bluuebunny/crossref_metadata_2025 huggingface dataset:
ABCB7 deficiency increases endoplasmic reticulum–mitochondria coupling and mTOR-independent autophagy flux in H9c2 cardiomyocytes
Authors: Chandan Shivanshu , Kosher Ganesh
Published: August 2023

ABCB7 deficiency during chronic cardiac hypertrophy contribute to mitochondrial dysfunction, metabolic shift and worsens cardiac function. Here, we explored that ABCB7 deficiency contribute to tethering of mito-ER and in turn mitochondrial dysfunction in H9c2 cells. We also investigated the mechanistic link between mitochondrial dysfunction and ABCB7 deficiency in these cells. Knockdown of ABCB7 was performed by siABCB7 plasmids or control vectors using lipofectamine 2000. To rescue the changes produced by siABCB7, ABCB7 overexpression was performed using ABCB7 overexpression vector. After knockdown or overexpression, cells were harvested for transmission electron microscopy (TEM), RT-PCR or Immunofluorescence analysis. Knockdown of ABCB7 in H9C2 cells resulted in enhanced tethering of mito.-ER contact sites, and increased mito.-ER distance. To our surprise, the downregulation of ABCB7 did not alter the cristae structure or morphology in these cells. On the mechanistic front, Knockdown of ABCB7 in H9C2 cells MTOR-independent AMPK-dependent macroautophagic/autophagic flux. ABCB7 downregulation did not result in cell death in these cells; this phenomenon could work independent of cell death in H9c2 cells.
GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment
Authors: Zanetti Andrea , Fares-Taie Lucas , Amiel Jeanne , Roger Jérôme , Audo Isabelle , Robert Matthieu , David Pierre , Jung Vincent , Goudin Nicolas , Guerrera Ida Chiara , Moriceau Stéphanie , Amana Danielle , Boddaert Nathalie , Briault Sylvain , Bruel Ange-Line , Gitiaux Cyril , Kaminska Karolina , Philip-Sarles Nicole , Quinodoz Mathieu , Santos Cristina , Coutinho Santos Luisa , Sigaudy Sabine , Soeiro e Sá Mariana , Sousa Ana Berta , Thauvin Christel , Rivolta Carlo , Kaplan Josseline , Rozet Jean-Michel , Perrault Isabelle
Published: August 2023

Spliceosome and ciliary dysfunctions can lead to remarkably similar clinical syndromes. Studying ten individuals with retinal dystrophy, neurological involvement, and skeletal abnormalities, suggestive of both spliceosomopathies and ciliopathies, we involved GPATCH11, a lesser-known GPATCH-domain-containing regulators of RNA metabolism. To elucidate GPATCH11 function, we employed fibroblasts from unaffected individuals and patients carrying a recurring mutation specifically removing the main part of the GPATCH-domain while preserving other domains. Additionally, we generated a mouse model replicating the patient’s genetic defect, exhibiting behavioural abnormalities and retinal dystrophy. Our findings revealed GPATCH11 unique subcellular localization, marked as foci staining pattern and a diffuse presence in the nucleoplasm, alongside its centrosomal localization, indicating roles in RNA and cilia metabolism. We show dysregulation of U4 snRNA in patient cells and dysregulation in both gene expression and spliceosome activity within the mutant mouse retina, impacting key processes such as photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism. These results highlight GPATCH11 roles in RNA metabolism, spliceosome regulation, and potential ciliary involvement. They underscore its significance in maintaining proper gene expression, contributing to retinal, neurological, and skeletal functions. Our research also demonstrates how studying rare genetic disorders can reveal broader gene functions, providing insights into GPATCH11 multifaceted roles.
JOINT CLINICAL AND MOLECULAR SUBTYPING OF COPD WITH VARIATIONAL AUTOENCODERS
Authors: Maiorino Enrico , De Marzio Margherita , Xu Zhonghui , Yun Jeong H. , Chase Robert P. , Hersh Craig P. , Weiss Scott T. , Silverman Edwin K. , Castaldi Peter J. , Glass Kimberly
Published: August 2023

Chronic Obstructive Pulmonary Disease (COPD) is a complex, heterogeneous disease. Traditional subtyping methods generally focus on either the clinical manifestations or the molecular endotypes of the disease, resulting in classifications that do not fully capture the disease’s complexity. Here, we bridge this gap by introducing a subtyping pipeline that integrates clinical and gene expression data with variational autoencoders. We apply this methodology to the COPDGene study, a large study of current and former smoking individuals with and without COPD. Our approach generates a set of vector embeddings, called Personalized Integrated Profiles (PIPs), that recapitulate the joint clinical and molecular state of the subjects in the study. Prediction experiments show that the PIPs have a predictive accuracy comparable to or better than other embedding approaches. Using trajectory learning approaches, we analyze the main trajectories of variation in the PIP space and identify five well-separated subtypes with distinct clinical phenotypes, expression signatures, and disease outcomes. Notably, these subtypes are more robust to data resampling compared to those identified using traditional clustering approaches. Overall, our findings provide new avenues to establish fine-grained associations between the clinical characteristics, molecular processes, and disease outcomes of COPD.
Validation of physical activity levels from shank-placed Axivity AX6 accelerometers
Authors: Gafoor Fatima , Ruder Matthew , Kobsar Dylan
Published: August 2023

