bluuebunny/crossref_metadata_2025 huggingface dataset:
American Cochlear Implant Alliance Task Force Guidelines for Clinical Assessment and Management of Cochlear Implantation in Children With Single-Sided Deafness
Authors: Park Lisa R. , Griffin Amanda M. , Sladen Douglas P. , Neumann Sara , Young Nancy M.
Published: February 2022

More children with single-sided deafness (SSD) are receiving cochlear implants (CIs) due to the expansion of CI indications. This unique group of pediatric patients has different needs than the typical recipient with bilateral deafness and requires special consideration and care. The goal of cochlear implantation in these children is to provide bilateral input to encourage the development of binaural hearing. Considerations for candidacy and follow-up care should reflect and measure these goals. The purpose of this document is to review the current evidence and provide guidance for CI candidacy, evaluation, and management in children with SSD.
Construction of a lung adenocarcinoma prognostic model based on N6-methyl-adenosine-related long noncoding RNA and screening of potential drugs based on this model
Authors: Hou Qinghua , Zhong Yanfeng , Liu Linzhuang , Wu Liusheng , Liu Jixian
Published: February 2022

Lung adenocarcinoma (LUAD) has a high mortality rate. N6-methyl-adenosine (m6A)-related long noncoding RNA (lncRNA) is associated with tumor prognosis. Our objective was to construct an m6A-related lncRNA prognostic model and screen potential drugs for the treatment of LUAD. The LUAD sequencing data were randomly divided into Train and Test cohorts. In the Train group, the LASSO Cox regression was used to construct the m6A-related lncRNA prognostic model. The LUAD tumor immune dysfunction and exclusion model was used to evaluate immunotherapy efficacy in LUAD. The ‘pRRophetic’ package was utilized to screen potential drugs for the treatment of LUAD. Eleven m6A-related lncRNAs were identified by LASSO Cox regression and were used to construct the risk model to calculate sample risk scores. Patients were divided into high- and low-risk groups based on their median risk scores. The LUAD data of The Cancer Genome Atlas database showed that the overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group in both cohorts. Multivariate Cox regression analysis showed that this risk model could serve as an independent prognostic factor of LUAD, and receiver operating characteristic curves suggested that m6A-related lncRNA prognostic signature has a good ability in predicting OS. Finally, nine potential drugs for LUAD treatment were screened based on this prognostic model. The prognostic model constructed based on the m6A-related lncRNAs facilitated prognosis prediction in LUAD patients. The screened therapeutic agents have potential application values and provide a reference for the clinical treatment of LUAD.
Clinical Management of Sleep and Sleep Disorders With Cannabis and Cannabinoids
Authors: Monti Jaime M. , Pandi-Perumal Seithikurippu R.
Published: February 2022

Phytocannabinoid derivatives are among the several compounds found in the cannabis plant. The phytocannabinoid chemicals Δ9-tetrahydrocannabinol (THC) and cannabidiol are mostly responsible for the drug's behavioral effects. Chronic cannabis administration has been shown to disrupt circadian rhythms and reduce the duration of the deepest phase (stage N3) of nonrapid eye movement sleep. Cannabidiol is thought to be responsible for the disruption of the circadian rhythm, whereas THC is thought to be accountable for the changes in sleep architecture. The quality of one's sleep has a significant impact on cannabis abstinence or relapse. As a result, the diminished sleep-promoting efficiency of cannabis in chronic users, as well as the resulting sleep difficulties once cannabis use is stopped, may sabotage attempts to quit and raise the risk of relapse. In individuals with obstructive sleep apnea who do not complain about the treatment process known as continuous positive airway pressure, cannabinoids are one of the treatments being considered. In this regard, preclinical investigations have demonstrated that combining the agent oleamide and THC aids in the stabilization of respiration in all stages of sleep as well as the maintenance of autonomic stability during sleep. The synthetic THC dronabinol was found to lower the apnea-hypopnea index in a clinical investigation and is regarded safe for the short-term treatment of obstructive sleep apnea. Patients experiencing nightmares who had been diagnosed with posttraumatic stress disorder were given the synthetic endocannabinoid receptor agonist nabilone. When compared with a placebo, the chemical proved helpful in reducing the frequency of nightmares. It is worth noting that a single study that looked at the effects of cannabidiol on REM behavior disorder found that symptoms improved. Based on the available findings, cannabinoids can be used as an alternate treatment for various sleep disorders. However, additional research is needed to corroborate the conclusions of these investigations.
Assessment of private variants in PRKN, PARK7 and PINK1 in Parkinson’s disease
Authors: Hu Jing , Waters Cheryl H. , Spiegelman Dan , Fon Edward A. , Yu Eric , Asayesh Farnaz , Krohn Lynne , Saini Prabhjyot , Alcalay Roy N. , Hassin-Baer Sharon , Gan-Or Ziv , Krainc Dimitri , Zhang BaoRong , Bustos Bernabe I. , Lubbe Steven J. ,   the International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: February 2022

