bluuebunny/crossref_metadata_2025 huggingface dataset:
An ensemble deep learning model with empirical wavelet transform feature for oral cancer histopathological image classification
Authors: Deo Bhaswati Singha , Pal Mayukha , Panigrahi Prasanta K. , Pradhan Asima
Published: November 2022

Oral squamous cell carcinoma (OSCC) has become quite prevalent across many countries and poor prognosis is one of the major reasons for the ensuing high mortality rate. It mainly occurs in sites such as tongue, tonsil, oropharynx, gum, floor and other parts of the mouth. For early detection, the widely used approach is biopsy, in which a small portion of the tissue is taken from the mouth and examined under a disinfected and secure microscope. However, these observations do not effortlessly distinguish between normal and cancerous cells. Diagnosis of OSCC is generally done by pathologists who mostly rely on their years of empirical experience from tissue biopsy sections. The possibilities of human errors increase while detecting the cells using microscopy biopsy images physically. With the growth of artificial intelligence, deep learning models have gained immense importance in recent years and have become one of the core technologies in numerous fields including the prediction of lung cancer, breast cancer, oral cancer, and various medical diagnosis. It not only enhances accuracy, but also fastens the image classification process, as a result, lowering human errors and workload. Here, we have made use of a customized deep-learning model for aiding pathologists in better OSCC detection from histopathological images. We accumulated and analyzed a complete set of 696 histopathological oral images, amongst them 80% have been taken in the training set, 10% of the images are included in the validation set, and the rest 10% for testing purposes. In this study, 2D empirical wavelet transform is used to extract features from the images; later an ensemble of two pre-trained models, namely Resnet50 and Densenet201 are used for the classification of images into normal and OSCC classes. The efficacy of the model is assessed and compared in terms of accuracy, sensitivity, specificity, and ROC AUC scores. The simulation results show that the proposed model has achieved an accuracy of 92.00%. Thus, this method may be utilized for assisting in the binary classification of oral histopathological images.
Simulated tempering-enhanced umbrella sampling improves convergence of free energy calculations of drug membrane permeation
Authors: Sousa Carla F. , Becker Robert A. , Lehr Claus-Michael , Kalinina Olga V. , Hub Jochen S.
Published: November 2022

Molecular dynamics simulations have been widely used to study solute permeation across biological membranes. The potential of mean force (PMF) for solute permeation is typically computed using enhanced sampling techniques such as umbrella sampling (US). For bulky drug-like permeants, however, obtaining converged PMFs remains challenging and often requires long simulation times, resulting in an unacceptable computational cost. Here, we augmented US with simulated tempering, introducing Simulated Tempering-enhanced US (STeUS), to improve the convergence of PMF calculations for the permeation of methanol and three common drug molecules. Simulate tempering helps to enhance sampling by varying the temperature of the system along a pre-defined temperature ladder. To obtain sufficient sampling of the umbrella histograms, which were computed only from the ground temperature, we modified the simulation time fraction spent at the ground temperature between 1/Kand 50%, whereKis the number of ST temperature states. We found that STeUS accelerates convergence compared to standard US, and the benefit of STeUS is system-dependent. For bulky molecules, for which standard US poorly converged, the application of ST was highly successful, leading to a more than five-fold accelerated convergence of the PMFs. For the small methanol solute, for which conventional US converges moderately, the application of ST is only beneficial if 50% of the STeUS simulation time is spent at the ground temperature. This study establishes STeUS as an efficient and simple method for PMF calculations, thereby strongly reducing the computational cost of routine high-throughput studies of drug permeability.
A Microfluidic Device to Simulate the Impact of Gut Microbiome in Cancer
Authors: Mittal Ekansh , Kang Youngbok (Abraham)
Published: November 2022

The gut microbiome has a role in the growth of many diseases such as cancer due to increased inflammation. There is an unmet need to identify novel strategies to investigate the effect of inflammation mediated by gut microbiome on cancer cells. However, there are limited biomimetic co-culture systems that allow to test causal relationship of microbiome on cancer cells. Here we developed a microfluidic chip that can simulate the interaction of the gut microbiome and cancer cells to test the effects of bacteria and inflammatory stress on cancer cells in vitro. To quantify the effect of bacteria on the growth of colorectal cancer cells, we cultured colorectal cancer cell line with Bacillus or lipopolysaccharide (LPS), which is a purified bacterial membrane and induce major inflammatory response, in the PDMS microfluidic device. We found that both LPS and Bacillus significantly accelerate the growth of colorectal cancer cells. These results show that the increased presence of certain bacteria can promote cancer cell growth and that these microfluidic chips can be used to test the specific correlation between bacteria and cancer cell growth. These microfluidic devices can have future implications for various cancer types and to identify treatment strategies.
Identification of variation inFibromelanosisregion on chromosome 20 for determining the purity of Indonesian Cemani chicken
Authors: Dharmayanthi Anik Budhi , Kinoshita Keiji , Khaerunnisa Isyana , Safitry Rona Saumy , Iryanto Syam Budi , Yohanna  , Sutikno  , Lompengeng Ishak Andi Baso , Zein M Syamsul Arifin , Satta Yoko , Akiyama Toyoko , Sumantri Cece
Published: November 2022

