bluuebunny/crossref_metadata_2025 huggingface dataset:
AnthropoAge, a novel approach to integrate body composition into the estimation of biological age
Authors: Fermín-Martínez Carlos A. , Márquez-Salinas Alejandro , Guerra Enrique C. , Zavala-Romero Lilian , Antonio-Villa Neftali Eduardo , Fernández-Chirino Luisa , Sandoval-Colin Eduardo , Barquera-Guevara Daphne Abigail , Muñoz Alejandro Campos , Vargas-Vázquez Arsenio , Paz-Cabrera César Daniel , Ramírez-García Daniel , Gutiérrez-Robledo Luis Miguel , Bello-Chavolla Omar Yaxmehen
Published: September 2021

Aging is believed to occur across multiple domains, one of which is body composition; however, attempts to integrate it into biological age (BA) have been limited. Here, we consider the sex-dependent role of anthropometry for prediction of 10-year all-cause mortality using data from 18,794 NHANES participants to generate and validate a new BA metric. Our data-driven approach pointed to sex-specific contributors for BA estimation: WHtR, arm and thigh circumferences for men; weight, WHtR, thigh circumference, subscapular and triceps skinfolds for women. We used these measurements to generate AnthropoAge, which predicted all-cause mortality (AUROC 0.876, 95%CI 0.864-0.887) and cause-specific mortality independently of race, sex, and comorbidities; AnthropoAge was a better predictor than PhenoAge for cerebrovascular, Alzheimer and COPD mortality. A metric of age acceleration was also derived and used to assess sexual dimorphisms linked to accelerated aging, where women had an increase in overall body mass plus an important subcutaneous to visceral fat redistribution, and men displayed a marked decrease in fat and muscle mass. Finally, we showed that consideration of multiple BA metrics may identify unique aging trajectories with increased mortality (HR for multidomain acceleration 2.43, 95%CI 2.25-2.62) and comorbidity profiles. A simplified version of AnthropoAge (S-AnthropoAge) was generated using only BMI and WHtR, all results were preserved using this metric. In conclusion, AnthropoAge is a useful proxy of BA that captures cause-specific mortality and sex dimorphisms in body composition, and it could be used for future multidomain assessments of aging to better characterize the heterogeneity of this phenomenon.

GRAPHICAL ABSTRACT
Revisiting the Use of Structural Similarity Index in Hi-C
Authors: Lee Hanjun , Blumberg Bruce , Lawrence Michael S. , Shioda Toshi
Published: September 2021

Identification of dynamic changes in chromatin conformation is a fundamental task in genetics. In 2020, Galan et al.1 presented CHESS (Comparison of Hi-C Experiments using Structural Similarity), a novel computational algorithm designed for systematic identification of structural differences in chromatin-contact maps. Using CHESS, the same group recently reported that chromatin organization is largely maintained across tissues during dorsoventral patterning of fruit fly embryos despite tissue-specific chromatin states and gene expression2. However, here we show that the primary outputs of CHESS–namely, the structural similarity index (SSIM) profiles–are nearly identical regardless of the input matrices, even when query and reference reads were shuffled to destroy any significant differences. This issue stems from the dominance of the regional counting noise arising from stochastic sampling in chromatin-contact maps, reflecting a fundamentally incorrect assumption of the CHESS algorithm. Therefore, biological interpretation of SSIM profiles generated by CHESS requires considerable caution.
Fluctuations in Neural Complexity During Wakefulness Relate To Conscious Level and Cognition
Authors: Mediano Pedro A.M. , Ikkala Aleksi , Kievit Rogier A. , Jagannathan Sridhar R. , Varley Thomas F. , Stamatakis Emmanuel A. , Bekinschtein Tristan A. , Bor Daniel
Published: September 2021

There has been considerable recent progress in measuring conscious level using neural complexity measures. For instance, such measures can reliably distinguish healthy awake from asleep subjects and vegetative state patients. However, this line of research has never explored the dynamics of conscious level during normal wakefulness. Being able to capture meaningful differences in conscious level during wakefulness may provide a vital new insight into the nature of consciousness, by demonstrating what biological, behavioural and cognitive factors relate to such differences. Here we take advantage of a large MEG and fMRI dataset of healthy adults, to examine within-subject conscious level fluctuations during resting state and tasks, by using a range of complexity measures. We first establish the validity of this approach in both neuroimaging domains by relating neural complexity measures to pre-existing techniques for capturing transitions of consciousness from full wakefulness into drowsiness and the earliest stages of sleep, finding decreased complexity as participants become increasingly drowsy. We further demonstrate that neural complexity measures in both MEG and fMRI change both within and between tasks, and relate to performance on an executive task, with higher complexity associated with better performance and faster reaction times. This approach provides a powerful new route to further explore the cognitive and neural underpinnings of consciousness.
Characterization of Cervical-Cranial Muscle Network in Correlation with Vocal Features
Authors: O’Keeffe Rory , Shirazi Seyed Yahya , Mehrdad Sarmad , Crosby Tyler , Johnson Aaron M. , Atashzar S. Farokh
Published: September 2021