Recessive mutations in PRKN, PARK7 and PINK1 are established causes of early-onset Parkinson’s disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] <1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset <50 years) and late-onset PD (≥50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.
Rich Experience Boosts Functional Connectome and High-Dimensional Coding in Hippocampal Network
Authors: Emery Brett Addison , Hu Xin , Khanzada Shahrukh , Kempermann Gerd , Amin Hayder
Published: February 2022

Challenging the brain with experiential richness creates tissue-level changes and synaptic plasticity, but the interjacent network level has not been accessible. We here show that environmental enrichment has unexpectedly far-reaching effects on network connectivity and multi-dimensional coding in the hippocampus. We present direct evidence that experience impacts local and global network connectivity, synchrony, and rhythmic dynamics. For this, we investigated the hippocampi from standard-housed mice (SD) and mice living in an enriched environment (ENR) using large-scaleex vivorecordings with a high-density microelectrode sensing array that – with the unprecedented spatiotemporal resolution–allowed simultaneous electrophysiological assessment across the entire circuit. In the absence of extrinsic electrical network stimulation, we found enhanced functional connectivity and high-dimensional coding in hippocampal-cortical networks of ENR mice. The mapped connectome illustrated a scale-free smallworld topology and an ENR-induced resilience to random failures. ENR enhanced large-scale spatiotemporal firing patterns, which facilitated efficient pattern separation and boosted the information encoded in the firing phases of slow oscillatory rhythms. Given that essentially all electrophysiological studies on network behaviors have been done on animals housed in stimulus-poor conditions, our SD mice showed the expected normal functionality. The literature consequently underestimates the extent of spontaneous network activity and connectivity under truly physiological conditions. Our results pave the way to unveil fundamental mechanisms of experience-dependent enhancement in the hippocampal network underlying high brain functions and provide markers for large-scale network remodeling and metaplasticity.
xcore: an R package for inference of gene expression regulators
Authors: Migdał Maciej , Winata Cecilia Lanny , Arakawa Takahiro , Takizawa Satoshi , Furuno Masaaki , Suzuki Harukazu , Arner Erik , Kaczkowski Bogumił
Published: February 2022

Elucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is one of the most common questions asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types. Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that the modeling can be done using ChiP-seq “signatures” directly, effectively skipping the motif finding and TFBS prediction steps. We present xcore, an R package that allows Transcription Factor activity modeling based on their ChiP-seq signatures and user’s gene expression data. We also provide xcoredata a companion data package that provides a collection of preprocessed ChiP-seq signatures. We demonstrate that xcore leads to biologically relevant predictions using TGF-beta induced epithelial-mesenchymal transition and rinderpest infection time-course CAGE data as examples.

Availability and Implementation

xcore and xcoredata R packages are freely available at www.github.com/bkaczkowski/xcore and www.github.com/mcjmigdal/xcoredata.

xcore user guide is available www.bkaczkowski.github.io/xcore/articles/xcore_vignette.html.

Contact

b.kaczkowski@gmail.com
Categorical bias as a crucial parameter in visual working memory: the effect of memory load and retention interval
Authors: Zhou Cherie , Lorist Monicque M. , Mathôt Sebastiaan
Published: February 2022

Visual information can be stored as continuous as well as categorical representations in visual working memory (VWM) to guide subsequent behavior. Yet it is still unclear what determines whether VWM is represented as continuous or categorical information, or as a mix of both. Recent studies have shown that color VWM representations adjust flexibly depending on the number of memory items as well as the duration that these items need to be maintained for. The current study aims to extend and replicate these crucial effects. In a delayed estimation task, participants memorized one to four colored objects presented at different spatial locations, followed by a delay of 100, 500, 1,000, or 2,000 ms. Next, a probe indicated the location of the color that participants needed to report. We measured the extent to which responses were biased in the direction of prototypical colors. Crucially, we implemented this categorical bias in an extension to the classic mixture model (Zhang & Luck 2008) in which the center of the error distribution is a crucial parameter that characterizes the extent to which VWM is biased by color categories. We found that VWM shows a strong categorical bias in all cases, and that this bias increases with increasing memory load; strikingly, this effect of memory load on categorical bias is stronger at longer intervals (1,000 ms or longer), as compared to shorter intervals, yet it peaks for intermediate memory loads as opposed to the highest memory load. Overall, our results suggest that when visual information needs to be maintained for one second or longer, VWM becomes more reliant on categorical representations as memory load increases.
Caecilian genomes reveal the molecular basis of adaptation, and convergent evolution of limblessness in snakes and caecilians
Authors: Ovchinnikov Vladimir , Uliano-Silva Marcela , Wilkinson Mark , Wood Jonathan , Smith Michelle , Oliver Karen , Sims Ying , Torrance James , Suh Alexander , McCarthy Shane A. , Durbin Richard , O’Connell Mary J.
Published: February 2022

