bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors
Authors: Ray Arja , Bassette Molly , Hu Kenneth H. , Pass Lomax F. , Courau Tristan , Samad Bushra , Combes Alexis , Johri Vrinda , Davidson Brittany , Wai Katherine , Ha Patrick , Hernandez Grace , Zaleta-Linares Itzia , Krummel Matthew F.
Published: September 2023

The anti-tumor function of CD8 T cells is limited through well-established pathways of T cell exhaustion (TEX). Strategies to capture emergent functional states amongst this dominant trajectory of dysfunction are necessary to find pathways to durable anti-tumor immunity. By leveraging transcriptional reporting (by the fluorescent protein TFP) of the T cell activation markerCd69,related to upstream AP-1 transcription factors, we define a classifier for potent versus sub-optimal CD69+ activation states arising from T cell stimulation. In tumors, this delineation acts an additional functional readout along the TEXdifferentiation trajectory, within and across TEXsubsets, marked by enhanced effector cytokine and granzyme B production. The more potent state remains differentially prominent in a T cell-mediated tumor clearance model, where they also show increased engagement in the microenvironment and are superior in tumor cell killing. Employing multimodal CITE-Seq in human head and neck tumors enables a similar strategy to identify Cd69RNAhiCD69+ cells that also have enhanced functional features in comparison to Cd69RNAloCD69+ cells, again within and across intratumoral CD8 T cell subsets. Refining the contours of the T cell functional landscape in tumors in this way paves the way for the identification of rare exceptional effectors, with imminent relevance to cancer treatment.

Graphical Abstract
MMORF—FSL’s MultiMOdal Registration Framework
Authors: Lange Frederik J. , Arthofer Christoph , Bartsch Andreas , Douaud Gwenaëlle , McCarthy Paul , Smith Stephen M. , Andersson Jesper L. R.
Published: September 2023

We present MMORF—FSL’s MultiMOdal Registration Framework—a newly released nonlinear image registration tool designed primarily for application to MRI images of the brain. MMORF is capable of simultaneously optimising both displacement and rotational transformations within a single registration framework by leveraging rich information from multiple scalar and tensor modalities. The regularisation employed in MMORF promotes local rigidity in the deformation, and we have previously demonstrated how this effectively controls both shape and size distortion, and leads to more biologically plausible warps. The performance of MMORF is benchmarked against three established nonlinear registration methods—FNIRT, ANTs and DR-TAMAS—across four domains: FreeSurfer label overlap, DTI similarity, task-fMRI cluster mass, and distortion. Results show that MMORF performs as well as or better than all other methods across every domain—both in terms of accuracy and levels of distortion. MMORF is available as part of FSL, and its inputs and outputs are fully compatible with existing workflows. We believe that MMORF will be a valuable tool for the neuroimaging community, regardless of the domain of any downstream analysis, providing state-of-the-art registration performance that integrates into the rich and widely adopted suite of analysis tools in FSL.
Species-specific epigenetic responses to drought stress of two sympatric oak species reflect their ecological preferences
Authors: Rubio B , Provost G Le , Brachi B , Gerardin T , Brendel O , Tost J. , Daviaud Christian , Gallusci P
Published: September 2023

In a context of climate change, it is necessary to decipher the strategies established by plants to cope with limited water supply.

Transcriptome, methylome and small RNA data were generated for two oak species with contrasting levels of drought tolerance (Quercus roburandQuercus petraea), under control and drought stress conditions

All data are in line with a species-specific response to drought stress consistent with their ecological preferences. The biological processes associated with genomic regions identified in all datasets were mainly associated with parietal processes inQ. petraea,which may explain in part its better tolerance to water deprivation.

A significant proportion of DNA methylation differences observed in control conditions between the two oak species were maintained during DS which may constitute a pool of epigenetic markers discriminating these two oak species. These markers were enriched in highly differentiated SNPs suggesting that some of them may be associated both with the ecological differences or intrinsic barriers to reproduction between the two species.

An integrative approach of the three datasets revealed genomic co-locations of potential importance for forest three adaptation to drought stress.
Randomness impacts specific priors building, visual exploration, and perception in object recognition
Authors: Gal Cécile , Țincaș Ioana , Moca Vasile V. , Ciuparu Andrei , Dan Loredana E. , Smith Marie L. , Gliga Teodora , Mureșan Raul C.
Published: September 2023

1.

