bluuebunny/crossref_metadata_2025 huggingface dataset:
Extraction of common task features in EEG-fMRI data using coupled tensor-tensor decomposition
Authors: Jonmohamadi Yaqub , Muthukumaraswamy Suresh , Chen Joseph , Roberts Jonathan , Crawford Ross , Pandey Ajay
Published: July 2019

The fusion of simultaneously recorded EEG and fMRI data is of great value to neuroscience research due to the complementary properties of the individual modalities. Traditionally, techniques such as PCA and ICA, which rely on strong strong non-physiological assumptions such as orthogonality and statistical independence, have been used for this purpose. Recently, tensor decomposition techniques such as parallel factor analysis have gained more popularity in neuroimaging applications as they are able to inherently contain the multidimensionality of neuroimaging data and achieve uniqueness in decomposition without imposing strong assumptions. Previously, the coupled matrix-tensor decomposition (CMTD) has been applied for the fusion of the EEG and fMRI. Only recently the coupled tensor-tensor decomposition (CTTD) has been proposed. Here for the first time, we propose the use of CTTD of a 4th order EEG tensor (space, time, frequency, and participant) and 3rd order fMRI tensor (space, time, participant), coupled partially in time and participant domains, for the extraction of the task related features in both modalities. We used both the sensor-level and source-level EEG for the coupling. The phase shifted paradigm signals were incorporated as the temporal initializers of the CTTD to extract the task related features. The validation of the approach is demonstrated on simultaneous EEG-fMRI recordings from six participants performing an N-Back memory task. The EEG and fMRI tensors were coupled in 9 components out of which 7 components had a high correlation (more than 0.85) with the task. The result of the fusion recapitulates the well-known attention network as being positively, and the default mode network working negatively time-locked to the memory task.
Endogenous activity modulates stimulus and circuit-specific neural tuning and perception
Authors: Li Yuanning , Ward Michael J. , Richardson R. Mark , G’Sell Max , Ghuman Avniel Singh
Published: July 2019

Perception reflects not only input from the sensory periphery, but also the endogenous neural state when sensory inputs enter the brain. Whether endogenous neural states influence perception only through global mechanisms, such as arousal, or can also perception in a neural circuit and stimulus specific manner remains largely unknown. Intracranial recordings from 30 pre-surgical epilepsy patients showed that endogenous activity independently modulated the strength of trial-by-trial neural tuning of different visual category-selective neural circuits. Furthermore, the same aspect of the endogenous activity that influenced tuning in a particular neural circuit also correlated with reaction time only for trials with the category of image that circuit was selective for. These results suggest that endogenous activity may influence neural tuning and perception through circuit-specific predictive coding processes.
Evidence of Chitin in the Ampullae of Lorenzini of Chondrichthyan Fishes
Authors: Phillips Molly , Tang W. Joyce , Robinson Matthew , Daza Daniel Ocampo , Hassan Khan , Leppert Valerie , Hirst Linda S. , Amemiya Chris T.
Published: July 2019

Chitin is synthesized by a variety of organisms using enzymes called chitin synthases and was recently discovered in a number of aquatic vertebrates. In our ongoing investigations into the presence of vertebrate chitin, we unexpectedly found evidence of the polysaccharide within the electrosensory organs, known as Ampullae of Lorenzini, of diverse chondrichthyan fishes. Experiments with histochemical reagents, chemical analyses, and enzymatic digestions suggested that chitin is a component of the hydrogel filling the structures. Further, in situ hybridization with a sequence from the little skate (Leucoraja erinacea) revealed that chitin synthase expression is localized to cells inside the organs. Collectively, these findings suggest that chondrichthyan fishes endogenously synthesize chitin and beg further investigation into the function of chitin in the electrosensory system.
State-specific gating of salient cues by midbrain dopaminergic input to basal amygdala
Authors: Lutas Andrew , Kucukdereli Hakan , Alturkistani Osama , Carty Crista , Sugden Arthur U. , Fernando Kayla , Diaz Veronica , Flores-Maldonado Vanessa , Andermann Mark L.
Published: July 2019

Basal amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area dopamine axons that innervate BA (VTADA→BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA→BA axons were activated by both rewards and punishments, and acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA→BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA→BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.
Comparing Functional Connectivity Matrices: A Geometry-Aware Approach applied to Participant Identification
Authors: Venkatesh Manasij , Jaja Joseph , pessoa Luiz
Published: July 2019