We present genome sequences for the caeciliansGeotrypetes seraphini(3.8Gb) andMicrocaecilia unicolor(4.7Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons the most abundant. We identify 1,150 orthogroups which are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception and immunity amongst others. We discover that caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog which is also mutated in snakes.In vivodeletions have shown ZRS is required for limb development in mice, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.
Genetic immune escape landscape in primary and metastatic cancer
Authors: Martínez-Jiménez Francisco , Priestley Peter , Shale Charles , Baber Jonathan , Rozemuller Erik , Cuppen Edwin
Published: February 2022

Immune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,457 uniformly processed Whole Genome Sequencing (WGS) tumor samples including 58 cancer types from 1,943 primary untreated patients and 4,514 metastatic patients. To effectively address the complexity of the Human Leukocyte Antigen (HLA-I) locus and to characterize its tumor status, we developed LILAC, an open-source integrative framework. We demonstrate that one in four tumors harbor GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is highly consistent between primary and metastatic tumors for most cancer types with few exceptions such as prostate and thyroid carcinomas that have increased immune evasion frequencies in metastatic tumors. Positive selection analysis revealed that GIE alterations are frequently selected for in tumor evolution and that focal LOH of HLA-I, unlike non-focal LOH of HLA-I, tends to lose the HLA allele that presents the largest neoepitope repertoire. We also unraveled tumor genomic features contributing to immune escape incidence, including DNA repair deficiency, APOBEC activity, tobacco associated mutation load and viral DNA integration. Finally, there is a strong tendency for mid and high tumor mutation burden (TMB) tumors to preferentially select LOH of HLA-I for GIE whereas hypermutated samples favor global immune evasion strategies. Our results indicate that genetic immune escape is generally a pre-metastatic event during tumor evolution and that tumors adapt different strategies depending on their neoepitope burden.
T cells use distinct topological and membrane receptor scanning strategies that individually coalesce during receptor recognition
Authors: Cai En , Beppler Casey , Eichorst John , Marchuk Kyle , Krummel Matthew F.
Published: February 2022

During immune surveillance, CD8 T cells scan the surface of antigen presenting cells using dynamic microvillar palpation and movements as well as by having their receptors pre-concentrated into patches. Here, we use real-time lattice light sheet microscopy to demonstrate the independence of microvillar and membrane receptor patch scanning. While T cell receptor (TCR) patches can distribute to microvilli, they do so stochastically and not preferentially as for other receptors such as CD62L. The distinctness of TCR patch movement from microvillar movement extends to many other receptors that form patches that also scan independently of the TCR. An exception to this is the CD8 co-receptor which largely co-migrates in patches that overlap with or are closely adjacent to those containing TCRs. Microvilli that assemble into a synapse contain various arrays of the engaged patches, notably of TCRs and the inhibitory receptor PD-1, creating a pastiche of occupancies that vary from microvillar contact to contact. In summary, this work demonstrates that localization of receptor patches within the membrane and on microvillar projections is stochastic prior to antigen detection and that such stochastic variation may play into the generation of many individually-composed receptor patch compositions at a single synapse.

Significance statement

Motile T cell microvilli palpate surfaces to facilitate surface scanning in a pattern that is independent of the movement of pre-formed patches of transmembrane antigen-receptors across those microvilli; once T cell receptors engage, the microvilli act to scaffold multiple receptors within a microvillar close-contact.
Investigation on How Dynamic Effective Connectivity Patterns Encode the Fluctuating Pain Intensity in Chronic Migraine
Authors: Bassez Iege , Van de Steen Frederik , Hackl Sophie , Jahn Pauline , Mayr Astrid , Marinazzo Daniele , Schulz Enrico
Published: February 2022

Chronic migraine is characterised by persistent headaches for more than 15 days per month; the intensity of the pain is fluctuating over time. Here, we explored the dynamic interplay of connectivity patterns between regions known to be related to pain processing and their relation to the ongoing dynamic pain experience. We recorded EEG from 80 sessions (20 chronic migraine patients in 4 separate sessions of 25 minutes). The patients were asked to continuously rate the intensity of their endogenous headache. On different time-windows, a dynamic causal model (DCM) of cross spectral responses was inverted to estimate connectivity strengths. For each patient and session, the evolving dynamics of effective connectivity were related to pain intensities and to pain intensity changes by using a Bayesian linear model. Hierarchical Bayesian modelling was further used to examine which connectivity-pain relations are consistent across sessions and across patients.

