bluuebunny/crossref_metadata_2025 huggingface dataset:
Shared Genomic Architectures of COVID-19 and Antisocial Behavior
Authors: Adams Charleen D. , Tielbeek Jorim J. , Boutwell Brian B.
Published: October 2021

Little is known about the genetics of norm violation and aggression (ASB) in relation to coronavirus disease 2019 (COVID-19). To investigate this, we used summary statistics from genome-wide association studies and linkage disequilibrium score regression to calculate a matrix of genetic correlations (rgs) for ASB, COVID-19, and various health and behavioral traits. After false-discovery rate correction, ASB was genetically correlated with COVID-19 (rg = 0.51; P = 1.54E-02) and 19 other traits. ASB and COVID-19 were both positively genetically correlated with having a noisy workplace, doing heavy manual labor, chronic obstructive pulmonary disease, and genitourinary diseases. ASB and COVID-19 were both inversely genetically correlated with average income, education years, healthspan, verbal reasoning, lifespan, cheese intake, and being breastfed as a baby. But keep in mind that rgs are not necessarily causal. And, if causal, their prevailing directions of effect (which causes which) are indiscernible from rgs alone. Moreover, the SNP-heritability estimates for both measures of COVID-19 were very low, restricting the overlap of genetic variance in absolute terms between the two traits. Nonetheless, our findings suggest that those with antisocial tendencies possibly have a higher risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those without antisocial tendencies. This may have been especially true early in the pandemic before vaccines against SARS-CoV-2 were available and before the emergence of the highly transmissible Omicron variant.
Association of Network Connectivity via Resting State Functional MRI with Consciousness, Mortality, and Outcomes in Neonatal Acute Brain Injury
Authors: Boerwinkle Varina L. , Sussman Bethany , Manjón Iliana , Mirea Lucia , Suleman Saher , Wyckoff Sarah N. , Bonnell Alexandra , Orgill Andrew , Tom Deborah
Published: October 2021

Background

An accurate and comprehensive test of integrated brain network function is needed for neonates during the acute brain injury period to inform on morbidity. This retrospective cohort study aimed to assess whether integrated brain network function by resting state functional MRI, acquired during the acute period in neonates with brain injury, is associated with acute exam, neonatal mortality, and 5-month outcomes.

Methods

This study included 40 consecutive neonates with resting state functional MRI acquired 1-22 days after suspected brain insult from March 2018 to July 2019 at Phoenix Childrens Hospital. Acute period exam and test results were assigned ordinal scores based on severity as documented by respective treating specialists. Analyses (Fisher exact, Wilcoxon-rank sum test, ordinal/multinomial logistic regression) examined association of resting state networks with demographics, presentation, neurological exam, electroencephalogram, anatomical MRI, magnetic resonance spectroscopy, passive task functional MRI, and outcomes of discharge condition, outpatient development, motor tone, seizure, and mortality.

Results

Subjects had a mean (standard deviation) gestational age of 37.8 (2.6) weeks, a majority were male (63%), with diagnosis of hypoxic ischemic encephalopathy (68%). Other findings at birth included mild distress (48%), moderately abnormal neurological exam (33%), and consciousness characterized as awake but irritable (40%). Significant associations after multiple testing corrections were detected for resting state networks: basal ganglia with outpatient developmental delay (odds ratio [OR], 14.5; 99.4% confidence interval [CI], 2.00-105; P<.001) and motor tone/weakness (OR, 9.98; 99.4% CI, 1.72-57.9; P<.001); language/frontal-parietal network with discharge condition (OR, 5.13; 99.4% CI, 1.22-21.5; P=.002) and outpatient developmental delay (OR, 4.77; 99.4% CI, 1.21-18.7; P=.002); default mode network with discharge condition (OR, 3.72; 99.4% CI, 1.01-13.78; P=.006) and neurological exam (P=.002 (FE); OR, 11.8; 99.4% CI, 0.73-191; P=.01 (OLR)); seizure onset zone with motor tone/weakness (OR, 3.31; 99.4% CI, 1.08-10.1; P=.003). Resting state networks were not detected in only three neonates, who died prior to discharge.

Conclusions

This study provides level 3 evidence (OCEBM Levels of Evidence Working Group) that the degree of abnormality of resting state networks in neonatal acute brain injury is associated with acute exam and outcomes. Total lack of brain network detection was only found in patients who did not survive.
Somatically mutated genes in fatty liver disease have minimal influence on germline risk
Authors: Mann Jake P. , Hoare Matthew
Published: October 2021

Background

Understanding the genetics of liver disease has the potential to facilitate clinical risk stratification. We recently identified six genes and one lncRNA enriched for acquired somatic mutations in patients with NAFLD and alcohol-related liver disease. We hypothesised that germline variation in these genes would be associated with risk of liver disease development and contribute to prognostication.

Methods

Genome-wide association study (GWAS) summary statistics were extracted from seven studies (>1.7 million participants) for variants near ACVR2A, ALB, CIDEB, FOXO1, GPAM, NEAT1 and TNRC6B for: aminotransferases, liver fat, HbA1c, diagnosis of NAFLD, ARLD, and cirrhosis. Findings were replicated using GWAS data from multiple independent cohorts. A phenome-wide association study was performed to examine for related metabolic traits, using both common and rare variants, including gene-burden testing.

