bluuebunny/crossref_metadata_2025 huggingface dataset:
Twist and chew: three-dimensional tongue kinematics during chewing in macaque primates
Authors: Feilich Kara L. , Laurence-Chasen J. D. , Orsbon Courtney , Gidmark Nicholas J. , Ross Callum F.
Published: December 2021

Three-dimensional (3D) tongue movements are central to performance of feeding functions by mammals and other tetrapods, but 3D tongue kinematics during feeding are poorly understood. Tongue kinematics were recorded during grape chewing by macaque primates using biplanar videoradiography. Complex shape changes in the tongue during chewing are dominated by a combination of flexion in the tongue's sagittal planes and roll about its long axis. As hypothesized for humans, in macaques during tongue retraction, the middle (molar region) of the tongue rolls to the chewing (working) side simultaneous with sagittal flexion, while the tongue tip flexes to the other (balancing) side. Twisting and flexion reach their maxima early in the fast close phase of chewing cycles, positioning the food bolus between the approaching teeth prior to the power stroke. Although 3D tongue kinematics undoubtedly vary with food type, the mechanical role of this movement—placing the food bolus on the post-canine teeth for breakdown—is likely to be a powerful constraint on tongue kinematics during this phase of the chewing cycle. The muscular drivers of these movements are likely to include a combination of intrinsic and extrinsic tongue muscles.
Long-wave equation for a confined ferrofluid interface: periodic interfacial waves as dissipative solitons
Authors: Yu Zongxin , Christov Ivan C.
Published: December 2021

We study the dynamics of a ferrofluid thin film confined in a Hele-Shaw cell, and subjected to a tilted non-uniform magnetic field. It is shown that the interface between the ferrofluid and an inviscid outer fluid (air) supports travelling waves, governed by a novel modified Kuramoto–Sivashinsky-type equation derived under the long-wave approximation. The balance between energy production and dissipation in this long-wave equation allows for the existence of dissipative solitons. These permanent travelling waves’ propagation velocity and profile shape are shown to be tunable via the external magnetic field. A multiple-scale analysis is performed to obtain the correction to the linear prediction of the propagation velocity, and to reveal how the nonlinearity arrests the linear instability. The travelling periodic interfacial waves discovered are identified as fixed points in an energy phase plane. It is shown that transitions between states (wave profiles) occur. These transitions are explained via the spectral stability of the travelling waves. Interestingly, multi-periodic waves, which are a non-integrable analogue of the double cnoidal wave, are also found to propagate under the model long-wave equation. These multi-periodic solutions are investigated numerically, and they are found to be long-lived transients, but ultimately abruptly transition to one of the stable periodic states identified.
Nonlinear system of PT-symmetric excitations and Toda vibrations integrable by the Darboux–Bäcklund dressing method
Authors: Vakhnenko Oleksiy O. , Verchenko Andriy P.
Published: December 2021

The nonlinear dynamics of coupledPT-symmetric excitations and Toda-like vibrations on a one-dimensional lattice are studied analytically and elucidated graphically. The nonlinear exciton-phonon system as the whole is shown to be integrable in the Lax sense inasmuch as it admits the zero-curvature representation supported by the auxiliary linear problem of third order. Inspired by this fact, we have developed in detail the Darboux–Bäcklund integration technique appropriate to generate a higher-rank crop solution by dressing a lower-rank (supposedly known) seed solution. In the framework of this approach, we have found a rather non-trivial four-component analytical solution exhibiting the crossover between the monopole and dipole regimes in the spatial distribution of intra-site excitations. This effect is inseparable from the pronounced mutual influence between the interacting subsystems in the form of specific nonlinear superposition of two essentially distinct types of travelling waves. We have established the criterion of monopole-dipole transition based upon the interplay between the localization parameter of Toda mode and the inter-subsystem coupling parameter.
Investigating climate tipping points under various emission reduction and carbon capture scenarios with a stochastic climate model
Authors: Mendez Alexander , Farazmand Mohammad
Published: December 2021

We study the mitigation of climate tipping point transitions using an energy balance model. The evolution of the global mean surface temperature is coupled with the

CO
2

concentration through the green-house effect. We model the

CO
2

concentration with a stochastic delay differential equation (SDDE), accounting for various carbon emission and capture scenarios. The resulting coupled system of SDDEs exhibits a tipping point phenomena: if

CO
2

concentration exceeds a critical threshold (around

478
 
ppm

), the temperature experiences an abrupt increase of about six degrees Celsius. We show that the

CO
2

concentration exhibits a transient growth which may cause a climate tipping point, even if the concentration decays asymptotically. We derive a rigorous upper bound for the