Recognising objects is a vital skill on which humans heavily rely to respond quickly and adaptively to their environment. Yet, we lack understanding on the role visual information sampling plays in this process, and its relation to the individual’s priors. To bridge this gap, the eye-movements of 18 adult participants were recorded during a free-viewing object-recognition task usingDotsstimuli (Moca et al., 2011). Participants viewed the stimuli in one of three orders: from most visible to least (Descending), least visible to most (Ascending) or in a randomised order (Random). This dictated the strength of their priors along the experiment. Adding to Moca et al.’s original finding that visibility order influenced participants’ recognition performance and visual exploration, we found that while orders allowing for stronger priors generally led participants to visually sample more informative locations, this was not the case ofRandomparticipants. Indeed, they appeared to behave naïvely, and their use of specific object-related priors seemed fully impaired, while they seemed to maintain the ability to use general task-related priors to guide their exploration. These findings have important implications for our understanding of perception, which appears markedly subjective even at the basic level of visual sampling and object perception.
Altered hierarchical gradients of intrinsic neural timescales in mild cognitive impairment and Alzheimer’s disease
Authors: Zhang Aiying , Wengler Kenneth , Zhu Xi , Horga Guillermo , Goldberg Terry E. , Lee Seonjoo ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older adults in the US and worldwide. Resting-state functional magnetic resonance imaging (rs-fMRI) has become a widely used neuroimaging tool to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of intrinsic neural signals using rs-fMRI, is thought to quantify the duration that neural information is stored in a local cortical circuit. The heterogeneity of the timescales is considered to be a basis of the functional hierarchy in the brain. In addition, INT captures an aspect of circuit dynamics relevant to excitation/inhibition (E/I) balance, which is thought to be broadly relevant for cognitive functions. Here we examined its relevance to AD. We used rs-fMRI data of 904 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The subjects were divided into 4 groups based on their baseline and end-visit clinical status, which were cognitively normal (CN), stable MCI, Converter, and AD groups. Linear mixed effect model and pairwise comparison were implemented to investigate the large-scale hierarchical organization and local differences. We observed high similarities between AD and Converter groups. Specifically, among the eight identified ROIs with distinct INT alterations in AD, three ROIs (inferior temporal, caudate, pallidum areas) exhibit stable and significant alteration in AD converter. In addition, distinct INT related pathological changes in stable MCI and AD/Converter were found. For AD and Converter groups, neural information is stored for a longer time in lower hierarchical order areas, while higher levels of hierarchy seem to be preferentially impaired in stable MCI leading to a less pronounced hierarchical gradient effect. These results inform that the INT holds great potential as an additional measure for AD prediction, a stable biomarker for clinical diagnosis and an important therapeutic target in AD.
Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo
Authors: Kober Daniel L. , Caballero Van Dyke Marley C. , Eitson Jennifer L. , Boys Ian N. , McDougal Matthew B. , Rosenbaum Daniel M. , Schoggins John W.
Published: September 2023

The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His10epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spike from multiple SARS-CoV-2 variants, and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrate protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agentsin vivoand suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses.
Convergent generation of atypical prions in knock-in mouse models of genetic prion disease
Authors: Mehra Surabhi , Bourkas Matthew E.C. , Kaczmarczyk Lech , Stuart Erica , Arshad Hamza , Griffin Jennifer K. , Frost Kathy L. , Walsh Daniel J. , Supattapone Surachai , Booth Stephanie A. , Jackson Walker S. , Watts Joel C.
Published: September 2023

Most cases of human prion disease arise due to spontaneous misfolding of wild-type or mutant prion protein. Though recapitulating spontaneous prion conversion in animal models has proven challenging, transgenic mice expressing the misfolding-prone bank vole prion protein (BVPrP) recreate certain key aspects of sporadic and genetic prion disease. However, it remains unclear whether spontaneous prion generation can occur in the absence of protein over-expression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knock-in mice expressing physiological levels of either wild-type or mutant BVPrP with isoleucine at codon 109. While mice expressing wild-type BVPrP remained free from neurological disease, a subset of knock-in mice expressing BVPrP with mutations that cause either fatal familial insomnia (D178N) or familial Creutzfeldt-Jakob disease (E200K) developed progressive neurological illness. Brains from spontaneously ill knock-in mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant prion protein. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP knock-in mice transmitted disease to mice expressing wild-type BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical both pre- and post-transmission, suggesting that both mutations guide the formation of a highly similar atypical prion strain. These findings imply that knock-in mice expressing mutant BVPrP spontaneously develop abona fideprion disease and that mutations causing prion diseases may share a uniform initial mechanism of action. Therefore, these mice represent useful tools for studying the early stages of genetic prion diseases.
Gamma-burst cortical activity in awake behaving macaques
Authors: Acland Benjamin T. , Palanca Ben Julian A. , Bijsterbosch Janine , Snyder Lawrence H.
Published: September 2023