Objective evaluation of physiological responses using non-invasive methods has attracted great interest regarding the assessment of vocal performance and disorders. This paper, for the first time, demonstrates that the topographical features of the cervical-cranial intermuscular coherence network generated using surface electromyography (sEMG) have a strong potential for detecting subtle changes in vocal performance. For this purpose, in this paper, 12 sEMG signals were collected from six cervical and cranial muscles bilaterally. Data were collected from four subjects without a history of a voice disorder performing a series of vocal tasks. The vocal tasks were varied phonation (an /a/ sustained for the maximal duration with combinations of two levels of loudness and two levels of pitch), a pitch glide from low to high, singing a familiar song, spontaneous speech, and reading with different loudness levels. The varied phonation tasks showed the median degree, and weighted clustering coefficient of the coherence-based intermuscular network ascends monotonically, with a high effect size (|rrb| = 0.52). The set of tasks, including pitch glide, singing, and speech, was significantly distinguishable using the network features as both degree and weighted clustering coefficient had a very high effect size (|rrb| > 0.83) across these tasks. Also, pitch glide has the highest degree and weighted clustering coefficient among all tasks (degree > 0.6, weighted clustering coefficient > 0.6). Spectrotemporal features performed far less effective than the proposed functional muscle network metrics to differentiate the vocal tasks. The highest effect size for spectrotemporal features was only |rrb| = 0.19. In this paper, for the first time, the power of a cervical-cranial muscle network has been demonstrated as a neurophysiological window to vocal performance. The results also shed light on the tasks with the highest network involvement, which may be potentially used in monitoring vocal disorders and tracking rehabilitation progress.
Traumatic Brain Injury Exacerbates Alzheimer’s Disease Pathology in the Retinas of TgF344-AD Rats
Authors: Secora Conner , Vielle Anne , Wang Athena Ching-Jung , Lenhart Patricia , Salcedo Ernesto , Johnson Noah R. , Ahmed Md. Mahuiddin , Chial Heidi J. , Boyd Timothy D. , Potter Huntington , Natalia Vergara M.
Published: September 2021

Alzheimer’s disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology.

Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a twotime unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.
Genetic effect modification of cis-acting C-reactive protein variants in cardiometabolic disease status
Authors: Zheng Jie , Tang Haotian , Lyon Matthew , Davies Neil M. , Walker Venexia , Floyd James S. , Austin Thomas R. , Shojaie Ali , Psaty Bruce M. , Gaunt Tom R. , Smith George Davey
Published: September 2021

Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18×10−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.
Biclique extension as an effective approach to predict novel interaction partners in metabolic compound-protein interaction networks
Authors: Thieme Sandra , Walther Dirk
Published: September 2021

Motivation

Metabolic networks are complex systems of connected chemical reactions with physical interactions between metabolites and proteins playing a critical role for both metabolic conversion and regulation. In this study, we aimed to predict previously unknown compound-protein interactions (CPI) by transferring the concept of biclique extension, which was developed in the context of drug-target interaction prediction and that is based on the rationale that interactions that readily extend an existing biclique are real, to metabolic CPI networks.

Results

We developed and tested a workflow to predict CPIs based on the concept of extending existing bicliques and applied it toE. coliand human using their respective known CPI network as input. Depending on the chosen biclique size, for theE. colinetwork we reached a sensitivity of 39% with an associated precision of 59%. For the larger human CPI network, a sensitivity of 78% with a false-positive rate of less than 5% and an associated precision of 75% was obtained. At more stringent settings, a precision as high as 95% was attainable at the expense of a lowered recall. Prediction performance significantly exceeded that obtained using randomized networks as input. Predicted novel interactions were tested for biomolecular function involvement, with TCA-cycle and ribosomal processes found associated with particularly pronounced statistical significance. As we demonstrate, our approach holds great potential to increase efficiency of experimental testing of CPIs and can readily be transferred to other species of interest.