CO
2

evolution which quantifies its transient and asymptotic growths, and provides sufficient conditions for evading the climate tipping point. Combining this upper bound with Monte Carlo simulations of the stochastic climate model, we investigate the emission reduction and carbon capture scenarios that would avert the tipping point.
Evidence for a vocal signature in the rat and its reinforcing effects: a key role for the subthalamic nucleus
Authors: Vielle Cassandre , Montanari Christian , Pelloux Yann , Baunez Christelle
Published: December 2021

Although rodents have a well-structured vocal form of communication, like humans and non-human primates, there is, to date, no evidence for a vocal signature in the well-known 50- and 22-kHz ultrasonic vocalizations (USVs) emitted by rats. Here, we show that rats can recognize the identity of the USV emitter since they choose to preferentially self-administer playback of 50-kHz USVs emitted by a stranger rat over those of their cagemate. In a second experiment, we show that only stranger, but not familiar, 50-kHz USVs reduce cocaine self-administration. Finally, to study the neurobiological substrate of these processes, we have shown that subthalamic nucleus (STN)-lesioned rats did not lever press much for any USV playback, whatever their emotional valence, nor did they seem able to differentiate familiar from stranger peer. Advocating for the existence of a vocal signature in rats, these results highlight the importance of ultrasonic communication in the socio-affective influence of behaviour, such as the influence of proximal social factors on drug consumption and confirm the role of the STN on this influence.
Sfaira accelerates data and model reuse in single cell genomics
Authors: Fischer David S. , Dony Leander , König Martin , Moeed Abdul , Zappia Luke , Tritschler Sophie , Holmberg Olle , Aliee Hananeh , Theis Fabian J.
Published: December 2021

Exploratory analysis of single-cell RNA-seq data sets is currently based on statistical and machine learning models that are adapted to each new data set from scratch. A typical analysis workflow includes a choice of dimensionality reduction, selection of clustering parameters, and mapping of prior annotation. These steps typically require several iterations and can take up significant time in many single-cell RNA-seq projects. Here, we introduce sfaira, which is a single-cell data and model zoo which houses data sets as well as pre-trained models. The data zoo is designed to facilitate the fast and easy contribution of data sets, interfacing to a large community of data providers. Sfaira currently includes 233 data sets across 45 organs and 3.1 million cells in both human and mouse. Using these data sets we have trained eight different example model classes, such as autoencoders and logistic cell type predictors: The infrastructure of sfaira is model agnostic and allows training und usage of many previously published models. Sfaira directly aids in exploratory data analysis by replacing embedding and cell type annotation workflows with end-to-end pre-trained parametric models. As further example use cases for sfaira, we demonstrate the extraction of gene-centric data statistics across many tissues, improved usage of cell type labels at different levels of coarseness, and an application for learning interpretable models through data regularization on extremely diverse data sets.
The alopecia areata phenotype is induced by the water avoidance stress test incchcr1-deficient mice
Authors: Zhao Qiao-Feng , Yoshihara Nagisa , Takagi Atsushi , Komiyama Etsuko , Oka Akira , Ikeda Shigaku
Published: December 2021

Background

We recently discovered a nonsynonymous variant in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene within the alopecia areata (AA) risk haplotype; mice engineered to carry the risk allele displayed a hair loss phenotype.

Objective

To further investigate the involvement of theCCHCR1gene in AA pathogenesis.

Methods

We developed an AA model using C57BL/6Ncchcr1gene knockout mice. Mice (6-8 weeks) were divided into two groups:cchcr1-/-mice and wild-type (WT) mice. Both groups were subjected to a water avoidance stress (WAS) test.

Results

Eight weeks after the WAS test, 25% ofcchcr1mice exhibited noninflammatory foci of alopecia on the dorsal skin. The foci resembled human AA in terms of gross morphology, trichoscopic findings and histological findings.

Conclusions

Our results strongly suggest thatCCHCR1is associated with AA pathogenesis and thatcchcr1-/-mice are a good model for investigating AA.