Results

There was no evidence of association between rare germline variants or SNPs near five genes (ACVR2A, ALB, CIDEB, FOXO1, and TNRC6B) and risk or severity of liver disease. Variants in GPAM were associated with liver fat (p=3.6×10-13), ALT (p=2.8×10-39), and serum lipid concentrations. Variants in NEAT1 demonstrated borderline significant associations with ALT (p=1.9×10-11) and HbA1c, but not with liver fat, as well as influencing waist-to-hip ratio, adjusted for BMI.

Conclusions

Despite strong selective advantage to acquire somatic mutations at these loci, there was no evidence of an association between germline variation and markers of liver disease, except in GPAM. Polygenic risk scores based on germline variation alone will not capture prognostic data from genes affected by somatic mutations.
The association between smoking and anal human papillomavirus in the HPV infection in Men Study
Authors: Umutoni Victoria , Schabath Matthew B. , Nyitray Alan G. , Wilkin Timothy , Villa Luisa , Lazcano-Ponce Eduardo , Giuliano Anna R. , Sudenga Staci L.
Published: October 2021

Background

Previous studies show an association between smoking and anal cancer. The objective of this study was to assess the association between smoking and anal HPV prevalence in men.

Methods

The HPV infection in Men (HIM) Study is a multinational study that enrolled HIV-negative men. At baseline anal specimens were collected from 1994 participants. HPV genotyping was assessed by Linear Array. Prevalence ratios (PR) were used to assess the association between smoking and anal HPV prevalence.

Results

Current smokers have a higher prevalence of any anal HPV (adjusted PR (aPR)=1.36, 95%CI: 1.06-1.73) and LR-HPV (aPR=1.59, 95%CI: 1.20-2.12) compared to never smokers. There were no difference in the prevalence of anal HPV between former and never smokers.

Smoking status was not associated with the prevalence of anal HPV among men that have sex with men (MSM). Among men that have sex with women (MSW), current smokers had an increased prevalence for LR-HPV (aPR=1.60 95% CI: 1.02-2.50) compared to never smokers.

Conclusions

While there was no difference in anal HPV prevalence among MSM by smoking status, MSW that currently smoked had a higher prevalence of LR-HPV. Futher research is needed to assess the role smoking in anal HPV persistence.
Elevated antibody titers in Abdala vaccinees evaluated by Elecsys® anti-SARS-CoV-2 S highly correlate with UMELISA SARS-CoV-2 ANTI RBD, ACE-2 binding inhibition and viral neutralization assays
Authors: Lemos-Pérez Gilda , Chávez-Valdés Sheila , González-Formental Hany , Freyre-Corrales Giselle , Vázquez-Arteaga Amalia , Álvarez-Acevedo Beatriz , Ávila-Díaz Lismary , Martínez-Rosales Ricardo U. , Chacón-Quintero Yahima , Coizeau-Rodríguez Edelgis , Palenzuela-Díaz Ariel , Noa-Romero Enrique , Guillén-Nieto Gerardo E.
Published: October 2021

SARS-CoV-2, a recently emerged coronavirus, is causing high morbidity and mortality worldwide since December 2019, posing an enormous health, social and economic problem. Obtaining effective treatments that can diminish deaths and sequelae and vaccines to slow or prevent viral transmission, and reduce disease severity and/or death are of utmost importance. Abdala is a Cuban vaccine based on the recombinant RBD subunit of the spike protein expressed in Pichia pastoris yeast. It demonstrated high efficacy (92.28 %) in phase III clinical trials for reducing transmission, and more than 90% effectiveness in reducing disease severity and mortality. Antibody titers were evaluated in 42 Abdala vaccinees using the Elecsys® Anti-SARS-CoV-2 S test. Fifteen days after immunization, sera from vaccinees showed high antibody titers (median of 1595 U/mL). The results obtained in this study also demonstrate correlation between the Cuban test UMELISA SARS-CoV-2 ANTI RBD used during the clinical trials and Elecsys® test results.

Highlights

Fifteen days after immunization with the Cuban Abdala vaccine, sera from vaccinees showed high antibody titers (median of 1595 U/mL).

There was high correlation between the Cuban test UMELISA SARS-CoV-2 ANTI RBD used during the vaccine clinical trials and Roche’s Elecsys® test results.

Abdala vaccinees reached antibody titers by the Elecsys® Anti-SARS-CoV-2 S test comparable to those of Pfizer/BionTech vaccine using the same test.
Assisted partner services for people who inject drugs: Index characteristics associated with untreated HIV in partners
Authors: Tseng Ashley S. , Sambai Betsy , Monroe-Wise Aliza , Mbogo Loice W. , Ludwig-Barron Natasha T. , Masyuko Sarah J. , Chohan Bhavna H. , Scott John D. , Sinkele William , Herbeck Joshua T. , Farquhar Carey , Guthrie Brandon L.
Published: October 2021

Objective

Identify characteristics of persons who inject drugs living with HIV (PWID-LWH) associated with greater assisted partner services (APS) efficiency in identifying partners in need of HIV care and treatment services.

