bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultra-sensitive measurement of brain penetration mechanics and blood vessel rupture with microscale probes
Authors: Obaid Abdulmalik , Wu Yu-Wei , Hanna Mina , Jáidar Omar , Nix William , Ding Jun , Melosh Nicholas
Published: September 2020

Microscale electrodes, on the order of 10-100 μm, are rapidly becoming critical tools for neuroscience and brain-machine interfaces (BMIs) for their high channel counts and spatial resolution, yet the mechanical details of how probes at this scale insert into brain tissue are largely unknown. Here, we performed quantitative measurements of the force and compression mechanics together with real-time microscopy forin vivoinsertion of a systematic series of microelectrode probes as a function of diameter (7.5–100 μm and rectangular Neuropixels) and tip geometry (flat, angled, and electrochemically sharpened). Results elucidated the role of tip geometry, surface forces, and mechanical scaling with diameter. Surprisingly, the insertion force post-pia penetration was constant with distance and did not depend on tip shape. Real-time microscopy revealed that at small enough lengthscales (<25 μm), blood vessel rupture and bleeding during implantation could be entirely avoided. This appears to occur via vessel displacement, avoiding capture on the probe surface which led to elongation and tearing for larger probes. We propose a new, three-zone model to account for the probe size dependence of bleeding, and provide mechanistic guidance for probe design.
An Integrated Multimodal Model of Alcohol Use Disorder Generated by Data-Driven Causal Discovery Analysis
Authors: Rawls Eric , Kummerfeld Erich , Zilverstand Anna
Published: September 2020

Objective

Alcohol use disorder (AUD) has high prevalence and adverse societal impacts, but our understanding of the factors driving AUD is hampered by a lack of studies that describe the complex multifactorial mechanisms driving AUD.

Methods

We used Causal Discovery Analysis (CDA) with data from the Human Connectome Project (HCP; n = 926 [54% female], 22% AUD [37% female]). Our outcome variable was number of AUD symptoms. We applied exploratory factor analysis (EFA) to parse phenotypic measures into underlying constructs, and assessed functional connectivity within 12 resting-state brain networks as an indicator of brain function. We then employed data-driven CDA to generate an integrated model relating phenotypic factors, fMRI network connectivity, and AUD symptom severity.

Results

EFA extracted 18 factors representing the wide HCP phenotypic space (100 measures). CDA produced an integrated multimodal model, highlighting a limited set of causes of AUD. The model proposed a hierarchy with causal influence propagating from brain function to cognition (fluid/crystalized cognition, language & working memory) to social (agreeableness/social support) to affective/psychiatric function (negative affect, low conscientiousness/attention, externalizing symptoms) and ultimately AUD severity. Every edge in the model was present atp< .001, and the SEM model overall provided a good fit (RMSEA = .06, Tucker-Lewis Index = .91).

Conclusions

Our data-driven model confirmed hypothesized influences of cognitive and affective factors on AUD, while underscoring that traditional addiction models need to be expanded to highlight the importance of social factors, amongst others. Results further demonstrated that it is possible to extract a limited set of causal factors of AUD, which can inform future research aimed at tracking factors that dynamically predict alcohol use trajectories. Lastly, the presented model identified potential treatment targets for AUD, including neuromodulation of the frontoparietal network, cognitive/affective interventions, and social interventions.
Host evolutionary history and ecological context modulate the adaptive potential of the microbiome
Authors: Henry Lucas P. , Fernandez Michael , Webb Andrew , Ayroles Julien F.
Published: September 2020

Can the microbiome serve as a reservoir of adaptive potential for hosts? To address this question, we leveraged ∼150 generations of experimental evolution inDrosophila melanogasterin a stressful, high-sugar (HS) diet. We performed a fully reciprocal transplant experiment using the control and evolved HS bacteria. If the microbiome confers benefits to hosts, then transplant recipients should gain fitness benefits compared to controls. Interestingly, we found that benefits do exist, but mismatches between fly evolution and microbiome exerted fitness costs by slowing development and reducing fecundity, especially in the stressful HS diet. The dominant HS bacteria (Acetobacter pasteurianus) uniquely encoded several genes to enable uric acid degradation, mediating the toxic effects of uric acid accumulation due to the HS diet for flies. Our study demonstrates that host genotype x microbiome x environment interactions have substantial effects on host phenotype, highlighting how host evolution and ecological context together shape the adaptive potential of the microbiome.
Stable but not rigid: Long-termin vivoSTED nanoscopy uncovers extensive remodeling of stable spines and indicates multiple drivers of structural plasticity
Authors: Steffens Heinz , Mott Alexander C. , Li Siyuan , Wegner Waja , Švehla Pavel , Kan Vanessa W. Y. , Wolf Fred , Liebscher Sabine , Willig Katrin I.
Published: September 2020