This cross-sectional study aimed to identify and validate cut-points for measuring physical activity using Axivity AX6 accelerometers positioned at the shank in older adults. Free-living physical activity was assessed in 35 adults aged 55 and older, where each participant wore a shank mounted Axivity and a waist mounted ActiGraph simultaneously for 72 hours. Optimized cut-points for each participant’s Axivity data were determined using an optimization algorithm to align with ActiGraph results. To assess validity between the physical activity assessments from the optimized Axivity cut-points, a leave-one-out cross validation was conducted. Bland-Altman plots with 95% limits of agreement, intraclass correlation coefficients (ICC), and mean differences were used for comparing the systems. The results indicated good agreement between the two accelerometers when classifying sedentary behaviour (ICC = 0.85) and light physical activity (ICC = 0.80), and moderate agreement when classifying moderate physical activity (ICC = 0.67) and vigorous physical activity (ICC = 0.70). Upon removal of a significant outlier, the agreement was slightly improved for sedentary behaviour (ICC = 0.86) and light physical activity (ICC = 0.82), but substantially improved for moderate physical activity (ICC = 0.81) and vigorous physical activity (ICC = 0.96). Overall, the study successfully demonstrated the capability of the resultant cut-point model to accurately classify physical activity using Axivity AX6 sensors placed at the shank.
Individualized, self-supervised deep learning for blood glucose prediction
Authors: Fuest Johannes , Tacke Marco , Ullman Leander , Washington Peter
Published: August 2023

The current standard for monitoring blood glucose levels in diabetes patients are continuous glucose monitoring (CGM) devices, which are costly and carry the risk of complications, such as allergic reactions or skin irritations from the adhesive used to attach the CGM sensor to the skin. CGM devices are also highly visible and can thus act as a discomforting disease-marker for diabetes patients. To mitigate these issues, we develop and test a novel method that is able to predict blood glucose levels with only non-invasive predictor variables and a very small number of target variable measurements by using individualization and self-supervised deep learning. Using only a single blood glucose measurements per week, our method (6387.47 glucose-specific MSE) outperforms traditional deep learning performed with hourly measurements (8191.23 glucose-specific MSE). Across eight experiments where blood glucose measurements are more than one hour apart, our approach outperforms traditional deep learning without exception. Our findings suggest that self-supervised, individualized deep learning could provide an avenue towards alternatives to CGM devices that would be less costly, non-invasive, and thus more accessible.
Regulatory variation controlling architectural pleiotropy in maize
Authors: Bertolini Edoardo , Rice Brian R. , Braud Max , Yang Jiani , Hake Sarah , Strable Josh , Lipka Alexander E. , Eveland Andrea L.
Published: August 2023

An early event in plant organogenesis is establishment of a boundary between the meristem and differentiating lateral organ. In maize (Zea mays), evidence suggests a common gene network functions at boundaries of distinct organs and contributes to pleiotropy between leaf angle and tassel branch number, two agronomic traits. To uncover regulatory variation at the nexus of these two traits, we used regulatory network topologies derived from specific developmental contexts to guide multivariate genome-wide association analyses. In addition to defining network plasticity around core pleiotropic loci, we identified new transcription factors that contribute to phenotypic variation in canopy architecture, and structural variation that contributes tocis-regulatory control of pleiotropy between tassel branching and leaf angle across maize diversity. Results demonstrate the power of informing statistical genetics with context-specific developmental networks to pinpoint pleiotropic loci and theircis-regulatory components, which can be used to fine-tune plant architecture for crop improvement.
sRNAfrag: A pipeline and suite of tools to analyze fragmentation in small RNA sequencing data
Authors: Nakatsu Ken , Jijiwa Mayumi , Khadka Vedbar , Nasu Masaki , Huo Matthew , Deng Youping
Published: August 2023