Design

Prospective cohort study

Methods

PWID-LWH (index participants) were enrolled and asked to provide contact information for sexual and injecting partners who were traced and offered HIV testing. APS efficiency was assessed by the number of indexes needed to interview (NNTI) to find one additional partner who was unaware of their HIV status or not on ART. We defined index participant characteristics associated with greater efficiency, defined as lower NNTIs.

Results

Among 783 indexes, the NNTI to identify one partner unaware of their HIV status was 7.1 and to identify one HIV-positive partner not on ART (regardless of status awareness) was 4.1. APS was provided to 977 partners and was more efficient in identifying partners who were not on ART (n=201) among indexes who were female (n=381, 49%; NNTI=2.9 vs. 5.7, p<0.001), unaware of their HIV status (n=74, 9.5%; NNTI=2.2 vs. 4.2, p=0.009), not on ART (n=158, 20%; NNTI=2.1 vs. 4.9; p<0.001), not enrolled in a methadone program (n=604, 77%; NNTI=3.3 vs. 10.4, p<0.001), reporting injecting <5 years (n=441, 56%; NNTI=3.3 vs. 5.0; p=0.005), or from Nairobi (n=452, 58%; NNTI=3.2 vs. 5.6, p<0.001).

Conclusions

Scaling up APS among PWID-LWH with certain characteristics could result in more efficient APS and greater partner engagement in HIV care.
Disrupted network segregation of the default mode network in autism spectrum disorder
Authors: Yang Bo , Wang Min , Zhou Weiran , Wang Xiuqin , Chen Shuaiyu , Yuan Lixia , Potenza Marc N. , Dong Guang-Heng
Published: October 2021

Background

Changes in the brain’s default mode network (DMN) in the resting state are closely related to autism spectrum disorder (ASD). Module segmentation can effectively elucidate the neural mechanism of ASD and explore the intra- and internetwork connections by means of the participation coefficient (PC).

Methods

Resting-state fMRI data from 269 ASD patients and 340 healthy controls (HCs) were used in the current study. The PC of brain network modules was calculated and compared between ASD subjects and HCs. In addition, we further explored the features according to different age groups and different subtypes of ASD. Intra- and internetwork differences were further calculated to find the potential mechanism underlying the results.

Results

ASD subjects showed significantly higher PC of the DMN than HC subjects. This difference was caused by lower intramodule connections within the DMN and higher internetwork connections between the DMN and networks. When the subjects were split into age groups, the results were verified in the 7-12 and 12-18 age groups but not in the adult group (18-25). When the subjects were divided according to different subtypes of ASD, the results were also observed in the classic autism and pervasive developmental disorder groups, but not in the Asperger disorder group. In addition, compared with the HC group, the ASD group showed significantly increased intranetwork connections between the DMN and the frontoparietal network.

Conclusions

Less developed network segregation in the DMN could be a valid biomarker for ASD, and this feature was validated with different measures. The current results provide new insights into the neural underpinnings of ASD and provide targets for potential interventions using brain modulation and behavioural training.
All-viral tracing of monosynaptic inputs to single birthdate-defined neurons in the intact brain
Authors: Jacobsen R Irene , Nair Rajeevkumar R , Obenhaus Horst A , Donato Flavio , Slettmoen Torstein , Moser May-Britt , Moser Edvard I
Published: October 2021

Neuronal firing patterns are the result of inputs converging onto single cells. Identifying these inputs, anatomically and functionally, is essential to understand how neurons integrate information. Single-cell electroporation of helper genes and subsequent local injection of recombinant rabies viruses enable precise mapping of inputs to individual cells in superficial layers of the intact cortex. However, access to neurons in deeper structures requires more invasive procedures, including removal of overlying tissue. We have developed a method that through a combination of virus injections allows us to target ≤4 hippocampal cells 48% of the time and a single cell 16% of the time in wildtype mice without the use of electroporation or tissue aspiration. We identify local and distant monosynaptic inputs that can be functionally characterised in vivo. By expanding the toolbox for monosynaptic circuit tracing, this method will help further our understanding of neuronal integration at the level of single cells.
Computational Fluid Dynamics Modeling of Aerosol Particle Transport through Lung Airway Mucosa
Authors: Bartlett Blake A. , Feng Yu , Fromen Catherine A. , Ford Versypt Ashlee N.
Published: October 2021