Ayam Cemani is a local Indonesian chicken with heavy pigmentation in plumage colour, skin, eyes, and inner body organs. This trait with dermal hyperpigmentation is identical toFibromelanosis(Fm) mutation in a Silkie chicken. The causal mutation of theFmtrait is due to an inverted duplication and junction of two genomic regions involving the Endothelin3 (EDN3) gene on chromosome 20. There are two duplication boundaries; one is specific to theFmallele, the other is common for bothFmandfm+allele. Determining birds that are homozygous or heterozygous at this locus is useful for unifying theFmtrait of Cemani populations. This study develops a method for determining the presence or absence ofFmmutation by PCR amplification using the inverted sequences specific to theFmallele. Further, it develops the restriction fragment length polymorphism (RFLP) method in regions common to theFmand wild-typefm+allele. We aim to establish a simple method for detecting homozygous (Fm/Fm) and heterozygous (Fm/fm+) individuals withFmmutation and to clarify the degree of fixation of theFmtrait in the Ayam Cemani populations and the association between the phenotype and genotype. The result showed that mostly, the phenotype for Cemani withFm/fm+genotype is reddish black in their comb; meanwhile, the Cemani with (Fm/Fm) genotype showed heavy black pigmentation. Our study concluded that using the PCR-RFLP method. We can discriminate betweenFmhomozygous and heterozygous birds in the Cemani population. Thus, this briefly genotyping method effectively maintains and protects the pure line of Cemani chicken.
A Novel Hypothesis for Migraine Disease Mechanism: The Creation of a New Attractor Responsible for Migraine Disease Symptoms
Authors: Garehdaghi Farnaz , Sarbaz Yashar , Baradari Elham
Published: November 2022

Migraine Disease (MD) is one of the primary headaches in which the pathophysiological mechanism is yet unknown. It is still unclear how the ictal phases’ periods are determined? Why can any small trigger sometimes initiate the ictal phase, and sometimes, even bigger triggers cannot? Considering the brain as a dynamic system and proposing a complex system model for that as a migraineur or a healthy subject is a viable method. Here, the interaction between whole neurons is analyzed rather than individual neurons. This model is a complex system with a chaotic attractor. With parameter alternations, this attractor changes from one scroll to double scroll, representing a healthy or a migraineur brain. In the proposed system, the attractor’s borders are the regions where every small trigger can start the ictal phase, while the outer areas are the non-sensitive brain situations. We believe that MD and Chua’s systems have certain behavioral similarities. This study aimed to explain the function of MD and offer a theory that adequately describes its behavior. Finally, it has been tried to discuss some physiological evidences such as Migraine Generator Network (MGN), Cortical Spreading Depression (CSD), and the role of Serotonin and other substances in relation to the expressed hypotheses. This insight may propose newer methods for preventing or curing MD. Knowing the functioning of dynamic systems and finding similar behaviors with MD on the one hand, as well as linking physiological and pathophysiological evidence with a quantitative model can be very useful in better understanding, managing, and controlling the MD.
AGouTI - flexible Annotation of Genomic and Transcriptomic Intervals
Authors: Kosiński Jan G. , Żywicki Marek
Published: November 2022

The recent development of high-throughput workflows in genomics and transcriptomics revealed that efficient annotation is essential for effective data processing and analysis. Although a variety of tools dedicated to this purpose is available, their functionality is limited. Here, we presentAGouTI– a universal tool for flexible annotation of any genomic or transcriptomic coordinates using known genomic features deposited in different publicly available databases in the form of GTF or GFF files. In contrast to currently available tools,AGouTIis designed to provide a flexible selection of genomic features overlapping or adjacent to annotated intervals, can be used on custom column-based text files obtained from different data analysis pipelines, and supports operations on transcriptomic coordinate systems.

Availability and Implementation

AGouTI was implemented using Python 3 and is freely available on GitHub (https://github.com/zywicki-lab/agouti), from the Python Package Index (https://pypi.org/project/AGouTI/) or Anaconda Cloud (https://anaconda.org/bioconda/agouti). We also provide a Galaxy wrapper available from the Galaxy Tool Shed (https://toolshed.g2.bx.psu.edu/view/janktoolshed/agouti/c204da8f836d).

Supplementary information

Supplementary Data are available at Publisher site online. Files for replicating the use-case scenario described in Supplementary Data are available at Zenodo:https://doi.org/10.5281/zenodo.7317210.

Contact

Marek.Zywicki@amu.edu.pl
Online decoding of covert speech based on the passive perception of speech
Authors: Moon Jae , Chau Tom
Published: November 2022

Background

Brain-computer interfaces (BCIs) can offer solutions to communicative impairments induced by conditions such as locked-in syndrome. While covert speech-based BCIs have garnered interest, a major issue facing their clinical translation is the collection of sufficient volumes of high signal-to-noise ratio (SNR) examples of covert speech signals which can typically induce fatigue in users. Fortuitously, investigations into the linkage between covert speech and speech perception have revealed spatiotemporal similarities suggestive of shared encoding mechanisms. Here, we sought to demonstrate that an electroencephalographic cross-condition machine learning model of speech perception and covert speech can successfully decode neural speech patterns during online BCI scenarios.