Fragments derived from small RNAs such as small nucleolar RNAs hold biological relevance. However, they remain poorly understood, calling for more comprehensive methods for analysis. We developed sRNAfrag, a standardized workflow and set of scripts to quantify and analyze sRNA fragmentation of any biotype. In a benchmark, it is able to detect loci of mature microRNAs fragmented from precursors and, utilizing multi-mapping events, the conserved 5’ seed sequence of miRNAs which we believe may extraoplate to other small RNA fragments. The tool detected 1411 snoRNA fragment conservation events between 2/4 eukaryotic species, providing the opportunity to explore motifs and fragmentation patterns not only within species, but between. Availability:https://github.com/kenminsoo/sRNAfrag.
Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone
Authors: Norton Emily S. , Whaley Lauren A. , Jones Vanessa K. , Brooks Mieu M. , Russo Marissa N. , Morderer Dmytro , Jessen Erik , Schiapparelli Paula , Ramos-Fresnedo Andres , Zarco Natanael , Carrano Anna , Rossoll Wilfried , Asmann Yan W. , Lam TuKiet T. , Chaichana Kaisorn L. , Anastasiadis Panos Z. , Quiñones-Hinojosa Alfredo , Guerrero-Cázares Hugo
Published: August 2023

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

Highlights

Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.

Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.

NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.

GBM stalls neurogenesis and promotes NPC senescence via CTSB.
A high-resolution gene expression atlas of the medial and lateral domains of the gynoecium of Arabidopsis
Authors: Luna-García Valentín , Bernal Gallardo Judith Jazmin , Rethoret-Pasty Martin , Pasha Asher , Provart Nicholas J. , de Folter Stefan
Published: August 2023

Angiosperms are characterized by the formation of flowers, and in their inner floral whorl, one or various gynoecia are produced. These female reproductive structures are responsible for fruit and seed production, thus ensuring the reproductive competence of angiosperms. InArabidopsis thaliana, the gynoecium is composed of two fused carpels with different tissues that need to develop and differentiate to consolidate a mature gynoecium and thus the reproductive competence of Arabidopsis. For these reasons, they have become the object of study for floral and fruit development. However, due to the complexity of the gynoecium, specific spatio-temporal tissues expression patterns are still scarce. In this study, we used precise laser-assisted microdissection and high-throughput RNA sequencing to describe the transcriptional profiles of the medial and lateral domain tissues of the Arabidopsis gynoecium. We provide evidence that the method used is reliable and that, in addition to corroborating gene expression patterns of previously reported regulators of these tissues, we found genes whose expression dynamics point to being involved in cytokinin and auxin homeostasis and in cell cycle progression. Furthermore, based on differential gene expression analyses, we functionally characterized several genes and found that they are involved in gynoecium development. This new resource is available via the Arabidopsis eFP browser and will serve the community in future studies on developmental and reproductive biology.
Human EEG and artificial neural networks reveal disentangled representations of object real-world size in natural images
Authors: Lu Zitong , Golomb Julie D.
Published: August 2023

Remarkably, human brains have the ability to accurately perceive and process the real-world size of objects, despite vast differences in distance and perspective. While previous studies have delved into this phenomenon, distinguishing this ability from other visual perceptions, like depth, has been challenging. Using the THINGS EEG2 dataset with high time-resolution human brain recordings and more ecologically valid naturalistic stimuli, our study uses an innovative approach to disentangle neural representations of object real-world size from retinal size and perceived real-world depth in a way that was not previously possible. Leveraging this state-of-the-art dataset, our EEG representational similarity results reveal a pure representation of object real-world size in human brains. We report a representational timeline of visual object processing: object real-world depth appeared first, then retinal size, and finally, real-world size. Additionally, we input both these naturalistic images and object-only images without natural background into artificial neural networks. Consistent with the human EEG findings, we also successfully disentangled representation of object real-world size from retinal size and real-world depth in all three types of artificial neural networks (visual-only ResNet, visual-language CLIP, and language-only Word2Vec). Moreover, our multi-modal representational comparison framework across human EEG and artificial neural networks reveals real-world size as a stable and higher-level dimension in object space incorporating both visual and semantic information. Our research provides a detailed and clear characterization of the object processing process, which offers further advances and insights into our understanding of object space and the construction of more brain-like visual models.
Evaluating public health effects of risk-based travel policy for the COVID-19 epidemic in Scotland
Authors: McLachlan Isobel , Huntley Selene , Leslie Kirstin , Bishop Jennifer , Redman Christopher , Yebra Gonzalo , Shaaban Sharif , Christofidis Nicolaos , Lycett Samantha , Holden Matthew T.G. , Robertson David L. , Smith-Palmer Alison , Hughes Joseph , Nickbakhsh Sema
Published: August 2023

Background

Decisions to impose temporary travel measures are less common as the global epidemiology of COVID-19 evolves. Risk-based travel measures may avoid the need for a complete travel ban, however evaluations of their effects are lacking. Here we investigated the public health effects of a temporary traffic light system introduced in the United Kingdom (UK) in 2021, imposing red-amber-green (RAG) status based on risk assessment.