Excitatory synapses on dendritic spines of pyramidal neurons are considered a central memory locus. To foster both continuous adaption as well as the storage of long-term information, spines need to be plastic and stable at the same time. Here we advancedin vivoSTED nanoscopy to superresolve distinct features of dendritic spines (head size, neck length and width) in mouse neocortex for up to one month. While LTP-dependent changes predict highly correlated modifications of spine geometry, we find both, uncorrelated dynamics, as well as correlated changes, indicating multiple independent drivers of spine remodeling. The magnitude of this remodeling suggests substantial fluctuations in synaptic strength, and is exaggerated in a mouse model of neurodegeneration. Despite this high degree of volatility, all spine features also exhibit persistent components that are maintained over long periods of time. Thus, at the nanoscale, stable dendritic spines exhibit a delicate balance of stability and volatility.
Design Principles Underlying Robust Adaptation of Complex Biochemical Networks
Authors: Araujo Robyn P. , Liotta Lance A.
Published: September 2020

Biochemical networks are often characterised by tremendous complexity – both in terms of the sheer number of interacting molecules (“nodes”) and in terms of the varied and incompletely understood interactions among these molecules (“interconnections” or “edges”). Strikingly, the vast and intricate networks of interacting proteins that exist within each living cell have the capacity to perform remarkably robustly, and reproducibly, despite significant variations in concentrations of the interacting components from one cell to the next, and despite mutability over time of biochemical parameters. Here we consider the ubiquitously observed and fundamentally important signalling response known as Robust Perfect Adaptation (RPA). We have recently shown that all RPA-capable networks, even the most complex ones, must satisfy an extremely rigid set of design principles, and are modular, being decomposable into just two types of network building-blocks – Opposer modules, and Balancer modules. Here we present an overview of the design principles that characterize all RPA-capable network topologies through a detailed examination of a collection of simple examples. We also introduce a diagrammatic method for studying the potential of a network to exhibit RPA, which may be applied without a detailed knowledge of the complex mathematical principles governing RPA.
TheClostridioides difficilespecies problem: global phylogenomic analysis uncovers three ancient, toxigenic, genomospecies
Authors: Knight Daniel R. , Imwattana Korakrit , Kullin Brian , Guerrero-Araya Enzo , Paredes-Sabja Daniel , Didelot Xavier , Dingle Kate E. , Eyre David W. , Rodríguez César , Riley Thomas V.
Published: September 2020

Clostridioides difficileinfection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen acrossC. difficileunderscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000C. difficilegenomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure ofC. difficilespecifically and taxonomy of thePeptostreptococcaceaein general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution ofC. difficileand close relatives. Beyond the taxonomic ramifications, this work impacts the diagnosis of CDI worldwide.
Integrative taxonomy reveals hidden species within the western AtlanticCallichirus majors. l. (Decapoda, Axiidea, Callichiridae)
Authors: Hernáez Patricio , Miranda Marcel S. , Rio Juliana P. P. , Pinheiro Marcelo A.A.
Published: September 2020

The ghost shrimpCallichirus major(Say, 1818) is widely distributed in the Atlantic Ocean from ∼23°N to ∼26°S, and has also been reported from the tropical eastern Pacific. Evidence has been accumulating over many years thatC. majoris actually a species complex. Yet, the nameC. majoris widely and frequently used in many kinds of research. The current lack of clarity in the use of the nameC. majorhas resulted in nomenclatural instability, but also in unreliability and miscommunication of the available ecological and distributional information. Existing morphological and molecular evidence is reviewed and new evidence presented for the specimens from the southern localities previously assigned toC. majors. l. actually being a new species. That new species is herein described based on morphological and molecular evidence. Additionally, a neotype is selected forC. majorin order to settle the defining characters ofC. majors. str. and, therefore, ensuring the correct use of this name.
Influence of sensory modality and control dynamics on human path integration
Authors: Stavropoulos Akis , Lakshminarasimhan Kaushik J. , Laurens Jean , Pitkow Xaq , Angelaki Dora E.
Published: September 2020

Path integration is a sensorimotor computation that can be used to infer latent dynamical states by integrating self-motion cues. We studied the influence of sensory observation (visual/vestibular) and latent control dynamics (velocity/acceleration) on human path integration using a novel motion-cueing algorithm. Sensory modality and control dynamics were both varied randomly across trials, as participants controlled a joystick to steer to a memorized target location in virtual reality. Visual and vestibular steering cues allowed comparable accuracies only when participants controlled their acceleration, suggesting that vestibular signals, on their own, fail to support accurate path integration in the absence of sustained acceleration. Nevertheless, performance in all conditions reflected a failure to fully adapt to changes in the underlying control dynamics, a result that was well explained by a bias in the dynamics estimation. This work demonstrates how an incorrect internal model of control dynamics affects navigation in volatile environments in spite of continuous sensory feedback.
At each site its diversity: DNA barcoding reveals remarkable earthworm diversity in neotropical rainforests of French Guiana
Authors: Maggia Marie-Eugénie , Decaëns Thibaud , Lapied Emmanuel , Dupont Lise , Roy Virginie , Schimann Heidy , Orivel Jérôme , Murienne Jérôme , Baraloto Christopher , Cottenie Karl , Steinke Dirk
Published: September 2020