Delivery of aerosols to the lung has great potential for the treatment of various lung diseases. However, the lungs are coated by a protective mucus layer whose complex properties make this form of delivery difficult. Mucus is a non-Newtonian fluid and is cleared from the lungs over time by ciliated cells. Further, its gel-like structure hinders the diffusion of particles through it. Any aerosolized treatment of lung diseases must have certain properties to circumvent the mucosal barrier, and these properties may vary between diseases, drugs, and patients. Using computational fluid dynamics, a model of this mucus layer was constructed to simulate the convective and diffusive transport of impacted aerosol particles. The model predicts the dosage fraction of particles of a certain size that penetrate the mucus and reach the underlying tissue, as well as the distance downstream of the dosage site where epithelial concentration is maximized. Reactions that may occur in solution are also considered, with simulated data for the interaction of a model virus and antibody. The model is modular so that various lung regions and patient health states may be simulated.
Metabolic Potential of Microbial Communities in the Hypersaline Sediments of the Bonneville Salt Flats
Authors: McGonigle Julia M. , Bernau Jeremiah A. , Bowen Brenda B. , Brazelton William J.
Published: October 2021

The Bonneville Salt Flats (BSF) appear to be entirely desolate when viewed from above, but in reality they host rich microbial communities just below the surface salt crust. In this study, we investigate the metabolic potential of the BSF microbial ecosystem. The predicted and measured metabolic activities provide new insights into the ecosystem functions of evaporite landscapes and are an important analog for potential subsurface microbial ecosystems on ancient and modern Mars. Hypersaline and evaporite systems have been investigated previously as astrobiological analogs for Mars and other salty celestial bodies. Still, these studies have generally focused on aquatic systems and cultivation-dependent approaches. Here, we present an ecosystem-level examination of metabolic pathways within the shallow subsurface of evaporites. We detected aerobic and anaerobic respiration as well as methanogenesis in BSF sediments. Metagenome-assembled genomes (MAGs) of diverse bacteria and archaea encoded a remarkable diversity of metabolic pathways, including those associated with carbon fixation, carbon monoxide oxidation, acetogenesis, methanogenesis, sulfide oxidation, denitrification, and nitrogen fixation. These results demonstrate the potential for multiple energy sources and metabolic pathways in BSF and highlight the possibility for vibrant microbial ecosystems in the shallow subsurface of evaporites.
Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer
Authors: Wellberg Elizabeth A , Corleto Karen A. , Checkley L. Allyson , Jindal Sonali , Johnson Ginger , Higgins Janine A. , Obeid Sarina , Anderson Steven M. , Thor Ann D. , Schedin Pepper J. , MacLean Paul S. , Giles Erin D.
Published: October 2021

Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNFα, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multifactorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.
Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI
Authors: Cauzzo Simone , Singh Kavita , Stauder Matthew , García-Gomar María Guadalupe , Vanello Nicola , Passino Claudio , Staab Jeffrey , Indovina Iole , Bianciardi Marta
Published: October 2021

Despite remarkable advances in mapping the functional connectivity of the cortex, the functional connectivity of subcortical regions is understudied in living humans. This is the case for brainstem nuclei that control vital processes, such as autonomic, limbic, nociceptive and sensory functions. This is because of the lack of precise brainstem nuclei localization, of adequate sensitivity and resolution in the deepest brain regions, as well as of optimized processing for the brainstem. To close the gap between the cortex and the brainstem, on 20 healthy subjects, we computed a correlation-based functional connectome of 15 brainstem nuclei involved in autonomic, limbic, nociceptive, and sensory function (superior and inferior colliculi, ventral tegmental area-parabrachial pigmented nucleus complex, microcellular tegmental nucleus-prabigeminal nucleus complex, lateral and medial parabrachial nuclei, vestibular and superior olivary complex, superior and inferior medullary reticular formation, viscerosensory motor nucleus, raphe magnus, pallidus, and obscurus, and parvicellular reticular nucleus – alpha part) with the rest of the brain. Specifically, we exploited 1.1mm isotropic resolution 7 Tesla resting-state fMRI, ad-hoc coregistration and physiological noise correction strategies, and a recently developed probabilistic template of brainstem nuclei. Further, we used 2.5mm isotropic resolution resting-state fMRI data acquired on a 3 Tesla scanner to assess the translatability of our results to conventional datasets. We report highly consistent correlation coefficients across subjects, confirming available literature on autonomic, limbic, nociceptive and sensory pathways, as well as high interconnectivity within the central autonomic network and the vestibular network. Interestingly, our results showed evidence of vestibulo-autonomic interactions in line with previous work. Comparison of 7 Tesla and 3 Tesla findings showed high translatability of results to conventional settings for brainstem-cortical connectivity and good yet weaker translatability for brainstem-brainstem connectivity. The brainstem functional connectome might bring new insight in the understanding of autonomic, limbic, nociceptive and sensory function in health and disease.
Myogenetic oligodeoxynucleotides as anti-nucleolin aptamers inhibit the growth of embryonal rhabdomyosarcoma cells
Authors: Nohira Naoki , Shinji Sayaka , Nakamura Shunichi , Nihashi Yuma , Shimosato Takeshi , Takaya Tomohide
Published: October 2021

Background

Embryonal rhabdomyosarcoma (ERMS) is the muscle-derived tumor retaining myogenic ability. iSN04 and AS1411, which are myogenetic oligodeoxynucleotides (myoDNs) serving as anti-nucleolin aptamers, have been reported to inhibit the proliferation and induce the differentiation of myoblasts. The present study investigated the effects of iSN04 and AS1411 on the growth of multiple ERMS1 cell lines in vitro.