Understanding the correlation structure associated with multiple brain measurements informs about potential “functional groupings” and network organization. The correlation structure can be conveniently captured in a matrix format that summarizes the relationships among a set of brain measurements involving two regions, for example. Such functional connectivity matrix is an important component of many types of investigation focusing on network-level properties of the brain, including clustering brain states, characterizing dynamic functional states, performing participant identification (so-called “fingerprinting”) understanding how tasks reconfigure brain networks, and inter-subject correlation analysis. In these investigations, some notion of proximity or similarity of functional connectivity matrices is employed, such as their Euclidean distance or Pearson correlation (by correlating the matrix entries). Here, we propose the use of a geodesic distance metric that reflects the underlying non-Euclidean geometry of functional correlation matrices. The approach is evaluated in the context of participant identification (fingerprinting): given a participant’s functional connectivity matrix based on resting-state or task data, how effectively can the participant be identified? Using geodesic distance, identification accuracy was over 95% on resting-state data, and exceeded the Pearson correlation approach by 20%. For whole-cortex regions, accuracy improved on a range of tasks by between 2% and as much as 20%. We also investigated identification using pairs of subnetworks (say, dorsal attention plus default mode), and particular combinations improved accuracy over whole-cortex participant identification by over 10%. The geodesic distance also outperformed Pearson correlation when the former employed a fourth of the data as the latter. Finally, we suggest that low-dimensional distance visualizations based on the geodesic approach help uncover the geometry of task functional connectivity in relation to that during resting-state. We propose that the use of the geodesic distance is an effective way to compare the correlation structure of the brain across a broad range of studies.
A hierarchy of migratory keratinocytes maintains the tympanic membrane
Authors: Frumm Stacey M. , Yu Kevin Shengyang , Chang Joseph , Briscoe Jordan A. , Lee Katharine P. , Byrnes Lauren E. , Sneddon Julie B. , Tward Aaron D.
Published: July 2019

Although the conductive function of the tympanic membrane (TM) is critical for hearing, it is unknown how the organ maintains cellular homeostasis. Using a combination of single-cell RNA sequencing, lineage tracing, whole-organ explant, and live-cell imaging, we demonstrate that the stem cells of the TM epidermis reside in a distinct location at the superior portion of the TM and, as progeny migrate inferiorly, Pdgfra+ fibroblasts maintain a niche supporting proliferation of committed progenitors, while keratinocytes distal from the niche differentiate. Thus, the TM has a three dimensional differentiation hierarchy of keratinocytes distinct from that at other epidermal sites. The TM represents a physiological context where, in the absence of injury, keratinocytes both transit through a proliferative committed progenitor state and exhibit directional lateral migration. This work forms a foundation for understanding common disorders of the TM and introduces a new model system for the understanding of keratinocyte biology.
NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells
Authors: Sahan Ayse Z , Venkova Tatiana , Sayed Ibrahim M. , Beswick Ellen J , Reyes Victor E. , Pinchuk Irina , Sahoo Debashis , Ghosh Pradipta , Hazra Tapas K , Das Soumita
Published: July 2019

The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; this response was more pronounced in Neil2 knockout (KO) mouse cells compared to wild type (WT) cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Interestingly, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. H. pylori-infected Neil2 KO mice showed higher inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of repair genes in gastric specimens showed the reduction of Neil2 level is linked to the GC progression. Taken together, our data suggest that down-regulation of NEIL2 is a plausible mechanism by which H. pylori infection derails DNA damage repair, amplifies the inflammatory response and initiates GCs.
Mechanisms underlying the response of mouse cortical networks to optogenetic manipulation
Authors: Mahrach Alexandre , Chen Guang , Li Nuo , van Vreeswijk Carl , Hansel David
Published: July 2019