Availability and implementation

The R code and datasets are available athttps://github.com/SandraThieme/BiPredict.
An innovative optical context to make honeybees crash repeatedly
Authors: Serres Julien R. , Morice Antoine H.P. , Blary Constance , Miot Romain , Montagne Gilles , Ruffier Franck
Published: September 2021

To investigate altitude control in honeybees, an optical context was designed to make honeybees crash. It has been widely accepted that honeybees rely on the optic flow generated by the ground to control their altitude. However, identifying an optical context capable of uncorrelating forward speed from altitude in honeybees’ flight was the first step towards enhancing the optical context to better understand altitude control in honeybees. This optical context aims to put honeybees in the same flight conditions as an open sky flight above mirror-smooth water. An optical manipulation, based on a pair of opposed horizontal mirrors, was designed to remove any visual information coming from the floor and ceiling. Such an optical manipulation reproduced quantitatively the seminal experiment of Heran & Lindauer (1963), and revealed that honeybees control their altitude by detecting the optic flow with a visual field that extends to approximately 165°.
Models as games: a novel approach for ‘gamesourcing’ parameter data and communicating complex models
Authors: Minderman Jeroen , Duthie A. Bradley , Jones Isabel L. , Thomas-Walters Laura , Bach Adrian , Nuttall Matthew , Bunnefeld Nils
Published: September 2021

1

Models have become indispensable tools in conservation science in the face of increasingly rapid loss of biodiversity through anthropogenic habitat loss and natural resource exploitation. In addition to their ecological components, accurately representing human decision-making processes in such models is vital to maximise their utility. This can be problematic as modelling complexity increases, making them challenging to communicate and parameterise.

Games have a long history of being used as science communication tools, but are less widely used as data collection tools, particularly in videogame form. We propose a novel approach to (1) aid communication of complex social-ecological models, and (2) “gamesource” human decision-making data, by explicitly casting an existing modelling framework as an interactive videogame.

We present players with a natural resource management game as a front-end to a social-ecological modelling framework (Generalised Management Strategy Evaluation, GMSE). Players’ actions replace a model algorithm making management decisions about a population of wild animals, which graze on crops and can thus lower agricultural yield. A number of non-player agents (farmers) respond through modelled algorithms to the player’s management, taking actions that may affect their crop yield as well as the animal population. Players are asked to set their own management goal (e.g. maintain the animal population at a certain level or improve yield) and make decisions accordingly. Trial players were also asked to provide any feedback on both gameplay and purpose.

We demonstrate the utility of this approach by collecting and analysing game play data from a sample of trial plays, in which we systematically vary two model parameters, and allowing trial players to interact with the model through the game interface. As an illustration, we show how variations in land ownership and the number of farmers in the system affects decision-making patterns as well as population trajectories (extinction probabilities).

We discuss the potential and limitations of this model-game approach in the light of trial player feedback received. In particular, we highlight how a common concern about the game framework (perceived lack of “realism” or relevance to a specific context) are actually criticisms of the underlying model, as opposed to the game itself. This further highlights both the parallels between games and models, as well as the utility of model-games to aid in communicating complex models. We conclude that videogames may be an effective tool for conservation and natural resource management, and that although they provide a promising means to collect data on human decision-making, it is vital to carefully consider both external validity and potential biases when doing so.
Not all that is gold glitters: PV-IRES-Cre mouse line shows low efficiency of labeling of parvalbumin interneurons in the perirhinal cortex
Authors: Nigro Maximiliano José , Kirikae Hinako , Kjelsberg Kasper , Nair Rajeevkumar Raveendran , Witter Menno P.
Published: September 2021

The wide diversity of cortical inhibitory neuron types populating the cortex allows the assembly of diverse microcircuits and endows these circuits with different computational properties. Thus, characterizing neuronal diversity is fundamental to describe the building blocks of cortical microcircuits and probe their function. To this purpose, the mouse has emerged as a powerful tool to genetically label and manipulate specific inhibitory cell-types in the mammalian brain. Among these cell-types, the parvalbumin-expressing interneuron type (PV-INs) is perhaps the most characterized. Several mouse lines have been generated to target PV-INs. Among these mouse lines, the PV-IRES-Cre lines is the most widely used and demonstrated a high specificity and efficiency in targeting PV-INs in different cortical areas. However, a characterization of the performance across cortical regions is still missing. Here we show that the PV-IRES-Cre mouse line labels only a fraction of parvalbumin immunoreactive neurons in perirhinal cortex and other association areas. Our results point to a yet uncharacterized diversity within the PV-INs and emphasize the need to characterize these tools in specific cortical areas.
A network model of glymphatic flow under different experimentally-motivated parametric scenarios
Authors: Tithof Jeffrey , Boster Kimberly A. S. , Bork Peter A. R. , Nedergaard Maiken , Thomas John H. , Kelley Douglas H.
Published: September 2021