Despite their recognized essential role in soil, earthworms in tropical environments are still understudied. The aim of this study was to re-evaluate the diversity at the regional scale, as well as to investigate the environmental and spatial drivers of earthworm communities. We sampled earthworm communities across a range of habitats at six locations in French Guiana using three different sampling methods. We generated 1675 DNA barcodes and combined them with data from a previous study. Together, all sequences clustered into 119 MOTUs which were used as proxy to assess species richness. Only two MOTUs were common between the six locations and 20.2 % were singletons, showing very high regional species richness and a high number of rare species. A canonical redundancy analysis was used to identify key drivers of the earthworm community composition. The RDA results and beta-diversity calculations both show strong species turnover and a strong spatial effect, resulting from dispersal limitations that are responsible for the current community composition. Sampling in different microhabitats allowed the discovery of 23 MOTUs that are exclusively found in decaying trunks and epiphytes, highlighting hidden diversity of earthworms outside of soil.
Exact decoding of the sequentially Markov coalescent
Authors: Ki Caleb , Terhorst Jonathan
Published: September 2020

In statistical genetics, the sequentially Markov coalescent (SMC) is an important framework for approximating the distribution of genetic variation data under complex evolutionary models. Methods based on SMC are widely used in genetics and evolutionary biology, with significant applications to genotype phasing and imputation, recombination rate estimation, and inferring population history. SMC allows for likelihood-based inference using hidden Markov models (HMMs), where the latent variable represents a genealogy. Because genealogies are continuous, while HMMs are discrete, SMC requires discretizing the space of trees in a way that is complicated and can lead to bias. In this work, we propose a method that circumvents this requirement, enabling SMC-based inference to be performed in the natural setting of a continuous state space. We derive fast, exact methods for frequentist and Bayesian inference using SMC. Compared to existing methods, ours requires minimal user intervention or parameter tuning, no numerical optimization or E-M, and is faster and more accurate.
Altered visual function in a larval zebrafish knockout of neurodevelopmental risk genepdzk1
Authors: Xie Jiaheng , Jusuf Patricia R. , Bui Bang V. , Dudczig Stefanie , Goodbourn Patrick T.
Published: September 2020

The humanPDZK1gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study (GWAS) identified links betweenPDZK1polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including post-synaptic density 95 (PSD-95),N-methyl-D-aspartate receptors (NMDAR), corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptors. To elucidate the role of PDZK1, we generatedpdzk1-knockout (pdzk1-KO)zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioural and functional levels using the optomotor response (OMR) and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1 and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks and 8 weeks of age. Relative to wild-type,pdzk1-KO larvae showed spatial-frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERGb-waves (suggestive of inner retinal dysfunction). However, these functional differences were not associated with gross synaptic or morphological retinal phenotypes. The findings corroborate a role forpdzk1in visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behaviour.
Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution
Authors: Zhang Shuyuan , Qiao Shuyuan , Yu Jinfang , Zeng Jianwei , Shan Sisi , Lan Jun , Tian Long , Zhang Linqi , Wang Xinquan
Published: September 2020

In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the “down” conformation, indicating they are more prone to adopt this receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. Through structure and sequence comparisons, we identified critical residues in the RBD that underlie the different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes and propose that N-linked glycans serve as conformational control elements of the RBD. These results collectively indicate that strong RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.
Heat Stress and PPE during COVID-19: Impact on health care workers’ performance, safety and well-being in NHS settings
Authors: Davey Sarah L , Lee Ben J , Robbins Timothy , Randeva Harpal , Thake C. Doug
Published: September 2020

Background

The impermeable nature of PPE worn by health care workers (HCWs) during the SARS-CoV-2 (COVID-19) pandemic can potentiate heat stress which may negatively impact the performance, safety and well-being of HCWs.

Aim

The aim of this study was to evaluate perceived levels of heat stress and its consequences in HCWs required to wear PPE during the COVID-19 pandemic in the UK.

Method

An anonymous online survey was distributed to HCWs required to wear Type 1 or 2 PPE in NHS settings to evaluate the perceived impact of PPE on: (1) physical and cognitive performance; (2) heat stress and heat-related symptoms; (3) frequency of removing PPE due to discomfort caused by heat stress; and (4) general working-life and well-being.

Results

The survey received 224 responses from 192 (85.7%) women and 32 (14.3%) men. Even though 71.9% of respondents wore the less thermally challenging PPE (i.e. Type 2), a median of 3 (IQR: 2,5) heat-related symptoms were reported including syncope (7.7%). A median of 1 (IQR: 0-3) cognitive task was adversely affected with attentional focus being the most affected. To relieve discomfort, 32.6% reported removing PPE on five or more occasions in a shift. Ninety two percent reported PPE made their job more difficult and 76.2% advised that physical performance was impaired. Respondents also highlighted concerns of dermatitis and pressure sores in the facial region (22.3%) amongst other factors.

