bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics, treatment and outcomes of myelodysplastic syndrome in two Finnish hospital districts
Authors: Tuominen Samuli , Miettinen Tatu , Dünweber Christina
Published: October 2023

Introduction

Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by changes in haematopoiesis and a high risk for progressing into acute myeloid leukemia (AML). In this retrospective registry based real-world study, from two Finnish hospital data lakes we characterized specialised health care treated MDS patients, their treatment landscape, outcomes, and healthcare resource utilization.

Methods

This study consisted of adult patients with MDS diagnosed in either of two hospital districts in Finland: hospital district of Southwest Finland (HDSF) and Pirkanmaa hospital district (PHD). Two different time windows were used depending on data availability: 1.1.2010-31.12.2019 (HDSF) and 1.1.2012-31.12.2019 (PHD). Electronic health record data, including demographics, diagnoses, and medications was accessed via the respective hospital data lakes and dates and causes of death data was collected from Statistics Finland.

Results

We identified 565 adult MDS patients, of whom 424 received active life-prolonging treatment at specialized healthcare and 141 were treated with watchful observation or supportive care at primary care. 72 patients were treated with azacitidine and 26 patients received allogeneic hematologic stem cell transplant. Median overall survival for the specialty healthcare treated patients was 27,5 months (95 confidence interval [CI] 24,1-35,2) and costs per patient year were 17 563€.

Conclusion

This hospital data lake-based analysis identified patient groups with differing disease severity and need for treatment. High-risk, azacitidine treated patients have suboptimal outcomes and high costs, highlighting the need for new therapeutic approaches to prevent disease progression and reduce disease burden.
Network alterations in temporal lobe epilepsy during non-rapid eye movement sleep and wakefulness
Authors: Rigoni I , Vorderwülbecke BJ , Carboni M , Roehri N , Spinelli L , Tononi G , Seeck M , Perogamvros L , Vulliémoz S
Published: October 2023

Objective

Investigate sleep and temporal lobe epilepsy (TLE) effects on EEG-derived brain networks.

Methods

High-density EEG was recorded during non-REM sleep (N2) and wakefulness in 23 patients and healthy controls (HC). Epochs without epileptic discharges were source-reconstructed in 72 brain regions and connectivity was estimated. Network integration (Efficiency, E) and segregation (Clustering Coefficient, CC) at global and hemispheric level (GE, avgCC, HE, HCC) were calculated. These were compared between groups across frequency bands and correlated with the individual proportion of wakefulness-or sleep-related seizures.

Results

Patients had higher delta GE, delta avgCC and theta avgCC than controls, irrespective of the vigilance state (TLE > HC, p<.01). During wakefulness, theta GE of patients was higher than controls (p<.001) and, for patients, theta GE during wakefulness was higher than during N2 (p<.05). Wake-to-sleep differences in TLE were notable only in the ipsilateral hemisphere (HE and HCC, p<.05). Only measures from wakefulness recordings correlated with the proportion of wakefulness-or sleep-related seizures.

Conclusions

TLE network alterations are more prominent during wakefulness and at lower frequencies. Increased integrationandsegregation suggest a pathological ‘small world’ configuration with a possible inhibitory role.

Significance

Network alterations in TLE occur and are easier to detect during wakefulness.
Polygenic effects on the risk of Alzheimer’s disease in the Japanese population
Authors: Kikuchi Masataka , Miyashita Akinori , Hara Norikazu , Kasuga Kensaku , Saito Yuko , Murayama Shigeo , Kakita Akiyoshi , Akatsu Hiroyasu , Ozaki Kouichi , Niida Shumpei , Kuwano Ryozo , Iwatsubo Takeshi , Nakaya Akihiro , Ikeuchi Takeshi ,   Alzheimer’s Disease Neuroimaging Initiative,   the Japanese Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

Background

Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer’s disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using GWAS statistics from Europeans.

Methods

In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n=565) and the North American ADNI (NA-ADNI) cohort (n=617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD.

Results

The PRS using 131 SNPs had an effect independent ofAPOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with theAPOEvariants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD inAPOEε4 noncarriers with a hazard rate of 2.22.

