bluuebunny/crossref_metadata_2025 huggingface dataset:
Fully Desktop Fabricated Flexible Graphene Electrocorticography (ECoG) Arrays
Authors: Hu Jia , Hossain Ridwan Fayaz , Navabi Zahra S. , Tillery Alana , Laroque Michael , Donaldson Preston D. , Swisher Sarah L. , Kodandaramaiah Suhasa B.
Published: July 2022

Flexible Electrocorticography (ECoG) electrode arrays that conform to the cortical surface and record surface field potentials from multiple brain regions provide unique insights into how computations occurring in distributed brain regions mediate behavior. Current flexible ECoG devices require highly specialized microfabrication methods, precluding the ability to fabricate customizable and low-cost flexible ECoG devices easily. Here we present a fully desktop fabricated flexible graphene ECoG array. First, we synthesized a stable, conductive ink via liquid exfoliation of Graphene in Cyrene. Next, we have established a stencil-printing process for patterning the graphene ink via laser-cut stencils on flexible polyimide substrates. Benchtop tests indicate that the graphene electrodes have good conductivity of ∼ 1.1 × 103 S·cm-1, flexibility to maintain their electrical connection under static bending, and electrochemical stability in a 15-day accelerated corrosion test. Chronically implanted graphene ECoG devices remain fully functional for up to 180 days, with average in vivo impedances of 24.72 ± 95.23 k Ω at 1 kHz. The ECoG device can measure spontaneous surface field potentials from mice under awake and anesthetized states and sensory stimulus-evoked responses. The stencil-printing fabrication process can be used to create Graphene ECoG devices with customized electrode layouts within 24 hours using commonly available laboratory equipment.
Readiness to retrieve memories of different ages: An ERP dissociation of orienting and difficulty
Authors: Leiker Emily K. , Johnson Jeffrey D.
Published: July 2022

A well-established finding in episodic memory research is that the likelihood of successful retrieval is affected by the ‘age’ of the targeted memory (i.e. based on the duration of the encoding-retrieval interval). Although such findings are usually interpreted in terms of the memory trace changing in quality or accessibility over time, there is growing evidence that memory performance also depends on preparatory attention and strategic orienting at the time of retrieval. Here, we investigated such readiness to retrieve, as indexed by event-related brain potentials (ERPs), when memory retrieval was aimed toward candidate traces of different ages. As retrieving remote versus recent memories is associated with increased difficulty, the current study was designed to dissociate difficulty from the memory age effects. Subjects encoded two lists of pictures separated by one week, with the items in each list presented once or four times. A series of memory tests targeting pictures from only one week-by-repetition condition at a time were then completed, while new pictures and those from the other conditions were rejected. Consistent with previous results, new-item ERPs were more positive over posterior scalp when recent compared to remote lists were targeted. Importantly, this difference remained when difficulty was matched, and the ERP correlates of difficulty were distinct in both timing and polarity from those of orienting. Together, these findings provide further support for the idea that the age of a targeted memory alone places different demands on readiness and can lead to the differential adoption of retrieval orienting strategies.
Diverse logics and grammar encode notochord enhancers
Authors: Song Benjamin P , Ragsac Michelle F , Tellez Krissie , Jindal Granton A , Grudzien Jessica L , Le Sophia H , Farley Emma K
Published: July 2022

The notochord is a key structure during chordate development. We have previously identified several enhancers regulated by Zic and ETS that encode notochord activity within the marine chordate Ciona robusta (Ciona). To better understand the role of Zic and ETS within notochord enhancers, we tested 90 genomic elements containing Zic and ETS sites for expression in developing Ciona embryos using a whole-embryo, massively parallel reporter assay. We discovered that 39/90 of the elements were active in developing embryos; however only 10% were active within the notochord, indicating that more than just Zic and ETS sites are required for notochord expression. Further analysis revealed notochord enhancers were regulated by three groups of factors: (1) Zic and ETS, (2) Zic, ETS and Brachyury (Bra), and (3) Zic, ETS, Bra and FoxA. One of these notochord enhancers, regulated by Zic and ETS, is located upstream of laminin alpha, a gene critical for notochord development in both Ciona and vertebrates. Reversing the ETS sites in this enhancer greatly diminish expression, indicating that enhancer grammar is critical for enhancer activity. Strikingly, we find clusters of Zic and ETS binding sites within the introns of mouse and human laminin alpha 1 with conserved enhancer grammar. Our analysis also identified two notochord enhancers regulated by Zic, ETS, FoxA and Bra binding sites: the Bra Shadow (BraS) enhancer located in close proximity to Bra, and an enhancer located near the gene Lrig. Randomizing the BraS enhancer demonstrates that although the Zic and ETS sites are necessary for enhancer activity, they are not sufficient. We find that FoxA and Bra sites contribute to BraS enhancer activity. Zic, ETS, FoxA and Bra binding sites occur within the Ciona Bra434 enhancer and vertebrate notochord Brachyury enhancers, suggesting a conserved regulatory logic. Collectively, this study deepens our understanding of how enhancers encode notochord expression, illustrates the importance of enhancer grammar, and hints at the conservation of enhancer logic and grammar across chordates.
Intranasal delivery of lipid nanoparticle encapsulated SARS-CoV-2 and RSV-targeting siRNAs reduces lung infection
Authors: Supramaniam Aroon , Tayyar Yaman , Clarke Daniel. T. W. , Kelly Gabrielle , Morris Kevin V. , McMillan Nigel A. J. , Idris Adi
Published: July 2022