The results reflect the multi-facetted clinical picture of the disease. Across all sessions, each patient with chronic migraine exhibited a distinct pattern of pain intensity-related cortical connectivity. The diversity of the individual findings are accompanied by inconsistent relations between the connectivity parameters and pain intensity or pain intensity changes at group level. This suggests a rejection of the idea of a common neuronal core problem for chronic migraine.
Evolutionary emergence of alternative stable states in shallow lakes
Authors: Ardichvili Alice Nadia , Loeuille Nicolas , Dakos Vasilis
Published: February 2022

Ecosystems under stress may respond abruptly and irreversibly through tipping points. Although much is explored on the mechanisms that affect tipping points and alternative stable states, little is known on how ecosystems with alternative stable states could have emerged in the first place. Here, we explore whether evolution by natural selection can lead to the emergence of ecosystems with tipping points using a toy model inspired by shallow lakes. Shallow lakes are the best-known example where a shift from a submersed macrophyte dominated state to a floating macrophyte dominated state in response to excess nutrient loading corresponds to a tipping point between alternative stable states. We model the evolution of the macrophyte's living depth in the lake, we identify the conditions under which the ancestor macrophyte population diversifies, and investigate whether alternate stable states dominated by different macrophyte phenotypes occur. Given the trade-off between access to light and nutrient along the water column, we show that asymmetry in competition for light is required for diversification, while alternative stable states require an additional competitive asymmetry, a priority effect to nutrient access. We find that eco-evolutionary dynamics may produce alternative stable states, but only under a restrictive range of conditions. Our analysis suggests that competitive asymmetries along opposing resource gradients may allow alternative stable states to emerge by natural selection.
Persistent horizontal and vertical, MR-induced nystagmus in resting state Human Connectome Project data
Authors: Go Cammille C , Taskin Huseyin O , Ahmadi Seyed-Ahmad , Frazzetta Giulia , Cutler Laura , Malhotra Saguna , Morgan Jessica IW , Flanagin Virginia L , Aguirre Geoffrey K
Published: February 2022

Objective

Strong magnetic fields from magnetic resonance (MR) scanners induce a Lorentz force that contributes to vertigo and persistent nystagmus. Prior studies have reported a predominantly horizontal direction for healthy subjects in a 7 Tesla (T) MR scanner, with slow phase velocity (SPV) dependent on head orientation. Less is known about vestibular signal behavior for subjects in a weaker, 3T magnetic field, the standard strength used in the Human Connectome Project (HCP). The purpose of this study is to characterize the form and magnitude of nystagmus induced at 3T.

Methods

Forty-two subjects were studied after being introduced head-first, supine into a Siemens Prisma 3T scanner. Eye movements were recorded in four separate acquisitions over 20 minutes. A biometric eye model was fit to the recordings to derive rotational eye position and then SPV. An anatomical template of the semi-circular canals was fit to the T2 anatomical image from each subject, and used to derive the angle of the B0 magnetic field with respect to the vestibular apparatus.

Results

Recordings from 37 subjects yielded valid measures of eye movements. The population-mean SPV ± SD for the horizontal component was −1.38 ± 1.27 deg/sec, and vertical component was −0.93 ± 1.44 deg/sec, corresponding to drift movement in the rightward and downward direction. Although there was substantial inter-subject variability, persistent nystagmus was present in half of subjects with no significant adaptation over the 20 minute scanning period. The amplitude of vertical drift was correlated with the roll angle of the vestibular system, with a non-zero vertical SPV present at a 0 degree roll.

Interpretation

Non-habituating vestibular signals of varying amplitude are present in resting state data collected at 3T.
Structural and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy
Authors: Liu Yun , Lin Weichun
Published: February 2022

Mutations in skeletal muscle α-actin (Acta1) cause a variety of myopathies. In a mouse model of congenital myopathy, heterozygous Acta1 (H40Y) knock-in (Acta1+/Ki) mice exhibit features of human nemaline myopathy, including premature lethality, severe muscle weakness, reduced mobility, and the presence of nemaline rods in muscle fibers. In this study, we investigated the structure and function of the neuromuscular junction (NMJ) in the Acta1+/Ki mice. We found marked impairments in NMJ structure in the mutant mice, including fragmented endplates and nerve terminals, reduced density of acetylcholine receptors (AChRs) on endplate membranes, reduced nerve occupancy at endplates, and increased numbers of muscle fiber subsynaptic nuclei. We compared the NMJs in three different types of muscles – the extensor digitorum longus (EDL, composed of fast-twitch muscle fibers), soleus (Sol, enriched in slow-twitch fibers) and the triangularis sterni muscle (TS, a mixed fiber type muscle). Among these three types of muscles, EDL was affected to the greatest extent, suggesting that fast-twitch fibers may be most susceptible to NMJ fragmentation in Acta1+/Ki nemaline myopathy.

Electrophysiological analysis of mutant NMJs showed a reduced quantal size (reduced mEPP amplitude), increased mEPP frequency, and increased quantal content, but normal EPP amplitude compared to wild type (WT) NMJs. The results suggest that affected synapses may have undergone homeostatic compensation to maintain normal levels of neurotransmitter release. In addition, paired-pulse facilitation was reduced and synaptic depression under repetitive nerve stimulation was enhanced, indicating shortterm synaptic plasticity was compromised in the mutant mice.