GABAergic interneurons can be subdivided into three subclasses: parvalbumin positive (PV), somatostatin positive (SOM) and serotonin positive neurons. With principal cells (PCs) they form complex networks. We examine PCs and PV responses in mouse anterior lateral motor cortex (ALM) and barrel cortex (S1) upon PV photostimulationin vivo. In layer 5, the PV response is paradoxical: photoexcitation reduces their activity. This is not the case in ALM layer 2/3. We combine analytical calculations and numerical simulations to investigate how these results constrain the architecture. Two-population models cannot account for the results. Networks with three inhibitory populations and V1-like architecture account for the data in ALM layer 2/3. Our data in layer 5 can be accounted for if SOM neurons receive inputs only from PCs and PV neurons. In both four-population models, the paradoxical effect implies not too strong recurrent excitation. It is not evidence for stabilization by inhibition.
Injury stimulates stem cells to resist radiation-induced apoptosis
Authors: Shiroor Divya A , Bohr Tisha E , Adler Carolyn E
Published: July 2019

Stem cells are continuously exposed to multiple stresses including radiation and tissue injury. Because stem cells are central drivers of tissue repair and regeneration, it is essential to understand how their behavior is influenced by these stressors. Planarians have an abundant population of stem cells that are rapidly eliminated after radiation exposure via apoptosis. Low doses of radiation eliminate the majority of these stem cells, allowing a few to remain [1]. Here, we combine radiation with injury to define how surviving stem cells respond to tissue damage. We find that injuries induce stem cells to persist, but only if injured within a defined window of time surrounding radiation, and only immediately adjacent to the wound. Stem cells persist for several days without any proliferation. Instead, they are retained near the wound due to suppression of apoptosis, which we quantify in stem cells by combining FACS with Annexin V staining. Tissue injury is known to induce apoptosis in differentiated cells [2], and we hypothesize that these dying cells confer apoptosis resistance onto nearby stem cells. Indeed, pharmacological induction of cell death with cycloheximide is sufficient to prolong survival of radiated stem cells even in the absence of injury. Together, our results suggest a model in which dying cells provide a transient protective signal to nearby stem cells, altering their susceptibility to radiation-induced apoptosis.
Anti-SSTR2 Antibody-Drug Conjugate for Neuroendocrine Cancer Therapy
Authors: Si Yingnan , Kim Seulhee , Guenter Rachael , Ou Jianfa , Lu Yun , Chen Kai , Zhang John , Whitt Jason , Carter Angela M. , Bibb James A. , Jaskula-Sztul Renata , Markert James M. , Zhou Lufang , Chen Herbert , “Margaret” Liu Xiaoguang
Published: July 2019

Neuroendocrine (NE) cancers include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo- and radio- therapies have marginal curative benefits. This study aimed to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). We first confirmed that somatostatin receptor 2 (SSTR2) is an ideal surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and 3 NET cell lines. We then developed a new monoclonal antibody (mAb, IgG1 and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells effectively. Finally, the ADC was evaluated in vivo using a NET xenografted mouse model to determine cancer targeting, maximal tolerated dosage, pharmacokinetics, and anti-cancer efficacy. The anti-SSTR2 ADC was able to exclusively target and kill NETs with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 mAb-based ADC has high therapeutic values for NET therapy.
Printable microscale interfaces for long-term peripheral nerve mapping and precision control
Authors: Otchy Timothy M. , Michas Christos , Lee Blaire , Gopalan Krithi , Gleick Jeremy , Semu Dawit , Darkwa Louis , Holinski Bradley J. , Chew Daniel J. , White Alice E. , Gardner Timothy J.
Published: July 2019

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying advanced peripheral interfacing technologies. Here, we present a microscale implantable device – the nanoclip – for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high-resolution recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation can achieve a high degree of functionally-relevant modulatory specificity within the small scale of the device. These results highlight the potential of new microscale design and fabrication techniques for the realization of viable implantable devices for long-term peripheral interfacing.
Population subspaces reflect movement intention for arm and brain-machine interface control
Authors: Lalazar H. , Murray J.M. , Abbott L.F. , Vaadia E.
Published: July 2019

Motor cortex is active during covert motor acts, such as action observation and mental rehearsal, when muscles are quiescent. Such neuronal activity, which is thought to be similar to the activity underlying overt movement, is exploited by neural prosthetics to afford subjects control of an external effector. We compared neural activity in primary motor cortex of monkeys who controlled a cursor using either their arm or a brain-machine interface (BMI) to identify what features of neural activity are similar or dissimilar in these two control contexts. Neuronal population activity parcellates into orthogonal subspaces, with some representations that are unique to arm movements and others that are shared between arm and BMI control. The shared subspace is invariant to the effector used and to biomechanical details of the movement, revealing a representation that reflects movement intention. This intention representation is likely the signal extracted by BMI algorithms for cursor control, and subspace orthogonality accounts for how neurons involved in arm control can drive a BMI while the arm remains at rest. These results provide a resolution to the long-standing debate of whether motor cortex represents muscle activity or abstract movement variables, and it clarifies various puzzling aspects of neural prosthetic research.
Thalamic and extra-thalamic connections of the Globus Pallidus in the human brain: The ultradirect pathway
Authors: Zheng Zhong S. , Monti Martin M.
Published: July 2019

