bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of dementia risk after age 50 between individuals with and without HIV infection
Authors: Lam Jennifer O. , Hou Craig E. , Hojilla J. Carlo , Anderson Alexandra N. , Gilsanz Paola , Alexeeff Stacey E. , Levine-Hall Tory , Hood Nicole , Lee Catherine , Satre Derek D. , Silverberg Michael J.
Published: December 2020

Objective:

To compare risk of dementia after age 50 by HIV status among individuals in a primary care setting.

Design:

Observational cohort study; participants were identified from 2013 to 2017 and followed through 2019.

Methods:

Participants were people with HIV (PWH) on antiretroviral therapy (ART) and demographically similar people without HIV (PWOH), all at least 50 years old and with no prior diagnosis of dementia. The study setting was Kaiser Permanente Northern California, an integrated healthcare delivery system in the United States. Incident dementia diagnoses and baseline data on sociodemographics, smoking, alcohol use, other substance use, and clinical factors were gathered from the electronic health record. Cumulative proportion of incident dementia by HIV status was assessed using Kaplan--Meier curves. Unadjusted and adjusted hazard ratios for incident dementia by HIV status were generated using Cox proportional hazards models with age as the time scale.

Results:

The study included 5381 PWH and 119 022 PWOH (average age at baseline: 57 and 58 years, respectively). Incident dementia was diagnosed in 117 PWH and 2427 PWOH. By age 80, 25.8% of PWH and 13.8% of PWOH had been diagnosed with dementia, corresponding with an unadjusted hazard ratio of 1.98 (95% CI 1.64–2.39). After adjustment for sociodemographic, substance use, and clinical factors, including frequency of outpatient visits, the risk of dementia among PWH remained elevated (vs. PWOH, adjusted hazard ratio = 1.58, 95% CI 1.31–1.92).

Conclusion:

Compared with PWOH, PWH were at 58% higher risk for dementia despite HIV treatment with ART. Research is needed to investigate the potential benefits of targeted risk factor management or earlier cognitive screening in this population.
Impact of HIV infection on baseline characteristics and survival of women with breast cancer
Authors: Brandão Mariana , Bruzzone Marco , Franzoi Maria-Alice , De Angelis Claudia , Eiger Daniel , Caparica Rafael , Piccart-Gebhart Martine , Buisseret Laurence , Ceppi Marcello , Dauby Nicolas , Carrilho Carla , Lunet Nuno , de Azambuja Evandro , Lambertini Matteo
Published: December 2020

Background:

As women living with HIV (WLWH) become older, their risk of developing breast cancer increases. Nonetheless, literature is conflicting regarding tumor stage, distribution of subtypes and overall survival among WLWH vs. HIV-negative women with breast cancer. We assessed differences in clinicopathological characteristics and overall survival between these two groups.

Methods:

Systematic review and meta-analysis using MEDLINE, Scopus, ISI Web of Knowledge, LILACS, SciELO and conference abstracts up to 1 January 2020. Cross-sectional/cohort studies comparing baseline characteristics (stage and/or subtypes) and/or overall survival of WLWH vs. HIV-negative women with breast cancer were included. We performed random-effects meta-analyses to estimate summary statistics and subgroup analyses according to region of the world.

Results:

Eighteen studies [4 from North America, 14 from sub-Saharan Africa (SSA)] were included, with 3174 WLWH and 2 394 598 HIV-negative women. WLWH from North America and SSA were more likely to present with stage III/IV disease compared with HIV-negative women – pooled odds ratio (pOR) 1.76 [95% confidence interval (CI):1.58–1.95] and pOR 1.23 (95% CI: 1.06–1.42), respectively. WLWH from SSA were also less likely to have estrogen receptor-positive/HER2-negative tumors (pOR 0.81; 95% CI: 0.66–0.99). After adjustment, WLWH had worse overall survival compared with HIV-negative women, both in North America [pooled adjusted hazard ratio (aHR) 2.45; 95% CI: 1.11–5.41] and SSA (aHR 1.43; 95% CI: 1.06–1.92).

Conclusion:

Compared with HIV-negative women, WLWH are diagnosed with breast cancer at a more advanced stage and have a worse overall survival. These results should raise awareness regarding the detection and survival gap among WLWH with breast cancer and further studies are needed to decipher the reasons behind these disparities.
International Core Outcome Set for Acute Simple Appendicitis in Children
Authors: Knaapen Max , Hall Nigel J. , Moulin Darcy , van der Lee Johanna H. , Butcher Nancy J. , Minneci Peter C. , Svensson Jan F. , St. Peter Shawn D. , Adams Susan , Nah Shireen A. , Skarsgard Erik D. , Zani Augusto , Emil Sherif , Suominen Janne S. , Aziz Dayang A. , Rai Rambha , Offringa Martin , van Heurn Ernst W. , Bakx Roel , Gorter Ramon R. ,   On behalf of the pediatric appendicitis COS development group
Published: December 2020

Objective:

To develop an international core outcome set (COS), a minimal collection of outcomes that should be measured and reported in all future clinical trials evaluating treatments of acute simple appendicitis in children.

Summary of Background Data:

A previous systematic review identified 115 outcomes in 60 trials and systematic reviews evaluating treatments for children with appendicitis, suggesting the need for a COS.