Conclusion

Heat stress experienced when PPE is worn negatively impacts the performance, safety and well-being of HCWs and patients. Therefore, modification to current working practices and current design of PPE is urgently required to improve HCWs’ resilience to pandemics of infectious diseases. Results suggest modifications to the design of the protective face mask and strict enforcement of specific work/rest ratios to limit the duration of PPE use would be immediate impactful interventions.
THE EFFECT OF DIOXIN ON LOW BIRTH WEIGHT IN SOUTHERN WEST VIRGINIA BETWEEN 1955 – 1969
Authors: Annie Frank H , Uejio Chris K , Embrey Sarah , Tager Alfred
Published: September 2020

Objective

The effect of low birth weight as a result of dioxin-based exposure has been investigated through the existing literature, but the debate on exact point source and production is still debated. The Monsanto factory located in Nitro, West Virginia produced Agent Orange from 1948 – 1969.

Methods

The vital statistics registry from the state of West Virginia of Kanawha county and Putnam county West Virginia. The production of dioxin and 2-4-5T was obtained from the legal files from (Civil Action No. 04-C-465) and the expert witness of Dr. Bruce Bell. In order to understand this relationship a time series analysis was conducted to compare 2-4-5T and dioxin and low-birthweight in Kanawha County and Putnam County, West Virginia.

Results

The results suggest dioxin within Kanawha county had a suggestive relationship associated with dioxin production and low birthweight from 1948-1969 had a suggestive relationship of (p= 0.042). The comparison county of Putnam had no statistically significant relationship between low birthweight and dioxin production (p= 0.203). Agent Orange (2-4-5t) was also considered and measured within the counties of Kanawha and Putnam Counties, within these two counties no statistically significant relationship was observed.

Conclusions

In conclusion the association between dioxin and low birthweight still requires more research but this analysis illustrates that there appears to be a suggestive relationship that exists within Kanawha County, West Virginia as related to the production of and effect of the by-product of dioxin.
Self-applied ELCSA is valid for rapid tracking of household food insecurity among pregnant women during the COVID-19 pandemic
Authors: Agampodi Thilini C. , Hromi-Fiedler Amber , Agampodi Suneth B. , Amarasinghe Gayani S. , wickramasinghe Nuwan D. , Jayasinghe Imasha U. , Hettiarachchi Ayesh U. , Perez-Escamilla Rafael
Published: September 2020

Background

Rapid household food insecurity (HFI) tracking has been identified as a priority in the context of the COVID-19 pandemic and its aftermath. We report the validation of the Latin American and Caribbean Food Security Scale (Escala Latinoamericana y Caribena de Seguridad Alimentaria -ELCSA) among pregnant women in Sri Lanka.

Methods

The adult eight-items of the English version of ELCSA was translated into Sinhala and Tamil. Cognitive testing (on ten pregnant women and five local experts) and psychometric validation of the self-administered HFI tool was conducted among pregnant women (n=269) attending the Rajarata Pregnancy Cohort (RaPCo) special clinics in Anuradhapura in February 2020. We assessed psychometric properties and fit using a one parameter logistic model (Rasch analysis) using STATA version 14 and WINSTEP software version 4.3.4. Concurrent validity was tested using psychological distress.

Results

The scale was internally consistent (Cronbach’s alpha = 0.79), had a good model fit (Rasch infit statistic range: 0.85 to 1.07). Item 8 (‘did not eat for the whole day’) was removed from the model fit analysis as it was not affirmed by anyone. Item severity scores ranged from -2.15 for ‘not eating a diverse diet’ to 4.43 for ‘not eating during the whole day’. Concurrent validity between HFI and psychological distress was confirmed (r=0.15, p<0.05).

Conclusions

The self-applied version of ELCSA-pregnancy in Sri Lanka (ELCSA-P-SL) is a valid and feasible tool to track HFI among pregnant women in similar contexts during the COVID-19 pandemic, where social distancing is a major concern and its aftermath.
Epidemiological characteristics of COVID-19 cases in non-Italian nationals notified to the Italian surveillance system
Authors: Fabiani Massimo , Mateo-Urdiales Alberto , Andrianou Xanthi , Bella Antonino , Del Manso Martina , Bellino Stefania , Rota Maria C. , Boros Stefano , Vescio Maria F. , D’Ancona Fortunato P. , Siddu Andrea , Punzo Ornella , Filia Antonietta , Brusaferro Silvio , Rezza Giovanni , Dente Maria G. , Declich Silvia , Pezzotti Patrizio , Riccardo Flavia ,   for the COVID-19 working group
Published: September 2020

Background

International literature suggests that disadvantaged groups are at higher risk of morbidity and mortality from SARS-CoV-2 infection due to poorer living/working conditions and barriers to healthcare access. Yet, to date, there is no evidence of this disproportionate impact on non-national individuals, including economic migrants, short-term travellers, and refugees.