Author summary

Alopecia areata is thought to affect 1-2% of the population. In severe alopecia areata, changes in appearance significantly reduce the patient’s quality of life, but there is no established treatment. Its pathogenic mechanism is thought to cause an autoimmune disease of the hair bulb of growing hair. Many genes and factors associated with AA onset form a background that easily causes such an immune reaction, and the causative genes related to alopecia areata are being elucidated worldwide. We were able to identify theCCHCR1gene as one of the causative genes by genome analysis. In this study, we createdCCHCR1-deficient mice using Cre/loxP technology and confirmed that 25% ofCCHCR1-deficient mice that underwent the WAS test for psychological stimulation developed hair loss similar to that observed in human alopecia areata. This suggests that theCCHCR1gene is a disease susceptibility gene for alopecia areata.
A measure of concurrent neural firing activity based on mutual information
Authors: Mijatovic Gorana , Loncar-Turukalo Tatjana , Bozanic Nebojsa , Faes Luca
Published: December 2021

Multiple methods have been developed in an attempt to quantify stimulus-induced neural coordination and to understand internal coordination of neuronal responses by examining the synchronization phenomena in neural discharge patterns. In this work we propose a novel approach to estimate the degree of concomitant firing between two neural units, based on a modified form of mutual information (MI) applied to a two-state representation of the firing activity. The binary profile of each single unit unfolds its discharge activity in time by decomposition into the state of neural quiescence/low activity and state of moderate firing/bursting. Then, the MI computed between the two binary streams is normalized by their minimum entropy and is taken as positive or negative depending on the prevalence of identical or opposite concomitant states. The resulting measure, denoted as Concurrent Firing Index based on MI (CFIMI), relies on a single input parameter and is otherwise assumption-free and symmetric. Exhaustive validation was carried out through controlled experiments in three simulation scenarios, showing that CFIMIis independent on firing rate and recording duration, and is sensitive to correlated and anti-correlated firing patterns. Its ability to detect non-correlated activity was assessed using ad-hoc surrogate data. Moreover, the evaluation of CFIMIon experimental recordings of spiking activity in retinal ganglion cells brought insights into the changes of neural synchrony over time. The proposed measure offers a novel perspective on the estimation of neural synchrony, providing information on the co-occurrence of firing states in the two analyzed trains over longer temporal scales compared to existing measures.
NIH Funding of COVID-19 Research in 2020: a Cross Sectional Study
Authors: Balaguru Logesvar , Dun Chen , Meyer Andrea , Hennayake Sanuri , Walsh Christi M. , Kung Christopher , Cary Brittany , Migliarese Frank , Dai Tinglong , Bai Ge , Sutcliffe Kathleen , Makary Martin A.
Published: December 2021

Objective

This study aims to characterize and evaluate the NIH’s grant allocation pattern of COVID-19 research.

Design

Cross sectional study

Setting

COVID-19 NIH RePORTER Dataset was used to identify COVID-19 relevant grants.

Participants

1,108 grants allocated to COVID-19 research.

Main Outcomes and Measures

The primary outcome was to determine the number of grants and funding amount the NIH allocated for COVID-19 by research type and clinical/scientific area. The secondary outcome was to calculate the time from the funding opportunity announcement to the award notice date.

Results

The NIH awarded a total of 56,169 grants in 2020, of which 2.0% (n=1,108) were allocated for COVID-19 research. The NIH had a $42 billion budget that year, of which 5.3% ($2.2 billion) was allocated to COVID-19 research. The most common clinical/scientific areas were social determinants of health (n=278, 8.5% of COVID-19 funding), immunology (n=211, 25.8%), and pharmaceutical interventions research (n=208, 47.6%). There were 104 grants studying COVID-19 non-pharmaceutical interventions, of which 2 grants studied the efficacy of face masks and 6 studied the efficacy of social distancing. Of the 83 COVID-19 funded grants on transmission, 5 were awarded to study airborne transmission of COVID-19, and 2 grants on transmission of COVID-19 in schools. The average time from the funding opportunity announcement to the award notice date was 151 days (SD: ±57.9).

Conclusion

In the first year of the pandemic, the NIH diverted a small fraction of its budget to COVID-19 research. Future health emergencies will require research funding to pivot in a timely fashion and funding levels to be proportional to the anticipated burden of disease in the population.
SARS-CoV-2 and endemic coronaviruses: Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children
Authors: Frutos Aaron M , Kubale John , Kuan Guillermina , Ojeda Sergio , Vydiswaran Nivea , Sanchez Nery , Plazaola Miguel , Patel May , Lopez Roger , Balmaseda Angel , Gordon Aubree
Published: December 2021

It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.
Inferring variant-specific effective reproduction numbers from combined case and sequencing data
Authors: Figgins Marlin D , Bedford Trevor
Published: December 2021