Methods

We analysed data on international flight passengers arriving into Scotland, COVID-19 testing surveillance, and SARS-CoV-2 whole genome sequences to quantify effects of the traffic light system on (i) international travel frequency, (ii) travel-related SARS-CoV-2 case importations, (iii) national SARS-CoV-2 case incidence, and (iv) importation of novel SARS-CoV-2 variants.

Results

International flight passengers arriving into Scotland had increased by 754% during the traffic light period. Amber list countries were the most frequently visited and ranked highly for SARS-CoV-2 importations and contribution to national case incidence. Rates of international travel and associated SARS-CoV-2 cases varied significantly across age, health board, and deprivation groups. Multivariable logistic regression revealed SARS-CoV-2 cases detections were less likely among travellers than non-travellers, although increasing from green-to-amber and amber-to-red lists. When examined according to travel destination, SARS-CoV-2 importation risks did not strictly follow RAG designations, and red lists did not prevent establishment of novel SARS-CoV-2 variants.

Conclusions

Our findings suggest that country-specific post-arrival screening undertaken in Scotland did not prohibit the public health impact of COVID-19 in Scotland. Travel rates likely contributed to patterns of high SARS-CoV-2 case importation and population impact.
Incidence and Predictors of Neuropsychiatric manifestations following a Traumatic Brain Injury in Referral Hospitals in Dodoma, Tanzania: a protocol of a prospective longitudinal observational study
Authors: Aslan Suluma , Nyundo Azan
Published: August 2023

Introduction

Traumatic Brain Injury (TBI) is any injury to the brain resulting from an external force leading to complications. TBI affects 27-69 million yearly, with high incidence in Africa and LMICs, and is attributed to motor traffic accidents. Within three to six months following moderate-to-severe TBI, the relative risk of any psychiatric disorder is significantly higher than in the general population. Post-TBI neuropsychiatric disorders include; depression with a prevalence of over 50%, apathy up to 72%, Post-traumatic stress disorder (26%), anxiety (9%), manic symptoms (5 - 9%) and psychosis (3 to 8%).

This study aims to determine the incidence and predictors of post-TBI neuropsychiatric manifestations among patients admitted at Referral hospitals in Dodoma.

Methods and analysis

This is a prospective longitudinal observational study in which patients admitted after moderate to severe TBI will be recruited after obtaining informed consent. Patients will be followed for six months; the diagnostic MINI International Neuropsychiatric Interview (M.I.N.I) tool will assess psychiatric disorders, and severity and progression of symptoms will be assessed using PHQ-9 for depressive symptoms, GAD7 for anxiety symptoms, PCL-5 for Post-traumatic Stress Disorders (PTSD), MoCA for cognitive assessment, AES for apathy and YMRS for manic symptoms at one, three and six months. The analysis will use logistic regression to determine the association between predictors and neuropsychiatric outcomes.

Ethics and dissemination

The ethical clearance has been secured from the institutional Research Review committee and ethical committee of the University of Dodoma with the reference number MA.84/261/12. The respective authorities provided permission to conduct the study within the premises of BMH and DRRH.

Strength and limitation

The diagnostic tool “International Neuropsychiatric Interview (M.I.N.I),” is highly reliable and sensitive as it utilizes both DSM-5 and ICD-10 criteria, and screening tools there are used have good validity and reliability in assessing the severity progression of neuropsychiatric symptoms.

The longitudinal prospective nature of the study offers a strong temporal association of the incidence, progression and associated factors of neuropsychiatric manifestations post-TBI.

The study excluded patients with a known history of psychiatric diagnosis that could influence the recurrence relapse of the present illness and the existence of another new psychiatric diagnosis after TBI.
Effects of post tuberculosis lung disease on survival in HIV-infected individuals with pulmonary hypertension: Insights from the Pan African Pulmonary Hypertension Cohort (PAPUCO) study
Authors: Katoto Patrick D.M.C. , Mukasa Sandra L. , Wolmarans Karen H. , Sani Mahmoud U. , Karaye Kamilu M. , Mbanze Irina , Damasceno Albertino , Mocumbi Ana O. , Dzudie Anastase , Sliwa Karen , Thienemann Friedrich
Published: August 2023

Introduction

Post-tuberculosis lung disease (PTLD) bears high mortality rates, primarily attributed to pulmonary vascular and cardiovascular complications. We investigated the impact of tuberculosis (TB) history on pulmonary hypertension (PH) prognosis within an HIV-burdened region.

Methods

We acquired sociodemographic, clinical, and echocardiographic data on 206 PH adults from the Pan African Pulmonary Hypertension cohort (PAPUCO), a prospective cohort study undertaken in four African countries. Cox-hazard regression models were constructed to assess how TB history interacts with diabetes, HIV-infection, and other chronic lung diseases (CLD), impacting death risks in PH patients.