Conclusions

We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences.
Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
Authors: Nithianandam Vanitha , Bukhari Hassan , Leventhal Matthew J. , Battaglia Rachel A. , Dong Xianjun , Fraenkel Ernest , Feany Mel B.
Published: October 2023

Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer’s disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recovered theDrosophilaortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We performed comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We found an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically defined a role for Appl in regulating autophagy through TGFβ signaling and documented the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer’s disease.
Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models
Authors: de Malglaive France , Barny Iris , Machroub Shahd , Fares-Taie Lucas , Cano Ema , Goudin Nicolas , Attie-Bittach Tania , Kaplan Josseline , Perrault Isabelle , Briseno-Roa Luis , Rozet Jean-Michel , Annereau Jean-Philippe
Published: October 2023

The retina’s sensitivity to light depends on the primary cilium of photoreceptors, known as the outer segment (OS). OS defects are a primary cause of inherited retinal dystrophies (IRDs) and can also indicate wider ciliary dysfunctions. One such IRD is Leber congenital amaurosis type 10 (LCA10), which occurs as a monosymptomatic retinal disease or the presenting symptom of syndromic ciliopathies within the Senior-Loken-Joubert-Meckel spectrum. LCA10 patients are born blind but retain dormant photoreceptors for decades, offering the potential for reactivation. AAV-based gene therapies for IRDs cannot accommodate the largeCEP290gene, prompting the search for innovative treatments.

LCA10 is caused by mutations inCEP290, which plays a vital role in ciliation, similar to cAMP signaling. Utilizing fibroblasts displaying variableCEP290mutations and associated ciliary defects, we show that exposure to Taprenepag, a specific PGE2 receptor agonist, substantially stimulated cAMP synthesis and consistently improved cilia formation and elongation. We also found that intraperitoneal injection of Taprenepag in mice reached the retina and slowed retinal degeneration, promoting OS formation, and improving light sensitivity in aCep290mutant mouse. These findings demonstrate the potential of Taprenepag to treat the CEP290-related visual dysfunction and suggest evaluation for other CEP290-related organ issues and ciliopathies.
Anti-Windup Protection Circuits for Biomolecular Integral Controllers
Authors: Filo Maurice , Gupta Ankit , Khammash Mustafa
Published: October 2023

Robust Perfect Adaptation (RPA) is a desired property of biological systems wherein a system’s output perfectly adapts to a steady state, irrespective of a broad class of perturbations. Achieving RPA typically requires the deployment of integral controllers, which continually adjust the system’s output based on the cumulative error over time. However, the action of these integral controllers can lead to a phenomenon known as “windup”. Windup occurs when an actuator in the system is unable to respond to the controller’s commands, often due to physical constraints, causing the integral error to accumulate significantly. In biomolecular control systems, this phenomenon is especially pronounced due to the positivity of molecular concentrations, inevitable promoter saturation and resource limitations. To protect against such performance deterioration or even instability, we present three biomolecular anti-windup topologies. The underlying architectures of these topologies are then linked to classical control-theoretic anti-windup strategies. This link is made possible due the development of a general model reduction result for chemical reaction networks with fast sequestration reactions that is valid in both the deterministic and stochastic settings. The topologies are realized as chemical reaction networks for which genetic designs, harnessing the flexibility of inteins, are proposed. To validate the efficacy of our designs in mitigating windup effects, we perform simulations across a range of biological systems, including a complex model of Type I diabetic patients and advanced biomolecular proportional-integral-derivative (PID) controllers. This work lays a foundation for developing robust and reliable biomolecular control systems, providing necessary safety and protection against windup-induced instability.
Collaborative Augmented Reconstruction for Scaled Production of 3D Neuron Morphology in Mouse and Human Brains
Authors: Zhang Lingli , Huang Lei , Yuan Zexin , Hang Yuning , Zeng Ying , Li Kaixiang , Wang Lijun , Zeng Haoyu , Chen Xin , Zhang Hairuo , Xi Jiaqi , Chen Danni , Gao Ziqin , Le Longxin , Chen Jie , Ye Wen , Liu Lijuan , Wang Yimin , Peng Hanchuan
Published: October 2023

Digital reconstruction of the intricate 3D morphology of individual neurons from microscopic images is widely recognized as a crucial challenge in both individual research laboratories and large-scale scientific projects focusing on cell types and brain anatomy. This task often fails both conventional manual reconstruction and state-of-the-art automatic reconstruction algorithms, even many of which are based on artificial intelligence (AI). It is also critical but challenging to organize multiple neuroanatomists to produce and cross-validate biologically relevant and agreeable reconstructions in scaled data production. Here we propose an approach based on collaborative human intelligence augmented by AI. Specifically, we have developed a Collaborative Augmented Reconstruction (CAR) platform for neuron reconstruction at scale. This platform allows for immersive interaction and efficient collaborative-editing of neuron anatomy using a variety of client devices, such as desktop workstations, virtual reality headsets, and mobile phones, enabling users to contribute anytime and anywhere and take advantage of several AI-based automation tools. We have tested CAR’s applicability for challenging mouse and human neurons towards a scaled and faithful data production. Our data indicate that the CAR platform is suitable for generating tens of thousands of neuronal reconstructions used in our companion studies.
Physically stressed bees expect less reward in an active choice judgement bias test
Authors: Procenko Olga , Read Jenny , Nityananda Vivek
Published: October 2023