Accurately estimating relative transmission rates of SARS-CoV-2 variants remains a scientific and public health priority. Recent studies have used the sample proportions of different variants from genetic sequence data to describe variant frequency dynamics and relative transmission rates, but frequencies alone cannot capture the rich epidemiological behavior of SARS-CoV-2. Here, we extend methods for infer- ring the effective reproduction number of an epidemic using confirmed case data to jointly estimate variant-specific effective reproduction numbers and frequencies of co-circulating variants using cases and sequences across states in the US from January 2021 to March 2022. Our method can be used to infer structured relationships be- tween effective reproduction numbers across time series allowing us to estimate fixed variant-specific growth advantages. We use this model to estimate the effective reproduction number of SARS-CoV-2 Variants of Concern and Variants of Interest in the United States and estimate consistent growth advantages of particular variants across different locations.
Proteomic Characterization of Acute Kidney Injury in Patients Hospitalized with SARS-CoV2 Infection
Authors: Paranjpe Ishan , Jayaraman Pushkala , Su Chen-Yang , Zhou Sirui , Chen Steven , Thompson Ryan , Del Valle Diane Marie , Kenigsberg Ephraim , Zhao Shan , Jaladanki Suraj , Chaudhary Kumardeep , Ascolillo Steven , Vaid Akhil , Kumar Arvind , Kozlova Edgar , Paranjpe Manish , O’Hagan Ross , Kamat Samir , Gulamali Faris F. , Kauffman Justin , Xie Hui , Harris Joceyln , Patel Manishkumar , Argueta Kimberly , Batchelor Craig , Nie Kai , Dellepiane Sergio , Scott Leisha , Levin Matthew A , He John Cijiang , Suarez-Farinas Mayte , Coca Steven G , Chan Lili , Azeloglu Evren U , Schadt Eric , Beckmann Noam , Gnjatic Sacha , Merad Miram , Kim-Schulze Seunghee , Richards Brent , Glicksberg Benjamin S , Charney Alexander W , Nadkarni Girish N
Published: December 2021

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of ∼4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.
The age-dependent immunogenicity after two doses of MVC-COV1901 vaccine
Authors: Lien Chia En , Lin Yi-Jiun , Lin Yi-Ling , Tai I-Chen , Chen Charles
Published: December 2021

A post-hoc analysis of the phase 2 data was performed for the SARS-COV-2 subunit protein vaccine MVC-COV1901. Anti-spike IgG, neutralization assays with live virus and pseudovirus were used to demonstrate age-dependent vaccine-induced antibody response to the vaccine. Results showed that an association exists between age and immune responses to the vaccine, providing further support for the need of booster shots, especially for the older age groups.
Vaccine breakthrough and the invasion dynamics of SARS-CoV-2 variants
Authors: Saad-Roy Chadi M. , Levin Simon A. , Gog Julia R. , Farrar Jeremy , Wagner Caroline E. , Metcalf C. Jessica E. , Grenfell Bryan T.
Published: December 2021

Vaccination provides a powerful tool for mitigating and controlling the COVID-19 pandemic. However, a number of factors reduce these potential benefits. The first problem arises from heterogeneities in vaccine supply and uptake: from global inequities in vaccine distribution, to local variations in uptake derived from vaccine hesitancy. The second complexity is biological: though several COVID-19 vaccines offer substantial protection against infection and disease, ‘breakthrough’ reinfection of vaccinees (and subsequent retransmission from these individuals) can occur, driven especially by new viral variants. Here, using a simple epidemiological model, we show that the combination of infection of remaining susceptible individuals and breakthrough infections of vaccinees can have significant effects in promoting infection of invading variants, even when vaccination rates are high and onward transmission from vaccinees relatively weak. Elaborations of the model show how heterogeneities in immunity and mixing between vaccinated and unvaccinated sub-populations modulate these effects, underlining the importance of quantifying these variables. Overall, our results indicate that high vaccination coverage still leaves no room for complacency if variants are circulating that can elude immunity, even if this happens at very low rates.
Modelling the recovery of elective waiting lists following COVID-19: scenario projections for England
Authors: Howlett Nicholas C , Wood Richard M
Published: December 2021

Background

A significant indirect impact of COVID-19 has been the increasing elective waiting times observed in many countries. In England’s National Health Service, the waiting list has grown from 4.4 million in February 2020 to 5.7m by August 2021.

Aims

The objective of this study was to estimate the trajectory of future waiting list size and waiting times to December 2025.

Methods

A scenario analysis was performed using computer simulation and publicly available data as of November 2021. Future demand assumed a phased return of various proportions (0, 25, 50 and 75%) of the estimated 7.1 million referrals ‘missed’ during the pandemic. Future capacity assumed 90, 100 and 110% of that provided in the 12 months immediately before the pandemic.