Methods:

The development process consisted of 4 phases: (1) an updated systematic review identifying all previously reported outcomes, (2) a 2-stage international Delphi study in which parents with their children and surgeons rated these outcomes for inclusion in the COS, (3) focus groups with young people to identify missing outcomes, and (4) international expert meetings to ratify the final COS.

Results:

The systematic review identified 129 outcomes which were mapped to 43 unique outcome terms for the Delphi survey. The first-round included 137 parents (8 countries) and 245 surgeons (10 countries), the second-round response rates were 61% and 85% respectively, with 10 outcomes emerging with consensus. After 2 young peoples' focus groups, 2 additional outcomes were added to the final COS (12): mortality, bowel obstruction, intraabdominal abscess, recurrent appendicitis, complicated appendicitis, return to baseline health, readmission, reoperation, unplanned appendectomy, adverse events related to treatment, major and minor complications.

Conclusion:

An evidence-informed COS based on international consensus, including patients and parents has been developed. This COS is recommended for all future studies evaluating treatment ofsimple appendicitis in children, to reduce heterogeneity between studies and facilitate data synthesis and evidence-based decision-making.
Changes in traumatic mechanisms of injury in Southern California related to COVID-19: Penetrating trauma as a second pandemic
Authors: Yeates Eric O. , Grigorian Areg , Barrios Cristobal , Schellenberg Morgan , Owattanapanich Natthida , Barmparas Galinos , Margulies Daniel , Juillard Catherine , Garber Kent , Cryer Henry , Tillou Areti , Burruss Sigrid , Penaloza-Villalobos Liz , Lin Ann , Figueras Ryan Arthur , Brenner Megan , Firek Christopher , Costantini Todd , Santorelli Jarrett , Curry Terry , Wintz Diane , Biffl Walter L. , Schaffer Kathryn B. , Duncan Thomas K. , Barbaro Casey , Diaz Graal , Johnson Arianne , Chinn Justine , Naaseh Ariana , Leung Amanda , Grabar Christina , Nahmias Jeffry
Published: December 2020

BACKGROUND

The COVID-19 pandemic resulted in a statewide stay-at-home (SAH) order in California beginning March 19, 2020, forcing large-scale behavioral changes and taking an emotional and economic toll. The effects of SAH orders on the trauma population remain unknown. We hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the SAH order.

METHODS

A multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons levels I and II trauma centers spanning seven counties in California was performed. Demographic data, injury characteristics, clinical data, and outcomes were collected. Patients were divided into three groups based on injury date: before SAH from January 1, 2020, to March 18, 2020 (PRE), after SAH from March 19, 2020, to June 30, 2020 (POST), and a historical control from March 19, 2019, to June 30, 2019 (CONTROL). POST was compared with both PRE and CONTROL in two separate analyses.

RESULTS

Across all periods, 20,448 trauma patients were identified (CONTROL, 7,707; PRE, 6,022; POST, 6,719). POST had a significantly increased rate of penetrating trauma (13.0% vs. 10.3%, p < 0.001 and 13.0% vs. 9.9%, p < 0.001) and gunshot wounds (4.5% vs. 2.4%, p = 0.002 and 4.5% vs. 3.7%, p = 0.025) compared with PRE and CONTROL, respectively. POST had a suicide attempt rate of 1.9% and a domestic violence rate of 0.7%, which were similar to PRE (p = 0.478, p = 0.514) and CONTROL (p = 0.160, p = 0.618).

CONCLUSION

This multicenter Southern California study demonstrated an increased rate of penetrating trauma and gunshot wounds after the COVID-19 SAH orders but no difference in attempted suicide or domestic violence rates. These findings may provide useful information regarding resource utilization and a target for societal intervention during the current or future pandemic(s).

LEVEL OF EVIDENCE

Epidemiological, level IV.
Joint Trajectory Inference for Single-cell Genomics Using Deep Learning with a Mixture Prior
Authors: Du Jin-Hong , Chen Tianyu , Gao Ming , Wang Jingshu
Published: December 2020

Trajectory inference methods are essential for analyzing the developmental paths of cells in single-cell sequencing datasets. It provides insights into cellular differentiation, transitions, and lineage hierarchies, helping unravel the dynamic processes underlying development and disease progression. However, many existing tools lack a coherent statistical model and reliable uncertainty quantification, limiting their utility and robustness. In this paper, we introduce VITAE (VariationalInference forTrajectory byAutoEncoder), a novel statistical approach that integrates a latent hierarchical mixture model with variational autoencoders to infer trajectories. The statistical hierarchical model enhances the interpretability of our framework, while the posterior approximations generated by our variational autoencoder ensure computational efficiency and provide uncertainty quantification of cell projections along trajectories. Specifically, VITAE enables simultaneous trajectory inference and data integration, improving the accuracy of learning a joint trajectory structure in the presence of biological and technical heterogeneity across datasets. We show that VITAE outperforms other state-of-the-art trajectory inference methods on both real and synthetic data under various trajectory topologies. Furthermore, we apply VITAE to jointly analyze three distinct single-cell RNA sequencing datasets of the mouse neocortex, unveiling comprehensive developmental lineages of projection neurons. VITAE effectively reduces batch effects within and across datasets and uncovers finer structures that might be overlooked in individual datasets. Additionally, we showcase VITAE’s efficacy in integrative analyses of multi-omic datasets with continuous cell population structures.
Aligning Bacteria and Synthetic Biomolecules with Engineered DNA Fibers
Authors: Burns Jonathan R.
Published: December 2020