Results

Among the participants, a history of TB, diabetes, and other CLD was found in 23%, 8%, and 12% respectively. Of the 47 (35%)/134 participants living with HIV-infection, 62% exhibited HIV/TB coinfection, with 45% experiencing recurrent TB episodes. Individuals with TB history faced a 1.82-fold higher PH-related mortality risk (adjusted Hazard Ratio [aHR]: 1.84; 95%CI: 1.00, 3.39; p=0.049). Concurrent TB and comorbidities amplified death risks for PH patients, significantly affecting CLD (aHR: 3.10; 95%CI: 1.47, 6.53; p=0.003), and showing borderline impact for HIV co-infection (aHR: 2.10; 95%CI: 0.97, 4.54; p=0.059), while not significantly influenced by diabetes history (aHR: 2.39; 95%CI: 0.32, 18.00; p=0.4), although clinically relevant.

Conclusion

Nearly one in every four patients diagnosed with PH in Africa have a history of TB and one in every three have HIV infection, which dramatically reduces their odds of survival. Our findings constitute a call to action to effectively address the neglected burden of PH among millions of patients suffering with TB diseases.
Optimising primary molecular profiling in NSCLC
Authors: Schouten R.D. , Schouten I. , Schuurbiers M.M.F. , van der Noort V. , Damhuis R.A.M. , van der Heijden E.H.F.M. , Burgers J.A. , Barlo N.P. , van Lindert A.S.R. , Maas K.W. , van den Brand J.J.G. , Smit A.A.J. , van Haarst J.M.W. , van der Maat B. , Schuuring E. , Blaauwgeers H. , Willems S.M. , Monkhorst K. , van den Broek D. , van den Heuvel M.M.
Published: August 2023

Introduction

Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting.

Methods

This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at leastEGFRandALKtesting. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing forEGFRandKRASmutations using droplet digital PCR was evaluated.

Results

Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling ofEGFRandALKwas performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p=0.049).EGFRandALKprofiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible.

Conclusion

This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.
Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses
Authors: Owens Katherine , Esmaeili-Wellman Shadisadat , Schiffer Joshua T.
Published: August 2023

The viral kinetics of documented SARS-CoV-2 infections exhibit a high degree of inter-individual variability. We identified six distinct viral shedding patterns, which differed according to peak viral load, duration, expansion rate and clearance rate, by clustering data from 768 infections in the National Basketball Association cohort. Omicron variant infections in previously vaccinated individuals generally led to lower cumulative shedding levels of SARS-CoV-2 than other scenarios. We then developed a mechanistic mathematical model that recapitulated 1510 observed viral trajectories, including viral rebound and cases of reinfection. Lower peak viral loads were explained by a more rapid and sustained transition of susceptible cells to a refractory state during infection, as well as an earlier and more potent late, cytolytic immune response. Our results suggest that viral elimination occurs more rapidly during omicron infection, following vaccination, and following re-infection due to enhanced innate and acquired immune responses. Because viral load has been linked with COVID-19 severity and transmission risk, our model provides a framework for understanding the wide range of observed SARS-CoV-2 infection outcomes.
Understanding the adaptive role of chromosomal inversions across large geographical scales: The potential of pool-seq data
Authors: Westram Anja M , Morales Hernán E. , Johannesson Kerstin , Butlin Roger , Faria Rui
Published: August 2023

A growing body of research shows that chromosomal inversions, where each arrangement is associated with a certain environment and maintains a set of adaptive alleles, make an important contribution to local adaptation. However, inversions often remain unexplored across large geographical scales. It is unclear whether inversions contribute to adaptation across species ranges, which environmental factors affect arrangement frequencies, and whether the adaptive content of the same arrangement varies between locations. Here, we discuss ideas of how allele frequency data (e.g. pool-sequencing data) can be used to learn about inversions in a simple and cost-effective way. If populations connected by migration differ in arrangement frequency, plotting their SNP allele frequencies against each other will reveal a parallelogram whose corners reflect arrangement frequencies. We demonstrate the usefulness of this approach in locally-adapted populations of the intertidal snailLittorina saxatilis(Olivi). For twelve inversions, we estimate arrangement frequencies in 20 populations across the European species range. While roughly half of the inversions contribute to adaptation to the well-studied contrast between wave-exposed and crab-infested habitats, the other half likely contribute to adaptation to shore height. We also find evidence for geographical variation in arrangement content, suggesting variation in adaptive role.
Response diversity is key to buffer ecosystem productivity against multiple environmental change drivers
Authors: Tatsumi Shinichi , Punwasi Neil , Roberto Adriano , Cadotte Marc W.
Published: August 2023