Results

As a worst case, the waiting list would reach 13.6m (95% CI: 12.4m to 15.6m) by Autumn 2022, if 75% of missed referrals returned and only 90% of pre pandemic capacity could be achieved. Under this scenario, the proportion of patients waiting under 18 weeks would reduce from 67.6% in August 2021 to 42.2% (37.4% to 46.2%) with the number waiting over 52 weeks reaching 1.6m (0.8m to 3.1m) by Summer 2023. At this time, 29.0% (21.3% to 36.8%) of patients would be leaving the waiting list before treatment. Waiting lists would remain pressured under even the most optimistic of scenarios considered, with 18-week performance struggling to maintain 60% (against the 92% constitutional target).

Conclusions

This study reveals the long-term challenge for the NHS in recovering elective waiting lists as well as potential implications for patient outcomes and experience.
Determinants of RSV epidemiology following suppression through pandemic contact restrictions
Authors: Koltai Mihaly , Krauer Fabienne , Hodgson David , van Leeuwen Edwin , Treskova-Schwarzbach Marina , Jit Mark , Flasche Stefan
Published: December 2021

Introduction

COVID-19 related non-pharmaceutical interventions (NPIs) led to a suppression of RSV circulation in winter 2020/21 throughout Europe and an off-season resurgence in Summer 2021 in several European countries. We explore how such temporary interruption may shape future RSV epidemiology and what factors drive the associated uncertainty.

Methods

We developed an age-structured dynamic transmission model to simulate pre-pandemic RSV infections and hospitalisations. We sampled parameters governing RSV seasonality, immunity acquisition and duration of post-infection immunity and retained those simulations that qualitatively fit the UK’s pre-pandemic epidemiology. From Spring 2020 to Summer 2021 we assumed a 50% reduced contact frequency, returning to pre-pandemic levels from mid-May 2021. We simulated transmission forwards until 2023 and evaluated the impact of the sampled parameters on the projected trajectories of RSV hospitalisations.

Results

Following a lifting of contact restrictions in summer 2021 the model replicated an out-of-season resurgence of RSV. If unmitigated, paediatric RSV hospitalisation incidence in the 2021/22 season was projected to increase by 32% to 67% compared to pre-pandemic levels. The size of the increase depended most on whether infection risk was primarily determined by immunity acquired from previous exposure or general immune maturation. While infants were less affected, the increase in seasonal hospitalisation incidence exceeded 100% in 1-2 year old children and 275% in 2-5 year old children, respectively, in some simulations where immunity from previous exposure dominated. Consequently, the average age of a case increased by 1 to 5 months, most markedly if there was strong immunity acquisition from previous exposure. If immunity to infection was largely determined by age rather than previous exposure, the 2021/22 season started earlier and lasted longer but with a peak incidence lower or similar to pre-pandemic levels. For subsequent seasons, simulations suggested a quick return to pre-pandemic epidemiology, with some slight oscillating behaviour possible depending on the strength of post-exposure immunity.

Conclusion

COVID-19 mitigation measures stopped RSV circulation in the 2020/21 season and generated immunity debt that will likely lead to a temporary increase in RSV burden in the season following the lifting of restrictions, particularly in 1 to 5 year old children. A more accurate understanding of immunity drivers for RSV is needed to better predict the size of such an increase and plan a potential expansion of pharmaceutical and non-pharmaceutical mitigation measures.
Angle-Tuned TMS Coils: Building Blocks for Brain Stimulation with Improved Depth-Spread Performance
Authors: Bagherzadeh Hedyeh , Meng Qinglei , Deng Zhi-De , Lu Hanbing , Hong Elliott , Yang Yihong , Choa Fow-Sen
Published: December 2021

Coordinated whole-brain neural dynamics are essential for proper control of the functionality of different brain systems. Multisite simultaneous or sequential stimulations may provide tools for mechanistic studies of brain functions and the treatment of neuropsychiatric disorders. Conventional circular and figure-8 Transcranial Magnetic Stimulation (TMS) coils occupy a large footprint, and it is difficult to reach desired multiple stimulation locations with close proximity for comprehensive multisite stimulations. These conventional coils, limited by the depth-spread tradeoff rule, also lack the required focality for targeted stimulations. In this work, we propose and demonstrate angle-tuned TMS (AT) coils with an intrinsically reduced footprint with their geometric arrangements of stacking and angle tuning. The stimulation depth can be adjusted with the coil stacking number, and the field spread can be reduced by increasing the tilted wire-wrapping angle of the coils. With either smaller or larger diameter coils than a standard commercial figure-8 coil, we show, theoretically and experimentally, improved field decay rate and field intensity, and the reduced field spread spot size at different stimulation depths. These results indicate that the proposed novel coil establishes a better depth-spread tradeoff curve than the conventional circular and figure-8 coils. This coil design has a simple and single element structure and provides a promising solution for an improved multisite brain stimulation performance and serves as the building block of more complex coils for further depth-spread improvements.
Differentiation signals from glia are fine-tuned to set neuronal numbers during development
Authors: Prasad Anadika R. , Lago-Baldaia Inês , Bostock Matthew P. , Housseini Zaynab , Fernandes Vilaiwan M.
Published: December 2021