DNA nanotechnology enables user-defined structures to be built with unrivalled control. However, the approach is currently restricted across the nanoscale, yet the ability to generate macroscopic DNA structures has enormous potential with applications spanning material, physical and biological science. I have employed DNA nanotechnology[1, 2]and developed a new macromolecular nanoarchitectonic[3]assembly method to produce DNA fibers with customizable properties. The process involves coalescing DNA nanotubes under high salt conditions to yield filament superstructures. Using this strategy, fibers over 100 microns long, with stiffnesses 10 times greater than cytoskeletal actin filaments can be fabricated. The DNA framework enables fibers to be functionalized with advanced synthetic molecules, including, aptamers, origami, nanoparticles and vesicles. In addition, the fibers can act as bacterial extracellular scaffolds and alignE.colicells in a controllable fashion. The results showcase the opportunities offered from DNA nanotechnology across the macroscopic scale. The new biophysical approach should find widespread use, from the generation of hybrid-fabric materials, platforms to study cell-cell interactions, to smart analytical and purification devices in biomedicine.
Blocking plasmodesmata in specific phloem cell types reduces axillary bud growth inArabidopsis thaliana
Authors: Paterlini Andrea , Dorussen Delfi , Fichtner Franziska , van Rongen Martin , Delacruz Ruth , Vojnović Ana , Helariutta Yrjö , Leyser Ottoline
Published: December 2020

The plasticity of above ground plant architecture depends on the regulated re-activation and growth of axillary meristems laid down in the axils of leaves along the stem, which often arrest as dormant buds. Plasmodesmata connecting plant cells might control the movement of regulators involved in this developmental switch. Constructs capable of occluding these structures were employed in phloem cell types, because of the importance of phloem in local and systemic trafficking. We show that over-accumulation of callose within companion cells of the Arabidopsis inflorescence reduces the growth rates of activated buds, but does not affect bud activation. Growth rate reductions were not dependent on the phloem-mobile strigolactone receptor, which regulates bud activation. Furthermore, there was no correlation with early bud sugar profiles, which can also affect bud activity and depend on phloem-mediated delivery. It is therefore possible that an as yet unknown mobile signal is involved in modulating branch growth rate.
ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)
Authors: Cardamone Maria Dafne , Gao Yuan , Kwan Julian , Hayashi Vanessa , Sheeran Megan , Xu Junxiang , English Justin , Orofino Joseph , Emili Andrew , Perissi Valentina
Published: December 2020

ADP-ribosylation is a reversible post-translational modification where an ADP-ribose moiety is covalently attached to amino acid side-chains of target proteins either as mono-ADP-ribose (MARylation or MAR) or poly-ADP-ribose chains (PARylation or PAR) by a class of enzymes called ADP-ribosyltransferases (ARTs). Although ADP-ribosylation is best known for its nuclear roles, ADP-ribosylation of extra nuclear proteins is increasingly recognized as a key regulatory strategy across cellular compartments. ADP-ribosylation of mitochondrial proteins, in particular, has been widely reported, even though the extent to which ADP-ribosylation of specific proteins regulates mitochondrial functions is unclear and the exact nature of mitochondrial ART enzymes is debated.

Here, we have identified Neuralized-like protein 4 (NEURL4) as a mitochondrial ART enzyme and profiled the NEURL4-dependent ADP-ribosylome in mitochondrial extracts from Hela cells by LC-MS/MS, using isobaric tandem mass tag (TMT) labeling for relative quantification. Comparison of WT and NEURL4-KO cells generated by CRISPR/Cas9 genome editing revealed that most ART activity associated with mitochondria is lost in absence of NEURL4. Putative NEURL4 targets include numerous mitochondrial proteins previously shown to be ADP-ribosylated. In particular, we show that NEURL4 enzymatic activity is required for the regulation of mtDNA integrity via poly-ADP-ribosylation of mitochondrial specific Ligase III (mtLIG3), the rate-limiting enzyme for mitochondrial DNA (mtDNA) Base Excision Repair (BER).

Collectively, our studies reveal that NEURL4 acts as the main mitochondrial ART enzyme under physiological conditions and provide novel insights in the regulation of mitochondria homeostasis through ADP-ribosylation.
A high-quality genome of the mangroveAegiceras corniculatumaids investigation of molecular adaptation to intertidal environments
Authors: Feng Xiao , Li Guohong , Xu Shaohua , Wu Weihong , Chen Qipian , Shao Shao , Liu Min , Wang Nan , Zhong Cairong , He Ziwen , Shi Suhua
Published: December 2020