Emotion-like states in animals are commonly assessed using judgment bias tests, which measure responses to ambiguous information. A few studies have recently used these tests to argue for the presence of emotion-like states in insects. However, the results from most of these studies could have other explanations, including changes in motivation and attention. To control for these explanations, we therefore developed a novel judgment bias test, requiring bumblebees to make an active choice indicating their interpretation of ambiguous stimuli. Bumblebees were trained to associate high or low rewards, delivered in two different reward chambers, with distinct colors. Two groups of bees were then physically stressed by shaking or trapping, while the third group served as a control. We subsequently presented the bees with ambiguous colors between the two learnt colors and noted which reward chamber they chose. When presented with ambiguous colors, stressed bees were less likely than control bees to enter the reward chamber previously associated with high reward. We modelled bee behavior using signal detection and drift diffusion models and showed that control bees and stressed bees were, respectively, more likely to respond optimistically and pessimistically to ambiguous cues. The signal detection model further showed that the behavior of stressed bees was explained by a reduction in their prior expectation of high rewards. Our findings thus provide strong evidence for emotion-like states in bees and suggest that their stress-induced pessimistic behavior is explained by a reduced expectation of higher rewards.
A dynamic link between respiration and arousal
Authors: Kluger Daniel S. , Gross Joachim , Keitel Christian
Published: October 2023

Viewing brain function through the lense of other physiological processes has critically added to our understanding of human cognition. Further advances though may need a closer look at the interactions between these physiological processes themselves. Here we characterise the interplay of the highly periodic, and metabolically vital respiratory process and fluctuations in arousal neuromodulation, a process classically seen as non-periodic. In data of three experiments (N = 56 / 27 / 25 women and men) we tested for covariations in respiratory and pupil size (arousal) dynamics. After substantiating a robust coupling in the largest dataset, we further show that coupling strength decreases during task performance compared with rest, and that it mirrors a decreased respiratory rate when participants take deeper breaths. Taken together, these findings suggest a stronger link between respiratory and arousal processes than previously thought. Moreover, these links imply a stronger coupling during periods of rest, and the effect of respiratory rate on the coupling suggests a driving role. As a consequence, studying the role of neuromodulatory arousal on cortical function may also need to consider respiratory influences.

Significance statement

We characterise the interplay of the respiratory rhythm and pupil diameter dynamics as a well-known proxy for arousal. Although we consistently find respiratory modulation of pupillary changes, they were most pronounced during periods of rest (compared to during task performance) and dependent on respiratory rate (deep vs. normal breathing).
A hitchhiker’s guide to Europe: mapping human-mediated dispersal of the invasive Japanese beetle
Authors: Borner Leyli , Martinetti Davide , Poggi Sylvain
Published: October 2023

Early detection of hitchhiking pests requires the identification of strategic entry points via transport. We propose a framework for achieving this in Europe using the Japanese beetle (Popillia japonica) as a case study. Human-mediated dispersal has been responsible for its introduction into several continents over the last century, including Europe where it is listed as a priority pest. Furthermore, interceptions far from the infested area confirm the risk of unintentional transport within continental Europe. Here, we analyse how three modes of transport - air, rail and road - connect the infested area to the rest of Europe. We ranked all European regions from most to least reachable from the infested area. We identified border regions and distant major cities that are readily reachable and observed differences between modes. We propose a composite reachability index combining the three modes, which provides a valuable tool for designing a continental surveillance strategy and prioritising highly reachable regions, as demonstrated by recent interceptions.

Significance statement

Species can be moved long distances by unintentional human transport. Such events can lead to their introduction into non-native areas where they can cause biological invasions. Using the case study of the Japanese beetle, a hitchhiker invasive insect, we propose a framework for identifying entry points for human-transported pests within Europe. We consider how the European infested area is connected to the rest of the continent by three modes of transport: air, rail and road. We propose a methodology that considers the three modes to identify potential entry points. This framework could assist authorities in designing surveillance strategies to achieve early detection of pests in Europe.
Chemotherapy activates inflammasomes to cause inflammation-associated bone loss
Authors: Wang Chun , Kaur Khushpreet , Xu Canxin , Abu-Amer Yousef , Mbalaviele Gabriel
Published: October 2023

Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g., cell-free DNA and ATP) and cytokines (e.g., IL-1β and IL-18). Accordingly, doxorubicin activated the absent in melanoma (AIM2) and NLR family pyrin domain containing 3 (NLRP3) inflammasomes in macrophages and neutrophils, causing inflammatory cell death pyroptosis and NETosis, which correlated with its leukopenic effects. Moreover, the effects of this chemotherapeutic agent on cytokine secretion, cell demise, and bone loss were attenuated to various extent in conditions of AIM2 and/or NLRP3 insufficiency. Thus, we found that inflammasomes are key players in bone loss caused by doxorubicin, a finding that may inspire the development of a tailored adjuvant therapy that preserves the quality of this tissue in patients treated with this class of drugs.
Staphyloccocus aureusbiofilm, in the absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune-suppressive genes in human monocytes
Authors: Bell Richard D , Cann E. Abrefi , Mishra Bikash , Valencia Melanie , Zhang Qiong , Yang Xu , Carli Alberto , Bostrom Mathias , Ivashkiv Lionel
Published: October 2023

Staphyloccocus aureus(S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI).S. aureusforms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic-resistant metabolic state. We developed an in vitro system to studyS. aureusbiofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data,S. aureusbiofilm induced expression of inflammatory genes such asTNFandIL1B, and their anti-inflammatory counter-regulator IL-10.S. aureusbiofilm also activated expression of PD-1 ligands that suppress T cell function, and of IL-1RA that suppresses differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm-encased bacteria that was heat resistant and > 3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita-PAMP. Induction of T cell suppressive genes byS. aureusbiofilm provides insights into mechanisms that suppress T cell immunity in PJI, and suggest that anti-PD-1 therapy that is modeled on immune checkpoint blockade for tumors may be beneficial in PJI.
NAMERS: a purpose-built reference DNA sequence database to support applied eDNA metabarcoding
Authors: Westfall Kristen M. , Singer Gregory A. C. , Kaushal Muneesh , Gilmore Scott R. , Fahner Nicole , Hajibabaei Mehrdad , Abbott Cathryn L.
Published: October 2023

Applied eDNA metabarcoding is increasingly being used to generate actionable results to inform management decisions, regulations, or policy development. Because of these important downstream considerations, optimizing workflow elements is now essential to increasing standardization, efficiency, and confidence of metabarcoding results. Reference DNA sequences are critical workflow elements that currently lack consistent approaches to generating, curating, or publishing. Here we present a complete (mitochondrial genome and nuclear ribosomal DNA cistron) and high quality reference DNA sequence library for the freshwater fishes of British Columbia, Canada. This resource is published as the Novel Applied eDNA Metabarcoding Reference Sequences (NAMERS) repository (https://namers.ca), a user-friendly and interactive website for specialists and non-specialists alike to explore and generate custom reference libraries for taxa and genes of interest. We demonstrate the power of NAMERS to optimize applied eDNA metabarcoding workflows at the study design stage by analyzing the number of primer mismatches and resolution power of existing metabarcoding markers. To meet the increasing demand for actionable eDNA metabarcoding applications, NAMERS demonstrates that high quality curated genomic information is within a reasonable reach. It is timely to establish this framework as the new gold standard and coordinate our efforts to generate this type of reference data at scale.
Conservation of the ancestral function of GTSF1 in transposon silencing in the unicellular eukaryoteParamecium tetraurelia
Authors: Wang Chundi , Lv Liping , Solberg Therese , Wen Zhiwei , Zhang Haoyue , Gao Feng
Published: October 2023

The PIWI-interacting RNA (piRNA) pathway is crucial for transposon repression and the maintenance of genomic integrity. Gametocyte specific factor 1 (GTSF1), an indispensable auxiliary factor of PIWI, was recently shown to potentiate the catalytic activity of PIWI in many metazoans. Whether the requirement of GTSF1 extends to PIWI proteins beyond metazoans is unknown. In this study, we identified a homolog of GTSF1 in the unicellular eukaryoteParamecium tetraurelia(PtGTSF1) and found that its role as a PIWI-cofactor is conserved. PtGTSF1 interacts with PIWI (Ptiwi09) and Polycomb Repressive Complex 2 (PRC2) and is essential for PIWI-dependent DNA elimination of transposons during sexual development. PtGTSF1 is crucial for the degradation of PIWI-bound small RNAs recognizing the organism’s own genomic sequences. Without PtGTSF1, self-matching small RNAs are not degraded and results in an accumulation of H3K9me3 and H3K27me3, which disturbs transposon recognition and slows down their elimination. Our results demonstrate that the PIWI-GTSF1 interaction also exists in unicellular eukaryotes with the ancestral function of transposon silencing.
Response of soil bacteria to PUREX chemicals suggests biomarker utility and bioremediation potential
Authors: Podowski Justin C , Forrester Sara , Antonopoulos Dionysios A. , Steeb Jennifer L. , Kent Angela D. , Davis James J , Schabacker Daniel S.
Published: October 2023

