsal medial regions of the brain default network (DN) following the experience of stress. However, these brain changes were not specific to the affective valence of stressful stimuli. The relationship between the DN dynamics and the measurements of psychological distress was mediated by MBI. Globally, our findings support a model in which MBI causally mediate brain-behavior interactions related to psychosocial stress in adolescents.
The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency
Authors: Yang Mingchong , Mo Zengshuo , Walsh Kelly , Liu Wen , Guo Xiaoyan
Published: October 2024

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of integrated stress response (ISR) in regulating mitophagy, a key mitochondrial stress pathway. Our findings show that the ISR suppresses mitophagy under non-depolarizing mitochondrial stress by positively regulating mitochondrial protein import, independent of ATF4 activation. Mitochondrial protein import is regulated by the rate of protein synthesis under both depolarizing and non-depolarizing stress.

Without ISR, increased protein synthesis overwhelms the mitochondrial import machinery, reducing its efficiency. Under depolarizing stress, mitochondrial import is heavily impaired even with active ISR, leading to significant PINK1 accumulation. In contrast, non-depolarizing stress allows more efficient protein import in the presence of ISR, resulting in lower mitophagy. Without ISR, mitochondrial protein import becomes severely compromised, causing PINK1 accumulation to reach the threshold necessary to trigger mitophagy. These findings reveal a novel link between ISR-regulated protein synthesis, mitochondrial import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
RNA elements required for the high efficiency of West Nile Virus-induced ribosomal frameshifting
Authors: Aleksashin Nikolay A. , Langeberg Conner J. , Shelke Rohan R. , Yin Tianhao , Cate Jamie H. D.
Published: October 2024

West Nile Virus (WNV), a member of theFlaviviridaefamily, requires programmed -1 ribosomal frameshifting (PRF) for translation of the viral genome. The efficiency of WNV frameshifting is among the highest observed to date. Despite structural similarities to frameshifting sites in other viruses, it remains unclear why WNV exhibits such a high frameshifting efficiency. Here we employed dual-luciferase reporter assays in multiple human cell lines to probe the RNA requirements for highly efficient frameshifting by the WNV genome. We find that both the sequence and structure of a predicted RNA pseudoknot downstream of the slippery sequence–the codons in the genome on which frameshifting occurs–are required for efficient frameshifting. We also show that multiple proposed RNA secondary structures downstream of the slippery sequence are inconsistent with efficient frameshifting. We mapped the most favorable distance between the slippery site and the pseudoknot essential for optimal frameshifting, and found the base of the pseudoknot structure likely is unfolded prior to frameshifting. Finally, we find that many mutations in the WNV slippery sequence allow efficient frameshifting, but often result in aberrant shifting into other reading frames. Mutations in the slippery sequence also support a model in which frameshifting occurs concurrent with or after translocation of the mRNA and tRNA on the ribosome. These results provide a comprehensive analysis of the molecular determinants of WNV-programmed ribosomal frameshifting and provide a foundation for the development of new antiviral strategies targeting viral gene expression.
Sequence termination cues drive habits via dopamine-mediated credit assignment
Authors: Magnard Robin , Cheng Yifeng , Zhou Joanna , Province Haley , Thiriet Nathalie , Janak Patricia H. , Vandaele Youna
Published: October 2024

Mesolimbic dopamine (DA) neurons are central to sequence learning and habit formation. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to investigate how sequence initiation and termination cues influence DA-driven behavioral strategies and learning. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in mediating credit assignment and driving the development of habitual action sequence execution.
Analysis of the underlying factors affecting BIM-LCA integration in the Ghanaian construction industry: a factor analysis approach
Authors: Danso Anthony Kwame , Edwards David John , Adjei Elvis Konadu , Adjei-Kumi Theophilus , Owusu-Manu De-Graft , Fianoo Stephen Israel , Thwala Wellington Didibhuku
Published: October 2024

Purpose

The integration of building information modelling (BIM) and life cycle assessment (LCA) is an effective means of achieving sustainability in the built environment. However, research remains scant on BIM-LCA integration in the Ghanaian construction industry (GCI). This study aims to evaluate the barriers to BIM-LCA integration in the GCI from the perspective of construction professionals.

Design/methodology/approach

Epistemologically relevant theory was developed using interpretivism and post-positivist principles and tested using primary quantitative data. Firstly, a comprehensive literature review identified and examined BIM-LCA integration barriers. Structured surveys of 216 Ghanaian construction professionals collected data on BIM-LCA integration barriers. Data was then analysed using exploratory factor analysis.

Findings

Findings revealed three clusters of barriers, namely, organisational barriers; technical complexity; and knowledge and education. These findings identify and recommend solutions to BIM-LCA integration barriers to standardise processes, raise awareness and integrate project management systems. BIM-LCA adoption will increase productivity, sustainability, construction sector employment (and skills development) and economic growth. This paper concludes with future research on how artificial intelligence and machine learning could improve BIM-LCA integration in building designs. Such work would reveal how new technologies can be used to overcome adoption barriers and promote sustainable building.

Originality/value

This research provides novel knowledge on the barriers to BIM-LCA adoption in Ghana. Practical recommendations for overcoming these barriers are also proposed, e.g. developing standardised procedures and protocols, increasing awareness and education and integrating BIM-LCA into project management systems.
Harnessing the power of ChatGPT to promote Construction Hazard Prevention through Design (CHPtD)
Authors: Uddin S.M. Jamil , Albert Alex , Tamanna Mahzabin
Published: October 2024

Purpose

Construction Hazard Prevention through Design (CHPtD) is recognized as a pivotal strategy for enhancing workplace safety. Despite its theoretical potential, practical implementation faces challenges, particularly regarding designers' familiarity with field-level operations and hazard recognition. This study aims to investigate whether ChatGPT can address these challenges by assisting in hazard recognition during CHPtD sessions.

Design/methodology/approach

The research utilized a randomized controlled experiment to assess ChatGPT as an intervention in supporting hazard recognition during CHPtD sessions. The study involves 162 civil and construction engineering student participants, representing future professionals. Participants engaged in hazard recognition during CHPtD sessions either with or without the assistance of ChatGPT.

Findings

Participants who utilized ChatGPT during CHPtD sessions demonstrated a significant improvement in hazard recognition, identifying approximately 40% more hazards compared to those who did not use ChatGPT. These findings underscore the efficacy of ChatGPT in supporting CHPtD efforts.

Practical implications

The results highlight the practical utility of harnessing ChatGPT in CHPtD sessions to enhance hazard recognition and ultimately promote workplace safety. By leveraging ChatGPT, designers and engineers can better anticipate and mitigate potential hazards during the design phase, thus creating a safer working environment for field workers.

Originality/value

This research contributes to addressing the challenges associated with implementing CHPtD by introducing ChatGPT as a valuable tool to support hazard recognition. By demonstrating the effectiveness of ChatGPT in enhancing hazard identification during CHPtD sessions, this study offers a novel approach to promoting the adoption of CHPtD and advancing workplace safety initiatives.