Mangroves have colonized extreme intertidal environments characterized by high salinity, hypoxia, and other abiotic stresses. During millions of years of evolution, mangroves have adapted to these habitats, evolving a series of highly specialized traits.Aegiceras corniculatum, a pioneer mangrove species that evolved salt secretion and crypto-vivipary, is an attractive ecological model to investigate molecular mechanisms underlying adaptation to intertidal environments. Here we report a high-quality reference genome ofA. corniculatumusing the PacBio SMRT sequencing technology, comprising 827 Megabases (Mb) and containing 32,092 protein-coding genes. The longest scaffold and N50 for the assembled genome are 13.76 Mb and 3.87 Mb. Comparative and evolutionary analyses revealed thatA. corniculatumexperienced a whole-genome duplication (WGD) event around 35 million years ago after the divergence betweenAegicerasandPrimula. We inferred that maintenance of cellular environmental homeostasis is an important adaptive process inA. corniculatum. The 14-3-3 protein-coding genes were retained after the recent WGD event, decoding a calcium signal to regulate Na+homeostasis.A. corniculatumhas more H+-ATPase coding genes, essential for the maintenance of low Na+concentration in the cells, than its relatives. Photosynthesis and oxidative-phosphorylation pathways are overrepresented among significantly expanded gene families and might supply the energy needed for salt secretion. Genes involved in natural antioxidant biosynthesis, contributing to scavenging reactive oxygen species against high salinity, have also increased in copy number. We also found that all homologs ofDELAY OF GERMINATION1(DOG1), a pivotal regulator of seed dormancy, lost their heme-binding ability inA. corniculatum. This loss may contribute to crypto-vivipary. Our study provides a valuable resource to investigate molecular adaptation to extreme environments in mangroves.
Brain dysfunction during warming is caused by oxygen limitation in larval zebrafish
Authors: Andreassen Anna H. , Hall Petter , Khatibzadeh Pouya , Jutfelt Fredrik , Kermen Florence
Published: December 2020

Understanding the physiological mechanisms that limit animal thermal tolerance is crucial in predicting how animals will respond to increasingly severe heatwaves. Despite its importance for understanding climate change impacts, these mechanisms underlying the upper thermal tolerance limits of animals are largely unknown. It has been hypothesised that the upper thermal tolerance in fish is limited by the thermal tolerance of the brain and that it is ultimately caused by a global brain depolarization. In this study, we developed methods for measuring the upper thermal limit (CTmax) in larval zebrafish (Danio rerio) with simultaneous recordings of brain activity using GCaMP6s calcium imaging in both free-swimming and agar-embedded fish. We discovered that during warming, CTmaxprecedes, and is therefore not caused by, a global brain depolarization. Instead, the CTmaxcoincides with a decline in spontaneous neural activity and a loss of neural response to visual stimuli. By manipulating water oxygen levels, we found that oxygen availability during heating affects both locomotor-related neural activity, the neural response to visual stimuli, and CTmax. Our results suggest that the mechanism limiting the upper thermal tolerance in zebrafish larvae is reduced oxygen availability causing impaired brain function.
In vitrononalcoholic fatty liver disease model with cyclo-olefin-polymer-based microphysiological systems
Authors: Wen Xiaopeng , Yamanaka Makoto , Terada Shiho , Kamei Ken-ichiro
Published: December 2020

Nonalcoholic fatty liver disease (NAFLD) is one of the common chronic liver conditions, whose treatment involves curing patients without liver transplantation. Understanding the mechanism of NAFLD initiation and progression would enable development of new diagnostic tools and drugs; however, until now, the underlying mechanisms of this condition remain largely unknown owing to the lack of experimental settings that can simplify the complicated NAFLD processin vitro. Microphysiological systems (MPSs) have long been used to recapture human pathophysiological conditionsin vitrofor applications in drug discovery. However, polydimethylsiloxane (PDMS) has been used in most of these MPSs as the structural material; it absorbs hydrophobic molecules, such as free fatty acids (FFAs), which are the key components that initiate NAFLD. Therefore, the current PDMS-based MPSs cannot be directly applied toin vitroNALFD modeling. In this work, we present anin vitroNAFLD model with an MPS made of cyclo-olefin polymer (COP), namely COP-MPS, to prevent absorption of FFAs. We demonstrated induction of the NAFLD-like phenotype in HepaRG hepatocyte-like cells cultured in the COP-MPS by introducing FFAs. The FFAs induced lipid accumulation in the HepaRG cells, resulting in inactivation of the apoptotic cells. We believe that the proposed COP-MPS can contribute toward investigations of NAFLD mechanisms and identification of new drugs to prevent the progression of liver disease and avoid liver transplantation.
Assessing Pain in a Noninvasive Manner by Measuring Changes in the Microcirculation
Authors: Shainshein Dana , Shenkman Louis , Khashan Ahmed , Bennun Meir , Fine Ilya
Published: December 2020