RNA interference (RNAi) is an emerging and promising therapy for a wide range of respiratory viral infections. This highly specific suppression can be achieved by the introduction of short-interfering RNA (siRNA) into mammalian systems, resulting in the effective reduction of viral load. Unfortunately, this has been hindered by the lack of a good delivery system, especially via the intranasal (IN) route. Here, we have developed an IN siRNA encapsulated lipid nanoparticle (LNP) in vivo delivery system that is highly efficient at targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) in infected mouse lungs. Importantly, IN siRNA delivery without the aid of LNPs abolishes anti-SARS-CoV-2 activity in vivo. Our approach using LNPs as the delivery vehicle overcomes the significant barriers seen with IN delivery of siRNA therapeutics and is a significant advancement in our ability to delivery siRNAs. The studies presented here demonstrates an attractive alternate therapeutic delivery strategy for the treatment of both future and emerging respiratory viral diseases.
Profiling and Quantification of Anthocyanins in Novel Purple-Pericarp Sweetcorn and Purple-Pericarp Maize
Authors: Anirban Apurba , Hong Hung T. , O’Hare Tim J
Published: July 2022

Anthocyanins, secondary metabolites of pigmented corns consisting of cyanidin-, pelargonidin- and peonidin-based glucoside. While cyanidin-peonidin types are responsible for purple-pigmentation, pelargonidin type is responsible for red-pigmentation. This study examined anthocyanin concentrations in a novel purple-pericarp shrunken2 sweetcorn ‘Tim’ lines in comparison to the parental purple-pericarp ‘Costa Rica’ maize’ and white sweetcorn ‘Tims-white’ lines. The study found similar concentrations of anthocyanin in both ‘Tim1’ and the ‘Costa Rica’, at sweetcorn eating stage, whereas ‘Tims-white’ has no detectable anthocyanin. Total anthocyanins found in the ‘Costa Rica’ and ‘Tim1’, ‘Tim2’, ‘Tim4’ and ‘Tim5’ lines were 255.79, 253.03, 238.10, 198.66, and 221.36 mg/100 g FW (fresh weight), respectively. In all the developed purple-sweetcorn ‘Tim’ lines along with the purple maize parent, the cyanidin-peonidin (purple) proportion of total anthocyanin was 78-93%, as the predominant anthocyanin pigment. The anthocyanin concentration in ‘Tim1’ at eating stage was significantly much higher than currently exists with other coloured fruits.
Longitudinal fundus imaging and its genome-wide association analysis provide evidence for a human retinal aging clock
Authors: Ahadi Sara , Wilson Kenneth A. , Babenko Boris , McLean Cory Y. , Bryant Drew , Pritchard Orion , Carrera Enrique M. , Lamy Ricardo , Stewart Jay M. , Varadarajan Avinash , Berndl Marc , Kapahi Pankaj , Bashir Ali
Published: July 2022

Biological age, distinct from an individual’s chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Deep learning approaches on imaging datasets of the eye have proven powerful for a variety of quantitative phenotype inference tasks and provide an opportunity to explore organismal aging and tissue health.

Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals’ chronological age. These predictions led to the concept of a retinal aging clock, “eyeAge”, which we employed for a series of downstream longitudinal analyses. eyeAge was used to predict chronological age on timescales under a year using longitudinal fundus imaging data from a subset of patients. To further validate the model, it was applied to a separate cohort from the UK Biobank. The difference between individuals’ eyeAge and their chronological age, hereafter “eyeAgeAccel”, was computed and used for genome-wide association analysis (GWAS).

