bluuebunny/crossref_metadata_2025 huggingface dataset:
Amplicon structure creates collateral therapeutic vulnerability in cancer
Authors: Bei Yi , Bramé Luca , Kirchner Marieluise , Fritsche-Guenther Raphaela , Kunz Sevrine , Bhattacharya Animesh , Köppke Julia , Proba Jutta , Wittstruck Nadine , Sidorova Olga A. , González Rocío Chamorro , Garcia Heathcliff Dorado , Brückner Lotte , Xu Robin , Giurgiu Mădălina , Rodriguez-Fos Elias , Koche Richard , Schmitt Clemens , Schulte Johannes H. , Eggert Angelika , Haase Kerstin , Kirwan Jennifer , Hagemann Anja I.H. , Mertins Philipp , Dörr Jan R. , Henssen Anton G.
Published: September 2022

Although DNA amplifications in cancers frequently harbor passenger genes alongside oncogenes, the functional consequence of such co-amplifications and their impact for therapy remains ill-defined. We discovered that passenger co-amplifications can create amplicon structure-specific collateral vulnerabilities. We present the DEAD-box helicase 1 (DDX1) gene as a bona fide passenger co-amplified with MYCN in cancers. Survival of cancer cells with DDX1 co-amplifications strongly depends on the mammalian target of rapamycin complex 1 (mTORC1). Mechanistically, aberrant DDX1 expression inhibits the tricarboxylic acid cycle through a previously unrecognized interaction with dihydrolipoamide S-succinyltransferase, a component of the alpha-ketoglutarate dehydrogenase complex. Cells expressing aberrant DDX1 levels compensate for the metabolic shift by enhancing mTORC1 activity. Consequently, pharmacological mTORC1 inhibition triggered cell death specifically in cells harboring the DDX1 co-amplification. This work highlights a significant contribution of passenger gene alterations to the therapeutic susceptibility of cancers.

Graphical abstract
SPUMONI 2: Improved pangenome classification using a compressed index of minimizer digests
Authors: Ahmed Omar , Rossi Massimiliano , Gagie Travis , Boucher Christina , Langmead Ben
Published: September 2022

Genomics analyses often use a large sequence collection as a reference, like a pangenome or taxonomic database. We previously described SPUMONI, which performs binary classification of nanopore reads using pangenomic matching statistics. Here we describe SPUMONI 2, an improved version that is faster, more memory efficient, works effectively for both short and long reads, and can solve multi-class classification problems with the aid of a novel sampled document array structure. By incorporating minimizers, SPUMONI 2 reduces index size by a factor of 2 compared to SPUMONI, yielding an index more than 65 times smaller than minimap2’s for a mock community pangenome. SPUMONI 2 also achieves a speed improvement of 3-fold compared to SPUMONI and 15-fold compared to minimap2. We show SPUMONI 2 achieves an advantageous mix of accuracy and efficiency for short and long reads, including in an adaptive sampling scenario. We further demonstrate that SPUMONI 2 can detect contaminated contigs in genome assemblies, and can perform multi-class metagenomic read classification.
Associations between methylation age and brain age in late adolescence
Authors: Sanders Faye , Baltramonaityte Vilte , Donohoe Gary , Davies Neil M , Dunn Erin C. , Cecil Charlotte A.M. , Walton Esther
Published: September 2022

Recent research suggests that biological age, based on DNA methylation or neuroimaging measures, may predict health traits in adulthood more accurately than chronological age. However, whether these findings apply to earlier stages in life is unknown. We therefore aimed to characterise the performance of and interdependence between measures of biological age during adolescence, leveraging longitudinal data from a subsample of young adolescents from the population-based ALSPAC cohort (n=386).

We derived four methylation age measures in late adolescence (17-19 years) and a measure of brain age derived from structural neuroimaging data (18-24 years). We then examined associations between these measures of biological age, and their relationship with five measures of physical, cognitive and mental health (8-18 years).

Brain age was largely independent of different measures of methylation age, after accounting for age, cell type composition, array and study (beta range: -0.60 to 0.60, all p>0.05). Smoking and BMI were associated with three measures of advanced methylation age (beta range: -0.35 to 0.52, all p<0.05), but not brain age. Depressive symptoms and cognitive ability were unrelated to all measures of biological age.

Our findings emphasize the variability of and independence between these methylation- and brain-based measures of age in adolescents. They also highlight the importance of tracking the mosaic of ageing in younger populations.
Activity in primate visual cortex is minimally driven by spontaneous movements
Authors: Talluri Bharath C. , Kang Incheol , Lazere Adam , Quinn Katrina R. , Kaliss Nicholas , Yates Jacob L. , Butts Daniel A. , Nienborg Hendrikje
Published: September 2022