Chemicals involved in plutonium uranium reduction extraction (PUREX) have the potential to be released from nuclear reprocessing facilities and accumulate in the environment. In order to understand how soil microbial communities respond to contamination by PUREX chemicals, we carried out a series of microcosm experiments, exposing chemically diverse soils to a range of concentrations of key chemicals used in the PUREX process. We tested 4 PUREX chemicals, and 5 soil types using 16S rRNA amplicon sequencing, determining that responses of microbial communities are dependent on the soil type in which they reside, and that tributyl phosphate exposure appears to generate the most reproducible and detectable shifts in microbial communities. We identified a number of key taxa that are consistently enriched in soils exposed to tributyl phosphate. These key taxa are either in the familyRhizobiaceaeor genusPseudomonas. The relative abundance of these key taxa is concentration dependent, and their abundance remains elevated at least 100 days post initial exposure. Using whole-shotgun metagenomic sequencing, we reconstructed the genomes of these key taxa and find a number of putative phosphotriesterase genes found only inRhizobiaceae. We find the abundance of phosphotriesterase genes is significantly higher in samples exposed to tributyl phosphate. These phosphotriesterase genes, which degrade tributyl phosphate into dibutyl phosphate and butanol, may serve as effective biomarkers for tributyl phosphate contaminated soil, as well as a method for future bioremediation.

Importance

Nuclear materials reprocessing facilities have the capacity to release toxic chemicals during normal operations or accidents. This study examines the ways in which chemicals involved with nuclear materials reprocessing impact microorganisms in the soil. Our intention was to understand the consequences of the release of these chemicals on ecosystems that may surround these reprocessing facilities. We find soil microbial communities change in response to some chemicals but not others, and that tributyl phosphate appears to generate the most reproducible and detectable shifts in microbial communities. Microorganisms in the familyRhizobiaceaeincrease in abundance in response to the addition of tributyl phosphate, and an examination of the genomes of these microbes suggest they may be able to break down tributyl phosphate to access the phosphosphate present in this chemical. Overall, this work demonstrates that changes in soil microbial communities in response to contamination with chemicals from nuclear materials reprocessing facilities may be predictable, and these responses could be leveraged to remediate contamination.
Allele biased transcription factor binding across human brain regions gives mechanistic insight into eQTLs
Authors: Moyers Belle A. , Loupe Jacob M. , Felker Stephanie A. , Lawlor James M.J. , Anderson Ashlyn G. , Rodriguez-Nunez Ivan , Bunney William E. , Bunney Blynn G. , Cartagena Preston M. , Sequeira Adolfo , Watson Stanley J. , Akil Huda , Mendenhall Eric M. , Cooper Gregory M. , Myers Richard M.
Published: October 2023

Transcription Factors (TFs) influence gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because genomic localization of TFs is in part driven by TF recognition of DNA sequence, variation in TF binding sites can disrupt TF-DNA associations and affect gene regulation. To identify variants that impact TF binding in human brain tissues, we quantified allele bias for 93 TFs analyzed with ChIP-seq experiments of multiple structural brain regions from two donors. Using graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signal between alleles at heterozygous variants within each tissue sample from each donor. Comparison of results from different brain regions within donors and the same regions between donors provided measures of allele bias reproducibility. We identified thousands of DNA variants that show reproducible bias in ChIP-seq for at least one TF. We found that alleles that are rarer in the general population were more likely than common alleles to exhibit large biases, and more frequently led to reduced TF binding. Combining ChIP-seq with RNA-seq, we identified TF-allele interaction biases with RNA bias in a phased allele linked to 6,709 eQTL variants identified in GTEx data, 3,309 of which were found in neural contexts. Our results provide insights into the effects of both common and rare variation on gene regulation in the brain. These findings can facilitate mechanistic understanding of cis-regulatory variation associated with biological traits, including disease.
Fabrication of Crescent Shaped Microparticles for Particle Templated Droplet Formation
Authors: Yang Yimin , Vagin Sergei I. , Rieger Bernhard , Destgeer Ghulam
Published: October 2023