Methods

In the current study, ten participants underwent a dyadic protocol whereby participants perceived the audio of a randomly chosen word and then subsequently mentally rehearsed it. Eight words were used during the offline sessions and subsequently narrowed down to three classes for the online session (two words, rest). The modelling was achieved by estimating a functional mapping derived from speech perception and covert speech signals of the same speech token (features were extracted via a Riemannian approach).

Results

While most covert speech BCIs deal with binary and offline classifications, we report an average ternary and online BCI accuracy of 75.3% (60% chance-level), reaching up to 93% in select participants. Moreover, we found that perception-covert modelling effectively enhanced the SNR of covert speech signals correlatively to their high-frequency correspondences.

Conclusions

These findings may pave the way to efficient and more user-friendly data collection for passively training such BCIs. Future iterations of this BCI can lead to a combination of audiobooks and unsupervised learning to train a non-trivial vocabulary that can support proto-naturalistic communication.

Significance Statement

Covert speech brain-computer interfaces (BCIs) provide new communication channels. However, these BCIs face practical challenges in collecting large volumes of high-quality covert speech data which can both induce fatigue and degrade BCI performance. This study leverages the reported spatiotemporal correspondences between covert speech and speech perception by deriving a functional mapping between them. While multiclass and online covert speech classification has previously been challenging, this study reports an average ternary and online classification accuracy of 75.3%, reaching up to 93% for select participants. Moreover, the current modelling approach augmented the signal-to-noise ratio of covert speech signals correlatively to their gamma-band correspondences. The proposed approach may pave the way toward a more efficient and user-friendly method of training covert speech BCIs.
Cultivation and Fluorescent in situ hybridization suggest that some shipworm species acquire endosymbiotic bacteria through indirect horizontal transmission
Authors: Speare Lauren , Distel Daniel L
Published: November 2022

Beneficial microbial symbionts provide essential functions for their host from nutrients to defense against disease. Whether hosts acquire their symbionts directly from parents (vertical transmission) or by sampling from the environment (horizontal transmission) can have dramatic impacts on host adaptability and, in the case of ecosystem engineers, ecosystem health. Wood-boring bivalve mollusks (Teredinidae shipworms) act as ecosystem engineers in marine environments, creating habitat out of submerged wood for fish and invertebrates. Essential to shipworm success is their community of endosymbiotic gill bacteria that produce the enzymes necessary for wood digestion. How shipworms acquire their symbionts, however, remains largely unexplored. Using culturing, fluorescencein-situhybridization, confocal microscopy, and tank experiments, we provide evidence suggesting the mode of symbiont transmission the shipworms for either the shipworm,Lyrodus pedicellatusorTeredo bartschior both. Symbiotic bacteria were not detected by cultivation or microscopy in brooding larvae within gravid adults or as veliger larvae collected from the water column, but were observed in adult specimens and juveniles that had begun burrowing into wood. These data suggest that the specimens examined have both aposymbiotic and symbiotic life phases and acquire their symbionts through indirect horizontal transmission. Our findings reveal how the long-term broodersL. pedicellatusand/orT. bartschiacquire their gill endosymbionts.

IMPORTANCE

How eukaryotic hosts acquire their microbial symbionts can have significant consequences for their ability to adapt to varied environments. Although wood-boring bivalve shipworms have diverse reproductive strategies and are found in unique environments across the globe, little is known about how they transmit their essential gill endosymbionts. We used the closely related shipworms,Lyrodus pedicellatusand/orTeredo bartschito study how these long-term brooding shipworms acquire their gill endosymbionts. Our work, unlike previous claims for the broadcast spawning speciesBankia setacaewhich reportedly transmits its symbionts directly from parent to offspring, suggests that juvenileL. pedicellatusand/orT. bartschiacquire their symbionts through horizontal transmission rather than directly from their parents. This work reveals the mechanism by which some brooding shipworm species acquire their symbionts, adding to our limited understanding of intracellular symbiont transmission of Teredinidae.
The ground offers acoustic efficiency gains for crickets and other calling animals
Authors: Brandt Erin E. , Duke Sarah , Wang Honglin , Mhatre Natasha
Published: November 2022

Male crickets attract females by producing calls with their forewings. Louder calls travel further and are more effective at attracting mates. However, crickets are much smaller than the wavelength of their call, and this limits their power output. A small group called tree crickets make acoustic tools called baffles which reduce acoustic short-circuiting, a source of dipole inefficiency. Here, we ask why baffling is uncommon among crickets. We hypothesize that baffling may be rare, because like other tools they offer insufficient advantage for most species. To test this, we modelled the calling efficiencies of crickets within the full space of possible natural wing sizes and call frequencies, in multiple acoustic environments. We then generated efficiency landscapes, within which we plotted 112 cricket species across 7 phylogenetic clades. We found that all sampled crickets, in all conditions, could gain efficiency from tool use. Surprisingly, we also found that calling from the ground significantly increased efficiency, with or without a baffle, by as much as an order of magnitude. We found that the ground provides some reduction of acoustic short-circuiting but also halves the air volume within which sound is radiated. It simultaneously reflects sound upwards, allowing recapture of a significant amount of acoustic energy through constructive interference. Thus, using the ground as a reflective baffle is an effective strategy for increasing calling efficiency. Indeed, theory suggests that this increase in efficiency is accessible not just to crickets, but to all acoustically communicating animals whether they are dipole or monopole sound sources.