The quantitative determination of the level of pain is one of the most challenging clinical problems. This article proposes a method for quantitative assessment of both acute and chronic levels of pain, based on the analysis of hemodynamic patterns measured using a non-invasive sensor. Hemodynamic characteristics were taken from the finger using a sensor measuring the dynamic scattering of light from the skin surface. Changes in hemodynamic parameters in patients with chronic pain were studied. One group of patients with chronic back pain required epidural injection for pain relief. The second group of patients had a Spinal Cord Stimulator implant which was switched off one hour before arriving at the clinic. Optical signals were collected before and after pain relief, either by epidural injection or by turning on the stimulator. Both groups reported their pain level using a standard numerical rating scale. Processing of the results showed that the changes in measured hemodynamic parameters corresponded in most cases to the changes in pain reported by patients following medical intervention. The results suggest that this new non-invasive measurement of pain can be used both for physiological studies and for monitoring various categories of patients suffering from pain.
Quantifying multivariate genotype-by-environment interactions, evolutionary potential and its context-dependence in natural populations of the water flea,Daphnia magna
Authors: Brunner Franziska S. , Reynolds Alan , Wilson Ian W. , Price Stephen , Paterson Steve , Atkinson David , Plaistow Stewart J.
Published: December 2020

Genotype-by-environment interactions (G x E) underpin the evolution of plastic responses in natural populations. Theory assumes that G x E interactions exist but empirical evidence from natural populations is equivocal and difficult to interpret because G x E interactions are normally univariate plastic responses to a single environmental gradient. We compared multivariate plastic responses of 43Daphnia magnaclones from the same population in a factorial experiment that crossed temperature and food environments. Multivariate plastic responses explained more than 30% of the total phenotypic variation in each environment. G x E interactions were detected in most environment combinations irrespective of the methodology used. However, the nature of G x E interactions was context-dependent and led to environment-specific differences in additive genetic variation (G-matrices). Clones that deviated from the population average plastic response were not the same in each environmental context and there was no difference in whether clones varied in the nature (phenotypic integration) or magnitude of their plastic response in different environments. Plastic responses to food were aligned with additive genetic variation (gmax) at both temperatures, whereas plastic responses to temperature were not aligned with additive genetic variation (gmax) in either food environment. These results suggest that fundamental differences may exist in the potential for our population to evolve novel responses to food versus temperature changes, and challenges past interpretations of thermal adaptation based on univariate studies.
eIF2B Conformation and Assembly State Regulate the Integrated Stress Response
Authors: Schoof Michael , Boone Morgane , Wang Lan , Lawrence Rosalie , Frost Adam , Walter Peter
Published: December 2020

The integrated stress response (ISR) is activated by phosphorylation of the translation initiation factor eIF2 in response to various stress conditions. Phosphorylated eIF2 (eIF2-P) inhibits eIF2’s nucleotide exchange factor eIF2B, a two-fold symmetric heterodecamer assembled from subcomplexes. Here, we monitor and manipulate eIF2B assemblyin vitroandin vivo.In the absence of eIF2B’s α-subunit, the ISR is induced because unassembled eIF2B tetramer subcomplexes accumulate in cells. Upon addition of the small-molecule ISR inhibitor ISRIB, eIF2B tetramers assemble into active octamers. Surprisingly, ISRIB inhibits the ISR even in the context of fully assembled eIF2B decamers, revealing an allosteric communication between the physically distant eIF2, eIF2-P, and ISRIB binding sites. Cryo-EM structures suggest a rocking motion in eIF2B that couples these binding sites. eIF2-P binding converts eIF2B decamers into ‘conjoined tetramers’ with greatly diminished activity. Thus, ISRIB’s effects in disease models could arise from eIF2B decamer stabilization, allosteric modulation, or both.
Brain-scale emergence of slow-wave synchrony and highly responsive asynchronous states based on biologically realistic population models simulated in The Virtual Brain
Authors: Goldman Jennifer S. , Kusch Lionel , Yalcinkaya Bahar Hazal , Depannemaecker Damien , Nghiem Trang-Anh E. , Jirsa Viktor , Destexhe Alain
Published: December 2020

Understanding the many facets of the organization of brain dynamics at large scales remains largely unexplored. Here, we construct a brain-wide model based on recent progress in biologically-realistic population models obtained using mean-field techniques. We use The Virtual Brain (TVB) as a simulation platform and incorporate mean-field models of networks of Adaptive Exponential (AdEx) integrate-and-fire neurons. Such models can capture the main intrinsic firing properties of central neurons, such as adaptation, and also include the typical kinetics of postsynaptic conductances. We hypothesize that such features are important to a biologically realistic simulation of brain dynamics. The resulting “TVB-AdEx” model is shown here to generate two fundamental dynamical states, asynchronous-irregular (AI) and Up-Down states, which correspond to the asynchronous and synchronized dynamics of wakefulness and slow-wave sleep, respectively. The synchrony of slow waves appear as an emergent property at large scales, and reproduce the very different patterns of functional connectivity found in slow-waves compared to asynchronous states. Next, we simulated experiments with transcranial magnetic stimulation (TMS) during asynchronous and slow-wave states, and show that, like in experimental data, the effect of the stimulation greatly depends on the activity state. During slow waves, the response is strong but remains local, in contrast with asynchronous states, where the response is weaker but propagates across brain areas. To compare more quantitatively with wake and slow-wave sleep states, we compute the perturbational complexity index and show that it matches the value estimated from TMS experiments. We conclude that the TVB-AdEx model replicates some of the properties of synchrony and responsiveness seen in the human brain, and is a promising tool to study spontaneous and evoked large-scale dynamics in the normal, anesthetized or pathological brain.
High resolution copy number inference in cancer using short-molecule nanopore sequencing
Authors: Baslan Timour , Kovaka Sam , Sedlazeck Fritz J. , Zhang Yanming , Wappel Robert , Lowe Scott W. , Goodwin Sara , Schatz Michael C.
Published: December 2020