Electrophysiological recordings during ketamine anesthesia have revealed a slow alternating pattern of high- and low- frequency activity (a “gamma-burst” pattern) that develops with the onset of general anesthesia. We examine the role of NMDA receptor antagonism in generating the gamma-burst pattern and the link between gamma-bursts and dissociative anesthesia. We compare the effects of ketamine with those of the highly selective NMDA receptor antagonist CGS 19755 on multi-site intracranial electrophysiology and behavior in rhesus macaques. Remarkably, we find that animals given a moderate dose of CGS 19755 are able to perform a difficult memory task, while at the same time showing electrophysiological activity similar to ketamine anesthesia, with one key difference: a lack of delta-band LFP modulation. This difference demonstrates that ketamine’s ability to drive strong delta-band oscillations relies on additional mechanisms beyond NMDA receptor antagonism alone, and points to a key role for the activity underlying delta-band oscillations in causing anesthesia.
survInTime - Exploring surveillance methods and data analysis on Brazilian respiratory syndrome dataset and community mobility changes
Authors: Martins Yasmmin Côrtes , da Silva Ronaldo Francisco
Published: September 2023

Background

The covid-19 pandemic brought negative impacts in almost every country in the world. These impacts were observed mainly in the public health sphere, with a rapid raise and spread of the disease and failed attempts to restrain it while there was no treatment. However, in developing countries, the impacts were severe in other aspects such as the intensification of social inequality, poverty and food insecurity. Specifically in Brazil, the miscommunication among the government layers conducted the control measures to a complete chaos in a country of continental dimensions. Brazil made an effort to register granular informative data about the case reports and their outcomes, while this data is available and can be consumed freely, there are issues concerning the integrity and inconsistencies between the real number of cases and the number of notifications in this dataset.

Results

We projected and implemented four types of analysis to explore the Brazilian public dataset of Severe Acute Respiratory Syndrome (srag dataset) notifications and the google dataset of community mobility change (mobility dataset). These analysis provides some diagnosis of data integration issues and strategies to integrate data and experimentation of surveillance analysis. The first type of analysis aims at describing and exploring the data contained in both datasets, starting by assessing the data quality concerning missing data, then summarizing the patterns found in this datasets. The Second type concerns an statistical experiment to estimate the cases from mobility patterns organized in periods of time. We also developed, as the third analysis type, an algorithm to help the understanding of the disease waves by detecting them and compare the time periods across the cities. Lastly, we build time series datasets considering deaths, overall cases and residential mobility change in regular time periods and used as features to group cities with similar behavior.

Conclusion

The exploratory data analysis showed the under representation of covid-19 cases in many small cities in Brazil that were absent in the srag dataset or with a number of cases very low than real projections. We also assessed the availability of data for the Brazilian cities in the mobility dataset in each state, finding out that not all the states were represented and the best coverage occurred in Rio de Janeiro state. We compared the capacity of place categories mobility change combination on estimating the number of cases measuring the errors and identifying the best components in mobility that could affect the cases. In order to target specific strategies for groups of cities, we compared strategies to cluster cities that obtained similar outcomes behavior along the time, highlighting the divergence on handling the disease.

Availability

https://github.com/YasCoMa/dashboard-srag-mobility
A chromosome-level reference genome of a Fabaceae species yam bean (Pachyrhizus erosus)
Authors: Bu Fengjiao , Jiang Fan , Zhang Caishun , Yuan Lihua , Fan Wei , Xiong Xinyao
Published: September 2023

Yam bean (Pachyrhizus erosusL.), belonging to the family Fabaceae, is an important but underutilized root crop. Here, we generated a high-quality chromosome-level reference genome of yam bean by PacBio HiFi and Hi-C sequencing, with assembly size of 539.0 Mb, contig N50 of 25.6 Mb, and BUSCO complete rate of 99.3%. Then, we anchored 94.4% of the contig sequences into 11 pseudo-chromosomes, and assembled the telomeres at 86.4% (19/22) of the chromosome-ends. A total of 44,692 protein-coding genes were predicted, with the BUSCO complete rate of 99.3%, comparable to that of the genome assembly. Compared to the previously reported yam bean genome, the current assembly has a 1,388-fold increase in contig N50 size, and 12.2% and 24.3% increase in BUSCO complete rate for the genome sequence and gene set, respectively. Evolutionary analysis revealed that yam bean diverged from the clade of soybean andPueraria lobatavar.montana22.5 MYA. This high-quality genome assembly will greatly facilitate the breeding of yam bean based on the genetic and genomic methods.
Uninheritable but widespread bacterial symbiont mediates insecticide detoxification of an agricultural invasive pestSpodoptera frugiperda
Authors: Zhang Yunhua , Ju Feng
Published: September 2023