Organisms process sensory information in the context of their own moving bodies, an idea referred to as embodiment. This idea is important for developmental neuroscience, and increasingly plays a role in robotics and systems neuroscience. The mechanisms that support such embodiment are unknown, but a manifestation could be the observation in mice of brain-wide neuromodulation, including in the primary visual cortex, driven by task-irrelevant spontaneous body movements. Here we tested this hypothesis in macaque monkeys, a primate model for human vision, by simultaneously recording visual cortex activity and facial and body movements. Activity in the visual cortex (V1, V2, V3/V3A) was associated with the animals’ own movements, but this modulation was largely explained by the impact of the movements on the retinal image. These results suggest that embodiment in primate vision may be realized by input provided by the eyes themselves.
Resting fMRI-guided TMS evokes subgenual anterior cingulate response in depression
Authors: Duprat Romain J. , Linn Kristin A. , Satterthwaite Theodore D. , Sheline Yvette I. , Liang Ximo , Bagdon Gabriela , Flounders Matthew W. , Robinson Heather , Platt Michael , Kable Joseph , Long Hannah , Scully Morgan , Deluisi Joseph A. , Thase Michael , Cristancho Mario , Reber Justin , Shinohara Russell T. , Oathes Desmond J.
Published: September 2022

Depression alleviation following treatment with repetitive transcranial magnetic stimulation (rTMS) tends to be more effective when TMS is targeted to cortical areas with high resting state functional connectivity (rsFC) with the subgenual anterior cingulate cortex (sgACC). However, it has not yet been confirmed that rsFC-guided TMS coil placement leads to TMS modulation of the sgACC. For each participant (N=115, 34 depressed patients), a peak rsFC cortical ‘hotspot’ for the sgACC and control targets were prospectively identified. Single pulses of TMS interleaved with fMRI readouts were then administered to these targets and established significant downstream fMRI BOLD responses in the sgACC. We then marked an association between TMS-evoked BOLD responses in the sgACC and rsFC between the stimulation site and sgACC. This effect was qualified by a difference between healthy and patient participants: only in depressed patients, positively connected sites of stimulation led to the strongest evoked responses in the sgACC. Our results highlight rsFC-based targeting as a viable strategy to causally modulate sgACC subcortical targets and further suggest that cortical sites with high positive rsFC to the sgACC might represent an alternative target for the treatment of depression.
Predicting microbial community compositions in wastewater treatment plants using artificial neural networks
Authors: Liu Xiaonan , Nie Yong , Wu Xiao-Lei
Published: September 2022

Activated sludge (AS) of wastewater treatment plants (WWTP) is one of the world’s largest artificial microbial ecosystems and the microbial community of the AS system is closely related to WWTP performance. However, how to predict its community structure is still unclear. Here, we used artificial neural networks (ANN) to predict the microbial compositions of AS systems collected from WWTPs located worldwide. We demonstrated that the microbial compositions of AS systems are predictable using our approach. The predictive accuracy R21:1 of Shannon-Wiener index reached 60.42%, and the average R21:1 of ASVs appearing in at least 10% of samples (ASVs>10%) and core taxa were 35.09% and 42.99%, respectively. We also found that the predictability of ASVs>10% was significantly positively correlated with their relative abundance and occurrence frequency, but significantly negatively correlated with potential migration rate. The typical functional groups such as nitrifiers, denitrifiers, polyphosphate-accumulating organisms (PAOs) and glycogen-accumulating organisms (GAOs), and filamentous organisms in AS systems could also be well recovered using an ANN model, with the R21:1 ranging from 32.62% to 56.81%. Furthermore, we found that industry wastewater source (IndConInf) had good predictive abilities, although its correlation with ASVs>10% in the Mantel test analysis was weak, which suggested important factors that cannot be identified using traditional methods may be highlight by the ANN model. Our results provide a better understanding of the factors affecting AS communities through the prediction of the microbial community of AS systems, which could lead to insights for improved operating parameters and control of community structure.
Successful working memory linked to theta connectivity patterns in the hippocampal-entorhinal circuit
Authors: Li Jin , Cao Dan , Yu Shan , Wang Haiyan , Imbach Lukas , Stieglitz Lennart , Sarnthein Johannes , Jiang Tianzi
Published: September 2022

Working memory (WM) is the ability to actively maintain information for a short time and is central to human behavior. Rodent studies have proposed that hippocampal-entorhinal communication supports WM maintenance. However, the exact neural mechanisms of this interaction in WM remains unclear in humans. To address these questions, we combined machine learning analyses with intracranial electroencephalography (iEEG) recordings from the hippocampus and the entorhinal cortex (EC) in human participants, who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated bidirectional hippocampal-EC information exchange via the theta band (2–8 Hz) and bidirectional cross-region theta-gamma phase-amplitude coupling (PAC). Further decoding analyses showed that the unidirectional inter-regional communication, with both theta oscillations in the hippocampus modulating EC gamma activity and theta band-coordinated information flow from the hippocampus, could decode correct performance at the level of participants. Taken together, our results demonstrate that theta functional coupling in the hippocampal-EC supports the maintenance of WM information via a specific pattern of frequency and direction. This connectivity-based coding could shed light on the neural mechanisms of WM processing.

