bluuebunny/crossref_metadata_2025 huggingface dataset:
Active exterior cloaking of an inclusion with evanescent multipole devices for flexural waves in thin plates
Authors: Allison F. J. P. , Selsil Ö. , Haslinger S. G.
Published: October 2022

We present an active exterior cloak for flexural waves propagating in a Kirchhoff plate of infinite extent. The evanescent multipole devices are characterized by Macdonald functions

K
n

of the required order, which, assuming time-harmonic vibrations, are solutions of the fourth-order biharmonic equation. It is shown that in the region of interfering waves, which emanate from the devices, a field is recreated which cancels the incident wave to yield a region of ‘stillness’. An inclusion is then positioned in this region for further investigation, with additional attention given to the boundary condition.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
Active exterior cloaking for the two-dimensional Helmholtz equation with complex wavenumbers and application to thermal cloaking
Authors: Cassier Maxence , DeGiovanni Trent , Guenneau Sébastien , Guevara Vasquez Fernando
Published: October 2022

We design sources for the two-dimensional Helmholtz equation that can cloak an object by cancelling out the incident field in a region, without the sources completely surrounding the object to hide. As in previous work for real positive wavenumbers, the sources are also determined by the Green identities. The novelty is that we prove that the same approach works for complex wavenumbers which makes it applicable to a variety of media, including media with dispersion, loss and gain. Furthermore, by deriving bounds on Graf’s addition formulas with complex arguments, we obtain new estimates that allow to quantify the quality of the cloaking effect. We illustrate our results by applying them to achieve active exterior cloaking for the heat equation.

This article is part of the theme issue ‘Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)’.
The Herschel-Quincke tube with modulated branches
Authors: Papathanasiou T. K. , Tsolakis E. , Spitas V. , Movchan A. B.
Published: October 2022

The Herschel-Quincke (HQ) tube concept for transmission loss in pipe systems is expanded to include cases of branches with modulated properties. Modulated waveguides, featuring corrugations in their geometry or speed of sound, are known to produce significant reflection even without the parallel branch of the HQ tube. The HQ tube, in its classical form, produces narrow banded transmission loss at frequencies related to the length, wavenumber and cross-section area of the parallel branch. The modulated Herschel-Quincke (MHQ) tube combines these attributes to produce enhanced transmission loss characteristics in terms of both width and number of transmission loss bands. Several modulated profiles for the speed of sound in different branches of the tube are considered and analytical expressions for the transmission loss and resonant conditions are derived. Detailed analysis of periodically stratified branch profiles demonstrates the effectiveness of the MHQ tube for fluid-borne noise attenuation in pipe systems.

This article is part of the theme issue 'Wave generation and transmission in multi-scale complex media and structured metamaterials (part 2)'.
An advanced sequence clustering and designation workflow reveals the enzootic maintenance of a dominant West Nile virus subclade in Germany
Authors: Santos Pauline Dianne , Günther Anne , Keller Markus , Homeier-Bachmann Timo , Groschup Martin H. , Beer Martin , Höper Dirk , Ziegler Ute
Published: October 2022

West Nile virus (WNV) is the most widespread arthropod-borne (arbo) virus and the primary cause of arboviral encephalitis globally. Members of WNV species genetically diverged and are classified into different hierarchical groups below species rank. However, the demarcation criteria for allocating WNV sequences into these groups remain individual, inconsistent, and the use of names for different levels of the hierarchical levels is unstructured. In order to have an objective and comprehensible grouping of WNV sequences, we developed an advanced grouping workflow using the “affinity propagation clustering”-algorithm and newly included the “agglomerative hierarchical clustering”-algorithm for the allocation of WNV sequences into different groups below species rank. In addition, we propose to use a fixed set of terms for the hierarchical naming of WNV below species level and a clear decimal numbering system to label the determined groups. For validation, we applied the refined workflow to WNV sequences that have been previously grouped into various lineages, clades, and clusters in other studies. Although our workflow regrouped some WNV sequences, overall, it generally corresponds with previous groupings. We employed our novel approach to the sequences from the WNV circulation in Germany 2020, primarily from WNV-infected birds and horses. Besides two newly defined minor (sub)clusters comprising only of three sequences each, subcluster 2.5.3.4.3c was the predominant WNV sequence group detected in Germany from 2018-20. This predominant subcluster was also associated with at least five human WNV-infections in 2019-20. In summary, our analyses imply that the genetic diversity of the WNV population in Germany is shaped by enzootic maintenance of the dominant WNV subcluster accompanied by sporadic incursions of other rare clusters and subclusters. Moreover, we show that our refined approach for sequence grouping yields meaningful results. Although we primarily aimed at a more detailed WNV classification, the presented workflow can also be applied to the objective genotyping of other virus species.
Super-resolution ultrasound imaging of cerebrovascular impairment in a mouse model of Alzheimer’s disease
Authors: Lowerison Matthew R. , Chandra Sekaran Nathiya Vaithiyalingam , Dong Zhijie , Chen Xi , You Qi , Llano Daniel A. , Song Pengfei
Published: October 2022