Genome copy number is an important source of genetic variation in health and disease. In cancer, clinically actionable Copy Number Alterations (CNAs) can be inferred from short-read sequencing data, enabling genomics-based precision oncology. Emerging Nanopore sequencing technologies offer the potential for broader clinical utility, for example in smaller hospitals, due to lower instrument cost, higher portability, and ease of use. Nonetheless, Nanopore sequencing devices are limited in terms of the number of retrievable sequencing reads/molecules compared to short-read sequencing platforms. This represents a challenge for applications that require high read counts such as CNA inference. To address this limitation, we targeted the sequencing of short-length DNA molecules loaded at optimized concentration in an effort to increase sequence read/molecule yield from a single nanopore run. We show that sequencing short DNA molecules reproducibly returns high read counts and allows high quality CNA inference. We demonstrate the clinical relevance of this approach by accurately inferring CNAs in acute myeloid leukemia samples. The data shows that, compared to traditional approaches such as chromosome analysis/cytogenetics, short molecule nanopore sequencing returns more sensitive, accurate copy number information in a cost effective and expeditious manner, including for multiplex samples. Our results provide a framework for the sequencing of relatively short DNA molecules on nanopore devices with applications in research and medicine, that include but are not limited to, CNAs.
Graph Theoretical Design of Biomimetic Aramid Nanofiber Nanocomposites as Insulation Coatings for Implantable Bioelectronics
Authors: Zhang Huanan , Vecchio Drew , Emre Ahmet , Rahmani Samantha , Cheng Chong , Zhu Jian , Misra Asish C. , Lahann Joerg , Kotov Nicholas A.
Published: December 2020

An insulation material combining crack and delamination resistance, flexibility, strong adhesion, and biocompatibility is vital for implantable bioelectronic devices of all types. Creating a material with the combination of all these properties is a particularly distinct challenge for implantable electrodes. Here we describe a nanocomposite material addressing these technological challenges based on aramid nanofibers (ANFs) whose unique mechanical properties are complemented by the epoxy resins with strong adhesion to various surfaces. The nanoscale structure of the ANF/epoxy nanocomposite coating replicates the nanofibrous organization of human cartilage, which is known for its exceptional toughness and longevity. The structural analogy between percolating networks of cartilage and ANF was demonstrated using Graph Theory (GT) analysis. The match of multiple GT indexes indicated the near identical organization pattern of cartilage and ANF/epoxy nanocomposite. When compared with the standard insulating material for bioelectronics,Parylene C,the ANF/epoxy nanocomposite demonstrates excellent interfacial adhesion, biocompatibility, and low inflammatory response. This study opens the possibility for the development of insulation materials suitable for different types of electronics for neural engineering and other biomedical applications. Also important, GT analysis makes possible structural characterization of complex biological and biomimetic materials.
Spectrum Degradation of Hippocampal LFP During Euthanasia
Authors: Zhou Y. , Sheremet A. , Kennedy J. P. , DiCola Nicholas M. , Maciel Carolina B. , Burke Sara N. , Maurer A.P.
Published: December 2020

Abstract

The hippocampal local field potential (LFP) exhibits a strong correlation with behavior. During rest, the theta rhythm is not prominent, but during active behavior, there are strong rhythms in the theta, theta harmonics, and gamma ranges. With increasing running velocity, theta, theta harmonics and gamma increase in power and in cross-frequency coupling, suggesting that neural entrainment is a direct consequence of the total excitatory input. While it is common to study the parametric range between the LFP and its complementing power spectra between deep rest and epochs of high running velocity, it is also possible to explore how the spectra degrades as the energy is completely quenched from the system. Specifically, it is unknown whether the 1/f slope is preserved as synaptic activity becomes diminished, as low frequencies are generated by large pools of neurons while higher frequencies comprise the activity of more local neuronal populations. To test this hypothesis, we examined rat LFPs recorded from the hippocampus and entorhinal cortex during barbiturate overdose euthanasia. Within the hippocampus, the initial stage entailed a quasi-stationary stage when the LFP spectrum exhibited power-law feature while the frequency components over 20 Hz exhibited a power decay with a similar decay rate. This stage was followed by a rapid collapse of power spectrum towards the absolute electrothermal noise background. As the collapse of activity occurred later in hippocampus compared with medial entorhinal cortex or visual cortex, it suggests that the ability of a neural network to maintain the 1/f slope with decreasing energy is a function of general connectivity. Broadly, these data support the energy cascade theory where there is a cascade of energy from large cortical populations into smaller loops, such as those that supports the higher frequency gamma rhythm. As energy is pulled from the system, neural entrainment at gamma frequency (and higher) decline first. The larger loops, comprising a larger population, are fault-tolerant to a point capable of maintaining their activity before a final collapse.
Squid: Simplifying Quantitative Imaging Platform Development and Deployment
Authors: Li Hongquan , Krishnamurthy Deepak , Li Ethan , Vyas Pranav , Akireddy Nibha , Chai Chew , Prakash Manu
Published: December 2020