Significance

Recent studies suggest a role for the hippocampus in working memory. How does the hippocampus coordinate with other brain regions to retain working memory information? The entorhinal cortex (EC) is the main gateway for information between the hippocampus and neocortex. To delineate whether (and how) the hippocampus and the entorhinal cortex interact during working memory and whether such interaction supports successful working memory, we used machine learning analyses of human intracranial EEG recordings while patients performed working memory tasks. Our results suggest that the human hippocampal-EC circuit supports working memory and is maintained in specific connectivity patterns, with a theta band (2–8 Hz)-coordinated unidirectional influence from the hippocampus to the EC. Our findings reveal that dynamic unidirectional interactions within the hippocampal-EC circuit underlie working memory and can contribute to a mechanistic circuit understanding of working memory.
Selective inhibition of excitatory synaptic transmission alters the emergent bursting dynamics of in vitro neural networks
Authors: Weir Janelle Shari , Christiansen Nicholas , Sandvig Axel , Sandvig Ioanna
Published: September 2022

Neurons in vitro connect to each other and form neural networks that display emergent electrophysiological activity. This activity begins as spontaneous uncorrelated firing in the early phase of development, and as functional excitatory and inhibitory synapses mature, the activity typically emerges as spontaneous network bursts. Network bursts are events of coordinated global activation among many neurons interspersed with periods of silencing and are important for synaptic plasticity, neural information processing, and network computation. While bursting is the consequence of balanced excitatory-inhibitory (E/I) interactions, the functional mechanisms underlying their evolution from physiological to potentially pathophysiological states, such as decreasing or increasing in synchrony, are still poorly understood. Synaptic activity, especially that related to maturity of E/I synaptic transmission, is known to strongly influence these processes. In this study, we used selective chemogenetic inhibition to target and disrupt excitatory synaptic transmission in in vitro neural networks to study functional response and recovery of spontaneous network bursts over time. We found that over time, inhibition resulted in increases in both network burstiness and synchrony. Our results indicate that the disruption in excitatory synaptic transmission during early network development likely affected inhibitory synaptic maturity which resulted in an overall decrease in network inhibition at later stages. These findings lend support to the importance of E/I balance in maintaining physiological bursting dynamics and, conceivably, information processing capacity in neural networks.
Invariance of object detection in untrained deep neural networks
Authors: Cheon Jeonghwan , Baek Seungdae , Paik Se-Bum
Published: September 2022

The ability to perceive visual objects with various types of transformations, such as rotation, translation, and scaling, is crucial for consistent object recognition. In machine learning, invariant object detection for a network is often implemented by augmentation with a massive number of training images, but the mechanism of invariant object detection in biological brains — how invariance arises initially and whether it requires visual experience — remains elusive. Here, using a model neural network of the hierarchical visual pathway of the brain, we show that invariance of object detection can emerge spontaneously in the complete absence of learning. First, we found that units selective to a particular object class arise in randomly initialized networks even before visual training. Intriguingly, these units show robust tuning to images of each object class under a wide range of image transformation types, such as viewpoint rotation. We confirmed that this “innate” invariance of object selectivity enables untrained networks to perform an object-detection task robustly, even with images that have been significantly modulated. Our computational model predicts that invariant object tuning originates from combinations of non-invariant units via random feedforward projections, and we confirmed that the predicted profile of feedforward projections is observed in untrained networks. Our results suggest that invariance of object detection is an innate characteristic that can emerge spontaneously in random feedforward networks.

Highlights

Object-selective units spontaneously emerge in untrained deep neural networks

Object selectivity maintains robustly in a wide range of image transformations

Feedforward model can explain spontaneous emergence of the invariance

Innate invariance enables invariant object detection without learning to variations
Probing visual sensitivity and attention in mice using reverse correlation
Authors: Lehnert Jonas , Cha Kuwook , Yang Kerry , Zheng Daniel F. , Khadra Anmar , Cook Erik P. , Krishnaswamy Arjun
Published: September 2022

Visual attention is a fundamental cognitive operation that allows the brain to evoke behaviors based on the most important stimulus features. Although mouse models offer immense potential to gain a circuit-level understanding of this phenomenon, links between visual attention and behavioral decisions in mice are not well understood. Here, we describe a new behavioral task for mice that addresses this limitation. We trained mice to detect weak vertical bars in a background of checkerboard noise while audiovisual cues manipulated their spatial attention. We then modified a reverse correlation method from human studies to link behavioral decisions to stimulus locations and features. We show that mice attended to stimulus locations just rostral of their optical axis, which was highly sensitive for vertically oriented stimulus energy whose spatial frequency matched those of the weak vertical bars. We found that the tuning of sensitivity to orientation and spatial frequency grew stronger during training, was multiplicatively scaled with attention, and approached that of an ideal observer. These results provide a new task to measure spatial- and feature-based attention in mice which can be leveraged with new recording methods to uncover attentional circuits.
LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation
Authors: Rousse Juliette , Royer Pierre-Joseph , Evanno Gwenaëlle , Lheriteau Elsa , Ciron Carine , Salama Apolline , Shneiker Françoise , Duchi Roberto , Perota Andrea , Galli Cesare , Cozzi Emmanuele , Blancho Gilles , Duvaux Odile , Brouard Sophie , Soulillou Jean-Paul , Bach Jean-Marie , Vanhove Bernard
Published: September 2022