Methods

We analysed data from the Italian surveillance system of all COVID-19 laboratory-confirmed cases tested positive from the beginning of the outbreak (20th of February) to the 19th of July 2020. We used multilevel negative-binomial regression models to compare the case-fatality rate and the rate of admission to hospital and intensive care unit (ICU) between Italian and non-Italian nationals. The analysis was adjusted for differences in demographic characteristics, pre-existing comorbidities, and period of diagnosis.

Results

We analysed 213,180 COVID-19 cases, including 15,974 (7.5%) non-Italian nationals. We found that, compared to Italian cases, non-Italian cases were diagnosed at a later date and were more likely to be hospitalised [(adjusted relative risk (ARR)=1.39, 95% confidence interval (CI): 1.33-1.44)] and admitted to ICU (ARR=1.19, 95% CI: 1.07-1.32), with differences being more pronounced in those coming from countries with lower HDI. We also observed an increased risk of death in non-Italian cases from low-HDI countries (ARR=1.32, 95% CI: 1.01-1.75).

Conclusions

A delayed diagnosis in non-Italian cases could explain their worse outcomes compared to Italian cases. Ensuring early access to diagnosis and treatment to non-Italians could facilitate the control of SARS-CoV-2 transmission and improve health outcomes in all people living in Italy, regardless of nationality.
The Association Between Obstructive Sleep Apnea Defined by 3 Percent Oxygen Desaturation or Arousal Definition and Self-Reported Cardiovascular Disease in the Sleep Heart Health Study
Authors: Quan Stuart F. , Budhiraja Rohit , Javaheri Sogol , Parthasarathy Sairam , Berry Richard B.
Published: September 2020

Background

Studies have established that OSA defined using a hypopnea definition requiring a ≥4% oxygen desaturation (AHI4%) is associated with cardiovascular (CVD) or coronary heart (CHD) disease. This study determined whether OSA defined using a hypopnea definition characterized by a ≥3% oxygen desaturation or an arousal (AHI3%A) is associated with CVD/CHD.

Methods

Data were analyzed from 6307 Sleep Heart Health Study participants who had polysomnography. Self-reported CVD included angina, heart attack, heart failure, stroke or previous coronary bypass surgery or angioplasty. Self-reported CHD included the aforementioned conditions but not stroke or heart failure. The association between OSA and CVD/CHD was examined using logistic regression models with stepwise inclusion of demographic, anthropometric, social/behavioral and co-morbid medical conditions. A parsimonious model in which diabetes and hypertension were excluded because of their potential to be on the causal pathway between OSA and CVD/CHD also was constructed.

Results

For CVD, the odds ratios and 95% confidence intervals for AHI3%A ≥30/hour were 1.39 (1.03-1.87) and 1.45 (1.09-1.94) in the fully adjusted and parsimonious models. Results for CHD were 1.29 (0.96-1.74) and 1.36 (0.99-1.85). In participants without OSA according to more stringent AHI4% criteria but with OSA using the AHI3%A definition, similar findings were observed.

Conclusion

OSA defined using an AHI3%A is associated with both CVD and CHD. Use of a more restrictive AHI4% definition will misidentify a large number of individuals with OSA who have CVD or CHD. These individuals may be denied access to therapy, potentially worsening their underlying CVD or CHD.
Development and clinical evaluation of non-viral genome specific targeted CAR T cells in relapsed/refractory B-cell non-Hodgkin lymphoma
Authors: Zhang Jiqin , Hu Yongxian , Yang Jiaxuan , Li Wei , Tian Yue , Wei Guoqing , Zhang Linjie , Zhao Kui , Qi Yalei , Tan Binghe , Zhang Mingming , Li Yi , Tian Qiliang , Fang Chunqian , Wu Yuxuan , Li Dali , Du Bing , Liu Mingyao , Huang He
Published: September 2020

In recent years, chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematological malignancies. However, using virus in manufacture of CAR T cells brings about several problems. The application of CRISPR/Cas9 genome editing technology emerges in constructing novel CAR T cells by disrupting endogenous genes. Here we successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. By targeting a CAR in AAVS1 safe harbor locus, we demonstrated that these CAR T cells behave comparable to those conventionally produced by lentivirus. Furthermore, PD1-knockin anti-CD19 CAR T cells show a superior ability to eradicate tumor cells with high PD-L1 expression. In the adoptive therapy for relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), we observed durable responses without serious adverse events and complete remission (CR) in patients treated with these PD1 knockout CAR T cells. Collectively, our results prove the safety and feasibility of non-viral genome specific integrated CAR T cells, thus providing a new potential strategy for cancer treatment using these novel CAR T cells.
Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia
Authors: Natarajan Karthick , Eisfeldt Jesper , Hammond Maria , Patra Kalicharan , Laffita-Mesa José Miguel , Andrade-Talavera Yuniesky , Birtele Marcella , Öijerstedt Linn , Fisahn André , Parmar Malin , Graff Caroline
Published: September 2020