Methods

Three patient-derived ERMS cell lines, ERMS1, KYM1, and RD, were used. Nucleolin expression and localization in these cells was confirmed by immunostaining. The effects of iSN04 or AS1411 on the growth of ERMS cells were examined by cell counting, EdU staining, quantitative RT-PCR (qPCR), and three-dimensional culture of tumorspheres.

Results

In all ERMS cell lines, nucleolin was abundantly expressed, and localized and concentrated in nucleoli, similar to myoblasts. Both iSN04 and AS1411 (10-30 μM) significantly decreased the number of all ERMS cells; however, their optimal conditions were different among the cell lines. iSN04 (10 μM) markedly reduced the ratio of EdU+cells, indicating the inhibition of cell proliferation. qPCR demonstrated that iSN04 suppressed the cell cycle, partially promoted myogenesis, but did not induce apoptosis. Finally, both iSN04 and AS1411 (10-30 μM) disrupted the formation and outgrowth of RD tumorspheres mimicking in vivo tumorigenesis.

Conclusions

ERMS cells expressed nucleolin, and their growth was inhibited by the anti-nucleolin aptamers, iSN04 and AS1411. The present study provides the first evidence that anti-nucleolin aptamers can be used as nucleic acid drugs for chemotherapy against ERMS.
Genomic identification, annotation, and comparative analysis of Vacuolar-type ATP synthase subunits in Diaphorina citri
Authors: Grace Rebecca , Massimino Crissy , Shippy Teresa D. , Tank Will , Hosmani Prashant S. , Flores-Gonzalez Mirella , Mueller Lukas A. , Hunter Wayne B. , Benoit Joshua B. , Brown Susan J. , D’Elia Tom , Saha Surya
Published: October 2021

Detailed annotation and comparative analysis were performed on the Asian citrus psyllid (ACP), Diaphorina citri, vacuolar-type ATP synthase (V-ATPase) to support the biological understanding and development of novel therapeutics to manage psyllid vectors. D. citri is a hemipteran insect that vectors the causative agent, the bacteria Candidatus Liberibacter asiaticus (CLas), of the citrus greening disease, Huanglongbing (HLB). Millions of citrus trees have been destroyed by citrus greening and every grove in Florida has been directly impacted. In eukaryotic organisms, V-ATPase is an abundant heterodimeric enzyme that serves the cell with essential compartment acidification through the active processes that transport protons across the membrane. Manual curation was completed on 15 putative V-ATPase genes in the D. citri genome. Comparative genomic analysis reveals that the D. citri V-ATPase subunits share domains and motifs with other insects, including the V-ATPase-A superfamily domain from the V-ATPase catalytic subunit A, which shares a 92% identity with Acyrthosiphon pisum. Phylogenetic analysis separates D. citri V-ATPase subunits into expected clades with orthologous sequences. Based on the results of annotation and comparative genomic analysis, RNAi therapies targeting D. citri V-ATPase genes, which have been successfully utilized in related hemipterans, are being pursued. Annotation of the D. citri genome is a critical step towards the development of directed-pest management that will lead to the reduced spread of the pathogens causing HLB throughout the citrus industry.
Heptanol-mediated phase separation determines phase preference of molecules in live cell membranes
Authors: Gupta Anjali , Lu Danqin , Balasubramanian Harikrushnan , Chi Zhang , Wohland Thorsten
Published: October 2021

Plasma membranes contain diverse nanoscale assemblies of lipid and protein domains. Specific localization of lipids and proteins in these domains is often essential for membrane function and integrity. Due to the nanoscale size and dynamic nature of membrane domains, identification of molecules residing in domains either is not possible with modern imaging techniques or requires advanced methods with high spatiotemporal resolution. Such methods need expensive equipment making these approaches inaccessible and thus difficult to implement at large scale. Here, we present a novel membrane fluidizer-induced clustering (MFIC) approach to identify the phase-preference of molecules in intact cell membranes. Experiments in phase-separated bilayers and live cells on molecules with known phase preference demonstrate that heptanol hyperfluidizes the membrane and stabilizes phase separation in cell membranes. The domain stabilization results in a transition of nano-to micron-sized clusters of associated molecules and allows identification of molecules localized in domains using routine microscopy techniques. This assay can be carried out on both genetically and extrinsically labelled molecules in live cell membranes, does not require any invasive sample preparation and can be carried out in 10-15 minutes. This inexpensive and easy to implement assay can be conducted at large-scale and will allow easy identification of molecules partitioning into domains.
Photosynthetic induction upon transfer from low to high light is affected by leaf nitrogen content in tomato
Authors: Sun Hu , Zhang Yu-Qi , Zhang Shi-Bao , Huang Wei
Published: October 2021