Significance Statement

Loudness is a crucial feature in acoustic communication. Animals attracting mates or warding off predators are expected to make themselves as loud as possible. Two long-standing, seemingly unrelated unsolved problems regarding loudness in the field of animal communication are: the rarity of acoustic tool use, and animals that call from reflective ground-like surfaces, known to be an impediment to sound propagation. These two ideas are related; by refocusing analysis from sound propagation to sound radiation, we show that the ground is not an impediment, but rather an acoustic aid that can boost loudness more than tool use. We also show that calling from a reflective surface is an alternative strategy to maximize call loudness that is available to all animals.
A universal differential expression prediction tool for single-cell and spatial genomics data
Authors: Vandenbon Alexis , Diez Diego
Published: November 2022

With the growing complexity of single-cell and spatial genomics data, there is an increasing importance of unbiased and efficient exploratory data analysis tools. One common exploratory data analysis step is the prediction of genes with different levels of activity in a subset of cells or locations inside a tissue. We previously developed singleCellHaystack, a method for predicting differentially expressed genes from single-cell transcriptome data, without relying on clustering of cells. Here we present an update to singleCellHaystack, which is now a universally applicable method for predicting differentially active features: 1) singleCellHaystack now accepts continuous features that can be RNA or protein expression, chromatin accessibility or module scores from single-cell, spatial and even bulk genomics data, and 2) it can handle 1D trajectories, 2-3D spatial coordinates, as well as higher-dimensional latent spaces as input coordinates. Performance has been drastically improved, with up to ten times reduction in computational time and scalability to millions of cells, making singleCellHaystack a suitable tool for exploratory analysis of atlas level datasets. singleCellHaystack is available as an R package and Python module
Risk factors for extended-spectrum beta-lactamase (ESBL) producingE. colicarriage among children in a food animal producing region of Quito, Ecuador
Authors: Amato Heather K. , Loayza Fernanda , Salinas Liseth , Paredes Diana , Garcia Daniela , Sarzosa Soledad , Saraiva-Garcia Carlos , Johnson Timothy J. , Pickering Amy J. , Riley Lee W. , Trueba Gabriel , Graham Jay P.
Published: November 2022

Background

The spread of antibiotic-resistant bacteria may be driven by human-animal-environment interactions, especially in regions with limited restrictions on antibiotic use, widespread food animal production, and free-roaming domestic animals. In this study, we aimed to identify risk factors related to domestic animals, backyard food animals, and commercial food animal production in Ecuadorian communities.

Methods & Findings

We conducted a repeated-measures study from 2018-2021 in 7 semi-rural parishes of Quito, Ecuador to identify determinants of third-generation cephalosporin-resistantE. coli(3GCR-EC) and extended-spectrum beta-lactamaseE. coli(ESBL-EC) in children and domestic animals. We used multivariable log-binomial regression models to estimate relative risks (RR) of 3GCR-EC and ESBL-EC carriage. We collected 1,699 child fecal samples from 600 households and 1,871 animal fecal samples from 376 of the same households. Risk factors for 3GCR-EC included living within 5 km of more than 5 commercial food animal operations (RR: 1.36; 95% Confidence Interval: 1.16, 1.59), household pig ownership (1.23; 1.02, 1.48), child pet contact (1.23; 1.09, 1.39), and rarely/never washing hands after contact with animals (1.15; 0.98, 1.34). Risk factors for ESBL-EC were dog ownership (1.43; 1.00, 2.04), child pet contact (1.54; 1.10, 2.16), placing animal feces on household land/crops (1.63; 1.09, 2.46), and combined exposures to both household food animals and commercial food animal operation drainage paths (1.80; 0.94, 3.45).

Conclusions

Policies and interventions that improve the safety of animal waste management in communities and in commercial food animal production operations may be necessary to curb the spread of resistant bacteria.
Risk factors and symptom clusters for Long Covid: analysis of United Kingdom symptom tracker app data
Authors: Ford Elizabeth , Parfitt Harley , McCheyne Ian , Kiss István Z. , Sellers Ruth
Published: November 2022

Background

Long Covid, characterised by symptoms after Covid-19 infection which persist for longer than 12 weeks, is becoming an important societal and economic problem. As Long Covid was novel in 2020, there has been debate regarding its aetiology and whether it is one, or multiple, syndromes. This study assessed risk factors associated with Long Covid and examined symptom clusters that might indicate sub-types.

Methods

4,040 participants reporting for >4 months in the Covid Symptom Study App were included. Multivariate logistic regression was undertaken to identify risk factors associated with Long Covid. Cluster analysis (K-modes and hierarchical agglomerative clustering) and factor analysis were undertaken to investigate symptom clusters.

Results

Long Covid affected 13.6% of participants. Significant risk factors included being female (P< 0.01), pre-existing poor health (P< 0.01), and worse symptoms in the initial illness. A model incorporating sociodemographics, comorbidities, and health status predicted Long Covid with an accuracy (AUROC) of 76%. The three clustering approaches gave rise to different sets of clusters with no consistent pattern across methods.