Anti-thymocyte/lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because of animal origin, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. To circumvent these drawbacks, LIS1 has been engineered as a glyco-humanized polyclonal antibody obtained by immunizing genetically modified pigs knocked out for major xeno-antigens αGal and Neu5Gc. It is Fc-silenced in humans and differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement and phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed-leucocyte-reactions. Preclinical evaluation in macaques showed that LIS1 impacted CD4+, CD8+ effector T cells but not T-reg, B cells or myeloid cells. Compared with rabbit ATG, LIS1 induced transient depletion of target T cells in the peripheral blood but was equivalent in preventing allograft rejection in a skin allograft model. The novel therapeutic modality of LIS1 might present advantages in induction treatment after organ transplantation by shortening the T-cell depletion period while maintaining adequate immunosuppression and reducing immunogenicity.
Sucrose-mediated formation and adhesion strength of Streptococcus mutans biofilms on titanium
Authors: Waldman Laura J. , Butera Tony , Boyd James D. , Grady Martha E.
Published: September 2022

Biofilms consist of bacterial cells surrounded by a matrix of extracellular polymeric substance (EPS), which protects the colony from many countermeasures, including antibiotic treatments. Biofilm EPS composition is affected by environmental factors. In the oral cavity, the presence of sucrose affects the growth of Streptococcus mutans that produce acids, eroding enamel and forming dental caries. Biofilm formation on dental implants commonly leads to severe infections and failure of the implant. This work determines the effect of sucrose concentration on biofilm EPS formation and adhesion of Streptococcus mutans, a common oral colonizer. Bacterial biofilms are grown with varying concentrations of sucrose on titanium substrates simulating dental implant material. Strategies for measuring adhesion for films such as peel tests are inadequate for biofilms, which have low cohesive strength and will fall apart when tensile loading is applied directly. The laser spallation technique is used to apply stress wave loading to the biofilm, causing the biofilm to delaminate at a critical tensile stress threshold. Biofilm formation and EPS structures are visualized at high magnification with scanning electron microscopy (SEM). Biofilm substrate coverage and adhesion strength of biofilms initially increase with increasing sucrose concentration, but then decrease as sucrose concentration continues to increase. For biofilms grown with non-zero concentrations of sucrose, S. mutans adhesion to the substrate is higher than the adhesion of osteoblast-like cells to the same substrates. These results suggest sucrose-mediated adhesion and formation on titanium of S. mutans biofilms may outcompete osteoblasts during osseointegration, which could explain higher rates of peri-implant disease associated with high sugar diets.
Single-Cell Transcriptomic Profiling of the Zebrafish Inner Ear Reveals Molecularly Distinct Hair Cell and Supporting Cell Subtypes
Authors: Shi Tuo , Beaulieu Marielle O. , Saunders Lauren M. , Fabian Peter , Trapnell Cole , Segil Neil , Crump J. Gage , Raible David W.
Published: September 2022

A major cause of human deafness and vestibular dysfunction is permanent loss of the mechanosensory hair cells of the inner ear. In non-mammalian vertebrates such as zebrafish, regeneration of missing hair cells can occur throughout life. While a comparative approach has the potential to reveal the basis of such differential regenerative ability, the degree to which the inner ears of fish and mammals share common hair cells and supporting cell types remains unresolved. Here we perform single-cell RNA sequencing of the zebrafish inner ear at embryonic through adult stages to catalog the diversity of hair cell and non-sensory supporting cells. We identify a putative progenitor population for hair cells and supporting cells, as well as distinct hair cells and supporting cell types in the maculae versus cristae. The hair cell and supporting cell types differ from those described for the lateral line system, a distributed mechanosensory organ in zebrafish in which most studies of hair cell regeneration have been conducted. In the maculae, we identify two subtypes of hair cells that share gene expression with mammalian striolar or extrastriolar hair cells. In situ hybridization reveals that these hair cell subtypes occupy distinct spatial domains within the two major macular organs, the utricle and saccule, consistent with the reported distinct electrophysiological properties of hair cells within these domains. These findings suggest that primitive specialization of spatially distinct striolar and extrastriolar hair cells likely arose in the last common ancestor of fish and mammals. The similarities of inner ear cell type composition between fish and mammals also support using zebrafish as a relevant model for understanding inner ear-specific hair cell function and regeneration.
RoboEM: automated 3D flight tracing for synaptic-resolution connectomics
Authors: Schmidt Martin , Motta Alessandro , Sievers Meike , Helmstaedter Moritz
Published: September 2022