Key points

Mice heterozygous for an Acta1 (H40Y) knock-in mutation exhibit clinical features of human nemaline myopathy. We report structural and functional alterations of neuromuscular synapses in these mutant mice. The NMJ impairments include endplate fragmentation, reduced endplate nerve occupancy, and increased numbers of subsynaptic nuclei in muscle fibers.

Neuromuscular synaptic transmission was compromised – demonstrating both increased quantal content and changes in short-term synaptic plasticity.

Increases in spontaneous neurotransmitter release and quantal content suggest homeostatic compensation of synapses to maintain normal transmitter release in the mutant NMJs.
Uncertainty Quantification in Variable Selection for Genetic Fine-Mapping using Bayesian Neural Networks
Authors: Cheng Wei , Ramachandran Sohini , Crawford Lorin
Published: February 2022

In this paper, we propose a new approach for variable selection using a collection of Bayesian neural networks with a focus on quantifying uncertainty over which variables are selected. Motivated by fine-mapping applications in statistical genetics, we refer to our framework as an “ensemble of single-effect neural networks” (ESNN) which generalizes the “sum of single-effects” regression framework by both accounting for nonlinear structure in genotypic data (e.g., dominance effects) and having the capability to model discrete phenotypes (e.g., case-control studies). Through extensive simulations, we demonstrate our method’s ability to produce calibrated posterior summaries such as credible sets and posterior inclusion probabilities, particularly for traits with genetic architectures that have significant proportions of non-additive variation driven by correlated variants. Lastly, we use real data to demonstrate that the ESNN framework improves upon the state-of-the-art for identifying true effect variables underlying various complex traits.
Automatic Generation of Interactive Multidimensional Phase Portraits
Authors: Ogunsan Oluwateniayo O. , Lobo Daniel
Published: February 2022

Mathematical models formally and precisely represent biological mechanisms with complex dynamics. To understand the possible behaviors of such systems, phase portrait diagrams can be used to visualize their overall global dynamics across a domain. However, producing these phase portrait diagrams is a laborious process reserved to mathematical experts. Here, we developed a computational methodology to automatically generate phase portrait diagrams to study biological dynamical systems based on ordinary differential equations. The method only needs as input the variables and equations describing a multidimensional biological system and it automatically outputs for each pair of dependent variables a complete phase portrait diagram, including the critical points and their stability, the nullclines of the system, and a vector space of the trajectories. Crucially, the portraits generated are interactive, and the user can move the visualized planar slice, change parameters with sliders, and add trajectories in the phase and time domains, after which the diagrams are updated in real time. The method is available as a user-friendly graphical interface or can be accessed programmatically with aMathematicapackage. The generated portraits and particular views can be saved as computable notebooks preserving the interactive functionality, an approach that can be adopted for reproducible science and interactive pedagogical materials. The method, code, and examples are freely-available athttps://lobolab.umbc.edu/autoportrait.
Manipulation-specific activity in motor and somatosensory cortex as mice handle food
Authors: Barrett John M. , Shepherd Gordon M. G.
Published: February 2022

Food-handling offers unique yet largely unexplored opportunities to investigate how cortical activity relates to forelimb movements in a natural, ethologically essential, and kinematically rich form of manual dexterity. To determine these relationships, we recorded spiking activity in mouse forelimb M1 and S1 and tongue/jaw M1. Activity in all areas was strongly modulated in close association with discrete active manipulation events that occurred intermittently as mice fed. Each area’s activity was also partly distinct in its overall timing and phasic/tonic temporal profile, attributable to area-specific composition of activity classes. Forelimb position could be accurately predicted from activity in all three regions. These results thus establish that cortical activity during food-handling is manipulation-specific, distributed, and broadly similar across multiple cortical areas, while also exhibiting area- and submovement-specific relationships with the fast kinematic hallmarks of this form of complex, free-object-handling manual dexterity.
The effect of carbamazepine on bone structure and strength in control and Osteogenesis Imperfecta (Col1a2+/p.G610C) mice
Authors: Blank Martha , McGregor Narelle E , Rowley Lynn , Kung Louise HW , Crimeen-Irwin Blessing , Poulton Ingrid J , Walker Emma C , Gooi Jonathan H , Lamande Shireen R. , Sims Natalie A , Bateman John F.
Published: February 2022

The inherited brittle bone disease osteogenesis imperfecta (OI) is commonly caused byCOL1A1andCOL1A2mutations that disrupt the collagen I triple helix. This causes intracellular endoplasmic reticulum (ER) retention of the misfolded collagen and can result in a pathological ER stress response. A therapeutic approach to reduce this toxic mutant load could be to stimulate mutant collagen degradation by manipulating autophagy and/or ER-associated degradation. Since carbamazepine (CBZ) both stimulates autophagy of misfolded collagen X and improves skeletal pathology in a metaphyseal chondrodysplasia model, we tested the effect of CBZ on bone structure and strength in 3 week-old male OICol1a2+/p.G610Cand control mice. Treatment for 3 or 6 weeks with CBZ, at the dose effective in metaphyseal chondrodysplasia, provided no therapeutic benefit toCol1a2+/p.G610Cmouse bone structure, strength, or composition, measured by micro-computed tomography, three point bending tests and Fourier-transform infrared microspectroscopy. In control mice however, CBZ treatment for 6 weeks impaired femur growth and led to lower femoral cortical and trabecular bone mass. These data, showing the negative impact of CBZ treatment on the developing mouse bones, raise important issues which must be considered in any human clinical applications of CBZ in growing individuals.
Time-lagged Flux in the Transition Path Ensemble: Flux Maximization and Relation to Transition Path Theory
Authors: Li Wenjin
Published: February 2022