Conclusions

Our model of risk factors may help clinicians predict patients at higher risk of Long Covid, so these patients can rest more, receive treatments, or enter clinical trials; reducing the burden of this long-term and debilitating condition. No consistent subtypes were identified.
The GxcM-Fbp17/RacC-WASP signaling cascade regulates polarized cortex assembly in migrating cells
Authors: Li Dong , Yang Yihong , Wang Yingjie , Chao Xiaoting , Huang Jiafeng , Singh Shashi P. , Zhang Chengyu , Lou Jizhong , Gao Pu , Huang Shanjin , Cai Huaqing
Published: November 2022

The actin-rich cortex plays a fundamental role in many cellular processes. Its architecture and molecular composition vary across cell types and physiological states. The full complement of actin assembly factors driving cortex formation and how their activities are spatiotemporally regulated remain to be fully elucidated. UsingDictyosteliumas a model for polarized and rapidly migrating cells, we show that GxcM, a RhoGEF localized specifically in the rear of migrating cells, functions together with F-BAR protein Fbp17, a small GTPase RacC, and the actin nucleation-promoting factor WASP to coordinately promote Arp2/3 complex-mediated cortical actin assembly. Over-activation of this signaling cascade leads to excessive actin polymerization in the rear cortex, whereas its disruption causes defects in cortical integrity and function. Therefore, different from its well-defined role in the formation of the front protrusions, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortical subcompartment in rapidly migrating cells.
Single-cell sequencing of Entorhinal Cortex Reveals Wide-Spread Disruption of Neuropeptide Networks in Alzheimer’s Disease
Authors: Li Manci , Larsen Peter A.
Published: November 2022

Alzheimer’s disease (AD) is a fatal neurodegenerative disease that involves early and significant neuropathological changes within the entorhinal cortex (EC). Many have reported on neuronal loss and synaptic dysfunction in the brains of AD patients and AD models. In parallel, abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in AD and other neurodegenerative diseases. However, the involvement of NPs has mostly been studied in the context of neurons; a cell type-specific examination of NP expression in AD brains is needed. Here, we aim to examine the NP networks in the EC of AD brains using single-nuclei and bulk transcriptomic data from other regions in the temporal cortex, focusing on the gene expression of NP and their cognate G-protein coupled receptors. We find that NP genes were expressed by all major cell types in the brain and there was a significant decrease in the quantity and the proportion of cells that express NPs in AD EC cells. On the contrary, the overall expression of GPCR genes showed an increase in AD cells, likely reflecting ongoing compensatory mechanisms in AD brains. In addition, we report that there was a disproportionate absence of cells expressing higher levels and greater diversity of NPs in AD brains. Finally, we established a negative correlation between age and the abundance of AD-associated NPs in the hippocampus, supporting that the disruption of the NP signaling network in the EC may contribute to the early pathogenesis of AD. In short, we report widespread disruption of the NP networks in AD brains at the single-cell level. In light of our results, we hypothesize that brain cells, especially neurons, that express high levels of NPs may exhibit selective vulnerability to AD. Moreover, it is likely AD brains undergo specific adaptive changes to fluctuating NP signaling, a process that can likely be targeted with therapeutic approaches aimed at stabilizing NP expression landscapes. Given that GPCRs are one of the most druggable targets for neurological diseases and disorders, we believe NP signaling pathways can be harnessed for future biomarkers and treatment strategies for AD.
Structural Reorganization Following a Brain Tumor: A Machine Learning Study Considering Desynchronized Functional Oscillations
Authors: Falcó-Roget Joan , Sambataro Fabio , Cacciola Alberto , Crimi Alessandro
Published: November 2022

Neuroimaging studies have allowed for non-invasive mapping of brain networks in brain tumors. Although tumor core and oedema are easily identifiable using standard MRI acquisitions, imaging studies often neglect signals, structures and functions within their presence. Therefore, both functional and diffusion signals, as well as their relationship with global patterns of connectivity reorganization, are poorly understood. Here, we explore functional activity and the structure of white matter fibers considering the contribution of the whole tumor in a surgical context. First, we find that intra-tumor signals do exist and are correlated with alterations present both in healthy tissue and resting-state networks. Second, we propose a fiber tracking pipeline capable of using anatomical information while still reconstructing bundles in tumoral and peritumoral tissue. Finally, using machine learning and healthy anatomical information, we predict structural rearrangement after surgery given the preoperative brain network. The generative model also disentangles complex patterns of connectivity reorganization for different types of tumors. Overall, we show the importance of carefully designing studies including MR signals within damaged brain tissues, as they exhibit and relate to non-trivial patterns of both structural and functional (dis-)connections or activity.
Individual-specific functional connectivity shows improved performance in detecting and predicting individualized symptoms of Alzheimer’s disease in elderly people with/without APOE ε4 allele
Authors: Hua Lin , Gao Fei , Xia Xiaoluan , Guo Qiwei , Zhao Yonghua , Yuan Zhen
Published: November 2022