Mapping neuronal networks from 3-dimensional electron microscopy data still poses substantial reconstruction challenges, in particular for thin axons. Currently available automated image segmentation methods, while substantially progressed, still require human proof reading for many types of connectomic analyses. RoboEM, an AI-based self-steering 3D flight system trained to navigate along neurites using only EM data as input, substantially improves automated state-of-the-art segmentations and replaces human proof reading for more complex connectomic analysis problems, yielding computational annotation cost for cortical connectomes about 400-fold lower than the cost of manual error correction.
Death Induced by Survival gene Elimination (DISE) is correlated with neurotoxicity in Alzheimer’s disease and aging
Authors: Paudel Bidur , Jeong Si-Yeon , Martinez Carolina Pena , Rickman Alexis , Haluck-Kangas Ashley , Bartom Elizabeth T. , Fredriksen Kristina , Affaneh Amira , Kessler John A. , Mazzulli Joseph R. , Murmann Andrea E. , Rogalski Emily , Geula Changiz , Ferreira Adriana , Heckmann Bradlee L. , Green Douglas R. , Sadleir Katherine R. , Vassar Robert , Peter Marcus E.
Published: September 2022

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways. Here, using Argonaute precipitation and RNAseq (Ago-RP-Seq), we analyze RISC-bound sRNAs to quantify 6mer seed toxicity in several model systems. In mouse AD models and aging brain, in induced pluripotent stem cell-derived neurons from AD patients, and in cells exposed to Aβ42 oligomers, RISC-bound sRNAs show a shift to more toxic 6mer seeds compared to controls. In contrast, in brains of “SuperAgers”, humans over age 80 who have superior memory performance, RISC-bound sRNAs are shifted to more nontoxic 6mer seeds. Cells depleted of nontoxic sRNAs are sensitized to Aβ42-induced cell death, and reintroducing nontoxic RNAs is protective. Altogether, the correlation between DISE and Aβ42 toxicity suggests that increasing the levels of nontoxic miRNAs in the brain or blocking the activity of toxic RISC-bound sRNAs could ameliorate neurodegeneration.
A membrane-associated light harvesting model is enabled by functionalized assemblies of gene-doubled TMV proteins
Authors: Dai Jing , Wilhelm Kiera B. , Bischoff Amanda J. , Pereira Jose H. , Dedeo Michel T. , García-Almedina Derek M. , Adams Paul D. , Groves Jay T. , Francis Matthew B.
Published: September 2022

Photosynthetic light harvesting requires efficient energy transfer within dynamic networks of light harvesting complexes embedded within phospholipid membranes. Artificial light harvesting models are valuable tools for understanding the structural features underpinning energy absorption and transfer within chromophore arrays. Most artificial light harvesting complexes are static or in the solution phase, rather than in a two-dimensional fluid environment as in natural photosynthesis. We have developed a method for attaching a protein-based light harvesting model to a supported lipid bilayer (SLB), which provides an extended fluid membrane surface stably associated with a solid substrate. The protein model consisted of the tobacco mosaic viral capsid proteins (TMV) that were gene-doubled to create a tandem dimer (dTMV). Assemblies of dTMV were shown to break the facial symmetry of the double disk to allow for differentiation between the disk faces. Single reactive lysine and cysteine residues were incorporated into opposing surfaces of each monomer of the dTMV assemblies. This allowed for the site-selective attachment of both chromophores for light absorption and a peptide for attachment to the SLB. A cysteine modification strategy using the enzyme tyrosinase was employed for the bioconjugation of a peptide containing a polyhistidine tag for association with SLBs. The dual-modified dTMV complexes showed significant association with SLBs and exhibited mobility on the bilayer. The techniques used herein offer a new method for protein-surface attachment and provide a platform for evaluating excited state energy transfer events in a dynamic, fully synthetic artificial light harvesting system.

Significance Statement

Here we have constructed a model photosynthetic membrane containing proteins, chromophores, lipids, and aqueous components, all of which can be modified in their composition. This model is based on an asymmetric disk assembly consisting of engineered tandem dimers of the tobacco mosaic viral capsid protein (dTMV). We have developed methods to achieve dye conjugation and attachment of a supported lipid bilayers (SLB) site selectively on distinct protein surfaces. These dye-labeled protein complexes exhibit mobility on the SLB, resulting in a dynamic model of light harvesting membranes using entirely synthetic components. Additionally, this unique asymmetric assembly of TMV and the facile methods for protein functionalization are expected to expand the tunability of model light harvesting systems.
Histone deacetylase 3 regulates microglial function through histone deacetylation
Authors: Meleady Laura , Towriss Morgan , Kim Jennifer , Bacarac Vince , Rowland Megan , Ciernia Annie Vogel
Published: September 2022

Background

As the primary innate immune cells of the brain microglia respond to damage and disease through pro-inflammatory release of cytokines and neuroinflammatory molecules. Histone acetylation is an activating transcriptional mark that regulates gene expression, which is altered in states of disease. Inhibition of histone deacetylase 3 (Hdac3) has been utilized in pre-clinical models of disease to dampen inflammation, but the molecular mechanisms underlying Hdac3’s regulation of inflammatory gene expression in microglia is not well understood.