Identifying insecticide resistance-related insect bacterial symbiont is a vital compass for promoting symbiont-based insecticide resistance management and insecticide-free insect pest control. Known insecticide-resistance-related symbionts lack universality and genetic manipulation, as either not widespread or unculturable. Here, we discovered a widespread symbiontEnterococcus casseliflavusof a significant invasive insect pest,Spodoptera frugiperda. This symbiont enhances host insecticide resistance to chlorantraniliprole by amide bond breaking and dehalogenation-related insecticide degradation, suggesting its great potential for Lepidoptera pest insecticide resistance management. Complying with the increase in exposure risk of chlorantraniliprole, theE. casseliflavusof insects’ symbionts rather than mammals or environmental strains were notably enriched with putative chlorantraniliprole degradation genes. We also found thatE. casseliflavuscan transmit horizontally with high efficiency (100%) through cross-diet and cannibalism rather than vertical transmission from mother insect to offspring. Moreover, the widespread infection ofE. casseliflavusin the field populations not only implies that an underlying symbiont-host co-evolution process driven by insecticide pressure might be underway, but also provides a novel therapeutic target of agricultural pests based on symbiont-targeted insect control (STIC).
Widespread impact of natural genetic variations in CRISPR/Cas9 outcomes
Authors: Li Victoria , Tadych Alicja , Wong Aaron , Zhang Zijun
Published: September 2023

CRISPR/Cas9 is a genome editing tool widely used in biological research and clinical therapeutics. Natural human genetic variations, through altering the sequence context of CRISPR/Cas9 target regions, can significantly affect its DNA repair outcomes and ultimately lead to different editing efficiencies. However, these effects have not been systematically studied, even as CRISPR/Cas9 is broadly applied to primary cells and patient samples that harbor such genetic diversity. Here, we present comprehensive investigations of natural genetic variations on CRISPR/Cas9 outcomes across the human genome. The utility of our analysis is illustrated in two case studies, on both preclinical discoveries of CD33 knockout in Chimeric Antigen Receptor (CAR)-T cell therapy, and clinical applications of TTR inactivation for treating ATTR amyloidosis. We further expand our analysis to genome scale, population stratified common variants that may lead to gene editing disparity. Our analyses demonstrate pitfalls of failing to account for the widespread genetic variations in Cas9 target selection, and how they can be effectively examined and avoided using our method. To facilitate broad access to our analysis, a web platform CROTONdb is developed, which provides predictions for all possible CRISPR/Cas9 target sites in the coding region, spanning over 5.38 million gRNA targets and 90.82 million estimated variant effects. We anticipate CROTONdb having broad clinical utilities in gene and cellular therapies.
Clinical prediction models combining routine clinical measures identify participants with youth-onset diabetes who maintain insulin secretion in the range associated with type 2 diabetes: The SEARCH for Diabetes in Youth Study
Authors: Jones Angus G , Shields Beverley M , Oram Richard A , Dabelea Dana M , Hagopian William A , Lustigova Eva , Shah Amy S , Knupp Julieanne , Mottl Amy K , D’Agostino Ralph B. , Williams Adrienne , Marcovina Santica M , Pihoker Catherine , Divers Jasmin , Redondo Maria J
Published: September 2023

Objective

With the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).

Methods

We studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting c-peptide ≥250 pmol/L (≥0.75ng/ml) after >3 years (median 74 months) of diabetes duration. Models included clinical measures at baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL-C), with and without islet autoantibodies (GADA, IA-2A) and a Type 1 Diabetes Genetic Risk Score (T1DGRS).

Results

Models using routine clinical measures with or without autoantibodies and T1DGRS were highly accurate in identifying participants with c-peptide ≥0.75 ng/ml (17% of participants; 2.3% and 53% of those with and without positive autoantibodies) (area under receiver operator curve [AUCROC] 0.95-0.98). In internal validation, optimism was very low, with excellent calibration (slope=0.995-0.999). Models retained high performance for predicting retained c-peptide in older youth with obesity (AUCROC 0.88-0.96), and in subgroups defined by self-reported race/ethnicity (AUCROC 0.88-0.97), autoantibody status (AUCROC 0.87-0.96), and clinically diagnosed diabetes types (AUCROC 0.81-0.92).

Conclusion

Prediction models combining routine clinical measures at diabetes diagnosis, with or without islet autoantibodies or T1DGRS, can accurately identify youth with diabetes who maintain endogenous insulin secretion in the range associated with type 2 diabetes.
The Impact of Body Mass Index on Robotic Surgery Outcomes in Endometrial Cancer
Authors: Kadoch Eva , Brezinov Yoav , Levin Gabriel , Racovitan Florentin , Lau Susie , Salvador Shannon , Gotlieb Walter H.
Published: September 2023

STRUCTURED ABSTRACT

OBJECTIVES

To compare surgical outcomes of patients with endometrial cancer who underwent robotic surgery across different BMI categories.