The response of photosynthetic CO2 assimilation to changes of illumination affects plant growth and crop productivity under natural fluctuating light conditions. However, the effects of nitrogen (N) supply on photosynthetic physiology after transition from low to high light are seldom studied. To elucidate this, we measured gas exchange and chlorophyll fluorescence under fluctuating light in tomato (Solanum lycopersicum) seedlings grown with different N conditions. After transition from low to high light, the induction speeds of net CO2 assimilation (AN), stomatal conductance (gs) and mesophyll conductance (gm) delayed with the decline in leaf N content. The times to reach 90% of maximum AN, gs and gm were negatively correlated to leaf N content. This delayed photosynthetic induction in plants grown under low N concentration was mainly caused by the slow induction response of gm rather than that of gs. Furthermore, the photosynthetic induction upon transfer from low to high light was hardly limited by photosynthetic electron flow. These results indicate that decreased leaf N content declines carbon gain under fluctuating light in tomato. Increasing the induction kinetics of gm has the potential to enhance the carbon gain of field crops grown in infertile soil.
Deep learning-based detection and segmentation of diffusion abnormalities in acute ischemic stroke
Authors: Liu Chin-Fu , Hsu Johnny , Xu Xin , Ramachandran Sandhya , Wang Victor , Miller Michael I. , Hillis Argye E. , Faria Andreia V. ,   the STIR and VISTA Imaging investigators
Published: October 2021

Background

Accessible tools to efficiently detect and segment diffusion abnormalities in acute strokes are highly anticipated by the clinical and research communities.

Methods

We developed a tool with deep learning networks trained and tested on a large dataset of 2,348 clinical diffusion weighted MRIs of patients with acute and sub-acute ischemic strokes, and further tested for generalization on 280 MRIs of an external dataset (STIR).

Results

Our proposed model outperforms generic networks and DeepMedic, particularly in small lesions, with lower false positive rate, balanced precision and sensitivity, and robustness to data perturbs (e.g., artefacts, low resolution, technical heterogeneity). The agreement with human delineation rivals the inter-evaluator agreement; the automated lesion quantification of volume and contrast has virtually total agreement with human quantification.

Conclusion

Our tool is fast, public, accessible to non-experts, with minimal computational requirements, to detect and segment lesions via a single command line. Therefore, it fulfills the conditions to perform large scale, reliable and reproducible clinical and translational research.

Plain Language Summary

Quantifying the volume and location of lesions caused by acute ischemic strokes is crucial for therapeutics and prognostic assessment. Research wise, it can be a window to observe relationships between anatomy and function. The definition of such lesions, mostly made by humans, is time- and work-consuming and uses subjective criteria. We used artificial intelligence in a large database of MRIs of patients with ischemic stroke to create an automated tool to detect and segment lesions derived from acute stroke. It outputs the lesion volumes and 3D segmentation maps. Our tool is fast, public, accessible to non-experts, run in local computers, with minimal computational requirements, fulfilling the conditions to perform large scale, reliable and reproducible clinical and translational research.
Metabolic Dysfunction Related Liver Disease as a Risk Factor for Cancer
Authors: Taylor Alasdair , Siddiqui Moneeza K , Ambery Philip , Armisen Javier , Challis Benjamin G. , Haefliger Carolina , Pearson Ewan R. , Doney Alex S.F. , Dillon John F. , Palmer Colin N.A.
Published: October 2021

The aim of this study was to investigate the association with obesity, diabetes and related liver dysfunction and the incidence of cancer.

This study was conducted with health record data available from the National Health Service in Tayside and Fife. GoDARTS, SHARE and Tayside and Fife diabetics, three Scottish cohorts of 13,695, 62,438, and 16,312 patients respectively were analysed in this study. Participants in GoDARTS were a volunteer sample, with half having T2DM. SHARE were a volunteer sample. Tayside and Fife diabetics was a population level cohort. Metabolic dysfunction-related liver disease (MDLD) was defined using ALT measurements, and individuals with alternative causes of liver disease (alcohol abuse, viruses etc) were excluded from the analysis. Other indicators of liver disease were analysed including the Fatty Liver Index, Fibrosis Score(FIB-4) and hospital admissions for NASH. The main outcomes were cancer incidence and cancer death.

MDLD associated with increased cancer incidence with a hazard ratio of 1.31 in a cox proportional hazards model adjusted for sex, type 2 diabetes, BMI, and smoking status (95% CI = 1.27 – 1.35, p < 0.0001). This was replicated in two further cohorts, and similar associations with cancer incidence were found for Fatty Liver Index (FLI), FIB-4 and NASH. Homozygous carriers of the common NAFLD risk variant PNPLA3 rs738409 had increased risk of cancer. (HR = 1.27 (1.02-1.58), p = 3.1×10−2). BMI was not independently associated with cancer incidence when MDLD was included as a covariate. MDLD was associated with increased risk of cancer death (HR = 1.40, 95% CI =1.33 - 1.47, p < 0.0001).

MDLD, FLI, FIB-4 and NASH associated with increased risk of cancer incidence and death. Further, we found evidence of a causal association between NAFLD and cancer using the established causal risk allele of PNPLA3 as a genetic instrument. NAFLD may be a major component of the relationship between obesity and cancer incidence.