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment of patients with Alzheimer’s disease. However, cerebrovascular disease and Alzheimer’s disease share several risk factors making it unclear whether cerebrovascular deficiency and Alzheimer’s disease pathology have additive effects on cognition or if cerebrovascular impairment merely exacerbates existing Alzheimer’s disease-associated cognitive decline. Additionally, early-stage Alzheimer’s disease typically involves hippocampal atrophy, complicating most efforts to elucidate the interplay between cerebral microvascular function and Alzheimer’s disease progression due to the necessity of probing deep-brain structures. The purpose of this study was to demonstrate the use of ultrasound localization microscopy on the 5xFAD mouse model of Alzheimer’s disease (3-month and 6-month-old cohorts) in comparison to age-matched wild-type controls, revealing microvascular scale reconstructions throughout the whole brain depth, to visualize and quantify Alzheimer’s disease-associated vascular impairments. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted hierarchical analysis of individual vessels and, in some cases, potentially allowed for decoupling of arteriole and venous flow contributions. Co-registered histological sectioning confirmed the regionalized hypo-perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition.

Significance statement

The study of the impact of cerebrovascular disease on Alzheimer’s disease pathology is complicated by the need to image deep-brain structures with high vascular fidelity. We demonstrate that ultrasound localization microscopy, a super-resolution acoustic imaging technique, is capable of imaging cerebrovasculature throughout the entire depth of the brain at a microvascular scale. This technology was applied to the 5xFAD mouse model of Alzheimer’s disease, where it was found that 5xFAD animals have significant impairments in vascular function in the entorhinal cortex and hippocampal region in comparison to age matched controls at the 3-month timepoint. Structural derangements in cerebrovasculature were only observed in the 6-month-old animal cohorts, with a maintained impairment in vascular function.
Ribosome-rescuer PELO catalyzes the oligomeric assembly of NLR family proteins via activating their ATPase
Authors: Wu Xiurong , Yang Zhang-Hua , Wu Jianfeng , Han Jiahuai
Published: October 2022

NOD-like receptors (NLRs) are pattern recognition receptors for diverse innate immune responses. Self-oligomerization after engagement with a ligand was a generally accepted model for the activation of each NLR. We report here that a catalyzer is required for the self-oligomerization. Protein pelota homolog (PELO, Dom34 in yeast), a well-known surveillance factor in translational quality control/ribosome rescue, interacts with all cytosolic NLRs and activates their ATPase. In the case of flagellin-initiated NLRC4 inflammasome activation, flagellin-bound NAIP5 recruits the first NLRC4 and then PELO is required for correctly assembling the rest of NLRC4s into the NLRC4 complex one by one by activating the NLRC4 ATPase. Stoichiometric and functional data revealed that PELO cannot be a structural constituent of NLRC4 inflammasome but a powerful catalyzer for its assembly. The catalytic role of PELO in the activation of cytosolic NLRs is unexpected and may break new ground for future studies of NLR family members.
Eliminating mother-to-child transmission of HIV in Tanzania calls for efforts to address factors associated with a low confirmatory test
Authors: Morris Baraka M. , Nyamhagata Mukome , Tarimo Edith , Sunguya Bruno
Published: October 2022

Background

Option B+ approach for prevention of mother-to-child transmission (PMTCT) has demonstrated the potential to eliminate pediatric HIV infections. Its success depends on early infant diagnosis (EID) of HIV among the exposed infants within the first 6 weeks, and a subsequent confirmatory HIV test at the 18th month. However, most mothers enrolled in the PMTCT-option B+ cascade of services in Tanzania do not turn-up for such confirmatory tests. We examined factors associated with the turning-up of mother-baby pairs on the PMTCT program for confirmatory HIV testing 18 months post-delivery in Tanzania.

Methods

This study utilized longitudinal data collected between 2015 and 2017 from 751 mother-baby pairs enrolled in the PMTCT-Option B+ approach in 79 health facilities from the 12 regions of Tanzania-mainland. Analysis was conducted using descriptive statistics to characterize the proportion of mother-baby pairs turning up for a confirmatory test and logistic regression analysis to examine factors associated with turning up for a confirmatory HIV testing at the 18th month.