With rapid developments in microscopy methods, highly versatile, robust and affordable implementations are needed to enable rapid and wide adoption by the biological sciences community. Here we report Squid, a quantitative imaging platform with a full suite of hardware and software components and configurations for deploying facility-grade widefield microscopes with advanced features like flat field fluorescence excitation, patterned illumination and tracking microscopy, at a fraction of the cost of commercial solutions. The open and modular nature (both in hardware and in software) lowers the barrier for deployment, and importantly, simplifies development, making the system highly configurable and experiments that can run on the system easily programmable. Developed with the goal of helping translate the rapid advances in the field of microscopy and microscopy-enabled methods, including those powered by deep learning, we envision Squid will simplify roll-out of microscopy-based applications - including at point of care and in low resource settings, make adoption of new or otherwise advanced techniques easier, and significantly increase the available microscope-hours to labs.
Amyloid fibril-based hydrogels for high-throughput tumor spheroid modeling
Authors: Singh Namrata , Patel Komal , Navalkar Ambuja , Kadu Pradeep , Datta Debalina , Chatterjee Debdeep , Shaw Abhishek , Jadhav Sachin , Maji Samir K.
Published: December 2020

Biomaterials mimicking extracellular matrices (ECM) for three-dimensional (3D) cultures have gained immense interest in tumor modeling andin vitroorgan development. Here, we introduce versatile, thixotropic amyloid hydrogels as a bio-mimetic ECM scaffold for 3D cell culture as well as high-throughput tumor spheroid formation using a drop cast method. The unique cross-β-sheet structure, sticky surface, and thixotropicity of amyloid hydrogels allow robust cell adhesion, survival, proliferation, and migration, which are essential for 3D tumor modeling with various cancer cell types. The spheroids formed show overexpression of the signature cancer biomarkers and confer higher drug resistance compared to two-dimensional (2D) monolayer cultures. Using breast tumor tissue from mouse xenograft, we showed that these hydrogels support the formation of tumor spheroids with a well-defined necrotic core, cancer-associated gene expression, higher drug resistance, and tumor heterogeneity reminiscent of the original tumor. Altogether, we have developed a rapid and cost-effective platform for generatingin vitrocancer models for the screening of anti-cancer therapeutics and developing personalized medicines.
IL-27R signaling serves as immunological checkpoint for NK cells to promote hepatocellular carcinoma
Authors: Aghayev Turan , Peshkova Iuliia O. , Mazitova Aleksandra M. , Titerina Elizaveta K. , Fatkhullina Aliia R. , Campbell Kerry S. , Grivennikov Sergei I. , Koltsova Ekaterina K.
Published: December 2020

Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor survival and limited therapeutic options. HCC has different etiologies, typically associated with viral or carcinogenic insults or fatty liver disease and underlying chronic inflammation presents as a major unifying mechanism for tumor promotion. On the other hand, mechanisms of how inflammatory response can regulate anti-cancer immunity in HCC remain incompletely understood.

Interleukin (IL)-27 receptor signaling plays an anti-inflammatory role in a variety of infectious and chronic inflammatory diseases. Here, using genetic and pharmacological approaches we found that IL-27 receptor (IL-27R) signaling promotes HCC developmentin vivo. Genetic loss of IL-27R suppressed HCC development in both toxin/carcinogen-induced diethylnitrosamine (DEN) and non-alcoholic steatohepatitis (NASH)-driven models. Elevated expression of IL-27RA rendered poor prognosis to HCC patients. Mechanistically, the pro-tumorigenic effect was mediated by immunoregulatory role of IL-27R signaling within the tumor microenvironment, particularly the suppression of Natural killer (NK) cells. IL-27R ablation enhanced the accumulation and activation of cytotoxic NK cells during acute liver injury and in HCC tumors, while depletion of NK cells abrogated the effect of genetic IL-27R disruption.

Taken together, our data suggest an unexpected role of IL-27R signaling as a novel immunological checkpoint regulating NK cell activity and promoting development of HCC of different etiologies.
Monkey V1 epidural field potentials provide significant information about stimulus location, size, shape, and color
Authors: Fischer Benjamin , Wegener Detlef
Published: December 2020

Brain signal recordings with epidural microarrays constitute a low-invasive approach for recording distributed neuronal signals. Epidural field potentials (EFPs) may serve as a safe and highly beneficial signal source for a variety of research questions arising from both basic and applied neuroscience. A wider use of these signals, however, is constrained by a lack of data on their specific information content. Here, we make use of the high spatial resolution and the columnar organization of macaque primary visual cortex (V1) to investigate whether and to what extent EFP signals preserve information about various visual stimulus features. Two monkeys were presented with different feature combinations of location, size, shape, and color, yielding a total of 375 stimulus conditions. Visual features were chosen to access different spatial levels of functional organization. We found that, besides being highly specific for locational information, EFPs were significantly modulated by small differences in size, shape, and color, allowing for high stimulus classification rates even at the single-trial level. The results support the notion that EFPs constitute a low-invasive, highly beneficial signal source for longer-term recordings for medical and basic research by showing that they convey significant and reliable information about constituent features of activating stimuli.
Impact of nitrogen and phosphorus addition on resident soil and root mycobiomes in beech forests
Authors: Clausing S. , Likulunga L.E. , Janz D. , Feng H.Y. , Schneider D. , Daniel R. , Krüger J. , Lang F. , Polle A.
Published: December 2020