Methods

Functional changes in immortalized microglia were characterized using a Hdac3 specific inhibitor RGFP966 in response to an immune challenge lipopolysaccharide (LPS). Flow cytometry and cleavage under tags & release using nucleases (CUT & RUN) were used to investigate global and promoter-specific histone acetylation changes, resulting in altered gene expression.

Results

Hdac3 inhibition enhanced neuroprotective functions of microglia in response to LPS through reduced nitric oxide release and increased baseline phagocytosis. Inhibition of Hdac3 enhanced histone acetylation globally and at specific gene loci, resulting in the release of gene repression at baseline and enhanced responses to LPS.

Conclusion

The findings suggest Hdac3 serves as a negative regulator of microglial gene expression, and that inhibition of Hdac3 facilitates the microglial response to inflammation and its subsequent resolution. Together, this work provides new mechanistic insights into therapeutic applications of Hdac3 inhibition which mediate reduced neuroinflammatory insults through microglial response.
Young Adults Use Whole-Body Feedback to Perceive Small Locomotor Disturbances
Authors: Liss Daniel J. , Carey Hannah D. , Allen Jessica L.
Published: September 2022

To prevent a fall when a disturbance to walking is encountered requires sensory information about the disturbance to be perceived, integrated, and then used to generate an appropriate corrective response. Prior research has shown that feedback of whole-body motion drives this corrective response. Here, we hypothesized that young adults also use whole-body motion to perceive locomotor disturbances. 15 subjects performed a locomotor discrimination task in which the supporting leg was slowed during stance every 8-12 steps to emulate subtle slips. The perception threshold of these disturbances was determined using a psychometrics approach and found to be 0.08 ± 0.03 m/s. Whole-body feedback was examined through center-of-mass (CoM) kinematics and whole-body angular momentum (WBAM). Perturbation-induced deviations of CoM and WBAM were calculated in response to the two perturbation levels nearest each subject’s perception threshold. Consistent with our hypothesis, we identified significantly higher perturbation induced deviations for perceived perturbations in sagittal-plane WBAM, anteroposterior CoM velocity, and mediolateral CoM position, velocity, and acceleration. Because whole body motion is not sensed directly but instead arises from the integration of various sensory feedback signals, we also explored local sensory feedback contributions to the perception of locomotor disturbances. Local sensory feedback was estimated through kinematic analogues of vision (head angle), vestibular (head angular velocity), proprioception (i.e., sagittal hip, knee, and ankle angles), and somatosensation (i.e., anterior-posterior & mediolateral center-of-pressure, COP). We identified significantly higher perturbation induced deviations for perceived perturbations in sagittal-plane ankle angle only. These results provide evidence for both whole-body feedback and ankle proprioception as important for the perception of subtle slip-like locomotor disturbances in young adults. Our interpretation is ankle proprioception is a dominant contributor to estimates of whole-body motion to perceive locomotor disturbances.
Proactive interhemispheric disinhibition supports response preparation during selective stopping
Authors: Wadsley Corey G. , Cirillo John , Nieuwenhuys Arne , Byblow Winston D.
Published: September 2022

Response inhibition is essential for terminating inappropriate actions. A substantial delay may occur in the response of the non-stopped effector when only part of a multi-effector action is terminated. This stopping-interference effect has been attributed to nonselective response inhibition processes and can be reduced with proactive cueing. This study aimed to elucidate the role of interhemispheric primary motor cortex (M1-M1) influences during selective stopping with proactive cueing. We hypothesized that stopping-interference would be reduced as stopping certainty increased, owing to proactive recruitment of interhemispheric facilitation or interhemispheric inhibition when cued to respond or stop, respectively. Twenty-three healthy human participants performed a bimanual anticipatory response inhibition paradigm with cues signaling the likelihood of a stop-signal occurring. Dual-coil transcranial magnetic stimulation was used to determine corticomotor excitability (CME), interhemispheric inhibition (IHI), and interhemispheric facilitation (IHF) in the left hand at rest and during response preparation. Response times slowed and stopping-interference decreased with cues signaling increased stopping certainty. Proactive response inhibition was marked by a reduced rate of rise and faster cancel time in electromyographical bursts during stopping. There was a nonselective release of IHI but not CME from rest to in-task response preparation, while IHF was not observed in either context. An effector-specific CME but not IHF or IHI reduction was observed when the left hand was cued to stop. These findings indicate that the stopping-interference effect can be reduced through proactive suppression. Interhemispheric M1-M1 channels modulate inhibitory tone that supports responding, but not selective stopping, in a proactive response inhibition context.