A dominant framework for understanding loss and recovery of consciousness, particularly in the context of severe brain injury, focuses on cortico-subcortical recurrent interactions, with a strong emphasis on excitatory thalamofugal projections. Recent work in healthy volunteers and patients, however, suggests a previously unappreciated role for the globus pallidus pars externa in maintaining a state of consciousness – a finding that is consistent with non-human animal work demonstrating the existence of direct (i.e., extrathalamic) pallido-cortical projections as well as their involvement in modulating electrocortical arousal and sleep. Leveraging on the high-quality Human Connectome Project dataset, we report for the first time in humans, in vivo evidence of (direct) pallido-cortical and pallido-thalamic projections, distinguishing between internal and external pallidal regions. Our data confirm, in humans, the existence of an “ultradirect” extra-thalamic pallido-cortical pathway, with the pars externa connecting preferentially, and extensively, to prefrontal cortex and the pars interna primarily connecting to sensorimotor cortical areas. Furthermore, we also report, for the first time in humans, the likely existence of a direct pathway uniting the globus pallidus pars externa and the medio-dorsal areas of thalamus often implicated in maintenance and recovery of consciousness. Consistent with the pallido-cortical connectivity results, the pars interna appeared to predominantly connect with the sensorimotor areas of thalamus. Collectively, these findings demonstrate the existence in humans of an extra-thalamic “ultradirect” pallido-cortical pathway and suggest a central role of the external segment of the globus pallidum in supporting consciousness.
Dendritic speeding of synaptic potentials in an auditory brainstem principal neuron
Authors: Srinivasan Geetha , Dagostin Andre , Leão Richardson N. , Balakrishnan Veeramuthu , Holcomb Paul , Jackson Dakota , Spirou George , von Gersdorff Henrique
Published: July 2019

Principal cells of the medial nucleus of the trapezoid body (MNTB) in the mammalian auditory brainstem receive most of their strong synaptic inputs directly on the cell soma. However, these neurons also grow extensive dendrites during the first four postnatal weeks. What are the functional roles of these dendrites? We studied the morphology and growth of the dendrites in the mouse MNTB using both electron microscopy and confocal fluorescence imaging from postnatal day 9 (P9; pre-hearing) to P30. The soma of principal cells sprouted 1 to 3 thin dendrites (diameter ~ 1.5 microns) by P21 to P30. Each dendrite bifurcated into 2-3 branches and spanned an overall distance of about 80 to 200 microns. By contrast, at P9-11 the soma had 1 to 2 dendrites that extended for only 25 microns on average. Patch clamp experiments revealed that the growth of dendrites during development correlates with a progressive decrease in the input resistance, whereas acute removal of dendrites during brain slicing leads to higher input resistances. Accordingly, recordings of excitatory postsynaptic potentials (EPSPs) evoked by afferent fiber stimulation show that EPSP decay is faster in P21-24 neurons with intact dendrites than in neurons without dendrites. This dendritic speeding of the EPSP reduces the decay time constant 5-fold, which will impact significantly synaptic current summation and the ability to fire high-frequency spike trains. These data suggest a novel role for dendrites in auditory brainstem neurons: the speeding of EPSPs for faster and more precise output signal transfer.