Rapidly growing evidence demonstrates that flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) – annular channels surrounding vasculature in the brain – is a critically-important component of neurophysiology. CSF inflow contributes during physiological conditions to clearance of metabolic waste and in pathological situations to edema formation. However, brain-wide imaging methods cannot resolve PVSs, and high-resolution methods cannot access deep tissue or be applied to human subjects, so theoretical models provide essential insight. We model this CSF pathway as a network of hydraulic resistances, built from published parameters. A few parameters have very wide uncertainties, so we focus on the estimated limits of their feasible ranges by analyzing different parametric scenarios. We identify low-resistance PVSs and high-resistance parenchyma (brain tissue) as the scenario that best explains experimental observations. Our results point to the most important parameters that should be measured in future experiments. Extensions of our modeling may help predict stroke severity or lead to neurological disease treatments and drug delivery methods.
Rescuing Biologically Relevant Consensus Regions Across Replicated Samples
Authors: Jalili Vahid , Cremona Marzia Angela , Palluzzi Fernando
Published: September 2021

Motivation

Protein-DNA binding sites of ChIP-seq experiments are identified where the binding affinity is significant based on a given threshold. The choice of the threshold is a trade-off between conservative region identification and discarding weak, but true binding sites.

Results

We argue the biological relevance of weak binding sites and the information they add when rescued. The sites are rescued using MSPC, which exploits replicates to lower the threshold required to identify a binding site while keeping a low false-positive rate. We extend MSPC to call consensus regions across any number of replicated samples, accounting for differences between biological and technical replicates. We observed several master transcription regulators (e.g., SP1 and GATA3) and HDAC2-GATA1 regulatory networks on rescued regions.

Availability and implementation

An implementation of the proposed method and the scripts to reproduce the performed analysis are freely available at https://genometric.github.io/MSPC/, MSPC is distributed as a command-line application, an R package available from Bioconductor (https://doi.org/doi:10.18129/B9.bioc.rmspc), and a C# library.
Domain General Processes for Interactive Touch
Authors: Buck Tao , DiCocco Courtney , Cuzzocreo Jennifer L. , Noah J. Adam , Zhang Xian , Hirsch Joy
Published: September 2021

The nexus model of social processing proposes that the right temporal parietal junction (rTPJ) serves as a neural hub for cognitive social functions. We test the hypothesis that the rTPJ is a domain general region including somatosensory social functions. Neuroimaging findings and cross-brain coherence for right- and left-hand handclasps with real vs. simulated hands were consistent with the domain general model.
Compositional phylogenomic modelling resolves the ‘Zoraptera problem’: Zoraptera are sister to all other polyneopteran insects
Authors: Tihelka Erik , Engel Michael S. , Lozano-Fernandez Jesus , Giacomelli Mattia , Yin Ziwei , Rota-Stabelli Omar , Huang Diying , Pisani Davide , Donoghue Philip C.J. , Cai Chenyang
Published: September 2021

The evolution of wings propelled insects to their present mega-diversity. However, interordinal relationships of early-diverging winged insects and the timescale of their evolution are difficult to resolve, in part due to uncertainties in the placement of the enigmatic and species-poor order Zoraptera. The ‘Zoraptera problem’ has remained a contentious issue in insect evolution since its discovery more than a century ago. This is a key issue because different placements of Zoraptera imply dramatically different scenarios of diversification and character evolution among polyneopteran. Here, we investigate the systematic placement of Zoraptera using the largest protein-coding gene dataset available to date, deploying methods to mitigate common sources of error in phylogenomic inference, and testing historically proposed hypotheses of zorapteran evolution. We recover Zoraptera as the earliest-diverging polyneopteran order, while earwigs (Dermaptera) and stoneflies (Plecoptera) form a monophyletic clade (Dermoplectopterida) sister to the remainder of Polyneoptera. The morphology and palaeobiology of stem-zorapterans are informed by Mesozoic fossils. The gut content and mouthparts of a male specimen ofZorotypus nascimbeneifrom Kachin amber (Cretaceous) reveal a fungivorous diet of Mesozoic zorapterans, akin to extant species. Based on a set of 42 justified fossil and stratigraphic calibrations, we recover a Devonian origin of winged insects and Polyneoptera, suggesting that these groups coincided with the rise of arborescence during the diversification of early terrestrial plants, fungi, and animals. Our results provide a robust framework for understanding the pattern and timescale of early winged insect diversification.
Negative immune regulation contributes to disease tolerance in Drosophila
Authors: Prakash Arun , Monteith Katy M. , Vale Pedro F.
Published: September 2021