EyeAge predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UKBiobank, respectively). Additionally, eyeAgeAccel was highly independent of blood marker-based measures of biological age (e.g. “phenotypic age”), maintaining an all-cause mortality hazard ratio of 1.026 even in the presence of phenotypic age. Longitudinal studies showed that the resulting models were able to predict individuals’ aging, in time-scales less than a year, with 71% accuracy. The individual-specific component to this prediction was confirmed with the identification of multiple GWAS hits in the independent UK Biobank cohort. The knockdown of the fly homolog to the top hit,ALKAL2, which was previously shown to extend lifespan in flies, also slowed age-related decline in vision in flies.

In conclusion, predicted age from retinal images can be used as a biomarker of biological aging that is independent from assessment based on blood markers. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.
The frequent occurrence and metabolic versatility of Marinifilaceae bacteria involved in organic matter mineralization as a key member in global deep sea
Authors: Li Jianyang , Dong Chunming , Lai Qiliang , Wang Guangyi , Shao Zongze
Published: July 2022

Transfer of animal and plant detritus of both terrestrial and marine origins to the deep sea occurs on the global scale. Microorganisms play an important role in mineralizing them therein, yet to identify in situ. Here we report the family Marinifilaceae that occurred as one of the most predominant bacteria thriving on the new inputs of plant and animal biomasses in both marginal and oceanic areas observed via in situ incubation about their differentiation, environmental adaption, and metabolic mechanisms underlying their prevalence in organic matter mineralizing communities. We described the metabolic features and in situ metabolizing activities of different subgroups (tentative genus level), based on the metagenomic and metatranscriptomic data. One representative subgroup MF-2 dominated plant detritus-enriched cultures and specialized in polysaccharide degradation by encoding many hydrolases involved in the hydrolysis of hemicellulose, pectin, starch, cellulose, and polysaccharides containing N-acetyl groups; this subgroup also encodes a manganese superoxide dismutase with the potential of lignin oxidation and possesses complete nitrogen fixation pathway to compensate for the shortage of nitrogen sources inside the plant detritus. In contrast, those dominating the animal tissue-supported microbiomes were more diverse and formed three subgroups, which distinguished themselves from MF-2 in carbon and nitrogen metabolisms. Regardless of differentiation in carbon and nitrogen metabolisms, they share in common in energy conservation through organic fermentation, and anaerobic respiration of diverse electron receptors. These results highlight the role of Marinifilaceae bacteria neglected before in organic matter mineralizing in marine environments coupling carbon and nitrogen cycling with metals and other elements.

IMPORTANCE

Microbial mineralization of organic matters has a significant impact on the global biogeochemical cycle. This report confirmed the role of Marinifilaceae in organic degradation in the oceans, with underestimated contribution in the ocean carbon cycling. It is the dominant taxon thriving on plant and animal biomasses in our in situ incubator, as well as in whale- and wood-falls. At least nine subgroups were revealed, and widely distributed in global oceans but merely predominant in organic-rich environments with an average relative abundance of 8.3 %. Different subgroups display a preference for the degradation of different macromolecules (polysaccharides, lignin, and protein) and adapt themselves to the environments via special metabolic metabolisms.
Drug degradation caused by mce3R mutations confers contezolid (MRX-I) resistance in Mycobacterium tuberculosis
Authors: Pi Rui , Chen Xiaomin , Meng Jian , Liu Qingyun , Chen Yiwang , Bei Cheng , Wang Chuan , Gao Qian
Published: July 2022

Contezolid (MRX-I), a safer antibiotic of the linezolid oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increase in MICs of contezolid compared with the parent strain but was still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene which encode a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive DHPO ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis.

IMPORTANCE

Tuberculosis (TB) is one of the leading causes of global death and the second deadliest infectious killer after COVID-19. Compared to drug-sensitive TB, the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is more difficult and less effective due to longer regimens and higher potential for clinical adverse events. Despite the undisputed medical success of linezolid on MDR/XDR-TB therapy, this drug suffers from severe safety limitation. The new NMPA-approved drug contezolid, as an analogue of linezolid, exhibits a superior safety profile and potent antitubercular activity. Since the less-toxic contezolid is a promising drug candidate to optimize the current longer-duration MDR/XDR-TB therapy, it would be of significance to determine the resistance profiles of contezolid in MTB. Here, we present the first exploration of the frequency, mutational targets and molecular mechanisms of contezolid resistance in MTB, which could provide theoretical guidance for its future clinical application.
Reproduction number of monkeypox in the early stage of the 2022 multi-country outbreak
Authors: Du Zhanwei , Shao Zengyang , Bai Yuan , Wang Lin , Herrera-Diestra Jose L , Fox Spencer J. , Ertem Zeynep , Lau Eric H. Y. , Cowling Benjamin J.
Published: July 2022