Crescent-shaped hydrogel microparticles have been shown to template uniform volume aqueous droplets upon simple mixing with aqueous and oil media for various bioassays. This emerging “lab on a particle” technique requires hydrogel particles with tunable material properties and dimensions. The crescent shape of the particles is attained by aqueous two-phase separation of polymers inside a spherical droplet followed by photopolymerization of the curable precursor. In this work, we have investigated the phase separation of photo-curable poly(ethylene glycol) diacrylate (PEGDA,Mw700) and dextran (Mw40,000) for tunable manufacturing of crescent-shaped particles. The particles’ morphology was precisely tuned by following a phase diagram, varying the UV intensity, and adjusting the flow rate ratio between the three streams, containing PEGDA, dextran, and oil, within a microfluidic droplet generation device. The fabricated particles with variable cavity sizes and outer diameters encapsulated uniform aqueous droplets upon mixing with a continuous oil phase. The particles were fluorescently labeled with red and blue emitting dyes at variable concentrations to produce six color-coded particles. The blue fluorescent dye showed a moderate response to the pH change from 1 to 7 in terms of an increase in emitted intensity. The fluorescently labeled particles were able to tolerate an extremely acidic solution (pH 1) but disintegrated within an extremely basic solution (pH 14). The particle-templated droplets were able to effectively retain the disintegrating particle and the fluorescent signal at pH 14, indicating completely segregated compartments.
Potential intrahospital dissemination ofPseudomonas aeruginosacarrying theblaIMP-1gene within a Tn7-like transposon
Authors: Zheng Lin , Wang Zixian , Guo Jingyi , Guan Jiayao , Li Quanliang , Lu Gejin , Jing Jie , Sun Shiwen , Sun Yang , Ji Xue , Jiang Bowen , Chen Ping , Yang Yanling , Zhu Lingwei , Guo Xuejun
Published: October 2023

We aimed to determine the molecular characteristics of carbapenem-resistantPseudomonas aeruginosa18081308 and 18083286 isolated from the urine and sputum of two Chinese patients respectively, and analyzed the formation mechanism of the genetic environment in which it carriesblaIMP-1. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired resistance genes, and virulence factors of these strains were identified. The carbapenem-resistantP. aeruginosastrains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same virulence factors (PLC, ExoSTY) and resistance genes (aacC2,tmrB, andblaIMP-1). Tn6411, a Tn7-like transposon carryingblaIMP-1, was found in both strains. Detailed genetic dissection was applied to this transposon to display the genetic environment ofblaIMP-1. TheaacC2-tmrBregion remnant-Tn6411backbone was the original structure of this type of transposon. A Tn402-like type 1 integron (intl1-aac(6’)-II-blaIMP-1) was inserted into it and formed a stable structure, which was localized in the chromosome by TnsD for transmission withinP. aeruginosa; the original structure of Tn7-like transposon was localized on the plasmid by TnsE for horizontal transmission between bacterial species.

The intrahospital dissemination ofP. aeruginosaST865 isolated in this study was episodic. TheblaIMP-1-carrying Tn7-like transposon might enhance their ability to survive under drug selection pressure and aggravate the difficulty in treating infections.
Genomic analyses of Asiatic Mouflon in Iran provide insights into the domestication and evolution of sheep
Authors: Wang Dong-Feng , Orozco-terWengel Pablo , Li Meng-Hua , Lv Feng-Hua
Published: October 2023

Background

Asiatic mouflon (O. gmelini) consists of several subspecies mainly distributed in Armenia, southern Azerbaijan, Cyprus, northern, southern, and western regions of Iran, and eastern and central regions of Turkey nowadays. Genome analyses of Asiatic mouflon in Iran revealed that they could have diverged from the direct ancestor of domestic sheep, and showed genetic introgression into domestic sheep after domestication. However, the impact of the Asiatic mouflon subspecies in Iran on sheep domestication remains unclear.

Results

Here, we conducted a comprehensive population genomics analysis of Asiatic mouflons in Iran with 780 whole-genome sequences, 767 whole mitogenomes, and 239 Y chromosomes. Whole-genome sequence analyses revealed two subpopulations of the Asiatic mouflons in Iran:O. gmelini_2 limited in Kabudan andO. gmelini_1 over a wide geographic area. Phylogenetic analyses of the Asiatic mouflons in Iran based on uniparental variants revealed a monophyletic lineage with the mitochondrial haplogroups C+E, and clustered into a monophyletic with Y-chromosomal lineage HY2 of sheep. Additionally, introgression tests detected significant signals of genetic introgression fromO. gmelini_2 to four sheep populations (e.g., Garut, Garole, Bangladeshi, and Sumatra) in South and Southeast Asia. In the four sheep populations, selective tests and introgression signals revealed that the wild introgression could have contributed to their small body size and local adaptation to the hot and humid environments in the Indian Peninsula.