Lay Summary

We found that individuals with metabolic dysfunction-related liver disease (MDLD) have higher overall cancer risk than healthy individuals, as well as increased risk of specific cancers such as colon, breast and lung. We also show that when MDLD is accounted for, obesity does not significantly increase overall cancer risk.
Mutations on non-structural proteins of SARS-CoV-2 are possibly responsible for adverse clinical outcomes
Authors: Ichikawa Takaya , Torii Shiho , Suzuki Hikoyu , Takada Akio , Suzuki Satoshi , Nakajima Masahide , Tampo Akihito , Kakinoki Yasutaka
Published: October 2021

Among a cluster of COVID-19 cases from the end of March through April 2021 in Asahikawa, we experienced the cases in which patients manifested severe clinical symptoms compared to patients who were infected before that. A hundred three patients (age range: 65 to 89 years old) enrolled in this study were divided into two groups, group A: the patients infected from November 2020 to March 2021, and group B: the patients in this cluster population. The mortality rates were 6.1% in group A and 16.2% in group B (OR: 2.97, 95%CI: 0.65-15.38). For the severity of disease, the patients in group B required higher oxygen flow rate in early course of admission (mild; p=0.892, moderate; p=0.117, severe; p=0.029). Whole viral genome sequences revealed five non-synonymous mutations by comparison of the isolates with each group. Of these, four were on non-structural proteins (NSPs) including nsp3, 6 and 15, and one was on S protein located near the C-terminus, suggesting that the mutations on NSPs could be responsible for adverse clinical outcomes in COVID-19 patients.
Modeling remdesivir antiviral efficacy in COVID-19 hospitalized patients of the randomized, controlled, open-label DisCoVeRy trial
Authors: Lingas Guillaume , Néant Nadège , Gaymard Alexandre , Belhadi Drifa , Peytavin Gilles , Hites Maya , Staub Thérèse , Greil Richard , Paiva Jose-Artur , Poissy Julien , Peiffer-Smadja Nathan , Costagliola Dominique , Yazdanpanah Yazdan , Wallet Florent , Gagneux-Brunon Amandine , Mentré France , Ader Florence , Burdet Charles , Guedj Jérémie , Bouscambert-Duchamp Maude ,   the DisCoVeRy study group
Published: October 2021

Despite several clinical studies, the antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. We analyzed nasopharyngeal normalized viral loads collected in the 29 days following randomization from 665 hospitalized patients included in the DisCoVeRy trial, allocated to either standard of care (SoC, N=329) or SoC + remdesivir for 10 days (N=336). We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in reducing viral production. To identify factors associated with viral kinetics, additional analyses were conducted stratified either on time of treatment initiation (≤ or > 7 days since symptom onset) or viral load at randomization (< or ≥ 3.5 log10 copies/104 cells). In our model, remdesivir reduced viral production by 2-fold on average (95%CI: 1.5-3.2). Using the estimated parameter of the model, simulations predict that remdesivir reduces time to viral clearance by 0.7 day compared to SoC, with large inter-individual variabilities (Inter-Quartile Range, IQR: 0.0-1.3 days). Exploratory analyses suggest that remdesivir had a larger impact in patients with a high viral load at randomization, reducing viral production by 5-fold on average (95%CI: 2.8-25), leading to a predicted median reduction in the time to viral clearance of 2.4 days (IQR: 0.9-4.5 days).

In summary, our model shows that remdesivir reduces viral production from infected cells by a factor 2, leading to a median reduction of 0.7 days in the time to viral clearance compared to SoC. The efficacy was larger in patients with high level of viral load at treatment initiation.

One sentence summary

Remdesivir reduces the time to SARS-CoV-2 clearance by 1 day in hospitalized patients, and up to 3 days in those with high viral load at admission.
Opposing subclasses of Drosophila ellipsoid body neurons promote and suppress sleep
Authors: Aleman Abigail , Omoto Jaison Jiro , Singh Prabhjit , Nguyen Bao-Chau , Kandimalla Pratyush , Hartenstein Volker , Donlea Jeffrey M.
Published: October 2021

Recent work in Drosophila has uncovered several neighboring classes of sleep-regulatory neurons within the central complex. However, the logic of connectivity and network motifs remains limited by the incomplete examination of relevant cell types. Using a recent genetic-anatomical classification of ellipsoid body ring neurons, we conducted a thermogenetic screen to assess sleep/wake behavior and discovered two opposing populations: sleep-promoting R3m and wake-promoting R3d neurons. Activation of these neurons influences sleep duration and architecture by prolonging or shortening sleep bouts, suggesting a key role in sleep maintenance. R3m and R3d neurons are GABAergic and require GABA synthesis for their effects on sleep. Finally, we use a fluorescent reporter for putative synaptic partners to embed these neurons within the known sleep-regulatory network; R3m and R3d neurons lay downstream of wake-active Helicon cells, and R3m neurons likely inhibit R3d neurons. Together, the data presented herein suggest a neural mechanism by which previously uncharacterized circuit elements operate within the sleep homeostat to stabilize sleep-wake states.
Periodic and Aperiodic Neural Activity Displays Age-Dependent Changes Across Early-to-Middle Childhood
Authors: Hill Aron T. , Clark Gillian M. , Bigelow Felicity J. , Lum Jarrad A. G. , Enticott Peter G.
Published: October 2021