Disease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance inDrosophila melanogasterwhen infected with four doses of the gram-negative bacterial pathogenPseudomonas entomophila. We find that while flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, UAS-RNAi knockdown of negative regulators of IMD (pirkandcaudal) substantially increased the per-pathogen-mortality in both males and females across all tested infectious doses. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.
Cryo-EM structures reveal high-resolution mechanism of a DNA polymerase sliding clamp loader
Authors: Gaubitz Christl , Liu Xingchen , Pajak Joshua , Stone Nicholas P. , Hayes Janelle A. , Demo Gabriel , Kelch Brian A
Published: September 2021

Sliding clamps are ring-shaped protein complexes that are integral to the DNA replication machinery of all life. Sliding clamps are opened and installed onto DNA by clamp loader AAA+ ATPase complexes. However, how a clamp loader opens and closes the sliding clamp around DNA is still unknown. Here, we describe structures of the S. cerevisiae clamp loader Replication Factor C (RFC) bound to its cognate sliding clamp Proliferating Cell Nuclear Antigen (PCNA) en route to successful loading. RFC first binds to PCNA in a dynamic, closed conformation that blocks both ATPase activity and DNA binding. RFC then opens the PCNA ring through a large-scale ‘crab-claw’ expansion of both RFC and PCNA that explains how RFC prefers initial binding of PCNA over DNA. Next, the open RFC:PCNA complex binds DNA and interrogates the primer-template junction using a surprising base-flipping mechanism. Our structures indicate that initial PCNA opening and subsequent closure around DNA do not require ATP hydrolysis, but are driven by binding energy. ATP hydrolysis, which is necessary for RFC release, is triggered by interactions with both PCNA and DNA, explaining RFC’s switch-like ATPase activity. Our work reveals how a AAA+ machine undergoes dramatic conformational changes for achieving binding preference and substrate remodeling.
Dysregulated coordination ofMAPTexon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD
Authors: Bowles Kathryn R. , Pugh Derian A. , Oja Laura-Maria , Jadow Benjamin M. , Farrell Kurt , Whitney Kristen , Sharma Abhijeet , Cherry Jonathan D. , Raj Towfique , Pereira Ana C. , Crary John F. , Goate Alison M.
Published: September 2021

Understanding regulation ofMAPTsplicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions.MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination ofMAPTexons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.
Unrestricted eye movements strengthen causal connectivity from hippocampal to oculomotor regions during scene construction
Authors: Ladyka-Wojcik Natalia , Liu Zhong-Xu , Ryan Jennifer D.
Published: September 2021

Scene construction is a key component of memory recall, navigation, and future imagining, and relies on the medial temporal lobes (MTL). A parallel body of work suggests that eye movements may enable the imagination and construction of scenes, even in the absence of external visual input. There are vast structural and functional connections between regions of the MTL and those of the oculomotor system. However, the directionality of connections between the MTL and oculomotor control regions, and how it relates to scene construction, has not been studied directly in human neuroimaging. In the current study, we used dynamic causal modeling (DCM) to interrogate effective connectivity between the MTL and oculomotor regions using a scene construction task in which participants’ eye movements were either restricted (fixed-viewing) or unrestricted (free-viewing). By omitting external visual input, and by contrasting free- versus fixed- viewing, the directionality of neural connectivity during scene construction could be determined. As opposed to when eye movements were restricted, allowing free viewing during construction of scenes strengthened top-down connections from the MTL to the frontal eye fields, and to lower-level cortical visual processing regions, suppressed bottom-up connections along the visual stream, and enhanced vividness of the constructed scenes. Taken together, these findings provide novel, non-invasive evidence for the causal architecture between the MTL memory system and oculomotor system associated with constructing vivid mental representations of scenes.