Conclusions

Our results suggested that the maternal haplogroups C+E and paternal lineage HY2 could have originated from the Asiatic mouflon in Iran. Also, our findings provide new insights into sheep domestication and subsequent introgressions from wild ancestors to domestic populations.
40 Hz Light Flickering Promotes Sleep through Cortical Adenosine Signaling
Authors: He Yan , Zhou Xuzhao , Xu Tao , Wu Zhaofa , Guo Wei , Xu Xi , Liu Yuntao , Zhang Yi , Shang Huiping , Yao Zhimo , Li Zewen , Li Zhihui , Feng Tao , Zhang Shaomin , Cunha Rodrigo A. , Huang Zhili , Li Yulong , Cai Xiaohong , Qu Jia , Chen Jiang-Fan
Published: October 2023

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 hours after flickering) in extracellular adenosine levels in the primary visual cortex and other brain regions, as a function of light frequency, intensity, and wavelength, with maximal effects observed at 40 Hz frequency. We discovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, and intracellular adenosine generation from calcium influx-triggered, AMPK- associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways) and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz light flickering for 30 min enhanced sleep in mice in a frequency-dependent manner. This somnogenic effect was absent in mice lacking ENT2 but replicated by administering adenosine to the visual cortex. Brief 40 Hz light flickering also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish adenosine signaling via ENT2 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.
Engineered blue-shifted melanopsins for subcellular optogenetics
Authors: Wijayaratna Dhanushan , Sacchetta Filippo , Pedraza Gonzalez Laura , Fanelli Francesca , Sugihara Tomohiro , Koyanagi Mitsumasa , Piyawardana Senuri , Ghotra Kiran , Thotamune Waruna , Terakita Akihisa , Olivucci Massimo , Karunarathne Ajith
Published: October 2023

Melanopsin (MeOp) is a G protein-coupled Receptor (GPCR) family photopigment, expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) that display remarkable functional diversity. In addition to non-image-forming visual functions, MeOp also controls signaling underlying the retina development, circadian clock, mood, and behavior. MeOp is bistable, recycles retinal, and can function under low retinaldehyde availability. It also activates multiple G protein heterotrimers. Though MeOp could be a versatile optogenetic tool, its potential, especially its utility for subcellular signaling control, is hampered by the broader spectral sensitivity spanning the entire visible range. Here, we use a recently reportedin silicotechnology called Automatic Rhodopsin Modeling (ARM) to identify blue-shifting mutations of MeOp and, ultimately, allow for imaging biosensors with red light without activating the opsin. Accordingly, ARM was used to construct validated quantum mechanics/molecular mechanics (QM/MM) models for mouse MeOp (mMeOp) to search and optimize a set of mutants featuring a blue-shifted light absorption. We demonstrate that four mutants of such can be successfully expressed and display the required resistance to activation by red light; however, they are activated by yellow, green, and blue light. Localized subcellular optical activation of these mutants in macrophage cells showed localized PIP3 generation and cell migration. Further characterization showed that MeOp blue-shifted mutants are also bistable. Altogether, our data demonstrate the computer-aided engineering feasibility of opsins with desired spectral properties for subcellular optogenetic applications.
Increased flexibility of CA3 memory representations following environmental enrichment
Authors: Ventura Silvia , Duncan Stephen , Ainge James A.
Published: October 2023

Environmental enrichment (EE) improves memory, particularly under conditions of high memory interference1–6. Here, we investigate the neural mechanisms facilitating improved memory following EE. Using associative recognition memory tasks that model the automatic and integrative nature of episodic memory, we find that EE-dependent improvements in difficult associative memory discriminations are related to increased adult hippocampal neurogenesis and sparser memory representations across the hippocampus. Additionally, by recording CA3 place cells as enriched and standard-housed rats explored the increasingly distinct shapes of a “morph” box, we report for the first time that EE changes the way CA3 place cells discriminate similar contexts. CA3 place cells of enriched rats show greater spatial tuning, increased firing rates, and enhanced remapping to contextual changes. These findings point to more precise and flexible CA3 memory representations in enriched rats. Increased spatial tuning and flexibility might support the well-established EE-dependent improvements in fine memory discrimination.

Highlights

EE improves discrimination of similar associative memories

EE-dependent memory improvements are related to increased adult neurogenesis

EE results in sparser hippocampal activity

EE increases spatial tuning, firing and remapping of CA3 place cells
TheListeria monocytogenespersistence factor ClpL is a potent stand-alone disaggregase
Authors: Bohl Valentin , Hollmann Nele Merret , Melzer Tobias , Katikaridis Panagiotis , Meins Lena , Simon Bernd , Flemming Dirk , Sinning Irmgard , Hennig Janosch , Mogk Axel
Published: October 2023