Significance Statement

Auditory circuits that compute sound localization express different types of specialized synapses. Some are capable of fast, precise and sustained synaptic transmission. As the paradigm example, principal cells of the MNTB receive a single calyx-type nerve terminal on their soma and this large excitatory synapse produces fast and brief supra-threshold EPSPs that can trigger trains of high frequency spikes. However, these neurons also extend thin and long dendrites with unknown function. We examined the relationship between dendritic morphology, passive electrical properties and EPSP waveform. We found that more mature neurons with intact dendrites have lower input resistances and short EPSP waveforms, ideally suited for conveying precise timing information, whereas immature neurons with shorter dendrites and higher input resistance have longer lasting EPSPs.
An Automated Addressable Microfluidics Device for Minimally Disruptive Manipulation of Cells and Fluids within Living Cultures
Authors: Tong Anh , Pham Quang Long , Shah Vatsal , Naik Akshay , Abatemarco Paul , Voronov Roman
Published: July 2019

According to the U.S. Department of Health & Human Services, nearly 115,000 people in the U.S needed a lifesaving organ transplant in 2018, while only ∼10% of them have received it. Yet, almost no artificial FDA-approved products are commercially available today – three decades after the inception of tissue engineering. It is hypothesized here that the major bottlenecks restricting its progress stem from lack of access to the inner pore space of the scaffolds. Specifically, the inability to deliver nutrients to, and clear waste from, the center of the scaffolds limits the size of the products that can be cultured. Likewise, the inability to monitor, and control, the cells after seeding them into the scaffold results in nonviable tissue, with an unacceptable product variability. To resolve these bottlenecks, we present a prototype addressable microfluidics device capable of minimally disruptive fluid and cell manipulations within living cultures. As proof-of-concept, we demonstrate its ability to perform additive manufacturing by seeding cells in spatial patterns (including co-culturing multiple cell types); and subtractive manufacturing by removing surface adherent cells via focused flow of trypsin. Additionally, we show that the device can sample fluids and perform cell “biopsies” (which can be subsequently sent for ex-situ analysis), from any location within its Culture Chamber. Finally, the on-chip plumbing is completely automated using external electronics. This opens the possibility to perform long-term computer-driven tissue engineering experiments, where the cell behavior is modulated in response to the minimally disruptive observations (e.g. fluid sampling and cell biopsies) throughout the entire duration of the cultures. It is expected that the proof-of-concept technology will eventually be scaled up to 3D addressable microfluidic scaffolds, capable of overcoming the limitations bottlenecking the transition of tissue engineering technologies to the clinical setting.
HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells
Authors: Ickler Julia , Francois Sandra , Widera Marek , Santiago Mario L. , Dittmer Ulf , Sutter Kathrin
Published: July 2019

The innate immune response induced by type I interferons (IFNs) play a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNa/b receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+CXCR4+T cells of HIV+patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIVin vivoreside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNa subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV−individuals and in plasma samples of HIV+patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+patients compared to healthy donors, nor in LPMCs after HIV-1 infectionex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection is unlikely dictated by changes in IFNAR2 expression.
CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)
Authors: He Weiling , Zhang Hui , Li Shuhua , Cui Yongmei , Zhu Ying , Zhu Junfeng , Lei Yiyan , Lin Run , Xu Di , Zhu Zheng , Jiang Wenting , Wang Han , Ke Zunfu
Published: July 2019

Lung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.

Abbreviations

LUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field
The Relationship between Body Mass Index and Poor Self-rated Health in the Korean Population
Authors: Sung Eun-Seok , Choi Chang Kyun , Jeong Ji-An , Shin Min-Ho
Published: July 2019

Objective

Several previous studies have evaluated associations between body mass index (BMI) and self-rated health (SRH); however, the results were inconsistent. This study aimed to examine the association between BMI and SRH in Korean adults.

Methods

The study was conducted in 214,997 adults who participated in the 2016 Korean Community Health Survey. Participants were categorized into four groups based on BMI: underweight (<18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥30.0 kg/m2). Multivariate Poisson regression analysis with sampling weights and robust variance estimators was performed to evaluate the relationship between BMI categories and poor SRH.

Results

There was a J-shaped association between BMI and poor SRH in both sexes, with the lowest risk observed in the normal weight group in both sexes. Compared with normal weight subjects, the age and lifestyle adjusted prevalence rate ratios for poor SRH were 1.61 (95% CI, 1.50–1.74) for underweight, 1.16 (95% CI, 1.11–1.21) for overweight, and 2.35 (95% CI, 2.13–2.58) for obese men; and 1.24 (95% CI, 1.17–1.32) for underweight, 1.26 (95% CI, 1.22–1.31) for overweight, and 1.77 (95% CI, 1.64–1.91) for obese women.