Monkeypox, a fast-spreading viral zoonosis outside of Africa in May 2022, has scientists on alert. We estimated the reproduction number to be 1.29 (95% CrI: 1.26, 1.33) by aggregating all cases in 70 countries as of July 22, 2022.
Effectiveness of the BNT162b2 vaccine against SARS-CoV-2 infection among children and adolescents in Qatar
Authors: Chemaitelly Hiam , AlMukdad Sawsan , Ayoub Houssein H. , Altarawneh Heba N. , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Al-Romaihi Hamad Eid , Butt Adeel A. , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: July 2022

Background

The BNT162b2 COVID-19 vaccine is authorized for children 5-11 years of age and adolescents 12-17 years of age, but in different dose sizes. We assessed BNT162b2 real-world effectiveness against SARS-CoV-2 infection among children and adolescents in Qatar.

Methods

Three matched, retrospective, target-trial, cohort studies were conducted to compare incidence of SARS-CoV-2 infection in the national cohort of vaccinated individuals to incidence in the national cohort of unvaccinated individuals. Associations were estimated using Cox proportional-hazards regression models.

Results

Effectiveness of the 10 µg dose for children against Omicron infection was 25.7% (95% CI: 10.0-38.6%). It was highest at 49.6% (95% CI: 28.5-64.5%) right after the second dose, but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI: 21.5-63.3%) among those aged 5-7 years and 16.6% (−4.2-33.2%) among those aged 8-11 years. Effectiveness of the 30 µg dose for adolescents against Omicron infection was 30.6% (95% CI: 26.9-34.1%), but many adolescents were vaccinated months earlier. Effectiveness waned with time after the second dose. Effectiveness was 35.6% (95% CI: 31.2-39.6%) among those aged 12-14 years and 20.9% (13.8-27.4%) among those aged 15-17 years. Effectiveness of the 30 µg dose for adolescents against pre-Omicron infection was 87.6% (95% CI: 84.0-90.4%) and waned relatively slowly after the second dose.

Conclusions

Pediatric vaccination is associated with modest and rapidly waning protection against Omicron infection. Adolescent vaccination is associated with stronger and more durable protection, perhaps because of the larger dose size. Age at such young age appears to play a role in determining vaccine protection, with greater protection observed in younger than older children or adolescents.
Visual Transformer and Deep CNN Prediction of High-risk COVID-19 Infected Patients using Fusion of CT Images and Clinical Data
Authors: Tehrani Sara Saberi Moghadam , Zarvani Maral , Amiri Paria , Azmi Reza , Ghods Zahra , Nourozi Narges , Raoufi Masoomeh , Safavi-Naini Seyed Amir Ahmad , Soheili Amirali , Abolghasemi Sara , Gharib Mohammad , Abbasi Hamid
Published: July 2022

Despite the globally reducing hospitalization rates and the much lower risks of Covid-19 mortality, accurate diagnosis of the infection stage and prediction of outcomes are clinically of interest. Advanced current technology can facilitate automating the process and help identifying those who are at higher risks of developing severe illness. Deep-learning schemes including Visual Transformer and Convolutional Neural Networks (CNNs), in particular, are shown to be powerful tools for predicting clinical outcomes when fed with either CT scan images or clinical data of patients.

This paper demonstrates how a novel 3D data fusion approach through concatenating CT scan images with patients’ clinical data can remarkably improve the performance of Visual Transformer and CNN models in predicting Covid-19 infection outcomes. Here, we explore and represent comprehensive research on the efficiency of Video Swin Transformers and a number of CNN models fed with fusion datasets and CT scans only vs a set of conventional classifiers fed with patients’ clinical data only. A relatively large clinical dataset from 380 Covid-19 diagnosed patients was used to train/test the models. Results show that the 3D Video Swin Transformers fed with the fusion datasets of 64 sectional CT scans+67 (or 30 selected) clinical labels outperformed all other approaches for predicting outcomes in Covid-19-infected patients amongst all techniques (i.e., TPR=0.95, FPR=0.40, F0.5 score=0.82, AUC=0.77, Kappa=0.6). Results indicate possibilities of predicting the severity of outcome using patients’ CT images and clinical data collected at the time of admission to hospital.
Contextual incongruency triggers memory reinstatement and the disruption of neural stability
Authors: Wu Xiongbo , Packard-Blasco Pau , García-Arch Josué , Bunzeck Nico , Fuentemilla Lluís
Published: July 2022