Heat stress can cause cell death by triggering the aggregation of essential proteins. In bacteria, aggregated proteins are rescued by the canonical Hsp70/AAA+ (ClpB) bi-chaperone disaggregase. Man-made, severe stress conditions applied during e.g. food-processing represent a novel threat for bacteria by exceeding the capacity of the Hsp70/ClpB system. Here, we report on the potent autonomous AAA+ disaggregase ClpL fromListeria monocytogenesthat provides enhanced heat resistance to the food-borne pathogen enabling persistence in adverse environments. ClpL shows increased thermal stability and enhanced disaggregation power compared to Hsp70/ClpB, enabling it to withstand severe heat stress and to solubilize tight aggregates. ClpL binds to protein aggregates via aromatic residues present in its N-terminal domain (NTD) that adopts a partially folded and dynamic conformation. Target specificity is achieved by simultaneous interactions of multiple NTDs with the aggregate surface. ClpL shows remarkable structural plasticity by forming diverse higher assembly states through interacting ClpL rings. NTDs become largely sequestered upon ClpL ring interactions. Stabilizing ring assemblies by engineered disulfide bonds strongly reduces disaggregation activity, suggesting that they represent storage states.
Increasing green leafy vegetable consumption through street food dishes in Lagos, Nigeria
Authors: Raaijmakers Ireen , Dijkxhoorn Youri , Snoek Harriette , Amoreoluwa Kikelomo , Adeboye Adedola , Talabi Olufolajimi , Plaisir Christine , Okoruwa Augustine Ehimen , Toye Oluwole , van Wagenberg Coen
Published: October 2023

Purpose

Despite its health benefits, vegetable consumption is low in urban Nigeria. Interventions have been successful in increasing urban Nigerians' vegetable intake in the home environment, but interventions doing so for popular out-of-home consumption are lacking. This study aimed to design, implement and assess an intervention to increase the vegetable intake of urban Nigerians through street foods.

Design/methodology/approach

A quasi-experimental design was applied in Lagos, Nigeria. During the intervention, 12 trained street food vendors (SFVs) actively promoted the health benefits of vegetables to their customers (using marketing statements and posters) and provided the option to buy an additional green leafy vegetables (GLVs) side dish to their meal. Purchases were observed, and a survey was conducted before and during the intervention to measure perceived meal quality and satisfaction. Six to eight weeks after the intervention, a mystery shopper visited the vendor to assess if they were still selling additional GLVs.

Findings

Almost half (46%) of the 1,506 observed customers bought additional GLVs during the intervention. Both at baseline (N = 452) and during intervention (N = 564), meal satisfaction was high. Users were on average more educated and older than non-users. Most vendors did not perceive the sale of additional GLVs as additional work. Six to eight weeks after the intervention, nine vendors (75%) were still selling additional GLVs.

Originality/value

This study showed that SFVs informing consumers on the potential health benefits of vegetables and offering these vegetables in street food dishes at a commercially viable price is an interesting option to increase vegetable intake.
Sustainability communication: how to communicate an inconvenient truth in the era of scientific mistrust
Authors: Voci Denise , Karmasin Matthias
Published: October 2023

Purpose

This conceptual paper aims to explore the current state of sustainability communication research, focusing on the challenges of communicating inconvenient truths in an era of scientific mistrust. Therefore, this study aims to (1) examine the existing research landscape in sustainability communication, (2) identify unresolved problems and challenges, and (3) propose strategies for counteract misinformation through targeted communication.

Design/methodology/approach

For this, the authors conducted a critical literature review and analyzed the resulting sample (n = 473 journal articles) by means of qualitative content analysis to (1) evaluate existing communication approaches dealing with the communication of sustainability's inconvenient truth, (2) identify stakeholder groups involved in sustainability communication, (3) discuss limitations of current communication approaches and (4) present recommendations on (more) effective communication strategies to address the unresolved issues in sustainability communication.

Findings

The analysis reveals that when it comes to sustainability communication and its unresolved problems, literature refers to four key stakeholder groups: (1) science deniers; (2) adaptation skeptics; (3) whitewashers and (4) world saviors. Furthermore, the analysis provides valuable insights into the complex dynamics involved in communicating sustainability, emphasizes the need for tailored approaches to engage and address the concerns of each stakeholder group, and exposes limitations in current communication methods and approaches. Accordingly, the analysis highlights the necessity of developing new theories, models and methods specific to sustainability communication to tackle its unique challenges effectively.

Research limitations/implications

Like our society, communication sciences need a fundamental transformation to meet sustainability communication's new challenges induced by the necessary shift toward sustainable development.

Originality/value

This paper provides a comprehensive overview of the current state of sustainability communication in research, specifically addressing the challenges of effectively communicating unpleasant news in the context of scientific mistrust. It fills a gap in existing literature by examining the progress made in addressing these issues and identifying the emerging challenges that need to be addressed.