Transition path ensemble is of special interest in reaction coordinate identification as it consists of reactive trajectories that start from the reactant state and end in the product one. As a theoretical framework for describing the transition path ensemble, the transition path theory has been introduced more than ten years ago and so far its applications have been only illustrated in several low-dimensional systems. Given the transition path ensemble, expressions for calculating flux, current (a vector field), and principal curve are derived here in the space of collective variables from the transition path theory and they are applicable to time-series obtained from molecular dynamics simulations of high-dimensional systems, i.e., the position coordinates as a function of time in the transition path ensemble. The connection of the transition path theory is made to a density-weighted average flux, a quantity proposed in a previous work to appraise the relevance of a coordinate to the reaction coordinate [W. Li, J. Chem. Phys. 156, 054117 (2022)]. Most importantly, as an extension of the existing quantities, time-lagged quantities such as flux and current are also proposed. The main insights and objects provided by these time-lagged quantities are illustrated in the application to the alanine peptide in vacuum.
Cross-neutralizing activity against Omicron could be obtained in SARS-CoV-2 convalescent patients who received two doses of mRNA vaccination
Authors: Kurahashi Yukiya , Furukawa Koichi , Sutandhio Silvia , Tjan Lidya Handayani , Iwata Sachiyo , Sano Shigeru , Tohma Yoshiki , Ohkita Hiroyuki , Nakamura Sachiko , Nishimura Mitsuhiro , Arii Jun , Kiriu Tatsunori , Yamamoto Masatsugu , Nagano Tatsuya , Nishimura Yoshihiro , Mori Yasuko
Published: February 2022

The SARS-CoV-2 variant Omicron is now under investigation. We evaluated cross-neutralizing activity against Omicron in COVID-19 convalescent patients (n=23) who had received two doses of an mRNA vaccination (BNT162b2 or mRNA-1273). Surprisingly and interestingly, after the second vaccination, the subjects’ neutralizing antibody titers including that against Omicron all became seropositive, and significant fold-increases (21.1–52.0) were seen regardless of the subjects’ disease severity. Our findings thus demonstrate that at least two doses of mRNA vaccination to SARS-CoV-2 convalescent patients can induce cross-neutralizing activity against Omicron.
Inflammatory and immune markers in HIV-infected older adults on long-term antiretroviral therapy: persistent elevation of sCD14 and of proinflammatory effector memory T cells
Authors: Watanabe Makiko , Jergovic Mladen , Davidson Lisa , LaFleur Bonnie J. , Castaneda Yvonne , Martinez Carmine , Smithey Megan J. , Stowe Raymond P. , Haddad Elias K. , Nikolich-Žugich Janko
Published: February 2022

HIV-positive patients whose viral loads are successfully controlled by active antiretroviral therapy (ART) show no clinical signs of AIDS. However, their lifespan is shorter compared to individuals with no HIV infection and they prematurely exhibit a multitude of chronic diseases typically associated with advanced age. It was hypothesized that immune system aging may correlate with, and provide useful biomarkers for, this premature loss of healthspan in HIV+ subjects. Here, we tested whether the immune correlates of aging, including cell numbers and phenotypes, inflammatory status and control of human cytomegalovirus (hCMV) in HIV-positive subjects on long-term successful ART (HIV+) may reveal increased “immunological age” compared to healthy, age-matched cohort (HC) in participants between 50 and 69 years of age. Specifically, we expected that younger HIV+ subjects may immunologically resemble older individuals without HIV. We found no evidence to support this hypothesis. While T cells from HIV+ participants displayed different expression of several differentiation and/or inhibitory/exhaustion markers in different T cell subpopulations, aging by a decade did not pronounce these changes. Similarly, while the HIV+ participants exhibited higher T cell responses and elevated inflammatory marker levels in plasma, indicative of chronic inflammation, this trait was not age-sensitive. We did find differences in immune control of hCMV, and, more importantly, a sustained elevation of sCD14 and of proinflammatory CD4 and CD8 T cell responses across age groups, pointing towards uncontrolled inflammation as a factor in reduced healthspan in successfully treated older HIV+ patients.
Psychological Distress and Metabolomic Markers: A Systematic Review
Authors: Zhu Yiwen , Jha Shaili C. , Shutta Katherine H. , Huang Tianyi , Balasubramanian Raji , Clish Clary B. , Hankinson Susan E. , Kubzansky Laura D.
Published: February 2022