To date, no reliable biomarkers are available that link individual-specific functional connectivity and patients’ individualized symptoms for early detection and prediction of Alzheimer’s disease (AD) in elderly people with specific genotypes. Meanwhile, functional magnetic resonance imaging (MRI) and machine learning are promising tools that can reveal the relationships between brain and behavior at individual level towards predicting the transition to AD. In this study, individual-specific functional connectivity was constructed in elderly participants with Apolipoprotein E (APOE) ε4 allele (N= 120) and without APOE ε4 allele (N= 115), respectively. In particular, machine learning based on a recursive feature selection technique was carried out to track multiple clinical symptoms among differing genotypes at individual level from normal aging (NA) and AD. It was found that the captured neuroimaging features in both APOE genotyping groups were able to distinguish the changes of clinical symptoms from NA to AD. Besides, our findings illustrated that the connections between individual-specific functional regions exhibited significantly higher correlation between estimated and observed scores in multiple clinical symptoms than those from atlas-based functional connectivity for both APOE genotyping groups, while no significant performance was detected when the data of two APOE genotyping groups were combined for the estimation models. Further, individual-specific between-network connectivity constitutes a major contributor for accessing cognitive symptoms in both APOE genotyping groups. Therefore, this study demonstrated the essential role of individual variation in cortical functional anatomy and the significance in combining brain and behavior for improving the accuracy in detection and prediction of AD in elderly people with specific genotypes.
The microbial composition and functional roles of different kombucha products in Singapore
Authors: Hooi Suet Li , Dwiyanto Jacky , Toh Kai Yee , Tan Gwendoline , Chong Chun Wie , Lee Jonathan Wei Jie , Lim Jeremy
Published: November 2022

Kombucha is a fermented tea traditionally known for its health-enhancing properties owing to the bioactive compounds generated by acetic acid bacteria (AAB) and lactic acid bacteria (LAB). We compared the distribution of AAB and LAB and their functional pathways across nine commercial kombucha products in Singapore using shotgun metagenomic sequencing. A high prevalence ofKomagataeibacterspecies includingKomagataeibacter saccharivorans(82.93% in B),Komagataeibacter xylinus(93.38% in D) andKomagataeibacter rhaeticus(92.20% and 30.62% in G and I) was detected in AAB-dominant kombucha. LAB-dominant kombucha was largely represented byBacillus coagulans(~99% in E and F) andLactobacillus nagelii(~60% in H). Despite differences in bacterial composition, both LAB-and AAB-dominant kombucha harbour pathways involved in the biosynthesis of short-chain fatty acids (SCFAs), amino and organic acids and vitamin B12. “Fatty acid and beta-oxidation II (peroxisome)” and “fatty acid and beta-oxidation I” were detected in the LAB but not the AAB-dominant kombucha.
Mechanistic divergence of piRNA biogenesis in Drosophila
Authors: Chary Shashank , Hayashi Rippei
Published: November 2022

Organisms require mechanisms to distinguish self and non-self RNA. This distinction is crucial to initiate the biogenesis of piRNAs. In Drosophila ovaries, PIWI-guided slicing and the recognition of piRNA precursor transcripts by the DEAD-box RNA helicase Yb are the two known mechanisms to licence an RNA for piRNA biogenesis in the germline and the soma, respectively. Both, the PIWI proteins and Yb are highly conserved across most Drosophila species and are thought to be essential to the piRNA pathway and for silencing transposons. However, we find that species closely related toD. melanogasterhave lost theybgene, as well as the PIWI geneAgo3. We show that the precursor RNA is still selected in the absence of Yb to abundantly generate transposon antisense piRNAs in the soma. We further demonstrate thatD. eugracilis, which lacksAgo3, is completely devoid of ping-pong piRNAs and exclusively produces phased piRNAs in the absence of slicing. Thus, there are more possible routes through which the piRNA pathway can achieve specificity than previously suggested.
Nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy (iU-ExM)
Authors: Louvel Vincent , Haase Romuald , Mercey Olivier , Laporte Marine. H. , Soldati-Favre Dominique , Hamel Virginie , Guichard Paul
Published: November 2022

Expansion microscopy is an approach of super-resolution fluorescence microscopy that does not yet achieve the precision of nanoscopy techniques such as single-molecule light microscopy (SMLM). Here, we developed an iterative ultrastructure expansion microscopy approach (iU-ExM), which now matches the SMLM resolution as demonstrated using standard references such as the nuclear pores. Applicable to both cells and tissues, iU-ExM allows a broad research community to access high precision super-resolution microscopy.
Multifaceted contributions ofDicer2to arbovirus transmission byAedes aegypti
Authors: Merkling Sarah Hélène , Crist Anna Beth , Henrion-Lacritick Annabelle , Frangeul Lionel , Gausson Valérie , Blanc Hervé , Baidaliuk Artem , Saleh Maria-Carla , Lambrechts Louis
Published: November 2022