METHODS

A retrospective study including all consecutive patients with endometrial cancer who underwent robotic surgery at a tertiary cancer center between December 2007 and December 2022. The study analyzed outcome measures, including blood loss, surgical times, length of hospitalization, perioperative complications, and conversion rates with the Kruskal-Wallis test for BMI group differences and the Chi-squared test for associations between categorical variables.

RESULTS

A total of 1,329 patients with endometrial cancer were included in the study. Patients were stratified by BMI: <30.0 (n=576; 43.3%), 30.0-39.9 (n=449; 33.8%), and ≥40.0 (n=304; 22.9%). There were no significant differences in post-anesthesia care unit (PACU) stay (p=0.105) and hospital stay (p=0.497) between the groups. The rate of post-op complications was similar across the groups, ranging from 8.0% to 9.5% (p=0.761). The rate of conversion to laparotomy was also similar across the groups, ranging from 0.7% to 1.0% (p=0.885). Women with a BMI ≥40.0 had a non-clinically relevant but greater median estimated blood loss (30 mL vs. 20 mL; p<0.001) and longer median operating room (OR) time (288 minutes vs. 270 minutes; p<0.001). Within the OR time, the median set-up time was longer for those with a higher BMI (58 minutes vs. 50 minutes; p<0.001). However, skin-to-skin time (209 minutes vs. 203 minutes; p=0.202) and post-op time (14 minutes vs. 13 minutes; p=0.094) were comparable between groups.

CONCLUSION

BMI does not affect the peri-operative outcome of patients undergoing robotic staging procedures for endometrial cancer.
Clinically actionable pharmacogenomic landscape of antidepressants and antipsychotics in Qatar: A population-based cohort study
Authors: Velayutham Dinesh , Bastaki Kholoud ,   the Qatar Genome Program Research Consortium, Ghuloum Suhaila , Azeem Muhammad Waqar , Pirmohamed Munir , Jithesh Puthen Veettil
Published: September 2023

Antidepressants and antipsychotics, commonly prescribed worldwide, exhibit significant variability in patient responses. Genetic variations contribute substantially to this variability, offering the potential for predicting individual responses through pharmacogenetic testing. Clinical guidelines provided by organizations like the Clinical Pharmacogenetic Implementation Consortium (CPIC) and the Dutch Pharmacogenetic Working Group (DPWG) facilitate the application of pharmacogenomics in clinical settings. Understanding the prevalence of actionable genetic variants and their associated response phenotypes is vital for effective pharmacogenomic integration, especially in under-served populations.

In this study, we analyzed the frequency distribution of actionable genetic variants in 6045 adult Qataris recruited by the Qatar Biobank, whose genomes were sequenced as part of the Qatar Genome Program, focusing on genes (CYP2C19, CYP2D6, CYP2B6, and CYP3A4) influencing psychotropic medication responses. Haplotypes and diplotypes were generated from 490 alleles, and metabolizer phenotypes were predicted based on established guidelines.

Our findings revealed that over 52% of Qatari individuals may possess actionable metabolizer phenotypes associated with CYP2C19, CYP2B6, and CYP2D6, impacting their response to tricyclic antidepressants. The frequency of actionable genetic variants for serotonin reuptake inhibitors ranged from approximately 2% to 51%, and for antipsychotics, it ranged from 0.1% to 32%, based on genetic variations in CYP3A4 and CYP2D6.

This study underscores the importance of assessing these genetic variants, particularly concerning commonly prescribed antidepressants like escitalopram and amitriptyline in Qatar. Implementing pharmacogenetic testing based on these findings can potentially enhance patient outcomes in psychiatric medication management.
Task performance to discriminate mild cognitive impairment from healthy aging
Authors: Stockbridge Melissa D. , Hillis Argye E.
Published: September 2023

Mild cognitive impairment (MCI) is clinical diagnosis that refers to individuals whose performance is below average on standardized cognitive tests, but who otherwise function independently in instrumental activities of daily living. Few prior studies have addressed the problem of selecting the optimal combination of behavioral instruments and cutoff scores for detecting MCI in an outpatient setting. The aim of this work is to provide insight into two related questions: (1) What is the relative sensitivity and specificity of a battery of standardized tests frequently used to assess for MCI, as defined using receiver operating characteristic (ROC)-based analysis? (2) What are the optimal “cut point” scores for distinguishing patients’ mildly impaired performance based on these instruments?