Neural circuit formation and function require that diverse neurons are specified in appropriate numbers. Known strategies for controlling neuronal numbers involve regulating either cell proliferation or survival. We used the Drosophila visual system to probe how neuronal numbers are set. Photoreceptors from the eye-disc induce their target field, the lamina, such that for every unit eye there is a corresponding lamina unit (column). Although each column initially contains ∼6 post-mitotic lamina precursors, only 5 differentiate into neurons, called L1-L5; the ‘extra’ precursor, which is invariantly positioned above the L5 neuron in each column, undergoes apoptosis. Here, we showed that a glial population called the outer chiasm giant glia (xgO), which resides below the lamina, secretes multiple ligands to induce L5 differentiation in response to EGF from photoreceptors. By forcing neuronal differentiation in the lamina, we uncovered that though fated to die, the ‘extra’ precursor is specified as an L5. Therefore, two precursors are specified as L5s but only one differentiates during normal development. We found that the row of precursors nearest to xgO differentiate into L5s and, in turn, antagonise differentiation signalling to prevent the ‘extra’ precursors from differentiating, resulting in their death. Thus, an intricate interplay of glial signals and feedback from differentiating neurons defines an invariant and stereotyped pattern of neuronal differentiation and programmed cell death to ensure that lamina columns each contain exactly one L5 neuron.
Improvement in peripherical visual attentional performance in professional soccer players following a single neurofeedback training
Authors: Assadourian Sacha , Lopes Antony Branco , Saj Arnaud
Published: December 2021

The effectiveness of EEG-neurofeedback (EEG-NFB) in modulating cognition has been the subject of much research for several years, particularly in relation to attentional functions in healthy subjects and those with attentional deficits. However, its effectiveness on sports performance remains poorly studied and its use is not widely practised among athletes, notably because of its accessibility and questionable effectiveness. The aim of this study is to show that this technology can be accessible, and that Alpha EEG-NFB is immediately effective. Fifteen professional soccer players took part in this study. Using a novel EEG headset that can be installed in less than one minute, and new processing software, the players performed two peripherical attentional tasks before and after, immediately and one month, a single Alpha EEG-NFB training session. The results showed a significant effect on both tasks immediately after EEG-NFB training, with a benefit of more than 30% and this performance continued after one month (20%). This study, the first to use this headset and software, shows that the improvement in sports performance can be related to cognitive performance, especially peripherical visual attentional functions. Furthermore, it demonstrates that the use of the EEG-NFB is accessible and effective for high-level athletes.
Physical model of electrical synapses in a neural network
Authors: Pekker M. , Shneider M.N.
Published: December 2021

A theoretical model of electrical synapses is proposed, in which connexons play the role of “nails” that hold unmyelinated areas of neurons at a distance of about 3.5 nm, and the electrical connection between them is provided by charging the membrane of an inactive neuron with currents generated in the intercellular electrolyte (saline) by the action potential in the active neuron. This mechanism is similar to the salutatory conduction of the action potential between the nodes of Ranvier in myelinated axons and the ephaptic coupling of sufficiently close spaced neurons.
Direct linkage detection with multimodal IVA fusion reveals markers of age, sex, cognition, and schizophrenia in large neuroimaging studies
Authors: Silva Rogers F. , Damaraju Eswar , Li Xinhui , Kochunov Peter , Belger Aysenil , Ford Judith M. , Mathalon Daniel H. , Mueller Bryon A. , Potkin Steven G. , Preda Adrian , Turner Jessica A. , van Erp Theo G.M. , Adali Tulay , Calhoun Vince D.
Published: December 2021

With the increasing availability of large-scale multimodal neuroimaging datasets, it is necessary to develop data fusion methods which can extract cross-modal features. A general framework, multidataset independent subspace analysis (MISA), has been developed to encompass multiple blind source separation approaches and identify linked cross-modal sources in multiple datasets. In this work we utilized the multimodal independent vector analysis model in MISA to directly identify meaningful linked features across three neuroimaging modalities — structural magnetic resonance imaging (MRI), resting state functional MRI and diffusion MRI — in two large independent datasets, one comprising of control subjects and the other including patients with schizophrenia. Results show several linked subject profiles (the sources/components) that capture age-associated decline, schizophrenia-related biomarkers, sex effects, and cognitive performance. For sources associated with age, both shared and modality-specific brain-age deltas were evaluated for association with non-imaging variables. In addition, each set of linked sources reveals a corresponding set of multi-tissue spatial patterns that can be studied jointly.
Slow conformational changes of blue light sensor BLUF proteins in milliseconds
Authors: Tokonami Shunrou , Onose Morihiko , Nakasone Yusuke , Terazima Masahide
Published: December 2021