Disclaimer

“This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.”
Pioglitazone improves deficits ofFmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling
Authors: Geoffroy Andréa , Habbas Karima , Zambo Boglarka , Schramm Laetitia , Duchon Arnaud , Flatter Eric , Fouillen Laetitia , Zumsteg Julie , Heintz Dimitri , Mandel Jean-Louis , Hérault Yann , Moine Hervé
Published: September 2020

Fragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling inFmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of theFmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.
DegeneratingDrosophilaLarval Epidermal Cells Drive Thorax Closure
Authors: Athilingam Thamarailingam , Parihar Saurabh Singh , Bhattacharya Rachita , Rizvi Mohd. Suhail , Kumar Amit , Sinha Pradip
Published: September 2020

Adult thorax formation inDrosophilabegins during pre-pupal development by fusion of its two contralateral progenitor halves, the heminotal epithelia (HE). HEs migrate and replace an underlying cell layer of thoracic larval epidermal cells (LECs) during a morphogenetic process called thorax closure. The LEC layer has so far been proposed to be a passive substrate over which HEs migrate before their zipping. By contrast, here we show that the pull forces generated within the LEC layer drive HE migration. During thorax closure, the LECs display actomyosin-mediated contraction, via enrichment of non-muscle myosin-II and actin, besides squamous-to-pseudostratified columnar epithelial transition and tissue shrinkage. This shrinkage of the LEC layer is further accompanied by cell extrusion and death, that prevent overcrowding of LECs, thereby promoting further shrinkage. The pull forces thus generated by the shrinking LEC layer are then relayed to the HEs by their mutual adhesions via βPS1 (Mys) and αPS3 (Scb) integrins. Suppression of cell death in the LEC layer by a gain of p35 leads to cell overcrowding, which impedes HE migration and zipping. Further, knockdown ofsqh, the light chain of non-muscle myosin II, in LECs or integrins (mysorscb) in either the LEC layer or in the HEs, or both abrogate thorax closure. Mathematical modeling also reveals the biophysical underpinnings of the forces that drive this tissue closure process wherein a degenerating LEC layer mediates its succession by the future adult primodia. These essential principles of thorax closure appear ancient in origin and recur in multiple morphogenetic contexts and tissue repair.
A comprehensive, FAIR file format for neuroanatomical structure modeling
Authors: Sullivan A. E. , Tappan S. J. , Angstman P. J. , Rodriguez A. , Thomas G. C. , Hoppes D. M. , Abdul-Karim M. A. , Heal M. L. , Glaser J. R.
Published: September 2020

With advances in microscopy and computer science, the technique of digitally reconstructing, modeling, and quantifying microscopic anatomies has become central to many fields of biological research. MBF Bioscience has chosen to openly document their digital reconstruction file format, Neuromorphological File Specification (4.0), available atwww.mbfbioscience.com/filespecification(Angstman et al. 2020). One of such technologies, the format created and maintained by MBF Bioscience is broadly utilized by the neuroscience community. The data format’s structure and capabilities have evolved since its inception, with modifications made to keep pace with advancements in microscopy and the scientific questions raised by worldwide experts in the field. More recent modifications to the neuromorphological data format ensure it abides by the Findable, Accessible, Interoperable, and Reusable (FAIR) data standards promoted by the International Neuroinformatics Coordinating Facility (INCF; Wilkinson et al. 2016). The incorporated metadata make it easy to identify and repurpose these data types for downstream application and investigation. This publication describes key elements of the file format and details their relevant structural advantages in an effort to encourage the reuse of these rich data files for alternative analysis or reproduction of derived conclusions.
Chronic stress induces sex-specific functional and morphological alterations in cortico-accumbal and cortico-tegmental pathways
Authors: Bittar Thibault P. , Pelaez Mari Carmen , Silva Jose Cesar Hernandez , Quessy Francis , Lavigne Andrée-Anne , Morency Daphnée , Blanchette Léa-Jeanne , Arsenault Eric , Cherasse Yoan , Seigneur Josée , Timofeev Igor , Sephton Chantelle F. , Proulx Christophe D. , Labonté Benoit
Published: September 2020

Background

The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown and the distinct contribution of these pathways to stress responses in males and females is unclear.

Methods

Behavioral stress responses were induced by 21 days of chronic variable stress (CVS) in male and female C57BL6 mice. An inter-sectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes.

Results

CVS induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after CVS. Finally, chemogenetic overactivation of the cortico-accumbal pathway triggered anxiety and behavioral despair in both sexes while its inhibition rescued the phenotype only in females.