Arthropod-borne viruses (arboviruses) transmitted byAedes aegyptimosquitoes are an increasing threat to global health. The small interfering RNA (siRNA) pathway is considered the main antiviral immune pathway of insects, and thus represents a potential key target in the development of novel transmission-blocking strategies against arboviruses. Although the antiviral function of the siRNA pathway inAe. aegyptiis well established, its effective impact on arbovirus transmission is surprisingly poorly understood. Here, we used CRISPR/Cas9-mediated gene editing to create a line ofAe. aegyptiin which we mutatedDicer2, a gene encoding the RNA sensor and key component of the siRNA pathway. OurDicer2null mutant line is viable and fertile, and only displays minor fitness defects despite being unable to produce siRNAs. The loss ofDicer2affects early viral replication and systemic viral dissemination of four medically significant arboviruses (chikungunya, Mayaro, dengue, and Zika viruses) representing two viral families. However, measures of virus transmission potential indicate thatDicer2null mutants and wild-type mosquitoes display an overall similar level of vector competence. Additionally,Dicer2null mutants undergo significant virus-induced mortality during infection with chikungunya virus, but not dengue virus. Together, our results define a multifaceted role forDicer2in the transmission of arboviruses byAe. aegyptimosquitoes and pave the way for further mechanistic investigations.
Inducible co-stimulatory molecule (ICOS) alleviates Paclitaxel induced peripheral neuropathy via an IL-10-mediated mechanism in female mice
Authors: Sankaranarayanan Ishwarya , Tavares-Ferreira Diana , Mwrigi Juliet , Mejia Galo , Burton Michael D. , Price Theodore J.
Published: November 2022

Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. This causes damage to peripheral nerves and the dorsal root ganglia (DRG). Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors. Neuro-immune interactions occur in CIPN and have been implicated both in the development and progression of the disease and disease resolution. We investigated the potential role of Inducible co-stimulatory molecule (ICOS) in the resolution of CIPN pain-like behaviors in mice. ICOS is an immune checkpoint molecule that is expressed on the surface of activated T cells and promotes proliferation and differentiation of T cells. We found that intrathecal administration of ICOS agonist antibody (ICOSaa) alleviates mechanical hypersensitivity caused by paclitaxel and facilitates the resolution of mechanical sensitivity in female mice. Administration of ICOSaa reduced astrocyte-gliosis in the spinal cord and satellite cell gliosis in the DRG of mice previously treated with paclitaxel. Mechanistically, ICOSaa intrathecal treatment promoted pain resolution by increasing interleukin 10 (IL-10) expression in the dorsal root ganglion. In line with these observations, blocking IL-10 receptor (IL-10R) activity occluded the effects of ICOSaa treatment on CIPN behavior in female mice. Suggesting a broader activity in neuropathic pain, ICOSaa also partially resolved mechanical hypersensitivity in the spared nerve injury (SNI) model. Our findings support a model wherein ICOSaa administration induces IL-10 expression to facilitate neuropathic pain relief in female mice. ICOSaa treatment is in clinical development for solid tumors and given our observation of T cells in the human DRG, ICOSaa therapy could be developed for combination chemotherapy - CIPN clinical trials.

Highlights

ICOS agonist antibody (ICOSaa) promotes pain resolution in female mice

DRG T cells appear to enter an anti-inflammatory phenotype by ICOSaa treatment

ICOSaa treatment increases DRG levels of IL-10 cytokine

ICOSaa effects in female mice are blocked by IL-10 sequestering treatment
Scene perception and visuospatial memory converge at the anterior edge of visually-responsive cortex
Authors: Steel Adam , Garcia Brenda D. , Goyal Kala , Mynick Anna , Robertson Caroline E.
Published: November 2022

To fluidly engage with the world, our brains must simultaneously represent both the scene in front of us and our memory of the immediate surrounding environment (i.e., local visuospatial context). How does the brain’s functional architecture enable sensory and mnemonic representations to closely interface, while also avoiding sensory-mnemonic interference? Here, we asked this question using first-person, head-mounted virtual reality (VR) and fMRI. Using VR, human participants of both sexes learned a set of immersive, real-world visuospatial environments in which we systematically manipulated the extent of visuospatial context associated with a scene image in memory across three learning conditions, spanning from a single field-of-view to a city street. We used individualized, within-subject fMRI to determine which brain areas support memory of the visuospatial context associated with a scene during recall (Exp. 1) and recognition (Exp. 2). Across the whole brain, activity in three patches of cortex was modulated by the amount of known visuospatial context, each located immediately anterior to one of the three scene perception areas of high-level visual cortex. Individual subject analyses revealed that these anterior patches corresponded to three functionally-defined place memory areas, which selectively respond when visually recalling personally familiar places. In addition to showing activity levels that were modulated by the amount of visuospatial context, multivariate analyses showed that these anterior areas represented the identity of the specific environment being recalled. Together, these results suggest a convergence zone for scene perception and memory of the local visuospatial context at the anterior edge of high-level visual cortex.