Conclusions

In a cross-sectional study using a nationally representative survey, there was a nonlinear relationship between BMI and poor SRH. This relationship was more prominent in men than in women. Prospective studies are needed to further clarify the relationship between BMI and SRH.
Neuronal Responses in Posterior Parietal Cortex during Learning of Implied Serial Order
Authors: Munoz Fabian , Jensen Greg , Kennedy Benjamin C. , Alkan Yelda , Terrace Herbert S. , Ferrera Vincent P.
Published: July 2019

Monkeys are able to learn the implied ordering of pairs of images drawn from an ordered set, without ever seeing all of the images simultaneously and without explicit spatial or temporal cues. The learning of implied order differs from learning of explicit visual or motor sequences. We recorded the activity of parietal neurons in rhesus macaques while they learned 7-item TI lists when only 2 items were presented on each trial. Behavior and ensemble neuronal activity were significantly influenced by the ordinal relationship of the stimulus pairs, specifically symbolic distance (the difference in rank) and joint ranks (the sum of the ranks). Symbolic distance strongly predicted decision accuracy, and learning was consistently faster as symbolic distance increased. An effect of joint rank on performance was also found nested within the symbolic distance effect. Across the population of neurons, there was significant modulation of firing correlated with the relative ranks of the two stimuli presented on each trial. Neurons exhibited selectivity for stimulus rank during learning, but not before or after. The observed behavior during learning is best explained by a virtual workspace model, not by associative or reward mechanisms. The neural data support a role for posterior parietal cortex in representing several variables that contribute to serial learning, particularly information about the ordinal ranks of the stimuli presented during a given trial. Thus, parietal cortex appears to belong to a neural substrate for learning and representing abstract relationships in a virtual workspace.
The Medicago truncatula Vacuolar Iron Transporter-Like proteins VTL4 and VTL8 deliver iron to endosymbiotic bacteria at different stages of the infection process
Authors: Walton Jennifer H. , Kontra-Kováts Gyöngyi , Green Robert T. , Domonkos Ágota , Horváth Beatrix , Brear Ella M. , Franceschetti Marina , Kaló Péter , Balk Janneke
Published: July 2019

The symbiotic relationship between legumes and rhizobium bacteria in root nodules has a high demand for iron. The host plant is known to provide iron to developing bacteroids, but questions remain regarding which transporters are involved. Here, we characterize two Vacuolar Iron Transporter-Like (VTL) proteins in Medicago truncatula that are specifically expressed during nodule development. VTL4 is mostly expressed during early infection and the protein was localized to membranes and the infection thread. vtl4 mutants were delayed in nodule development. VTL8 is closely related to SEN1 in Lotus japonicus and expressed in the late stages of bacteroid differentiation. The VTL8 protein was localized to the symbiosome membrane. A mutant line lacking the tandemly-arranged VTL4 – VTL8 genes, named 13U, was unable to develop functional nodules and failed to fix nitrogen, which was restored by expression of VTL8 alone. Using a newly developed lux reporter to monitor iron status of the bacteroids, a slight decrease in luminescence was observed in vtl4 mutants and a strong decrease in the 13U mutant. Iron transport capability of VTL4 and VTL8 was shown by yeast complementation. Taken together, these data indicate that VTL-type transporters are the main route for delivering iron to symbiotic rhizobia.
The effect of semantic brightness on pupil size: A replication with Dutch words
Authors: Mathôt Sebastiaan , Sundermann Leevke , van Rijn Hedderik
Published: July 2019

Theories of embodied language hold that word processing is automatically accompanied by sensory and motor simulations. For example, when you read the word ‘sun’, a sensory simulation of brightness as well as a motor simulation of pupil constriction would be automatically triggered. Consistent with this notion, Mathôt, Grainger, and Strijkers (2017) found that the eye’s pupil was slightly smaller after reading single words that were associated with brightness (e.g. ‘sun’) as compared to darkness (e.g. ‘night’); that is, the pupil light response was modulated by the semantic brightness of words. However, (other) key findings within the field of embodied language have proven difficult to replicate, and we therefore felt that it was crucial to replicate the effect of semantic brightness on pupil size. To this end, we conducted a close-but-non-identical replication of two key experiments from Mathôt, Grainger, and Strijkers (2017): one experiment with visually presented words, and one experiment with spoken words. Both experiments were successfully replicated. We propose that cognitive modulations of the pupil light response reflect activity in visual brain areas; therefore, the effect of semantic brightness on pupil size can be used as a marker for the involvement of visual brain areas in language processing, and thus to address a wide variety of key questions within psycholinguistics.
Transcriptional terminators allow leak-free chromosomal integration of genetic constructs in cyanobacteria
Authors: Kelly Ciarán L. , Taylor George M. , Satkute Aiste , Dekker Linda , Heap John T.
Published: July 2019