Conclusions

Our results suggest that by changing the activity of transcriptional programs controlling neuronal plasticity, CVS interferes with the morphological and synaptic properties of the cortico-accumbal and tegmental pathways differently in males and females contributing to the expression of anxiety and depressive-like behaviors distinctly in a sex-specific fashion.
Quantification of extracellular vesicles with unaltered surface membranes using an internalized oligonucleotide tracer and droplet digital PCR applied to modeling ofin vivokinetics
Authors: De Luca Thomas , Stratford Robert E. , Edwards Madison E. , Ferreira Christina R. , Benson Eric A.
Published: September 2020

Extracellular vesicles (EVs) continue to attract interest for their potential role in targeted therapeutics and as biomarkers of disease and drug response. In order to achieve clinical utility, it is important to determine the pharmacokinetic parameters of candidate EVs during preclinical development usingin vivoanimal models. To date, no methods exist for studying EV kinetics without modification to surface ligands that may affect normal behavior. Here we introduce an accessible method for labeling and quantifying EVs administered to conscious animals, without disrupting endogenous ligands. Our method relies upon established laboratory techniques and can be tailored to a variety of biological questions. Digital PCR is leveraged to detect a non-homologous oligonucleotide tracer introduced into the vesicles, allowing for quantification over a wide dynamic range. Using an application of this method, we found differences in thein vivokinetics of EVs from three different cell types using non-linear mixed effects modeling. We propose that this method will provide a complementary approach for the of study EV ligand-receptor interactions in the context of EV uptake and targeted therapeutics.
Enrichment of novelVerrucomicrobia, BacteroidetesandKrumholzibacteriain an oxygen-limited, methane- and iron-fed bioreactor inoculated with Bothnian Sea sediments
Authors: Martins Paula Dalcin , de Jong Anniek , Lenstra Wytze K. , van Helmond Niels A. G. M. , Slomp Caroline P. , Jetten Mike S. M. , Welte Cornelia U. , Rasigraf Olivia
Published: September 2020

Microbial methane oxidation is a major biofilter preventing larger emissions of this powerful greenhouse gas from marine coastal areas into the atmosphere. In these zones, various electron acceptors such as sulfate, metal oxides, nitrate or oxygen can be utilized. However, the key microbial players and mechanisms of methane oxidation are poorly understood. In this study, we inoculated a bioreactor with methane- and iron-rich sediments from the Bothnian Sea in order to investigate microbial methane and iron cycling under low oxygen concentrations. Using metagenomics, we observed shifts in the microbial community over approximately 2.5 years of bioreactor operation. Marker genes for methane and iron cycling, as well as respiratory and fermentative metabolism, were investigated. Metagenome-assembled genomes representing novelVerrucomicrobia, BacteroidetesandKrumholzibacteriawere recovered and revealed potential for methane oxidation, organic matter degradation, and iron cycling, respectively. This work brings new insights into the identity and metabolic versatility of microorganisms that may be members of such functional guilds in coastal marine sediments and highlights that the methane biofilter in these sediments may be more diverse than previously appreciated.

Importance

Despite the essential role of microorganisms in preventing most methane in the ocean floor to reach the atmosphere, comprehensive knowledge on the identity and the mechanisms employed by these microorganisms is still lacking. This is problematic because such information is needed to understand how the ecosystem functions in the present and how microorganisms may respond to climate change in the future. Here, we enriched and identified novel taxa potentially involved in methane and iron cycling in an oxygen-limited bioreactor inoculated with methane- and iron-rich coastal sediments. Metagenomic analyses provided hypotheses about the mechanisms they may employ, such as the use of oxygen at very low concentrations. The implication of our results is that in more shallow sediments, where oxygen-limited conditions are present, the methane biofilter is potentially composed of novel, metabolically versatileVerrucomicrobiathat could contribute to mitigating methane emissions from coastal marine zones.
Basolateral amygdala parvalbumin neurons report aversive prediction error to constrain fear learning
Authors: Yau Joanna Oi-Yue , Chaichim Chanchanok , Power John M. , McNally Gavan P.
Published: September 2020

Animals, including humans, use prediction error to guide learning about danger in the environment. The basolateral amygdala (BLA) is obligatory for this learning and BLA excitatory projection neurons are instructed by aversive prediction error to form fear associations. Complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons, form the intrinsic microcircuitry of the BLA to control projection neuron activity. Whether BLA PV interneurons are also sensitive to prediction error and how they use this error to control fear learning remains unknown. We used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats to address these issues. We show that BLA PV neurons control fear learning about aversive events but not learning about their omission. Furthermore, during fear learning BLA PV neurons express the activity signatures of aversive prediction error: greater activity to unexpected than expected aversive events and greater activity to better rather than poorer predictors of these events. Crucially, we show that BLA PV neurons act to limit fear learning across these variations in prediction error. Together, this demonstrates that prediction error instructs and regulates BLA fear association formation in a cell-type specific manner. Whereas BLA projection neurons use prediction error signals to form and store fear associations, BLA PV interneurons use prediction error signals to constrain fear association formation.