Two hundred forty outpatient behavioral neurology evaluations were retrospectively analyzed. All work was conducted with the formal approval of the Johns Hopkins University School of Medicine Institutional Review Board. All instruments that were evaluated performed very well in the detection of dementia (mean AUC = 0.8). However, fewer tasks performed acceptably in the detection of MCI (mean AUC = 0.7). Instruments that performed best in the detection of MCI tended to have higher total possible scores or not to reflect a score out of a total number possible.

Cognitive screening tools, like the MMSE, did not perform well in the detection of MCI, raising important considerations for their interpretation. No one task in isolation is sufficient to detect MCI, and behavioral performance is not the only relevant consideration in differential diagnosis. However, these findings highlight the relative weakness of many assessments when used to build a comprehensive profile of a very large portion of outpatients presenting at clinic, those whose deficits are more subtle.
Working together to control mutation: how collective peroxide detoxification determines microbial mutation rate plasticity
Authors: Green Rowan , Wang Hejie , Botchey Carol , Zhang Nancy , Wadsworth Charles , McBain Andrew J , Paszek Pawel , Krašovec Rok , Knight Christopher G
Published: September 2023

Mutagenesis is responsive to many environmental factors. Evolution therefore depends on the environment not only for selection but also in determining the variation available in a population. One such environmental dependency is the inverse relationship between mutation rates and population density in many microbial species. Here we determine the mechanism responsible for this mutation rate plasticity. Using dynamical computational modelling andin vivomutation rate estimation we show that the negative relationship between mutation rate and population density arises from the collective ability of microbial populations to control concentrations of hydrogen peroxide. We demonstrate a loss of this density-associated mutation rate plasticity whenEscherichia colipopulations are deficient in the degradation of hydrogen peroxide. We further show that the reduction in mutation rate in denser populations is restored in peroxide degradation-deficient cells by the presence of wild-type cells in a mixed population. Together, these model-guided experiments provide a mechanistic explanation for density-associated mutation rate plasticity, applicable across all domains of life, and frames mutation rate as a dynamic trait shaped by microbial community composition.
A SUMO E3 ligase promotes long non-coding RNA transcription to regulate small RNA-directed DNA elimination
Authors: Shehzada Salman , Noto Tomoko , Saksouk Julie , Mochizuki Kazufumi
Published: September 2023

Small RNAs target their complementary chromatin regions for gene silencing through nascent long non-coding RNAs (lncRNAs). In the ciliated protozoanTetrahymena, the interaction between Piwi-associated small RNAs (scnRNAs) and the nascent lncRNA transcripts from the somatic genome has been proposed to induce target-directed small RNA degradation (TDSD), and scnRNAs not targeted for TDSD later target the germline-limited sequences for programmed DNA elimination. In this study, we show that the SUMO E3 ligase Ema2 is required for the accumulation of lncRNAs from the somatic genome and thus for TDSD and completing DNA elimination to make viable sexual progeny. Ema2 interacts with the SUMO E2 conjugating enzyme Ubc9 and enhances SUMOylation of the transcription regulator Spt6. We further show that Ema2 promotes the association of Spt6 and RNA polymerase II with chromatin. These results suggest that Ema2-directed SUMOylation actively promotes lncRNA transcription, which is a prerequisite for communication between the genome and small RNAs.
A tale of two receptors: simultaneous targeting of NMDARs and 5-HT4Rs exerts additive effects against stress
Authors: Chen Briana K. , Luna Victor M. , Jin Michelle , Shah Abhishek , Shannon Margaret E. , Pauers Michaela , Williams Brenna L. , Pham Vananh , Hunsberger Holly C. , Gardier Alain M. , Mendez-David Indira , David Denis J. , Denny Christine A.
Published: September 2023

BACKGROUND

Serotonin (5-HT) receptors andN-methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of (R,S)-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT4R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.

METHODS

A single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis.

RESULTS

We found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC.

CONCLUSIONS

Our results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.
Nutrient colimitation is a quantitative, dynamic property of microbial populations
Authors: Held Noelle A. , Krishna Aswin , Crippa Donat , Battaje Rachana Rao , Devaux Alexander J. , Dragan Anastasia , Manhart Michael
Published: September 2023