Significance statement

Response inhibition is essential for terminating inappropriate actions and, in some cases, may be required for only part of a multi-effector action. The present study examined interhemispheric influences between the primary motor cortices during selective stopping with proactive cueing. Stopping selectivity was greater with increased stopping certainty and marked by proactive response inhibition of the hand cued to stop. Inhibitory interhemispheric influences were released during response preparation but were not affected by proactive cueing. These findings indicate that between-hand stopping can be selective with proactive cueing, but cue-related improvements are unlikely to reflect advance engagement of interhemispheric influences between primary motor cortices.
Specimen, Biological Structure, and Spatial Ontologies in Support of a Human Reference Atlas
Authors: Herr Bruce W. , Hardi Josef , Quardokus Ellen M. , Bueckle Andreas , Chen Lu , Wang Fusheng , Caron Anita R. , Osumi-Sutherland David , Musen Mark A. , Börner Katy
Published: September 2022

The Human Reference Atlas (HRA) is defined as a comprehensive, three-dimensional (3D) atlas of all the cells in the healthy human body. It is compiled by an international team of experts that develop standard terminologies linked to 3D reference objects describing anatomical structures. The third HRA release (v1.2) covers spatial reference data and ontology annotations for 26 organs. Experts access the HRA annotations via spreadsheets and view reference models in 3D editing tools. This paper introduces the Common Coordinate Framework Ontology (CCFO) v2.0.1 that interlinks specimen, biological structure, and spatial data together with the CCF API which makes the HRA programmatically accessible and interoperable with Linked Open Data (LOD). We detail how real-world user needs and experimental data guide CCFO design and implementation, present CCFO classes and properties together with examples of their usage, and report on technical validation performed. The CCFO graph database and API are used in the HuBMAP portal, Virtual Reality Organ Gallery, and other applications that support data queries across multiple, heterogeneous sources.
Synchronous multi-segmental activity between metachronal waves controls locomotion speed in Drosophila larvae
Authors: Liu Yingtao , Hasegawa Eri , Nose Akinao , Zwart Maarten F. , Kohsaka Hiroshi
Published: September 2022

The ability to adjust the speed of locomotion is essential for survival. In limbed animals, the frequency of locomotion is modulated primarily by changing the duration of the stance phase. The underlying neural mechanisms of this selective modulation remain an open question. Here, we report a neural circuit controlling a similarly selective adjustment of locomotion frequency in Drosophila larvae. Drosophila larvae crawl using peristaltic waves of muscle contractions. We find that larvae adjust the frequency of locomotion mostly by varying the time between consecutive contraction waves, reminiscent of limbed locomotion. A specific set of muscles, the lateral transverse (LT) muscles, co-contract in all segments during this phase, the duration of which sets the duration of the interwave phase. We identify two types of GABAergic interneurons in the LT neural network, premotor neuron A26f and its presynaptic partner A31c, which exhibit segmentally synchronized activity and control locomotor frequency by setting the amplitude and duration of LT muscle contractions. Altogether, our results reveal an inhibitory central circuit that sets the frequency of locomotion by controlling the duration of the period in between peristaltic waves. Further analysis of the descending inputs onto this circuit will help understand the higher control of this selective modulation.
Postoperative mortality analysis of national Japanese Diagnosis Procedure Combination database with a focus on regional comparisons and changes over time
Authors: Kunisawa Susumu
Published: September 2022

PURPOSE

This study aimed to investigate postoperative mortality from all surgeries at the prefecture level using nationwide database, Japanese Diagnosis Procedure Combination (DPC) database, and to show those with visible changes over time or variations among areas.

METHODS

Data were provided in accordance with the guidelines and application as indicated on the Ministry of Health, Labor and Welfare (MHLW), Japan. The number of cases and in-hospital mortality were calculated for each representative surgery for each hospitalization by fiscal year of discharge from 2011 to 2018 and by prefecture. Values of ≥10 in each aggregated data cell are presented.

RESULTS

The aggregated result data contain 474,154 records, with about 2000 different surgical codes. Only in the 16,890 data, more than 10 mortalities were recorded, which can be used in the mortality analysis. In the analyses of artificial head insertion, cerebral aneurysm neck clipping, coronary artery and aortic bypass grafting, and tracheotomy, regional differences and a declining trend were observed in some categories.

CONCLUSION

In addition to considering categories that can be used in the analysis, careful consideration must be given to the inclusion of background context such as quality of care.
Economic evaluation of participatory women’s groups scaled up by the public health system to improve birth outcomes in Jharkhand, eastern India
Authors: Haghparast-Bidgoli Hassan , Ojha Amit , Gope Rajkumar , Rath Shibanand , Pradhan Hemanta , Rath Suchitra , Kumar Amit , Nath Vikash , Basu Parabita , Copas Andrew , Houweling Tanja A.J. , Minz Akay , Baskey Pradeep , Ahmed Manir , Chakravarthy Vasudha , Mahanta Riza , Palmer Tom , Skordis Jolene , Nair Nirmala , Tripathy Prasanta , Prost Audrey
Published: September 2022