The neurodevelopmental period spanning early-to-middle childhood represents a time of significant growth and reorganisation throughout the cortex. Such changes are critical for the emergence and maturation of a range of social and cognitive processes. Here, we utilised both eyes open and eyes closed resting-state electroencephalography (EEG) to examine maturational changes in both oscillatory (i.e., periodic) and non-oscillatory (aperiodic, ‘1/f-like’) activity in a large cohort of participants ranging from 4-to-12 years of age (N=139, average age=9.41 years, SD=1.95). The EEG signal was parameterised into aperiodic and periodic components, and linear regression models were used to evaluate if chronological age could predict aperiodic exponent and offset, as well as well as peak frequency and power within the alpha and beta ranges. Exponent and offset were found to both decrease with age, while aperiodic-adjusted alpha peak frequency increased with age; however, there was no association between age and peak frequency for the beta band. Age was also unrelated to aperiodic-adjusted spectral power within either the alpha or beta bands, despite both frequency ranges being correlated with the aperiodic signal. Overall, these results highlight the capacity for both periodic and aperiodic features of the EEG to elucidate age-related functional changes within the developing brain.
Dynamic proton-dependent motors power Type IX secretion and gliding adhesin movement inFlavobacterium
Authors: Vincent Maxence S. , Hervada Caterina Comas , Sebban-Kreuzer Corinne , Guenno Hugo Le , Chabalier Maïalène , Kosta Artemis , Guerlesquin Françoise , Mignot Tâm , McBride Mark , Cascales Eric , Doan Thierry
Published: October 2021

Motile bacteria usually rely on external apparatus like flagella for swimming or pili for twitching. By contrast, gliding bacteria do not rely on obvious surface appendages to move on solid surfaces.Flavobacterium johnsoniaeand other bacteria in the Bacteroidetes phylum use adhesins whose movement on the cell surface supports motility. InF. johnsoniae, secretion and helicoidal motion of the main adhesin SprB are intimately linked and depend on the type IX secretion system (T9SS). Both processes necessitate the proton motive force (PMF), which is thought to fuel a molecular motor that comprises the GldL and GldM cytoplasmic membrane proteins. Here we show thatF. johnsoniaegliding motility is powered by the pH gradient component of the PMF. We further delineate the interaction network between the GldLM transmembrane helices (TMH) and show that conserved glutamate residues in GldL TMH are essential for gliding motility, although having distinct roles in SprB secretion and motion. We then demonstrate that the PMF and GldL trigger conformational changes in the GldM periplasmic domain. We finally show that multiple GldLM complexes are distributed in the membrane suggesting that a network of motors may be present to move SprB along a helical path on the cell surface. Altogether, our results provide evidence that GldL and GldM assemble dynamic membrane channels that use the proton gradient to power both T9SS-dependent secretion of SprB and its motion at the cell surface.
Cyclooxygenase production of PGE2 promotes phagocyte control of A. fumigatus hyphal growth in larval zebrafish
Authors: Thrikawala Savini , Niu Mengyao , Keller Nancy P. , Rosowski Emily E.
Published: October 2021

Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae.

Author Summary

Invasive aspergillosis causes mortality in >50% of infected patients. It is caused by a free-living fungus Aspergillus fumigatus which releases thousands of airborne spores. While healthy individuals clear inhaled spores efficiently, in immunocompromised individuals these spores grow into filamentous hyphae and destroy lungs and other tissues causing invasive aspergillosis. The immune mechanisms that control this fungal growth in healthy people are still largely unknown. Here, we used a larval zebrafish model of A. fumigatus infection to determine that cyclooxygenase enzymes, which are the target of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen, are important to control the fungus. Innate immune cells use cyclooxygenase signaling to prevent hyphal growth and tissue destruction. Our study provides new insights into the mechanisms that immune cells deploy to stop invasive growth of A. fumigatus and inform development of future strategies to combat invasive aspergillosis.
Mechanical coupling of supracellular stress amplification and tissue fluidization during exit from quiescence
Authors: Lång Emma , Pedersen Christian , Lång Anna , Blicher Pernille , Klungland Arne , Carlson Andreas , Bøe Stig Ove
Published: October 2021

Cellular quiescence is a state of reversible cell cycle arrest that is associated with tissue dormancy. Timely regulated entry into and exit from quiescence is important for processes such as tissue homeostasis, tissue repair, stem cell maintenance, developmental processes and immunity. Here we show that quiescent human keratinocyte monolayers contain an actinomyosin-based system that facilitates global viscoelastic flow upon serum-stimulated exit from quiescence. Mechanistically, serum exposure causes rapid amplification of pre-existing contractile sites leading to a burst in monolayer stress that subsequently drives monolayer fluidization. The stress magnitude after quiescence exit correlates with quiescence depth, and a critical stress level must be reached to overcome the cell sheet displacement barrier. The study shows that static quiescent cell monolayers are mechanically poised for motility and identifies global stress amplification as a mechanism for tissue fluidization.