Evidence shows that biodiversity promotes primary productivity. However, it is unclear whether such biodiversity–productivity relationships persist under increasing numbers of environmental changes in the current Anthropocene. Here, we use theoretical and experimental approaches to demonstrate that variation in species’ responses to changing environments determines the ability of ecological communities to maintain productivity under multiple types of environmental change. Our theory shows that this response diversity determines whether biodiversity–productivity relationships are enhanced or impaired by environmental changes. Communities with high response diversity are expected not only to be productive in a particular environment but to maintain that productivity under multiple conditions. Nevertheless, our theory also predicts that such buffering effects fade with increasing negative environmental impacts on communities. Consistent with this prediction, our biodiversity experiment reveals impaired biodiversity–productivity relationships under multiple environmental change drivers with a negative mean impact. Our results suggest that, in the face of growing multiplicity of environmental changes, policies should encourage conservation of local biota, enabling communities to respond to unprecedented environments that may arise.
Cuticular hydrocarbon profiles of Himalayan bumble bees (Hymenoptera:BombusLatreille) are species-specific and show local and elevation related variation
Authors: Narah Jaya , Streinzer Martin , Chakravorty Jharna , Megu Karsing , Spaethe Johannes , Brockmann Axel , Schmitt Thomas
Published: August 2023

Bumble bees are important pollinators in natural environments and agricultural farmlands and are in particular adapted to harsh environments like high mountain habitats. In these environments, animals are exposed to low temperature and face the risk of desiccation. The Eastern Himalayas are one of the recognized biodiversity hotspots worldwide. The area covers subtropical rainforest with warm temperature and high precipitation as well as high mountain ranges with peaks reaching up to 6000 m, shaping a diverse floral and faunal community at the different altitudinal zones. We investigated the cuticular hydrocarbon profiles of four bumble bee species occurring at different elevational ranges in Arunachal Pradesh, the northeast most state in India. At 17 locations along an elevational gradient we collected workers of two species from lower elevations (B. albopleuralisandB. breviceps;∼ 100m - 3000m asl) and two species from higher elevations (B. prshewalskyiandB. mirus; ∼ 2800m - 4,500m asl). The CHC profiles of all four species showed a significant degree of variation in the composition of hydrocarbons, indicating species specificity. We also found clear correlation with elevation. The weighted mean chain length of the hydrocarbons significantly differed between the low and high altitudinal species, and the proportion of saturated hydrocarbons in CHC profiles significantly increased with the elevational range of the bumble bee species. Thus, these four species of bumble bees in the eastern Himalayas seem to adapt their CHC composition to elevation by decreasing water permeability of their cuticle, similar to insects living in dry mountains or deserts habitats.
A noncanonical repressor function of JUN restrains YAP activity and suppresses YAP-dependent liver cancer growth
Authors: Kurlishchuk Yuliya , Vranesic Anita Cindric , Jessen Marco , Kipping Alexandra , Kim KyungMok , Cramer Paul , Eyss Björn von
Published: August 2023

Yes-associated protein (YAP) and its homologue, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effector of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. The AP-1 complex binds together with YAP/TAZ to many common sites and they form a positive feed-forward to induce gene expression.

Here, we report that the AP-1 component c-JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of c-JUN is independent of its heterodimeric AP-1 partner c-FOS demonstrating that it is independent of the canonical AP-1 function to induce target gene expression. Since c-JUN is itself by YAP/TAZ, our work identifies a negative feedback loop that buffers YAP/TAZ activity at joint sites. This negative feedback loop needs to get disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ.

Our results thus demonstrate an additional layer of control for the important interplay of YAP/TAZ and AP-1.
Slow but flexible or fast but rigid? Discrete and continuous processes compared
Authors: Priorelli Matteo , Stoianov Ivilin Peev
Published: August 2023

Abstract

A tradeoff exists when dealing with complex tasks composed of multiple steps. High-level cognitive processes can find the best sequence of actions to achieve a goal in uncertain environments, but they are slow and require significant computational demand. In contrast, lower-level processing allows reacting to environmental stimuli rapidly, but with limited capacity to determine optimal actions or to replan when expectations are not met. Through reiteration of the same task, biological organisms find the optimal tradeoff: from action primitives, composite trajectories gradually emerge by creating task-specific neural structures. The two frameworks of active inference – a recent brain paradigm that views action and perception as subject to the samefree energy minimizationimperative – well capture high-level and low-level processes of human behavior, but how task specialization occurs in these terms is still unclear. In this study, we compare two strategies on a dynamic pick-and-place task: a hybrid (discrete-continuous) model with planning capabilities and a continuous-only model with fixed transitions. Both models rely on a hierarchical (intrinsic and extrinsic) structure, well suited for defining reaching and grasping movements, respectively. Our results show that continuous-only models perform better and with minimal resource expenditure but at the cost of less flexibility. Finally, we propose how discrete actions might lead to continuous attractors and compare the two frameworks with different motor learning phases, laying the foundations for further studies on bio-inspired task adaptation.
Inferring laminar origins of MEG signals with optically pumped magnetometers (OPMs): a simulation study
Authors: Helbling Saskia
Published: August 2023