BLUF (blue light sensor using flavin) proteins consist of flavin-binding BLUF domains and functional domains. Upon blue light excitation, the hydrogen bond network around the flavin chromophore changes, and the absorption spectrum in the visible region exhibits red-shift. Ultimately, the light information received in the BLUF domain is transmitted to the functional region. It has been believed that this red-shift is complete within nanoseconds. Contrary to this commonly accepted scheme, in this study, slow reaction kinetics were discovered in milliseconds (τ1- and τ2-phase) for all the BLUF proteins examined (AppA, OaPAC, BlrP1, YcgF, PapB, SyPixD, and TePixD). Despite extensive reports on BLUF, this is the first clear observation of the BLUF protein absorption change with the duration in the millisecond time region. From the measurements of some domain-deleted mutants of OaPAC and two chimeric mutants of PixD proteins, it was found that the slower dynamics (τ2-phase) are strongly affected by the size and nature of the C-terminal region adjacent to the BLUF domain. Hence, this millisecond reaction is a significant indicator of conformational changes in the C-terminal region, which is essential for the biological functions. On the other hand, the τ1-phase commonly exists in all BLUF proteins, including any mutants. The origin of the slow dynamics was studied using site-specific mutants. These results clearly show the importance of Trp in the BLUF domain. Based on this, a reaction scheme for the BLUF reaction is proposed.

Graphical Abstract
Reliable hypotheses testing in animal social network analyses: global index, index of interactions and residual regression
Authors: Sosa Sebastian , Pasquaretta Cristian , Puga-Gonzalez Ivan , Dobson F Stephen , Viblanc Vincent A , Hoppitt William
Published: December 2021

Animal social network analyses (ASNA) have led to a foundational shift in our understanding of animal sociality that transcends the disciplinary boundaries of genetics, spatial movements, epidemiology, information transmission, evolution, species assemblages and conservation. However, some analytical protocols (i.e., permutation tests) used in ASNA have recently been called into question due to the unacceptable rates of false negatives (type I error) and false positives (type II error) they generate in statistical hypothesis testing. Here, we show that these rates are related to the way in which observation heterogeneity is accounted for in association indices. To solve this issue, we propose a method termed the “global index” (GI) that consists of computing the average of individual associations indices per unit of time. In addition, we developed an “index of interactions” (II) that allows the use of the GI approach for directed behaviours. Our simulations show that GI: 1) returns more reasonable rates of false negatives and positives, with or without observational biases in the collected data, 2) can be applied to both directed and undirected behaviours, 3) can be applied to focal sampling, scan sampling or “gambit of the group” data collection protocols, and 4) can be applied to first- and second-order social network measures. Finally, we provide a method to control for non-social biological confounding factors using linear regression residuals. By providing a reliable approach for a wide range of scenarios, we propose a novel methodology in ASNA with the aim of better understanding social interactions from a mechanistic, ecological and evolutionary perspective.
Genetic, parental and lifestyle factors influence telomere length
Authors: Andreu-Sánchez Sergio , Aubert Geraldine , Ripoll-Cladellas Aida , Henkelman Sandra , Zhernakova Daria V. , Sinha Trishla , Kurilshikov Alexander , Cenit Maria Carmen , Bonder Marc Jan ,   Lifelines cohort study, Franke Lude , Wijmenga Cisca , Fu Jingyuan , van der Wijst Monique G.P. , Melé Marta , Lansdorp Peter , Zhernakova Alexandra
Published: December 2021

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1,046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Coupling these measurements to single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.
Noninvasive Stimulation of Peripheral Nerves using Temporally-Interfering Electrical Fields
Authors: Botzanowski Boris , Donahue Mary J. , Ejneby Malin Silverå , Gallina Alessandro L. , Ngom Ibrahima , Missey Florian , Acerbo Emma , Byun Donghak , Carron Romain , Cassarà Antonino M. , Neufeld Esra , Jirsa Viktor , Olofsson Peder S. , Głowacki Eric Daniel , Williamson Adam
Published: December 2021