Resource availability dictates how fast and how much microbial populations grow. Quantifying the relationship between microbial growth and resource concentrations makes it possible to promote, inhibit, and predict microbial activity. Microbes require many resources, including macronutrients (e.g., carbon and nitrogen), micronutrients (e.g., metals), and complex nutrients like vitamins and amino acids. When multiple resources are scarce, as occurs in nature, microbes may experience resource colimitation in which more than one resource limits growth simultaneously. Despite growing evidence for colimitation, the data is difficult to interpret and compare due to a lack of quantitative measures of colimitation and systematic tests of resource conditions. We hypothesize that microbes experience a continuum of nutrient limitation states and that nutrient colimitation is common in the laboratory and in nature. To address this, we develop a quantitative theory of resource colimitation that captures the range of possible limitation states and describes how they can change dynamically with resource conditions. We apply this approach to clonal populations ofEscherichia colito show that colimitation occurs in common laboratory conditions. We also show that growth rate and growth yield are colimited differently, reflecting their different underlying biology. Finally, we analyze environmental data to provide intuition for the continuum of limitation and colimitation conditions in nature. Altogether our results provide a quantitative framework for understanding and quantifying colimitation of microbes in biogeochemical, biotechnology, and human health contexts.
PCR-based survey of methane-cycling archaea in methane-soaked subsurface sediments of Guaymas Basin, Gulf of California
Authors: Hinkle John E. , Mara Paraskevi , Beaudoin David , Edgcomb Virginia P. , Teske Andreas P.
Published: September 2023

The Guaymas Basin in the Gulf of California is characterized by active seafloor spreading, rapid deposition of organic-rich sediments, steep geothermal gradients, and abundant methane of mixed thermogenic and microbial origin. Subsurface sediment samples from eight drilling sites with distinct geochemical and thermal profiles were selected for DNA extraction and PCR amplicifation to explore the diversity of methane-cycling archaea in the Guaymas Basin subsurface. We performed PCR amplifications with general (mcrIRD), and ANME-1 specific primers that target the alpha (α) subunit of methyl coenzyme M reductase (mcrA). Diverse ANME-1 lineages associated with anaerobic methane oxidation were detected in seven out of the eight drilling sites, preferentially around the methane-sulfate interface, and in several cases showed preferences for specific sampling sites. Phylogenetically, most ANME-1 sequences from the Guaymas Basin subsurface were related to marine mud volcanoes, seep sites, and the shallow marine subsurface. The most frequently recovered methanogenic phylotypes were closely affiliated with the hyperthermophilicMethanocaldococcaceae, and found at the hydrothermally influenced Ringvent site. The coolest drilling site, in the northern axial trough of Guaymas Basin, yielded the greatest diversity of methanogen lineages. Our survey indicates potential for extensive microbial methane cycling within subsurface sediments of Guaymas Basin.
The herpesvirus UL49.5 protein hijacks a cellular C-degron pathway to drive TAP transporter degradation
Authors: Wąchalska Magda , Riepe Celeste , Ślusarz Magdalena J. , Graul Małgorzata , Borowski Lukasz S. , Qiao Wenjie , Foltynska Michalina , Carette Jan E. , Bieńkowska-Szewczyk Krystyna , Szczesny Roman J. , Kopito Ron R. , Lipińska Andrea D.
Published: September 2023

The transporter associated with antigen processing (TAP) is a key player in the MHC class I-restricted antigen presentation and an attractive target for immune evasion by viruses. Bovine herpesvirus 1 (BoHV-1) impairs TAP-dependent antigenic peptide transport through a two-pronged mechanism in which binding of the UL49.5 gene product to TAP both inhibits peptide transport and promotes its proteasomal degradation. How UL49.5 promotes TAP degradation is unknown. Here, we use high-content siRNA and genome-wide CRISPR-Cas9 screening to identify CLR2KLHDC3as the E3 ligase responsible for UL49.5-triggered TAP disposal in human cells. We propose that the C-terminus of UL49.5 mimics a C-end rule degron that recruits the E3 to TAP and engages the CRL2 E3 in ER-associated degradation.

SIGNIFICANCE

Herpesviruses are masters of immune evasion. Most often, they hijack host cellular pathways to modulate the antiviral immune response. Varicellovirus UL49.5 orthologs have evolved as inhibitors of the transporter associated with antigen processing (TAP) and, this way, major modulators of the MHC class I-restricted antigen presentation. This study identifies the long-sought molecular mechanism exploited by bovine herpesvirus 1-encoded UL49.5 to trigger proteasomal degradation of TAP. Our findings demonstrate that the viral protein hijacks host cell CRL2-ubiquitin conjugation and ER-associated degradation pathways to promote TAP degradation. These findings advance the understanding of how herpesviruses can manipulate the cellular machinery.
Interpretable Metric Learning in Comparative Metagenomics: The Adaptive Haar-like Distance
Authors: Gorman Evan , Lladser Manuel E.
Published: September 2023