We explore the potential of optically-pumped magnetometers (OPMs) to infer the laminar origins of neural activity non-invasively. OPM sensors can be positioned closer to the scalp than conventional cryogenic MEG sensors, opening an avenue to higher spatial resolution when combined with high-precision forward modelling. By simulating the forward model projection of single dipole sources onto OPM sensor arrays with varying sensor densities and measurement axes, and employing sparse source reconstruction approaches, we find that laminar inference with OPM arrays is possible at relatively low sensor counts at moderate to high signal-to-noise ratios (SNR). We observe improvements in laminar inference with increasing spatial sampling densities and number of measurement axes. Surprisingly, moving sensors closer to the scalp is less advantageous than anticipated - and even detrimental at high SNRs. Biases towards both the superficial and deep surfaces at very low SNRs and a notable bias towards the deep surface when combining empirical Bayesian beamformer (EBB) source reconstruction with a whole-brain analysis pose further challenges. Adequate SNR through appropriate trial numbers and shielding, as well as precise co-registration, is crucial for reliable laminar inference with OPMs.
Harmonic decomposition of spacetime (HADES) framework characterises the spacetime hierarchy of the DMT brain state
Authors: Vohryzek Jakub , Cabral Joana , Timmermann Christopher , Atasoy Selen , Roseman Leor , Nutt David J , Carhart-Harris Robin L , Deco Gustavo , Kringelbach Morten L
Published: August 2023

The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. In this study, we develop the Harmonic Decomposition of Spacetime (HADES) framework that characterises how different harmonic modes defined inspaceare expressed overtime, and, as a proof-of-principle, demonstrate the sensitivity and robustness of this approach to specific changes induced by the serotonergic psychedelic N,N-Dimethyltryptamine (DMT) in healthy participants. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease specifically in the second functional harmonic, which represents the uni- to transmodal functional hierarchy of the brain, supporting the hypothesis that functional hierarchy is changed in psychedelics. Moreover, HADES’ dynamic spacetime measures of fractional occupancy, life time and latent space provide a precise description of the significant changes of the spacetime hierarchical organization of brain activity in the psychedelic state.
Characterisation of the butyrate production pathway in probiotic MIYAIRI588 by a combined whole genome-proteome approach
Authors: Wood Liam , Omorotionmwan Bunmi B , Blanchard Adam M , Dowle Adam , Bishop Anne L , Griffin Ruth
Published: August 2023

Butyrate is a short chain fatty acid with important industrial applications produced by chemical synthesis. With consumer demand for green products, the fermentative production of butyric acid by microorganisms such asClostridiumis attracting interest.Clostridium butyricumferments non-digested dietary fibre in the colon to produce butyrate which has multiple health benefits, and certain strains are exploited as probiotics, such as MIYAIRI588 (CBM588). Knowledge of the genes encoding enzymes involved in butyrate production and determining those that are rate-limiting due to low concentrations, could enable strain engineering for higher yields. To this end whole genome sequencing of CBM588 was performed and a circular chromosome, a megaplasmid and the previously reported cryptic plasmid, pCBM588, identified. All genes involved in the butyrate production pathway were found on the chromosome. To identify rate-limiting steps, the relative abundance of the encoded enzymes was assessed by liquid chromatography-mass spectrometry (LC-MS) of total cytosolic proteins. Phosphotransbutyrylase (Ptb) was the least abundant closely followed by butyrate kinase (Buk) and crotonase (Crt). Analysis of upstream regulatory sequences revealed the potential importance of an intact Shine-Dalgarno sequence. Results of this study can now guide bioengineering experiments to improve butyrate yields and enhance the performance of CBM588 as a probiotic.
Structural framework for the understanding spectroscopic and functional signatures of the cyanobacterial Orange Carotenoid Protein families
Authors: Sluchanko Nikolai N. , Maksimov Eugene G. , Slonimskiy Yury B. , Varfolomeeva Larisa A. , Bukhanko Antonina Y. , Egorkin Nikita A. , Tsoraev Georgy V. , Khrenova Maria G. , Ge Baosheng , Qin Song , Boyko Konstantin M. , Popov Vladimir O.
Published: August 2023