Schemas, or internal representation models of the environment, are thought to be central in organising our everyday life behaviour by giving stability and predictiveness to the structure of the world. However, when an element from an unfolding event mismatches the schema-derived expectations, the coherent narrative is interrupted and an update to the current event model representation is required. Here, we asked whether the perceived incongruence of an item from an unfolding event and its impact on memory relied on the disruption of neural stability patterns preceded by the neural reactivation of the memory representations of the just-encoded event. Our study includes data from 3 different experiments whereby participants encoded images of target objects preceded by trial-unique sequences of events depicting daily routine. We found that neural stability patterns gradually increased throughout the ongoing exposure to a schema-consistent episodic narrative and that the brain stability pattern was interrupted when the encoding of an object of the event was lowly congruent within the ongoing schema representation. We found that the decrease in neural stability for low-congruence items was best seen at ∼1000 ms from object encoding onset when compared to high-congruence items and that this effect was preceded by an enhanced N400 ERP and an increased degree of neural reactivation of the just-encoded episode for low-congruence items. Current results offer new insights into the neural mechanisms and their temporal orchestration that are engaged during online encoding of schema-consistent episodic narratives and the detection of incongruencies.
Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas
Authors: Burdziak Cassandra , Alonso-Curbelo Direna , Walle Thomas , Barriga Francisco M. , Reyes José , Xie Yubin , Zhao Zhen , Zhao Chujun Julia , Chen Hsuan-An , Chaudhary Ojasvi , Masilionis Ignas , Choo Zi-Ning , Gao Vianne , Luan Wei , Wuest Alexandra , Ho Yu-Jui , Wei Yuhong , Quail Daniela , Koche Richard , Mazutis Linas , Nawy Tal , Chaligné Ronan , Lowe Scott W. , Pe’er Dana
Published: July 2022

The response to tumor-initiating inflammatory and genetic insults can vary amongst morphologically indistinguishable cells, suggesting yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we perform single-cell analyses on normal, inflamed, pre-malignant and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identify heterogeneous cell-states that are primed for diverse late-emerging neoplastic fates and link these to chromatin remodeling at cell-cell communication loci. Using a new inference approach, we reveal signaling gene modules and tissue-level crosstalk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that we validate by genetic perturbation in mice. Our results uncover a neoplasia-specific tissue remodeling program that may be exploited for pancreas cancer interception.

One-Sentence Summary

Single-cell analysis reveals that enhanced epigenetic plasticity drives pro-neoplastic crosstalk in early pancreatic cancer.
SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology
Authors: Lee Alfred Kihoon , Yi Nayoung , Khaled Husam , Feller Benjamin , Chofflet Nicolas , Takahashi Hideto
Published: July 2022

Amyloid-β oligomers (AβOs), toxic peptide aggregates found in Alzheimer’s disease (AD), cause synapse pathology. AβOs interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in Aβ pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and AβOs with β-NRXs and rescue effects of SorCS1 on AβO-induced synaptic pathology. Like AβOs, SorCS1 binds to NRX1β through the histidine-rich-domain (HRD) of NRX1β, and SorCS1 and AβOs compete for NRX1β binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1β on the axon surface, and axonal expression of SorCS1 rescues AβO-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as AβO-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of AβO-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.
Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease
Authors: Kecheliev Vasil , Spinelli Francesco , Herde Adrienne , Haider Ahmed , Mu Linjing , Klohs Jan , Ametamey Simon M. , Ni Ruiqing
Published: July 2022

Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aimed to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAβ mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for Aβ deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB2R antibody was performed on brain slices from arcAβ mice 17 months of age. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056 and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAβ and nontransgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAβ mice compared to NTL mice. CB2R immunofluorescence was higher in the glial cells inside 6E10-positive amyloid-β deposits than peri-plaque with a low background. Ex vivo autoradiography showed that the binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAβ and NTL mice at 6, 17 and 24 months. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAβ and NTL mice at 6, 17 or 24 months. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in a model of AD-related cerebral amyloidosis/AD mouse model, emphasizing CB2R as a suitable target for imaging neuroinflammation.
Rhesus Infant Nervous Temperament Predicts Peri-Adolescent Central Amygdala Metabolism & Behavioral Inhibition Measured by a Machine-Learning Approach
Authors: Holley D , Campos LJ , Zhang Y , Capitanio JP , Fox AS
Published: July 2022

Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)—a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)—as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders—and how this relationship is mediated by alterations in the EAc—could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.
Survival of Campylobacter jejuni in Acanthamoebae castellanii provides mechanistic insight into host pathogen interactions
Authors: Nasher Fauzy , Lehri Burhan , Horney Megan F , Stabler Richard A , Wren Brendan W
Published: July 2022

Campylobacter jejuni is the leading cause of bacterial foodborne gastroenteritis world-wide but is rarely transferred between human hosts. Although a recognized microaerophile, C. jejuni is incapable of growing in an aerobic environment. The persistence and transmission of this pathogen outside its warm-blooded avian and mammalian hosts is poorly understood. Acanthamoebae species, are predatory protists and form an important ecological niche with several bacterial species. Here, we investigate the interaction of C. jejuni and Acanthamoebae castellanii at the single-cell level. We observe that a subpopulation of C. jejuni cells can resist killing by A. castellanii and non-digested bacteria are released into the environment where they can persist. In addition, we observe that A. castellanii can harbor C. jejuni even upon encystment. Transcriptome analyses of C. jejuni interactions revealed similar survival mechanisms when infecting both A. castellanii and warm-blooded hosts. In particular, nitrosative stress defense mechanisms and flagellum function are important as confirmed by mutational analyses. This study describes a new host-pathogen interaction for C. jejuni and confirms that amoebae are transient hosts for the persistence, adaptability and potential transmission of C. jejuni.
Optimal control of gene regulatory networks for morphogen-driven tissue patterning
Authors: Pezzotta A. , Briscoe J.
Published: July 2022

The organised generation of functionally distinct cell types in developing tissues depends on establishing spatial patterns of gene expression. In many cases, this is directed by spatially graded chemical signals – known as morphogens. In the influential “French Flag Model”, morphogen concentration is proposed to instruct cells to acquire their specific fate. However, this mechanism has been questioned. It is unclear how it produces timely and organised cell-fate decisions, despite the presence of changing morphogen levels, molecular noise and individual variability. Moreover, feedback is present at various levels in developing tissues introducing dynamics to the process that break the link between morphogen concentration, signaling activity and position. Here we develop an alternative approach using optimal control theory to tackle the problem of morphogen-driven patterning. In this framework, intracellular signalling is derived as the control strategy that guides cells to the correct fate while minimizing a combination of signalling levels and the time taken. Applying this approach demonstrates its utility and recovers key properties of the patterning strategies that are found in experimental data. Together, the analysis offers insight into the design principles that produce timely, precise and reproducible morphogen patterning and it provides an alternative framework to the French Flag paradigm for investigating and explaining the control of tissue patterning.
The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation
Authors: Bernkopf Marie , Abdullah Ummi B. , Bush Stephen J. , Wood Katherine , Ghaffari Sahar , Giannoulatou Eleni , Koelling Nils , Maher Geoffrey J. , Thibault Loïc M. , Williams Jonathan , Blair Edward M. , Kelly Fiona Blanco , Bloss Angela , Burkitt-Wright Emma , Canham Natalie , Deng Alexander T. , Dixit Abhijit , Eason Jacqueline , Elmslie Frances , Gardham Alice , Hay Eleanor , Holder Muriel , Homfray Tessa , Hurst Jane A. , Johnson Diana , Jones Wendy D. , Kini Usha , Kivuva Emma , Kumar Ajith , Lees Melissa M. , Leitch Harry G. , Morton Jenny E. V. , Németh Andrea H. , Ramachandrappa Shwetha , Saunders Katherine , Shears Deborah J. , Side Lucy , Splitt Miranda , Stewart Alison , Stewart Helen , Suri Mohnish , Clouston Penny , Davies Robert W. , Wilkie Andrew O. M. , Goriely Anne
Published: July 2022

Next-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians’ ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.
TGFβ−induced embryonic cell senescence at the origin of the Cornelia de Lange syndrome
Authors: Hachoud Céline , Chaabani Faten , Watrin Erwan , Wuelling Manuela , Peters Heiko , Cormier-Daire Valérie , Pucéat Michel
Published: July 2022

Cornelia de Lange Syndrome (CdLS) largely caused by mutation of the cohesin loader NIPBL is a rare developmental disorder affecting the formation of many organs. Besides a short body size and neurological defects, more than half of CdLS children feature various cardiac malformations.