Random forests have emerged as a promising tool in comparative metagenomics because they can predict environmental characteristics based on microbial composition in datasets whereβ-diversity metrics fall short of revealing meaningful relationships between samples. Nevertheless, despite this efficacy, they lack biological insight in tandem with their predictions, potentially hindering scientific advancement. To overcome this limitation, we leverage a geometric characterization of random forests to introduce a data-driven phylogeneticβ-diversity metric, the adaptive Haar-like distance. This new metric assigns a weight to each internal node (i.e., split or bifurcation) of a reference phylogeny, indicating the relative importance of that node in discerning environmental samples based on their microbial composition. Alongside this, a weighted nearest-neighbors classifier, constructed using the adaptive metric, can be used as a proxy for the random forest while maintaining accuracy on par with that of the original forest and another state-of-the-art classifier, CoDaCoRe. As shown in datasets from diverse microbial environments, however, the new metric and classifier significantly enhance the biological interpretability and visualization of high-dimensional metagenomic samples.

Author summary

Traditional phylogeneticβ-diversity metrics, particularly weighted and unweighted UniFrac, have had great success in comparing and visualizing high-dimensional metagenomic samples. Nonetheless, these metrics rely upon pre-established biological assumptions that might not capture key microbial players or relationships between some samples. On the contrary, supervised machine learning algorithms, such as random forests, can often capture intricate relationships between microbial samples; however, unveiling these relationships is often challenging due to the intricate inner mechanisms inherent to these algorithms.

The adaptive Haar-like distance integrates the merits ofβ-diversity metrics and random forests, allowing for precise, intuitive, and visual comparison of metagenomic samples, offering valuable scientific insight into the distinctions and associations among microbial environments.
Genomic and Phenotypic Comparison of Polyhydroxyalkanoates Producing Strains of genusCaldimonas/Schlegelella
Authors: Musilova Jana , Kourilova Xenie , Hermankova Kristyna , Bezdicek Matej , Ieremenko Anastasiia , Dvorak Pavel , Obruca Stanislav , Sedlar Karel
Published: September 2023

Polyhydroxyalkanoates (PHAs) have emerged as an ecologically friendly alternative to conventional polyesters. In this study, we present a comprehensive analysis of the genomic and phenotypic characteristics of three non-model thermophilic bacteria known for their ability to produce PHAs:Schlegelella aquaticaLMG 23380T,Caldimonas thermodepolymeransDSM 15264, andC. thermodepolymeransLMG 21645 accompanied by a comparison with the type strainC. thermodepolymeransDSM 15344T. We have assembled the first complete genomes of these three bacteria and performed the structural and functional annotation. This analysis has provided valuable insights into the biosynthesis of PHAs and has allowed us to propose a comprehensive scheme for the carbohydrate metabolism in the studied bacteria. Through phylogenomic analysis, we have confirmed the synonymity betweenCaldimonasandSchlegelellagenera, and further demonstrated thatS. aquaticaandS. koreensis, currently classified as orphan species, belong to theCaldimonasgenus.

The genomic and phenotypic analysis ofSchlegelella aquaticaLMG 23380TandCaldimonas thermodepolymeransDSM 15264 and LMG 21645 sheds light on the production of sustainable polyesters known as polyhydroxyalkanoates (PHAs). The genome assembly and functional annotation highlight key genes related to PHA production and other important traits. Notably,C. thermodepolymeransstands out with its uniquexyloperon, making it a highly promising candidate for biotechnological PHA production from xylose-rich lignocellulosic resources. The study emphasizes the importance of a polyphasic approach combining genotypic and phenotypic analyses in prokaryotic taxonomy, emphasizing the need for exploration in the genomic era. By uncovering the key traits of these bacteria, this research opens new horizons towards sustainable production of environmentally friendly polyesters.
Primate Saccade Rhythmicity
Authors: Näher Tim , Zhang Yufeng , Pandinelli Martina , Fries Pascal
Published: September 2023

Active sensing behaviors in rodents display theta (4-8 Hz) rhythmicity. Whether similar rhythmicity exists in primate saccadic eye movements has remained a matter of debate. We studied saccade dynamics in 22 human participants and two macaque monkeys, examining the influence of different visual stimuli and tasks. Inter-saccadic intervals (ISIs) reliably revealed a characteristic duration and under certain conditions clear theta rhythmicity. Rhythmicity was strongest for saccades with short ISIs. Surprisingly, the degree of rhythmicity was not due to spatial regularity of the visual scene, but it was shaped by task demands. Macro- and micro-saccade ISIs shared similar characteristic durations. Naturally occurring micro-saccades provided evidence that ISIs can become more regular without becoming faster. During free-viewing, subsequent ISIs show long-range correlation structure and the visual system switched between states of low and high rhythmicity. Humans and macaques showed similar saccade dynamics, suggesting a potential common evolutionary trait in primate active visual sensing.