The Orange Carotenoid Protein (OCP) is a unique photoreceptor crucial for cyanobacterial photoprotection. Best studiedSynechocystissp. PCC 6803 OCP belongs to the large OCP1 family. Downregulated by the Fluorescence Recovery Protein (FRP) in low-light, high-light-activated OCP1 binds to the phycobilisomes and performs non-photochemical quenching. Recently discovered families OCP2 and OCP3 remain structurally and functionally underexplored, and no systematic comparative studies have ever been conducted. Here we present two first crystal structures of OCP2 from morphoecophysiologically different cyanobacteria and provide their comprehensive structural, spectroscopic and functional comparison with OCP1, the recently described OCP3 and all-OCP ancestor. Structures enable correlation of spectroscopic signatures with the effective number of hydrogen and discovered herechalcogenbonds anchoring the ketocarotenoid in OCP and rationalize the observed differences in OCP/FRP and OCP/phycobilisome functional interactions. These data are expected to foster OCP research and applications in optogenetics, targeted carotenoid delivery and cyanobacterial biomass engineering.
Exploiting Substrate Specificities of 6-O-Sulfotransferases to Enzymatically Synthesize Keratan Sulfate Oligosaccharides
Authors: Wu Yunfei , Vos Gael , Huang Chin , Chapla Digantkumar , Kimpel Anne L.M. , Moremen Kelley W. , de Vries Robert P. , Boons Geert-Jan
Published: August 2023

Keratan sulfate (KS) is a glycosaminoglycan that is widely expressed in the extracellular matrix of various tissue types where it is involved in many biological processes. Herein, we describe a chemo-enzymatic approach to prepare well-defined KS oligosaccharides by exploiting known and newly discovered substrate specificities of relevant sulfotransferases. The premise of the approach is that recombinant GlcNAc-6-O-sulfotransferases (CHST2) only sulfates terminal GlcNAc moieties to give GlcNAc6S that can be galactosylated by B4GalT4. Furthermore, CHST1 can modify internal galactosides of a poly-LacNAc chain, however, it was found that a GlcNAc6S residue greatly increases the reactivity of CHST1 of a neighboring and internal galactoside. The presence of a 2,3-linked sialoside further modulates the site of modification by CHST1, and a galactoside flanked by 2,3-Neu5Ac and GlcNAc6S is preferentially sulfated over other Gal residues. The substrate specificities of CHST1 and 2 were exploited to prepare a panel of KS oligosaccharides including selectively sulfatedN-glycans. The compounds and several other reference derivatives were used to construct a microarray that was probed for binding by several plant lectins, Siglec proteins and hemagglutinins of influenza viruses. It was found that not only the sulfation pattern but also presentation of epitopes as part of anO- orN-glycan determines binding properties.
Ascertainment bias in the genomic test of positive selection on regulatory sequences
Authors: Jiang Daohan , Zhang Jianzhi
Published: August 2023

Evolution of gene expression mediated bycis-regulatory changes is thought to be an important contributor to organismal adaptation, but identifying adaptivecis-regulatory changes is challenging due to the difficulty in knowing the expectation under no positive selection. A new approach for detecting positive selection on transcription factor binding sites (TFBSs) was recently developed, thanks to the application of machine learning in predicting transcription factor (TF) binding affinities of DNA sequences. Given a TFBS sequence from a focal species and the corresponding inferred ancestral sequence that differs from the former atnsites, one can predict the TF binding affinities of manyn-step mutational neighbors of the ancestral sequence and obtain a null distribution of the derived binding affinity, which allows testing whether the binding affinity of the real derived sequence deviates significantly from the null distribution. Applying this test genomically to all experimentally identified binding sites of three TFs in humans, a recent study reported positive selection for elevated binding affinities of TFBSs. Here we show that this genomic test suffers from an ascertainment bias because, even in the absence of positive selection for strengthened binding, the binding affinities of known human TFBSs are more likely to have increased than decreased in evolution. We demonstrate by computer simulation that this bias inflates the false positive rate of the selection test. We propose several methods to mitigate the ascertainment bias and show that almost all previously reported positive selection signals disappear when these methods are applied.
ATP Mediates Phase Separation of Disordered Basic Proteins by Bridging Intermolecular Interaction Networks
Authors: Kota Divya , Prasad Ramesh , Zhou Huan-Xiang
Published: August 2023

ATP is an abundant molecule with crucial cellular roles as the energy currency and a building block of nucleic acids and for protein phosphorylation. Here we show that ATP mediates the phase separation of basic intrinsically disordered proteins (bIDPs). In the resulting condensates, ATP is highly concentrated (apparent partition coefficients at 200-5000) and serves as bridges between bIDP chains. These liquid-like droplets have some of the lowest interfacial tension (∼25 pN/μm) but high zero-shear viscosities (1-15 Pa s) due to the bridged protein networks, and yet their fusion has some of the highest speeds (∼1 μm/ms). The rapid fusion manifests extreme shear thinning, where the apparent viscosity is lower than zero-shear viscosity by over 100-fold, made possible by fast reformation of the ATP bridges. At still higher concentrations, ATP does not dissolve bIDP droplets but results in aggregates and fibrils.