Highlights

The role of eye movements in mentally constructing scene imagery was investigated

Restricting eye movements impaired vividness of constructed scene imagery

Making eye movements strengthened connectivity from memory to oculomotor regions
Maturation of human intestinal epithelium from pluripotency in vitro
Authors: Kilik Umut , Yu Qianhui , Holtackers Rene , Seimiya Makiko , da Silveira dos Santos Aline Xavier , Treutlein Barbara , Spence Jason R. , Camp J. Gray
Published: September 2021

Methods to generate human intestinal tissue from pluripotent stem cells (PSCs) open new inroads into modeling intestine development and disease. However, current protocols require organoid transplantation into an immunocompromised mouse to achieve matured and differentiated epithelial cell states. Inspired by developmental reconstructions from primary tissues, we establish a regimen of inductive cues that enable stem cell maturation and epithelial differentiation entirely in vitro. We show that the niche factor Neuregulin1 (NRG1) promotes morphological change from proliferative epithelial cysts to matured epithelial tissue in three-dimensional cultures. Single-cell transcriptome analyses reveal differentiated epithelial cell populations, including diverse secretory and absorptive lineages. Comparison to multi-organ developmental and adult intestinal cell atlases confirm the specificity and maturation state of cell populations. Altogether, this work opens a new direction to use in vitro matured epithelium from human PSCs to study human intestinal epithelium development, disease, and evolution in controlled culture environments.
Prioritizing candidate peptides for cancer vaccines by PEPPRMINT: a statistical model to predict peptide presentation by HLA-I proteins
Authors: Zhou Laura Y. , Zou Fei , Sun Wei
Published: September 2021

Recent development of cancer immunotherapy has opened unprecedented avenues to eliminate tumor cells using the human immune system. Cancer vaccines composed of neoantigens, or peptides unique to tumor cells due to somatic mutations, have emerged as a promising approach to activate or strengthen the immune response against cancer. A key step to identifying neoantigens is computationally predicting which somatically mutated peptides are presented on the cell surface by a human leukocyte antigen (HLA). Computational prediction relies on large amounts of high-quality training data, such as mass spectrometry data of peptides presented by one of several HLAs in living cells. We developed a complete pipeline to prioritize neoantigens for cancer vaccines. A key step of our pipeline is PEPPRMINT (PEPtide PResentation using a MIxture model and Neural neTwork), a model designed to exploit mass spectrometry data to predict peptide presentation by HLAs. We applied our pipeline to DNA sequencing data of 60 melanoma patients and identified a group of neoantigens that were more immunogenic in tumor cells than in normal cells. Additionally, the neoantigen burden estimated by PEPPRMINT was significantly associated with activity of the immune system, suggesting these neoantigens could induce an immune response.
The genomic context for aflatoxin B1-degrading Pseudomonas strains
Authors: Tang Jiahong , Deng Dun , Song Maopeng , Liu Zhichang , Ma Sanmei , Wang Yongfei
Published: September 2021

The whole genomes of three strains were sequenced and annotated. COG (Clusters of Orthologous Groups) and GO (Gene Ontology) annotations of the protein-coding genes from three strains show a conservation of genome-wide protein functions in genus Pseudomonas. However, the AFB1-degrading strains HAI2 and HT3 harbor much more genes belonged to the pathway of xenobiotics biodegradation and metabolism than non-degrading strain 48. Besides, the enzyme families potentially involved in the AFB1 degradation of bacteria are more abundant in the two AFB1-degrading strains. A pan-genome profile was then formed by comparing the genomes against other reference genomes of the corresponding Pseudomonas species. Accordingly, a total of 1,528 genes were found to be specific in AFB1-degrading strains, and 65 genes of them are related to oxidoreductase activity.
Genetic studies of human-chimpanzee divergence using stem cell fusions
Authors: Song Janet H.T. , Grant Rachel L. , Behrens Veronica C. , Kucka Marek , Roberts Kingman Garrett A. , Soltys Volker , Chan Yingguang Frank , Kingsley David M.
Published: September 2021