In forest soils, the pools of N and P available for microbes and plants are strongly dependent on soil properties. Here, we conducted a P and N fertilization experiment to disentangle the effects of nutrient availability on soil-residing, root-associated and ectomycorrhizal fungi in beech (Fagus sylvativa) forests differing in P availability. We tested the hypothesis that in P-poor forests, P fertilization leads to enhanced fungal diversity in soil and roots, resulting in enhanced P nutrition of beech and that N fertilization aggravates P shortage, shifting the fungal communities towards nitrophilic species. In response to fertilizer treatments (1x 50 kg ha−1P, 5x 30 kg ha−1N within 2 years), the labile P fractions increased in soil and roots, regardless of plant-available P in soil. Root total P decreased in response to N fertilization and root total P increased at the low P site in response to P addition. The relative abundances of ectomycorrhizal fungi, but not their species richness, increased in response to P or N addition in comparison with that of saprotrophic fungi. While some fungal orders (Trechisporales, Atheliales, Cantharellales) were moderately decreased in response to fertilizer treatments, Boletales increased in response to P and Russulaes to N addition. N or P fertilization resulted in functional trade-off, shifting away from saprotrophic towards symbiotrophic potential. Our results suggest that chronic exposure of forest ecosystems to increased nutrient inputs may overcome the resistance of the resident mycobiome structures resulting in nutritional imbalance and loss of forest ecosystem services.
NanoFAST: Structure-based design of a small fluorogen-activating protein with only 98 amino acids
Authors: Mineev Konstantin S. , Goncharuk Sergey A. , Goncharuk Marina V. , Povarova Natalia V. , Baleeva Nadezhda S. , Smirnov Alexander Yu. , Myasnyanko Ivan N , Ruchkin Dmitry A. , Bukhdruker Sergey , Remeeva Alina , Mishin Alexey , Borshchevskiy Valentin , Gordeliy Valentin , Arseniev Alexander S. , Gorbachev Dmitriy A. , Gavrikov Alexey S. , Mishin Alexander S. , Baranov Mikhail S.
Published: December 2020

One of the essential characteristics of any tag used in bioscience and medical applications is its size. The larger the label, the more it may affect the studied object, and the more it may distort its behavior. In this paper, using NMR spectroscopy and X-ray crystallography, we have studied the structure of fluorogen-activating protein FAST both in the apo form and in complex with the fluorogen. We shown that significant change in the protein occurs upon interaction with the ligand. While the protein is completely ordered in the complex, its apo form is characterized by higher mobility and disordering of its N-terminus. We used structural information to design the shortened FAST (which we named nanoFAST) by truncating 26 N-terminal residues. Thus, we created the shortest genetically encoded tag among all known fluorescent and fluorogen-activating proteins, which is composed of only 98 amino acids.
Secondary rewards acquire enhanced incentive motivation via increasing anticipatory activity of the lateral orbitofrontal cortex
Authors: Yang X , Liu X , Zeng Y , Wu R , Zhao W , Xin F , Yao S , Kendrick KM , Ebstein RP , Becker B
Published: December 2020

The motivation to strive for and consume primary rewards such as palatable food is bound by internal satiation and devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Satiation procedures combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreased hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that – in contrast to primary reinforcers - secondary reinforcers can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.
Genetic diversity ofBemisia tabaciGenn. characterized by analysis of ISSR and cytochrome c oxidase subunit I at Qassim, Saudia Arabia
Authors: Abdel-Baky Nagdy F. , Brown J. K. , Aldeghairi M. A. , Motawei M. I. , Rehan Medhat
Published: December 2020

Problems of Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) that increased and escalated in the last 40 years seem to be related to one or more aggressive biotypes that appeared to spread steadily worldwide. As well, some biological characteristics of B. tabaci have led some entomologists to change and multiply their methodology to update with the change in the pest genetic structures. This study is the 1st of its kind in Qassim region in KSA in respect ofB. tabacibiotypes. Four identification methods (Squash Silverleaf Symptoms (SSL), cross mating, Cytochrome oxidase subunit I (COI) sequences, and ISSR-PCR analysis) were carried out to determine the biotypes of B. tabaci at Qassim regions. Slight SSL symptoms were observed with varying degrees on squash leaves caused byB. tabacipopulation at Qassim, KSA. Cross-mating among the populations that have the same or similar genetic structures produced fertilized offspring, females and males with higher sex ratios in favor of females, and produced a higher number of eggs. Whereas, B. tabaci populations that varied greatly in their genetic structures produced unfertilized eggs, which produce males only. In the same trend, ISSR-PCR analysis revealed that B. tabaci populations at Qassim regions varied genetically and gathered into four genetic groups. In conclusion, COI analysis is a perfect tool for classification between biotypes in B. tabaci. Therefore, this study declares thatB. tabacithat colonized and infest Qassim horticulture has not the same genetic structures but belonging to B biotypes. It could be named asBemisiaspecies complex.