An estimated 2.4 million newborn infants died in 2020, 80% of them in sub-Saharan Africa and South Asia. To achieve the Sustainable Development Target for neonatal mortality reduction, countries with high mortality need to implement evidence-based, cost-effective interventions at scale. Our study aimed to estimate the cost, cost-effectiveness, and benefit-cost ratio of a participatory women’s groups intervention scaled up by the public health system in Jharkhand, eastern India. The intervention was evaluated through a pragmatic cluster non-randomised controlled trial in six districts. We estimated the cost of the intervention from a provider perspective, with a 42-month time horizon for 20 districts. We estimated costs using a combination of top-down and bottom-up approaches. All costs were adjusted for inflation, discounted at 3% per year, and converted to 2020 International Dollars (INT$). Incremental cost-effectiveness ratios (ICERs) were estimated using extrapolated effect sizes for the impact of the intervention in 20 districts, in terms of cost per neonatal deaths averted and cost per life year saved. We assessed the impact of uncertainty on results through one-way and probabilistic sensitivity analyses. We also estimated benefit-cost ratio using a benefit transfer approach. Total intervention costs for 20 districts were INT$ 15,017,396. The intervention covered an estimated 1.6 million livebirths across 20 districts, translating to INT$ 9.4 per livebirth covered. ICERs were estimated at INT$ 1,272 per neonatal death averted or INT$ 41 per life year saved. Net benefit estimates ranged from INT$ 1,046 million to INT$ 3,254 million, and benefit-cost ratios from 71 to 218. Our study suggests that participatory women’s groups scaled up by the public health system are highly cost-effective in improving neonatal survival and have a very favourable return on investment. The intervention can be scaled up in similar settings within India and other countries.
Effectiveness and acceptability of an opt-out nudge to promote influenza vaccination among medical residents in Nice, France: a randomized controlled trial
Authors: Barbaroux Adriaan , Serati Ilaria
Published: September 2022

Background

Nudges have been proposed as an effective tool to promote influenza vaccination of healthcare workers. To be successful, nudges must match the needs of the target healthcare workers population and be acceptable.

Objective

To evaluate the effectiveness and the acceptability of an opt-out nudge promoting influenza vaccination among medical residents.

Methods

The hypothesis were that an opt-out nudge would be effective, better accepted when applied to patients than to residents, and that prior exposure to a nudge and being vaccinated increase its acceptability and residents’ sense of autonomy (the feeling of being in control of their choice about whether to get vaccinated). Residents were randomly divided into two parallel experimental arms: a nudge group and a control group. The nudge consisted in offering participants an appointment for a flu shot, while leaving them the choice to refuse or to reschedule it.

Results

The analysis included 260 residents. Residents in nudge group were more likely to be vaccinated than residents in control group. There was a strong consensus among the residents that it is very acceptable to nudge their peers and patients. Acceptability for residents and patients did not differ. Acceptability was better among residents exposed to the nudge and residents who were vaccinated. Residents considered that the nudge does not reduce their control over whether to get a flu shot. The sense of autonomy was associated with nudge’s acceptability.

Conclusion

An opt-out nudge to promote influenza vaccination among medical residents can be effective and very well accepted. These data suggest that this approach can complement other vaccination promoting interventions and be eventually extended to other healthcare workers’ categories and to general population, but should consider its ethical implications. More studies are needed to assess the nudge’s effectiveness and acceptability on other populations.

Key messages

Nudging is one of the most efficient techniques to improve vaccination coverage.

Changing defaults may be effective in promoting vaccination and well accepted.

Changing defaults does not lower the feeling of control over choices.

The sense of autonomy related to a nudge is correlated to its acceptability.

Behavior adoption increases the sense of autonomy related to a nudge.

Using defaults for nudge should take into account the ethical implications.
Teacher- and Parent-Reported Trajectories of Challenging Behavior Among Individuals with Autism
Authors: Rosen Nicole E. , Schiltz Hillary K. , Lord Catherine
Published: September 2022

People with autism spectrum disorder (ASD) frequently exhibit challenging behaviors throughout the lifespan, which can have pervasive effects on quality of life. Challenging behaviors have been shown to change over time as a function of various individual-level factors (e.g., cognitive ability), yet research is primarily limited to parent-reported measures. To expand upon this work, the present study aimed to examine trajectories of teacher- and parent-reported challenging behaviors (i.e., hyperactivity, irritability, social withdrawal) and to test whether predictors including ASD features, verbal intelligence quotient, and consistency in reporter impact these trajectories among individuals with ASD or non-spectrum delays from ages 9 to 18. Multilevel models revealed that, according to both teacher and parent report, participants showed the greatest improvement in hyperactivity, less but still notable improvement in irritability, and stable levels of social withdrawal over time. Higher cognitive ability and fewer ASD features emerged as important individual differences related to fewer challenging behaviors. The multi-informant perspective and longitudinal design provide novel insight into the manifestations of these challenging behaviors across different contexts and across time. Findings highlight the importance of addressing challenging behaviors as these behaviors tend to persist throughout development in both home and school contexts, especially for children with particular diagnostic and cognitive profiles.

Lay Summary

According to both teacher and parent report, youth with autism showed the greatest improvement in hyperactivity, less but still notable improvement in irritability, and stable levels of social withdrawal from school-age to adolescence. Fewer autism features and greater cognitive ability were related to fewer challenging behaviors. This study’s use of multiple reporters (e.g., teachers and parents) across time provided insight into the persistence of challenging behaviors in the home and school settings and across development.