Significance statement

As we move through the world, the visual scene around us is integrated with our memory of the wider visuospatial context. Here, we sought to understand how the functional architecture of the brain enables coexisting representations of the current visual scene and memory of the surrounding environment. Using a combination of immersive virtual reality and fMRI, we show that memory of visuospatial context outside the current field-of-view is represented in a distinct set of brain areas immediately anterior and adjacent to the perceptually-oriented scene-selective areas of high-level visual cortex. This functional architecture would allow efficient interaction between immediately adjacent mnemonic and perceptual areas, while also minimizing mnemonic-perceptual interference.
Quantification of Early Gait Development: Expanding the Application of Catwalk Technology to an Infant Rhesus Macaque Model
Authors: Kabakov Sabrina A , Crary Emma , Menna Viktorie , Razo Elaina R , Eickhoff Jens C , Dulaney Natalie R , Drew John R , Bach Kathryn , Poole Aubreonna M , Stumpf Madison , Mitzey Ann M , Malicki Kerri B , Schotzko Michele L , Pickett Kristen A , Schultz-Darken Nancy J , Emborg Marina E , O'Connor David H , Golos Thaddeus G , Mohr Emma L. , Ausderau Karla K
Published: November 2022

Background: Understanding gait development is essential for identifying motor impairments in neurodevelopmental disorders. Defining typical gait development in a rhesus macaque model is critical prior to characterizing abnormal gait. The goal of this study was to 1) explore the feasibility of using the Noldus Catwalk to assess gait in infant rhesus macaques and 2) provide preliminary normative data of gait development during the first month of life. New method: The Noldus Catwalk was used to assess gait speed, dynamic and static paw measurements, and interlimb coordination in twelve infant rhesus macaques at 14, 21, and 28 days of age. All macaque runs were labeled as a diagonal or non-diagonal walking pattern. Results: Infant rhesus macaques primarily used a diagonal (mature) walking pattern as early as 14 days of life. Ten infant rhesus macaques (83.3%) were able to successfully walk across the Noldus Catwalk at 28 days of life. Limited differences in gait parameters were observed between timepoints because of the variability within the group at 14, 21, and 28 days. Comparison with existing methods: No prior gait analysis system has been used to provide objective quantification of gait parameters for infant macaques. Conclusions: The Catwalk system can be utilized to quantify gait in infant rhesus macaques less than 28 days old. Future applications to infant rhesus macaques could provide a better understanding of gait development and early differences within various neurodevelopmental disorders.
Detection of mitotic neuroblasts provides additional evidence of steady state neurogenesis in the adult small intestinal myenteric plexus
Authors: Gorecki Anastazja M. , Slosberg Jared , Hong Su Min , Seika Philippa , Puttapaka Srinivas , Migden Blake , Gulko Anton , Singh Alpana , Zhang Chengxiu , Gurumurthy Rohin , Kulkarni Subhash
Published: November 2022

Maintenance of normal structure of the enteric nervous system (ENS), which regulates key gastrointestinal functions, requires robust homeostatic mechanisms, since by virtue of its location within the gut wall, the ENS is subject to constant mechanical, chemical, and biological stressors. Using transgenic and thymidine analogue-based experiments, we previously discovered that neuronal turnover – where continual neurogenesis offsets ongoing neuronal loss at steady state – represents one such mechanism. Although other studies confirmed that neuronal death continues into adulthood in the myenteric plexus of the enteric nervous system (ENS), the complicated nature of thymidine analogue presents challenges in substantiating the occurrence of adult neurogenesis. Therefore, it’s vital to employ alternative, well-recognized techniques to substantiate the existence of adult enteric neurogenesis in the healthy gut. Here, by using established methods of assessing nuclear DNA content and detecting known mitotic marker phosphor-histone H3 (pH3) in Hu+adult ENS cells, we show that ∼10% of adult murine small intestinal myenteric Hu+cells, and ∼20% of adult human small intestinal myenteric Hu+cells show evidence of mitosis and hence are cycling neuroblasts. We observe that proportions of Hu+cycling neuroblasts in the adult murine ENS neither vary with ganglia size, nor do they differ significantly between two intestinal regions – duodenum and ileum, or between sexes. Confocal microscopy provides further evidence of cytokinesis in Hu+cells. The presence of a significant population of cycling neuroblasts in adult ENS provide further evidence of steady state neurogenesis in the adult ENS.
Discovery and validation of the binding poses of allosteric fragment hits to PTP1b: From molecular dynamics simulations to X-ray crystallography
Authors: Greisman Jack B. , Willmore Lindsay , Yeh Christine Y. , Giordanetto Fabrizio , Shahamadtar Sahar , Nisonoff Hunter , Maragakis Paul , Shaw David E.
Published: November 2022

Fragment-based drug discovery has led to six approved drugs, but the small size of the chemical fragments used in such methods typically results in only weak interactions between the fragment and its target molecule, which makes it challenging to experimentally determine the three-dimensional poses fragments assume in the bound state. One computational approach that could help address this difficulty is long-timescale molecular dynamics (MD) simulation, which has been used in retrospective studies to recover experimentally known binding poses of fragments. Here, we present the results of long-timescale MD simulations that we used to prospectively discover binding poses for two series of fragments in allosteric pockets on a difficult and important pharmaceutical target, protein-tyrosine phosphatase 1b (PTP1b). Our simulations reversibly sampled the fragment association and dissociation process. One of the binding pockets found in the simulations has not to our knowledge been previously observed with a bound fragment, and the other pocket adopted a very rare conformation. We subsequently obtained high-resolution crystal structures of members of each fragment series bound to PTP1b, and the experimentally observed poses confirmed the simulation results. To the best of our knowledge, our findings provide the first demonstration that MD simulations can be used prospectively to determine fragment binding poses to previously unidentified pockets.