To mimic the disease and test a therapeutic strategy, we generated a C57/Bl6Nipbl+/-mouse model of the disease. These mice featured a severe delay in both embryonic and postnatal growth. TheNipbl-deficient embryonic and neonatal hearts developed ventricular hypertrophy, aortic and valve defects associated with a persistent truncus arteriosus and a ventricular septal defect. Muscles derived from the second heart field were deficient in theNipblhaplo-insufficient mouse embryos. The adult hearts then featured a severe aortic senescence phenotype and a stenosis resulting in an increase in aortic flux velocity and persistent left ventricular hypertrophy. Using proteomics and RNA-sequencing in embryos, we identified a dysregulated TGFβ pathway in the outflow tract of embryonic hearts as well as the presence of senescent cells as early as in E13.5Nipbl+/-embryonic hearts, limb primordium cartilage as well as in different post-natal tissues including muscle and brain cortex. Treatment of pregnantNipbl+/-mice with a TGFβR (ALK5) inhibitor from E9.5 to E13.5 prevented cell -senescence and rescued the cardiac phenotype as well as the body size of mice at birth.

Altogether our data revealed that an exacerbated TGFβ pathway associated with cell senescence is at the origin of many defects in a CdL mouse model. This druggable pathway opens the path toward a potential preventive and/or therapeutic strategy for post-natal CdLS patients.
Neural integration and segregation revealed by a joint time-vertex connectome spectral analysis
Authors: Rué-Queralt Joan , Mancini Valentina , Rochas Vincent , Latrèche Caren , Uhlhaas Peter J , Michel Christoph M. , Plomp Gijs , Eliez Stephan , Hagmann Patric
Published: July 2022

Brain oscillations are produced by the coordinated activity of large groups of neurons and different rhythms are thought to reflect different modes of information processing. These modes, in turn, are known to occur at different spatial scales. Nevertheless, how these rhythms support different modes of information processing at the brain scale is not yet fully understood. Here we present “Joint Time-Vertex Connectome Spectral Analysis”, a framework for characterizing the spectral content of brain activity both in time (temporal frequencies) and in space (spatial connectome harmonics). This method allows us to estimate the contribution of integration (global communication) and segregation (functional specialization) mechanisms at different temporal frequency bands in source-reconstructed M/EEG signals, thus providing a better understanding of the complex interplay between different information processing modes. We validated our method on two different datasets, an auditory steady-state response (ASSR) and a visual grating task. Our results suggest that different information processing mechanisms are carried out at different frequency channels: while integration seems to be a specific mechanism occurring at low temporal frequencies (alpha and theta), segregation is only observed at higher temporal frequencies (high and low gamma). Crucially, the estimated contribution of the integration and segregation mechanisms predicts performance in a behavioral task, demonstrating the neurophysiological relevance of this new framework.
Contrast Subgraphs Allow Comparing Homogeneous and Heterogeneous Networks Derived from Omics Data
Authors: Lanciano Tommaso , Savino Aurora , Porcu Francesca , Cittaro Davide , Bonchi Francesco , Provero Paolo
Published: July 2022

Biological networks are often used to describe the relationships between relevant entities, in particular genes and proteins, and are a powerful tool for functional genomics. Many important biological problems can be investigated by comparing biological networks between different conditions, or networks obtained with different techniques. We show that contrast subgraphs, a recently introduced technique to identify the most important structural differences between two networks, provide a versatile tool for comparing gene and protein networks of diverse origin. We show in three concrete examples how contrast subgraphs can provide new insight in functional genomics by extracting the gene/protein modules whose connectivity is most altered between two conditions or experimental techniques.
Allosteric Regulation of a Synaptic Vesicle Glutamate Transporter
Authors: Li Fei , Eriksen Jacob , Oses-Prieto Juan A. , Gomez Yessica K. , Xu Hongfei , Finer-Moore Janet , Nguyen Phuong , Bowen Alisa , Nelson Andrew , Burlingame Alma , Grabe Michael , Stroud Robert M. , Edwards Robert H.
Published: July 2022