Complete genome sequencing has identified millions of DNA changes that differ between humans and chimpanzees. Although a subset of these changes likely underlies important phenotypic differences between humans and chimpanzees, it is currently difficult to distinguish causal from incidental changes and to map specific phenotypes to particular genome locations. To facilitate further genetic study of human-chimpanzee divergence, we have generated human and chimpanzee auto-tetraploids and allo-tetraploids by fusing induced pluripotent stem cells (iPSCs) of each species. The resulting tetraploid iPSCs can be stably maintained and retain the ability to differentiate along ectoderm, mesoderm, and endoderm lineages. RNA sequencing identifies thousands of genes whose expression differs between humans and chimpanzees when assessed in single-species diploid or auto-tetraploid iPSCs. Analysis of gene expression patterns in inter-specific allo-tetraploid iPSCs shows that human-chimpanzee expression differences arise from substantial contributions of both cis-acting changes linked to the genes themselves, and trans-acting changes elsewhere in the genome. To enable further genetic mapping of species differences, we tested chemical treatments for stimulating genome-wide mitotic recombination between human and chimpanzee chromosomes, and CRISPR methods for inducing species-specific changes on particular chromosomes in allo-tetraploid cells. We successfully generated derivative cells with nested deletions or inter-specific recombination on the X chromosome. These studies identify a long distance cis-regulatory domain of the Fragile X-associated gene (FMR1), confirm an important role for the X chromosome in trans-regulation of other expression differences, and illustrate the potential of this system for more detailed mapping of the molecular basis of human and chimpanzee evolution.

Significance Statement

Comparative studies of humans and chimpanzees have revealed many anatomical, physiological, behavioral, and molecular differences. However, it has been challenging to map these differences to particular chromosome regions. Here, we develop a genetic approach in fused stem cell lines that makes it possible to map human-chimpanzee molecular and cellular differences to specific regions of the genome. We illustrate this approach by mapping chromosome regions responsible for species-specific gene expression differences in fused tetraploid cells. This approach is general, and could be used in the future to map the genomic changes that control many other humanchimpanzee differences in various cell types or organoids in vitro.
Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in animal model: Involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways
Authors: Lai Chencen , Ding Yuanting , Chen Qian , Su Songbai , Liu Heng , Ni Ruiqing , Tang Zhi
Published: September 2021

Alzheimer’s disease is pathologically featured by abnormal accumulation of amyloid-beta plaque, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation including excessive zinc released by presynaptic neurons plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimer’s disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, synaptic and cognitive impairment, has not been fully elucidated in vivo. Here we assessed in the effect of pathological concentration of zinc in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were lateral ventricularly-injected with zinc and treated with rapamycin (intraperitoneal injection) for one week and assessed using Morris water maze. Evaluation of the oxidative stress, tau phorsphylation and synaptic impairment were performed using the hippocampus tissue of the rats by biochemical assays and immunofluorescence staining. Results from Morris water maze showed that the capacity of spatial memory is impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356, and decreased levels of Nrf2 and HO□1 in SH-SY5Y cells and in zinc-treated rats compared with control groups. Increased expressions of reactive oxygen species were observed in zinc sulfate-induced SH-SY5Y cells as well as in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued the zinc-induced increases in mTOR/p70S6K activations, tau phosphorylation and oxidative stress, as well as Nrf2/HO□1 inactivation, cognitive impairment and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress and synaptic impairment, by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO □ 1 activity.
Local adaptation to novel habitats and climatic changes in a wild tomato species via selective sweeps
Authors: Wei Kai , Silva-Arias Gustavo A , Tellier Aurélien
Published: September 2021

Positive selection is the driving force underpinning local adaptation, and leaves footprints of selective sweeps at the underlying major genes. Quantifying the timing of selection and revealing the genetic bases of adaptation in plants species occurring in steep and varying environmental gradients is crucial to predict a species’ ability colonize new niches.

We use whole genome sequence data from six populations across three different habitats of the wild tomato species Solanum chilense to infer the past demographic history and search for genes under strong positive selection. We then correlate current and past climatic projections with the demographic history, allele frequencies, the age of selection events, and distribution shifts.

We find evidence for several selective sweeps targeting regulatory networks involved in root hair development in low altitude, and response to photoperiod and vernalization in high altitude populations. These sweeps occur in a concerted fashion in a given regulatory gene network at particular periods of substantial climatic change.