Cyanobacteria are promising candidates for sustainable bioproduction of chemicals from sunlight and carbon dioxide. However, the genetics and metabolism of cyanobacteria are less well understood than model heterotrophic organisms, and the suite of well characterised cyanobacterial genetic tools and parts is less mature and complete. Transcriptional terminators use specific RNA structures to halt transcription and are routinely used in both natural and recombinant contexts to achieve independent control of gene expression and ‘insulate’ genes and operons from one another. Insulating gene expression can be particularly important when heterologous/synthetic genetic constructs are inserted at genomic locations where transcriptional read-through from chromosomal promoters occurs, resulting in poor control of expression of the introduced genes. To date, few terminators have been described and characterised in cyanobacteria. In this work, nineteen heterologous, synthetic or putative native Rho-independent (intrinsic) terminators were tested in the model freshwater cyanobacterium,Synechocystissp. PCC 6803, from which eleven strong terminators were identified. A subset of these strong terminators was then used to successfully insulate a chromosomally-integrated rhamnose-induciblerhaBADexpression system from hypothesised ‘read-through’ from a neighbouring chromosomal promoter, resulting in greatly improved inducible control. The addition of validated strong terminators to the cyanobacterial toolkit will allow improved independent control of introduced genes.
Considerations for metabarcoding-based port biological baseline surveys aimed at marine non-indigenous species monitoring and risk-assessments
Authors: Rey Anaïs , Basurko Oihane C. , Rodriguez-Ezpeleta Naiara
Published: July 2019

Monitoring introduction and spread of non-indigenous species via maritime transport and performing risk assessments require port biological baseline surveys. Yet, the comprehensiveness of these surveys is often compromised by the large number of habitats present in a port, the seasonal variability and the time-consuming morphological approach used for taxonomic identification. Metabarcoding represents a promising alternative for rapid comprehensive port biological baseline surveys, but its application in this context requires further assessments.

We applied metabarcoding (based on barcodes of the Cytochrome c oxidase subunit I and of the 18S ribosomal RNA gene) to 192 port samples collected i) from diverse habitats (water column – including environmental DNA and zooplankton, sediment and fouling structures), ii) at different sites (from inner to outer estuary), and iii) during the four seasons of the year.

By comparing the biodiversity metrics derived from each sample group, we show that each sampling method resulted in a distinct community profile and that environmental DNA alone cannot substitute for organismal sampling, and that, although sampling at different seasons and locations resulted in higher observed biodiversity, operational results can be obtained by sampling selected locations and seasons.

By assessing the taxonomic composition of the samples, we show that metabarcoding data allowed the detection of previously recorded non-indigenous species as well as to reveal presence of new ones, even if in low abundance.

Synthesis and application. Our comprehensive assessment of metabarcoding for port biological baseline surveys sets the basics for cost-effective, standardized and comprehensive monitoring of non-indigenous species and for performing risk assessments in ports. This development will contribute to the implementation of the recently entered into force International Convention for the Control and Management of Ships’ Ballast Water and Sediments.
Linking alpha oscillations, attention and inhibitory control in adult ADHD with EEG neurofeedback
Authors: Deiber Marie-Pierre , Hasler Roland , Colin Julien , Dayer Alexandre , Aubry Jean-Michel , Baggio Stéphanie , Perroud Nader , Ros Tomas
Published: July 2019