Psychological distress is a multifactorial construct that refers to non-specific symptoms of depression, anxiety, posttraumatic stress disorder (PTSD), or stress more generally. A systematic review of metabolomic markers associated with distress has the potential to reveal underlying molecular mechanisms linking distress to adverse health outcomes. The current systematic review extends prior reviews of clinical depressive disorders by synthesizing 39 existing studies that examined metabolomic markers for PTSD, anxiety disorders, and subclinical psychological distress in biological specimens. Most studies were based on small sets of pre-selected candidate metabolites, with few metabolites overlapping between studies. Vast heterogeneity was observed in study design and inconsistent patterns of association emerged between distress and metabolites. To gain a more robust understanding of distress and its metabolomic signatures, future research should include 1) large, population-based samples and longitudinal assessments, 2) replication and validation in diverse populations, 3) and agnostic metabolomic strategies profiling hundreds of targeted and nontargeted metabolites. Addressing these research priorities will improve the scope and reproducibility of future metabolomic studies of psychological distress.

Highlights

Literature on metabolomic markers of distress beyond clinical depression is scarce

Most existing studies were candidate based and had little overlap of targets

Vast heterogeneity exists in methods and patterns of findings from studies reviewed

Critical gaps in sample selection, study design, and methods need to be addressed
Joint modeling of survival and backwards recurrence outcomes: an analysis of factors associated with fertility treatment
Authors: Guo Siyuan , Zhang Jiajia , McLain Alexander C.
Published: February 2022

The increase in methods focused on various types of survival outcomes has allowed practitioners to analyze data that are difficult or expensive to prospectively observe. Still, there are populations that are challenging to study. For example, obtaining a representative sample of couples attempting to become pregnant is difficult due to the dynamic nature of the population. This has led to an increase in the use of cross-sectional designs yielding backwards recurrent survival outcomes. In this paper, we consider the analysis of a survival outcome where subjects are observed if they are at-risk for a separate dependent survival outcome. The motivation for this problem is to determine which factors are associated with time-to-fertility-treatment (TTFT) among women currently attempting pregnancy in a cross-sectional sample. We propose appending a marginal accelerated failure time (AFT) model on TTFT with a conditional model on time-to-pregnancy (TTP) given TTFT to account for their dependence and avoid biases. We address challenges that arise due to the censoring of TTFT and the resulting increased computational complexity. The performance is validated via comprehensive simulation studies. We apply our approach to data from the National Survey of Family Growth to estimate the association insurance type has on TTFT, and estimate the impact of fertility treatment on TTP.
The effect of job strain and worksite social support on reported side effects of COVID-19 vaccine: a prospective study of employees in Japan
Authors: Sasaki Natsu , Kuroda Reiko , Tsuno Kanami , Imamura Kotaro , Kawakami Norito
Published: February 2022

Objectives

This prospective study aimed to examine the association of job demands, job control, and the lack of supervisor and coworker support with side effects after receiving COVID-19 vaccination in a sample of employees in Japan.

Methods

The data were retrieved from an online panel of full-time employees (E- COCO- J). The analysis included participants who were employed and were not vaccinated at baseline (June 2021) but received vaccination at a four-month follow-up (October 2021). An 11-item scale measured the side effects of COVID-19 vaccines. Four types of psychosocial working conditions (i.e., job demands, job control, and supervisor and coworker support) were measured using the Brief Job Stress Questionnaire (BJSQ). Multiple linear regression analyses were conducted to examine the relationship between the psychosocial working conditions and side effects of COVID-19 vaccines, adjusting for gender, age, educational attainment, marital status, occupation, chronic disease, dose of vaccination, anxiety from potential side effects of vaccines, fear and worry about COVID-19, and psychological distress at baseline.

Results

Overall, 747 employees were included in the analysis. The average number of side effects was 3.78 (SD=2.19): Arm pain (81.1%), fatigues (64.1%), muscle pains (63.3%), and fever (37.5 degrees Celsius +) (53.5%) were reported more frequently. Coworker support score was significantly and negatively associated with the numbers of side effects (standardized β=-0.122, p=0.017). Women, young age, second time vaccination, and high psychological distress were significantly associated with several side effects.

Conclusions

Employees with low coworker support may be more likely to have side effects after COVID-19 vaccinations. The findings of this study could inform employees with low coworker support that increasing workplace support may reduce the side effects.

Highlights

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The effect of poor psychosocial working conditions on side effects after COVID-19 vaccinations was unknown.

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Poor coworker support at baseline was significantly associated with increased side effects after COVID-19 vaccinations.