Significance Statement

The capacity to predict sources of danger in the environment is essential for survival. This capacity is supported by associative learning mechanisms that are triggered when the danger experienced is greater than the danger expected. Here we show that the activity of parvalbumin positive GABAergic interneurons in the rat basolateral amygdala neurons report this difference between the danger expected and the danger experienced and that they use this difference to limit the amount of fear which is learned.
A bacterial effector uncovers a metabolic pathway involved in resistance to bacterial wilt disease
Authors: Wang Yaru , Morcillo Rafael J. L. , Yu Gang , Zhao Achen , Xue Hao , Rufian Jose S. , Sang Yuying , Macho Alberto P.
Published: September 2020

Bacterial wilt caused by the soil-borne pathogenRalstonia solanacearumis a devastating disease worldwide. Upon plant colonization,R. solanacearumreplicates massively, causing plant wilting and death; collapsed infected tissues then serve as a source of inoculum. In this work, we show that the metabolic pathway mediated by pyruvate decarboxylases (PDCs), activated in response to low oxygen and involved in drought stress tolerance, contributes to resistance against bacterial wilt disease. Arabidopsis and tomato plants with deficient PDC activity are more susceptible to bacterial wilt, and treatment with either pyruvic acid or acetic acid (substrate and product of the PDC pathway, respectively) enhances resistance. An effector protein secreted byR. solanacearum, RipAK, interacts with PDCs and inhibits their oligomerisation and enzymatic activity. This work reveals a metabolic pathway involved in resistance to biotic and abiotic stresses, and a bacterial virulence strategy to promote disease and the completion of the pathogenic life cycle.
Why the COVID-19 pandemic is a traumatic stressor
Authors: Bridgland Victoria M. E. , Moeck Ella K. , Green Deanne M. , Swain Taylor L. , Nayda Diane , Matson Lucy A. , Hutchison Nadine P. , Takarangi Melanie K.T.
Published: September 2020

The COVID-19 pandemic does not fit into prevailing Post-traumatic Stress Disorder (PTSD) models, or diagnostic criteria, yet emerging research shows traumatic stress symptoms as a result of this ongoing global stressor. Current pathogenic event models focus on past, and largely direct, trauma exposure to certain kinds of life-threatening events. Nevertheless, among a sample of online participants (N= 1,040) in five western countries, we found participants had PTSD-like symptoms for events that had not happened and when participants had been directly (e.g., contact with virus)orindirectly exposed to COVID-19 (e.g., via media). Moreover, 13.2% of our sample were likely PTSD-positive, despite types of COVID-19 “exposure” (e.g., lockdown) not fitting DSM-5 criteria. The emotional impact of “worst” experienced/anticipated events best predicted PTSD-like symptoms. Our findings add to existing literature supporting apathogenic event memorymodel of traumatic stress.
Steady state evoked potential (SSEP) responses in the primary and secondary somatosensory cortices of anesthetized cats: nonlinearity characterized by harmonic and intermodulation frequencies
Authors: Kawashima Yota , Li Rannee , Chen Spencer Chin-Yu , Vickery Richard Martin , Morley John W. , Tsuchiya Naotsugu
Published: September 2020

When presented with an oscillatory sensory input at a particular frequency,F[Hz], neural systems respond with the corresponding frequency,f[Hz], and its multiples. When the input includes two frequencies (F1andF2) and they are nonlinearly integrated in the system, responses at intermodulation frequencies (i.e.,n1*f1+n2*f2[Hz], wheren1andn2are non-zero integers) emerge. Utilizing these properties, the steady state evoked potential (SSEP) paradigm allows us to characterize linear and nonlinear neural computation performed in cortical neurocircuitry. Here, we analyzed the steady state evoked local field potentials (LFPs) recorded from the primary (S1) and secondary (S2) somatosensory cortex of anesthetized (ketamine-xylazine) cats while we presented slow (F1=23Hz) and fast (F2=200Hz) somatosensory vibration to the contralateral paw pads and digits. Over 9 experimental sessions, we recorded LFPs fromN=1620 andN=1008 bipolar-referenced sites in S1 and S2 using electrode arrays. Power spectral analyses revealed strong responses at 1) the fundamental (f1,f2), 2) its harmonic, 3) the intermodulation frequencies, and 4) broadband frequencies (50-150Hz). To compare the computational architecture in S1 and S2, we employed simple computational modeling. Our modeling results necessitate nonlinear computation to explain SSEP in S2 more than S1. Combined with our current analysis of LFPs, our paradigm offers a rare opportunity to constrain the computational architecture of hierarchical organization of S1 and S2 and to reveal how a large-scale SSEP can emerge from local neural population activities.