Abnormal patterns of electrical oscillatory activity have been repeatedly described in adult ADHD. In particular, the alpha rhythm (8-12 Hz), known to be modulated during attention, has previously been considered as candidate biomarker for ADHD. In the present study, we asked adult ADHD patients to self-regulate their own alpha rhythm using neurofeedback (NFB), in order to examine the modulation of alpha oscillations on attentional performance and brain plasticity. Twenty-five adult ADHD patients and 22 healthy controls underwent a 64-channel EEG-recording at resting-state and during a Go/NoGo task, before and after a 30 min-NFB session designed to reduce (desynchronize) the power of the alpha rhythm. Alpha power was compared across conditions and groups, and the effects of NFB were statistically assessed by comparing behavioral and EEG measures pre-to-post NFB. Firstly, we found that relative alpha power was attenuated in our ADHD cohort compared to control subjects at baseline and across experimental conditions, suggesting a signature of cortical hyper-activation. Both groups demonstrated a significant and targeted reduction of alpha power during NFB. Interestingly, we observed a post-NFB increase in resting-state alpha (i.e. rebound) in the ADHD group, which restored alpha power towards levels of the normal population. Importantly, the degree of post-NFB alpha normalisation during the Go/NoGo task correlated with individual improvements in motor inhibition (i.e. reduced commission errors and slower reaction times in NoGo trials) only in the ADHD group. Overall, our findings offer novel supporting evidence implicating alpha oscillations in inhibitory control, as well as their potential role in the homeostatic regulation of cortical excitatory/inhibitory balance.

Highlights

Resting alpha power is reduced in adult ADHD suggesting cortical hyper-activation

Adult ADHD patients successfully reduce alpha power during neurofeedback

A post-neurofeedback rebound normalizes alpha power in adult ADHD

Alpha power rebound correlates with improvement of inhibitory control in adult ADHD
TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons
Authors: Bowie Emily , Goetz Sarah C.
Published: July 2019

Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. However, their function, particularly on neurons in the adult brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11). Here, we show that conditional knockout ofTtbk2in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of human SCA11 including motor coordination deficits, loss of synaptic connections to Purkinje cells (PCs), and eventual loss of PCs. We also find that theTtbk2conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking geneIft88in adult mice results in nearly identical cerebellar phenotypes to those of theTtbk2knockout, supporting disruption of ciliary signaling as a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining adult neuronal function, and offers novel insights into the mechanisms involved in neurodegeneration.
Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice
Authors: Bravo Isabel M. , Luster Brennon R. , Flanigan Meghan E. , Perez Patric J. , Cogan Elizabeth S. , Schmidt Karl T. , McElligott Zoe A.
Published: July 2019

Persons suffering from opioid use disorder (OUD) experience long-lasting dysphoric symptoms well into extended periods of withdrawal. This protracted withdrawal syndrome is notably characterized by heightened anxiety. Here we investigate if an exacerbated withdrawal model of acute morphine dependence results in lasting behavioral adaptation 6 weeks into forced abstinence. We found that our exacerbated morphine withdrawal paradigm produced distinct impairments in elevated-plus maze, open field, and social interaction tests in male and female mice. These findings will be relevant for future investigation examining the neural mechanisms underlying these behaviors, and will aid in uncovering physiological sex differences in response to opioid withdrawal.
Engineering microscale systems for fully autonomous intracellular neural interfaces
Authors: Kumar Swathy Sampath , Baker Michael S. , Okandan Murat , Muthuswamy Jit
Published: July 2019

Conventional electrodes and associated positioning systems for intracellular recording from single neurons in vitro and in vivo are large and bulky, which has largely limited their scalability. Further, acquiring successful intracellular recordings is very tedious, requiring a high degree of skill not readily achieved in a typical laboratory. We report here a robotic, MEMS-based intracellular recording system to overcome the above limitations associated with form-factor, scalability and highly skilled and tedious manual operations required for intracellular recordings. This system combines three distinct technologies: 1) novel microscale, glass-polysilicon penetrating electrode for intracellular recording, 2) electrothermal microactuators for precise microscale movement of each electrode and 3) closed-loop control algorithm for autonomous positioning of electrode inside single neurons. Here, we demonstrate the novel, fully integrated system of glass-polysilicon microelectrode, microscale actuators and controller for autonomous intracellular recordings from single neurons in the abdominal ganglion of Aplysia Californica (n = 5 cells). Consistent resting potentials (< −35 mV) and action potentials (> 60 mV) were recorded after each successful penetration attempt with the controller and microactuated glass-polysilicon microelectrodes. The success rate of penetration and quality of intracellular recordings achieved using electrothermal microactuators were comparable to that of conventional positioning systems. The MEMS-based system offers significant advantages: 1) reduction in overall size for potential use in behaving animals, 2) scalable approach to potentially realize multi-channel recordings and 3) a viable method to fully automate measurement of intracellular recordings. This system will be evaluated in vivo in future rodent studies.