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Informing workers with low coworker support about the findings may help them prepare for the side effect and motivate them to improve coworker support to reduce side effects.
Individuals with Metabolic Syndrome show altered fecal lipidomic profiles with no signs of intestinal inflammation or increased intestinal permeability: a pilot study
Authors: Coleman Mia J. , Espino Luis M. , Lebensohn Hernan , Zimkute Marija V. , Yaghooti Negar , Ling Christina L. , Gross Jessica M. , Listwan Natalia , Cano Sandra , Garcia Vanessa , Lovato Debbie M. , Tigert Susan L. , Jones Drew , Gullapalli Rama R. , Rakov Neal E. , Perez Euriko G. Torrazza , Castillo Eliseo F.
Published: February 2022

Metabolic Syndrome (MetS) is a clinical diagnosis where patients exhibit three out of the five risk factors: hypertriglyceridemia, low HDL cholesterol, hyperglycemia, hypertension or increased abdominal obesity. MetS arises due to dysregulated metabolic pathways that culminate with insulin resistance and put individuals at risk to develop various comorbidities with far-reaching medical consequences such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease. As it stands, the exact pathogenesis of MetS as well as the involvement of the gastrointestinal tract in MetS is not fully understood. Our study aimed to evaluate intestinal health in human subjects with MetS with the goal to evaluate for any signs of underlying gut inflammation, increased intestinal permeability, and alterations in host-microbiota metabolism as assessed by fecal metabolites. No signs of intestinal inflammation or increased intestinal permeability were observed in MetS group compared to our control group. However, we found a significant increase in 417 lipid features of the gut lipidome in our MetS cohort. An identified fecal lipid, diacyl-glycerophosphocholine, showed a strong correlation with several MetS risk factors. An although our MetS cohort showed no signs of intestinal inflammation they presented with increased levels of serum TNFα that also correlated with increasing triglyceride and fecal diacyl-glycerophosphocholine levels, and decreasing HDL cholesterol levels. Taken together, our main results show MetS subjects show major alterations in fecal lipid profiles suggesting alterations in intestinal host-microbiota metabolism that may arise before concrete signs of gut inflammation or intestinal permeability become apparent. Lastly, we posit fecal metabolomics could serve as a non-invasive, accurate screening method for both MetS and NAFLD.
Transcranial photobiomodulation enhances visual working memory capacity in humans
Authors: Zhao Chenguang , Li Dongwei , Kong Yuanjun , Liu Hongyu , Hu Yiqing , Niu Haijing , Jensen Ole , Li Xiaoli , Liu Hanli , Song Yan
Published: February 2022

Transcranial photobiomodulation (tPBM) is a novel and noninvasive intervention, which has shown promise for improving cognitive performances. Whether tPBM can modulate brain activity and thereby enhance working memory (WM) capacity in humans remains unclear. In this study, we delivered double-blind and sham-control tPBM with different wavelengths to the prefrontal cortex (PFC) in 90 healthy participants and conducted four electroencephalography (EEG) experiments to investigate whether individual visual working memory capacity and related neural response could be modulated. We found that 1064 nm tPBM applied to the right PFC has both a substantial impact on visual working memory capacity and occipitoparietal contralateral delay activity (CDA), no matter orientation or color feature of the memorized objects. Importantly, the CDA set-size effect during the retention mediated the effect between 1064 nm tPBM and subsequent WM performance. However, these behavioral benefits and the corresponding changes of CDA set-size effect were absent with tPBM at 852 nm wavelength or with the stimulation on the left PFC. Our findings provide converging evidence that 1064 nm tPBM applied on the right PFC can improve visual working memory capacity, as well as explain the individual’s electrophysiological changes about behavioral benefits.
The circ_0002538/miR-138-5p/PLLP axis regulates Schwann cell migration and myelination in diabetic peripheral neuropathy
Authors: Liu Yutian , Xu Zhao , Liu Wei , Ren Sen , Xiong Hewei , Jiang Tao , Chen Jing , Kang Yu , Li Qianyun , Wu Zihan , Machens Hans-Gu□nther , Yang Xiaofan , Chen Zhenbing
Published: February 2022

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, but the underlying molecular pathogenesis remains unclear. Accumulating evidence indicates that circular RNAs (circRNAs) play vital roles in DPN, while their expressions and functions in Schwann cell (SC) are rarely reported. Here, we performed protein profiling and circRNA sequencing on the peripheral nerves of patients with or without DPN. A total of 265 differentially expressed proteins were identified in DPN by protein profiling, which mainly enrich in myelination according to Gene Ontology analysis. Further, 15637 circRNAs were identified by circRNA sequencing, of which 11 were verified to be dysregulated. Among them, circ_0002538 was found to be downregulated in DPN and chosen for further investigation. Functional experiments revealed that circ_0002538 overexpression promoted SC migration and relieved demyelination in DPN. Mechanistic studies revealed that circ_0002538 could promote PLLP expression by sponging miR-138-5p, while lack of circ_0002538 led to PLLP deficiency, which further suppressed SC migration and caused demyelination. The present research provided novel insights into the pathogenesis of DPN, in which the circ_0002538/miR-138-5p/PLLP axis was suppressed in SCs and hence caused demyelination. These findings expanded the role of circRNAs in DPN and provided potential therapeutic targets for DPN.