We decipher the genetic bases and the timing of local adaptation during plant colonization of semi-arid habitats using a unique combination of genome scans for selection and modelling of past climatic data.
Single EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer
Authors: Ferguson Scott , Yang Katherine S. , Zelga Piotr , Liss Andrew S. , Carlson Jonathan , del Castillo Carlos Fernandez , Weissleder Ralph
Published: September 2021

Tumor cell derived extracellular vesicles (EV) are being explored as circulating biomarkers for cancer detection. Up to now however, clinical results have been mixed for a number of reasons including the predominant use of bulk measurements, the inability to differentiate tumor from host cell derived vesicles, the general absence of uniquely identifying biomarkers and the unknown frequency of stochastically distributed biomarkers into single circulating vesicles. We hypothesized that a single EV analysis (sEVA) technique could potentially improve diagnostic accuracy necessary to detect early cancers but the actual biomarker frequency and practical detection limits are currently unknown. Using pancreatic cancer, we carefully analyzed the composition of putative cancer markers in 11 established and new patient derived models. In parental PDAC cells positive for KRASmutand/or P53mutproteins only ∼40% of EVs were also positive (range: 30-64%). This rate of positivity increased to 57% when additional PDAC biomarkers were considered (MUC1, EGFR, ⍺FG-P4OH) in cell lines. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmutand P53mutprotein was detectable at much lower levels, generally in < 0.1% of vesicles. With the analytical capabilities of sEVA however, 15 of the 16 patients with stage 1 PDAC expressed low levels of biomarker positive EV. Using a modeling approach, we estimate that the current PDAC detection limit is at ∼0.1 cm3tumor volume, below clinical imaging capabilities. These findings establish the potential for single-EV analysis for early cancer detection.
Amino Acid Composition and Charge Based Prediction of Antisepsis Peptides by Random Forest Machine Learning Algorithm
Authors: Rathore Aayushi , Saini Anu , Kaur Navjot , Singh Aparna , Dutta Ojasvi , Bamhotra Mrinal , Saini Avneet , Saini Sandeep
Published: September 2021

Sepsis is a severe infectious disease with high mortality, and it occurs when chemicals released in the bloodstream to fight an infection trigger inflammation throughout the body and it can cause a cascade of changes that damage multiple organ systems, leading them to fail, even resulting in death. In order to reduce the possibility of sepsis or infection antiseptics are used and process is known as antisepsis. Antiseptic peptides (ASPs) show properties similar to antigram-negative peptides, antigram-positive peptides and many more. Machine learning algorithms are useful in screening and identification of therapeutic peptides and thus provide initial filters or built confidence before using time consuming and laborious experimental approaches. In this study, various machine learning algorithms like Support Vector Machine (SVM), Random Forest (RF), K-Nearest Neighbour (KNN) and Logistic Regression (LR) were evaluated for prediction of ASPs. Moreover, the characteristics physicochemical features of ASPs were also explored to use them in machine learning. Both manual and automatic feature selection methodology was employed to achieve best performance of machine learning algorithms. A 5-fold cross validation and independent data set validation proved RF as the best model for prediction of ASPs. Our RF model showed an accuracy of 97%, Matthew’s Correlation Coefficient (MCC) of 0.93, which are indication of a robust and good model. To our knowledge this is the first attempt to build a machine learning classifier for prediction of ASPs.
Ecological and social pressures interfere with homeostatic sleep regulation in the wild
Authors: Loftus JC , Harel R , Nuñez CL , Crofoot MC
Published: September 2021

Sleep is fundamental to the health and fitness of all animals. The physiological importance of sleep is underscored by the central role of homeostasis in determining sleep investment – following periods of sleep deprivation, individuals experience longer and more intense sleep bouts. Yet, most studies of sleep have been conducted in highly controlled settings, disconnected from the ecological and social context that may exert pressures on sleep patterns in conflict with homeostatic regulation. Using tri-axial accelerometry and GPS to track the sleep patterns of a group of wild baboons (Papio anubis) at multiple temporal and spatial scales, we found that ecological and social pressures indeed interfere with homeostatic sleep regulation. Baboons sacrificed time spent sleeping when in less familiar locations and when sleeping in proximity to more group-mates, regardless of how much they had slept the prior night or how much they had physically exerted themselves the preceding day. Moreover, we found that the collective dynamics characteristic of social animal groups persist into the sleep period, as baboons exhibited synchronized patterns of waking throughout the night, particularly with nearby group-mates. Thus, for animals whose fitness depends critically on avoiding predation and developing social relationships, maintaining sleep homeostasis may be only secondary to remaining vigilant when sleeping in risky habitats and interacting with group-mates during the night. Our results highlight the importance of studying sleep in ecologically relevant contexts, where the adaptive function of sleep patterns directly reflect the complex trade-offs that have guided its evolution.