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation noninvasively without surgically implanted devices is enabling for fundamental research and clinical translation. Here we demonstrate how relatively high frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 – 4 Hz) between the two carriers. We validate this principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, we demonstrate how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve. Our method is simple, relying on repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.
A salvaging strategy enables stable metabolite provisioning among free-living bacteria
Authors: Gude Sebastian , Pherribo Gordon J. , Taga Michiko E.
Published: December 2021

All organisms rely on complex metabolites such as amino acids, nucleotides, and cofactors for essential metabolic processes. Some microbes synthesize these fundamental ingredients of life de novo, while others rely on uptake to fulfill their metabolic needs. Although certain metabolic processes are inherently ‘leaky’, the mechanisms enabling stable metabolite provisioning among microbes in the absence of a host remain largely unclear. In particular, how can metabolite provisioning among free-living bacteria be maintained under the evolutionary pressure to economize resources? Salvaging, the process of ‘recycling and reusing’, can be a metabolically efficient route to obtain access to required resources. Here, we show experimentally how precursor salvaging in engineered Escherichia coli populations can lead to stable, long-term metabolite provisioning. We find that salvaged cobamides (vitamin B12 and related enzyme cofactors) are readily made available to non-productive population members, yet salvagers are strongly protected from overexploitation due to partial metabolite privatization. We also describe a previously unnoted benefit of precursor salvaging, namely the removal of the non-functional, proliferation-inhibiting precursor. As long as compatible precursors are present, any microbe possessing the terminal steps of a biosynthetic process can, in principle, forgo de novo biosynthesis in favor of salvaging. Consequently, precursor salvaging likely represents a potent, yet overlooked, alternative to de novo biosynthesis for the acquisition and provisioning of metabolites in free-living bacterial populations.
Islet primary cilia motility controls insulin secretion
Authors: Cho Jung Hoon , Li Zipeng A. , Zhu Lifei , Muegge Brian D. , Roseman Henry F. , Utterback Toby , Woodhams Louis G. , Bayly Philip V. , Hughes Jing W.
Published: December 2021

Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here we show that primary cilia in pancreatic beta cells exhibit movement that is required for glucose-dependent insulin secretion. Beta cell cilia contain motor proteins conserved from those found in classic motile cilia, and their 3D motion is dynein-driven and dependent on ATP and glucose metabolism. Inhibition of cilia motion blocks beta cell calcium influx and insulin secretion. Beta cells from humans with type 2 diabetes have altered expression of cilia motility genes. Our findings redefine primary cilia as dynamic structures possessing both sensory and motile function and establish that pancreatic beta cell cilia movement plays a critical role in controlling insulin secretion.
Linnemannia elongata (Mortierellaceae) stimulates Arabidopsis thaliana aerial growth and responses to auxin, ethylene, and reactive oxygen species
Authors: Vandepol Natalie , Liber Julian , Yocca Alan , Matlock Jason , Edger Patrick , Bonito Gregory
Published: December 2021

Harnessing the plant microbiome has the potential to improve agricultural yields and protect plants against pathogens and/or abiotic stresses, while also relieving economic and environmental costs of crop production. While previous studies have gained valuable insights into the underlying genetics facilitating plant-fungal interactions, these have largely been skewed towards certain fungal clades (e.g. arbuscular mycorrhizal fungi). Several different phyla of fungi have been shown to positively impact plant growth rates, including Mortierellaceae fungi. However, the extent of the plant growth promotion (PGP) phenotype(s), their underlying mechanism(s), and the impact of bacterial endosymbionts on fungal-plant interactions remain poorly understood for Mortierellaceae. In this study, we focused on the symbiosis between soil fungus Linnemannia elongata (Mortierellaceae) and Arabidopsis thaliana (Brassicaceae), as both organisms have high-quality reference genomes and transcriptomes available, and their lifestyles and growth requirements are conducive to research conditions. Further, L. elongata can host bacterial endosymbionts related to Mollicutes and Burkholderia. The role of these endobacteria on facilitating fungal-plant associations, including potentially further promoting plant growth, remains completely unexplored. We measured Arabidopsis aerial growth at early and late life stages, seed production, and used mRNA sequencing to characterize differentially expressed plant genes in response to fungal inoculation with and without bacterial endosymbionts. We found that L. elongata improved aerial plant growth, seed mass and altered the plant transcriptome, including the upregulation of genes involved in plant hormones and “response to oxidative stress”, “defense response to bacterium”, and “defense response to fungus”. Furthermore, the expression of genes in certain phytohormone biosynthetic pathways were found to be modified in plants treated with L. elongata. Notably, the presence of Mollicutes- or Burkholderia-related endosymbionts in Linnemannia did not impact the expression of genes in Arabidopsis or overall growth rates.