Concentration of neurotransmitter inside synaptic vesicles (SVs) underlies the quantal nature of synaptic transmission. In contrast to many transporters, SV uptake of the principal excitatory neurotransmitter glutamate is driven by membrane potential. To prevent nonquantal efflux of glutamate after SV exocytosis, the vesicular glutamate transporters (VGLUTs) are allosterically inhibited by the neutral pH of the synaptic cleft. We have now determined high-resolution structures of VGLUT2 with a cyclic analog of glutamate bound that defines the mechanism of substrate recognition, a positively charged cytoplasmic vestibule that electrostatically attracts the negatively charged substrate, and modification by palmitoylation that promotes retrieval of the transporter after exocytosis. The structure also incorporates an extensive, cytoplasmic network of electrostatic interactions that acts as a gate. Functional analysis shows how this cytoplasmic gate confers the allosteric requirement for lumenal H+ required to restrict VGLUT activity to SVs.
Comparative genome-scale constraint-based metabolic modeling reveals key lifestyle features of plant-associated Pseudomonas spp
Authors: Poncheewin Wasin , van Diepeningen Anne D. , van der Lee Theo AJ , Schaap Peter J. , Martins dos⍰Santos Vitor A. P. , Suarez-Diez Maria
Published: July 2022

Plant Growth Promoting Rhizobacteria (PGPR) dwell in the rhizosphere, the area surrounding the root of plants, and enhance growth of the host through different mechanisms: they can protect plants against pathogens, assist in nutrient gathering, and in increasing stress tolerance. Hence, developing strategies to enhance their performance is important to increase crop productivity. Specific solutions are necessary to enhance the performance of the beneficials while simultaneously avoiding nurturing of pathogens. This requires insights into the mechanisms underlying these microbials interactions. Pseudomonas is one of the most studied genera and contains both beneficials and pathogenic species. Hence, we used comparative genome-scale constraint-based metabolic modeling to reveal key features of both classes of Pseudomonads and which can provide leads for the possible interventions regarding these solutions. Models of 75 plant-growth promoting rhizosphere and 33 epiphytic pathogenic Pseudomonas strains were automatically reconstructed and validated using phenotype microarray (Biolog) data. The models were used for compositional analysis and 12 representative strains, 6 of each group, were further selected for extensive simulation. The analyses reveal differences in the potential for metabolite uptake and transport between these two distinct classes that suggest their nutrient preferences and their differences in, among other, D-ornithine acquisition mechanisms. The models enable simulation of metabolic state of root exudates. Simulations highlighted and summarized the differences in pathway utilization and intracellular states between two groups. The insights obtained will be very valuable to broader such studies of rhizobiome and to possibly develop strategies to improve crop productivity by supporting the beneficial microbiome while reducing pathogen activities.
Evaluating the capabilities and challenges of layer-fMRI VASO at 3T
Authors: Huber Laurentius (Renzo) , Kronbichler Lisa , Stirnberg Rüdiger , Ehses Philipp , Stöcker Tony , Fernández-Cabello Sara , Poser Benedikt A. , Kronbichler Martin
Published: July 2022

Sub-millimeter functional imaging has the potential to capture cortical layer-specific functional information flow within and across brain systems. Recent sequence advancements of fMRI signal readout and contrast generations resulted in wide adaptation of layer-fMRI protocols across the global ultra-high-field (UHF) neuroimaging community. However, most layer-fMRI applications are confined to one of ≈100 privileged UHF imaging centers, and sequence contrasts with unwanted sensitivity to large draining veins. In this work, we propose the application of vein-signal free vascular space occupancy (VASO) layerfMRI sequences at widely accessible 3T scanners. Specifically, we implement, characterize, and apply a cerebral blood volume (CBV)-sensitive VASO fMRI at a 3T scanner setup, as it is typically used in the majority of cognitive neuroscience and clinical neuroscience fMRI studies. We find that the longer , and stronger relative T1 contrast at 3T can account for some of the lower z-magnetization in the inversion-recovery VASO sequence compared to 7T and 9.4T. In the main series of experiments (N=16), we test the utility of this setup for motor tasks and find that-while being limited by thermal noise-3T layer-fMRI VASO is feasible within conventional scan durations. In a series of auxiliary studies, we furthermore explore the generalizability of the developed layer-fMRI protocols for a larger range of study designs including: visual stimulation, whole brain movie watching paradigms, and cognitive tasks with weaker effect sizes. We hope that the developed imaging protocols will help to increase accessibility of vein-signal free layer-fMRI imaging tools to a wider community of neuroimaging centers.

Graphical abstract
APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer
Authors: Tian Yuhua , Wang Xin , Cramer Zvi , Rhoades Joshua , Estep Katrina N. , Ma Xianghui , Tzivelekidis Stephanie Adams , Katona Bryson W , Johnson F Brad , Yu Zhengquan , Blanco Mario Andres , Lengner Christopher , Li Ning
Published: July 2022

Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector β-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive β-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.