Results

A total of 751 mother-baby records were observed only and 44.2% (95% CI: 40.7 – 47.8) of them received the HIV confirmatory test at 18 months. Mothers aged 25 years or above (adults’ mothers) were 1.44 more likely to turn up for confirmatory HIV-testing than young mothers; mothers with partners tested for HIV were 1.74 more likely to have confirmatory HIV-testing compared with partners not tested for HIV; newly HIV-positive mothers diagnosed on enrolment were 28% less likely to turn up their babies for confirmatory HIV-testing compared to known HIV-positive mothers; mothers with treatment supporters were 1.58 more likely to receive confirmatory HIV-testing compared to mothers without one, and mothers with babies whose DBS-PCR-1 was collected were 3.61 more likely to have confirmatory HIV-testing than those who didn’t collect DBS-PCR-1.

Conclusion

This study reveals that the turn-up for confirmatory HIV testing at 18 months among mother-baby pairs enrolled in the Option B+ approach is still low in Tanzania. This turn-up is associated with low maternal age, having a male partner who has not tested for HIV, lack of experience with HIV services, lack of treatment supporters, and failure to take the first DBS-PCR HIV test within the first two months post-delivery.
The ZMYND8 chromatin factor protects cardiomyocyte identity and function in the mouse heart
Authors: Kekūpaʻa Knutson Andrew , Avelar Abigail , Shohet Ralph V.
Published: October 2022

Appropriate gene expression within cardiomyocytes is coordinated by chromatin factors and is essential for heart function. We investigated the role of the chromatin reader ZMYND8 in the mouse heart using null and conditional knockouts (Zmynd8-cKO). While full-lengthZmynd8is not required for cardiomyocyte development,Zmynd8-cKOmice develop cardiomegaly, decreased cardiac function, and premature death compared to controls. Transcriptome analysis ofZmynd8-cKOcardiomyocytes reveals illegitimate expression of transcripts normally limited to skeletal muscle. Additionally, we observe integration of TNNI2 skeletal troponin into cardiac sarcomeres of mutant mice. We conclude that ZMYND8 is necessary to maintain appropriate cardiomyocyte gene expression and cardiac function.
The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?
Authors: Romanowska Julia , Nustad Haakon E. , Page Christian M. , Denault William R.P. , Bohlin Jon , Lee Yunsung , Magnus Maria C. , Haftorn Kristine L. , Gjerdevik Miriam , Novakovic Boris , Saffery Richard , Gjessing Håkon K. , Lyle Robert , Magnus Per , Håberg Siri E. , Jugessur Astanand
Published: October 2022

Background

Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate DNAm differences on the X chromosome.

Materials and Methods

The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). The replication cohort consisted of 149 ART and 58 non-ART neonates from the Australian “Clinical review of the Health of adults conceived following Assisted Reproductive Technologies” (CHART) study. The Illumina EPIC array was used to measure DNA methylation (DNAm) in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (“XWASs” hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. For replication purposes, we ran an analogous model to our main model on the CHART dataset.

Results and conclusions

In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted even after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental infertility as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was inUBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were inEIF2S3andAMOT. These three loci also displayed differential DNAm in the CHART cohort. Overall, genes that co-localized with the significant CpGs and DMRs are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism. These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to naturally-conceived.
Losses resulting from deliberate exploration trigger beta oscillations in frontal cortex
Authors: Chernyshev Boris V. , Pultsina Kristina I. , Tretyakova Vera D. , Miasnikova Aleksandra S. , Prokofyev Andrey O. , Kozunova Galina L. , Stroganova Tatiana A.
Published: October 2022

We examined the neural signature of directed exploration by contrasting MEG beta (16-30 Hz) power changes between disadvantageous and advantageous choices in the two-choice probabilistic reward task. We analyzed the choices made after the participants have learned the probabilistic contingency between choices and their outcomes, i.e., acquired the inner model of choice values. Therefore, rare disadvantageous choices might serve explorative, environment-probing purposes. The study brought two main findings. Firstly, decision making leading to disadvantageous choices took more time and evidenced greater large-scale suppression of beta oscillations than its advantageous alternative. Additional neural resources recruited during disadvantageous decisions strongly suggest their deliberately explorative nature. Secondly, an outcome of disadvantageous and advantageous choices had qualitatively different impact on feedback-related beta oscillations. After the disadvantageous choices, only losses – but not gains – were followed by late beta synchronization in frontal cortex. Our results are consistent with the role of frontal beta oscillations in the stabilization of neural representations for selected behavioral rule when explorative strategy conflicts with value-based behavior. Punishment for explorative choice being congruent with its low value in the reward history is more likely to strengthen, through punishment-related beta oscillations, the representation of exploitative choices consistent with the inner utility model.
Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice
Authors: Green Cara L. , Trautman Michaela E. , Babygirija Reji , Jain Raghav , Chaiyakul Krittisak , Pak Heidi H. , Bleicher Anneliese , Novak Grace , Sonsalla Michelle M. , Yeh Chung-Yang , Calubag Mariah F. , Liu Teresa T. , Flores Victoria , Newman Sarah , Ricke Will A. , Matkowskyj Kristina A. , Ong Irene M. , Simcox Judith , Lamming Dudley W.
Published: October 2022

Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.
HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate
Authors: Bell Benjamin N. , Bruun Theodora U. J. , Friedland Natalia , Kim Peter S.
Published: October 2022

HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1 infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the pre-hairpin intermediate, is not well understood. Here we show that two inhibitors targeting distinct highly-conserved regions of the pre-hairpin intermediate have strikingly consistent neutralization potencies (within ∼100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the pre-hairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
Cell division history encodes directional information of fate transitions
Authors: Wang Kun , Hou Liangzhen , Lu Zhaolian , Wang Xin , Zi Zhike , Zhai Weiwei , He Xionglei , Curtis Christina , Zhou Da , Hu Zheng
Published: October 2022

Single-cell RNA-sequencing (scRNA-seq) enables systematic mapping of cellular differentiation trajectories. However, inferring the cell-fate transitions under diseases or perturbations is still challenging due to the high cellular plasticity. Here, we demonstrate that monotonically expressed genes (MEGs) along cell divisions record the directions of state transitions regardless of the cellular processes. We developed a computational framework (PhyloVelo) to identify MEGs and reconstruct a novel transcriptomic velocity field by leveraging both scRNA-seq and phylogenetic information. PhyloVelo accurately recovered linear, bifurcated and convergent differentiations in simulations and C. elegans. It outperformed current approaches for delineating cellular trajectories in embryo development and tumor evolution through analysis of five CRISPR/Cas9-based lineage tracing datasets. Together, our study unveils an internal cellular clock and provides a powerful method for cellfate analysis in diverse biological contexts.
High selectivity of frequency induced transcriptional responses
Authors: Givré Alan , Colman-Lerner Alejandro , Dawson Silvina Ponce
Published: October 2022

Cells continuously interact with their environment, detect its changes and generate responses accordingly. This requires interpreting the variations and, in many occasions, producing changes in gene expression. In this paper we use information theory and a simple transcription model to analyze the extent to which the resulting gene expression is able to identify and assess the intensity of extracellular stimuli when they are encoded in the amplitude, duration or frequency of a transcription factor’s nuclear concentration. We find that the maximal information transmission is, for the three codifications, ~ 1.5 – 1.8 bits, i.e., approximately 3 ranges of input strengths can be distinguished in all cases. The types of promoters that yield maximum transmission for the three modes are all similarly fast and have a high activation threshold. The three input modulation modes differ, however, in the sensitivity to changes in the parameters that characterize the promoters, with frequency modulation being the most sensitive and duration modulation, the least. This turns out to be key for signal identification. Namely, we show that, because of this sensitivity difference, it is possible to find promoter parameters that yield an information transmission within 90% of its maximum value for duration or amplitude modulation and less than 1 bit for frequency modulation. The reverse situation cannot be found within the framework of a single promoter transcription model. This means that pulses of transcription factors in the nucleus can selectively activate the promoter that is tuned to respond to frequency modulations while prolonged nuclear accumulation would activate several promoters at the same time. Thus, frequency modulation is better suited than the other encoding modes to allow the identification of external stimuli without requiring other mediators of the transduction.
Proximity Analysis of Native Proteomes Reveals Interactomes Predictive of Phenotypic Modifiers of Autism and Related Neurodevelopmental Conditions
Authors: Gao Yudong , Trn Matthew , Shonai Daichi , Zhao Jieqing , Soderblom Erik J. , Garcia-Moreno S. Alexandra , Gersbach Charles A. , Wetsel William C. , Dawson Geraldine , Velmeshev Dmitry , Jiang Yong-hui , Sloofman Laura G. , Buxbaum Joseph D. , Soderling Scott H.
Published: October 2022

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving high specificity spatial interactomes compared to prior methods. The resulting native proximity interactomes are enriched for human genes dysregulated in the brain of autistic individuals and reveal unexpected and highly significant interactions with other lower-confidence autism risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networksin vivorelevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.
CBD resistantSalmonellastrains are susceptible to Epsilon 34 phage tailspike protein
Authors: Ibrahim Iddrisu , Ayariga Joseph Atia , Xu Junhuan , Adebanjo Ayomide , Samuel-Foo Michelle , Ajayi Olufemi S.
Published: October 2022

The rise of antimicrobial resistance is a global public health crisis that threatens the effective control and prevention of infections. Due to the emergence of pandrug-resistant bacteria, most antibiotics have lost their efficacy. Meanwhile, the development of new antimicrobials has stagnated, which leads to the creation of new and unconventional treatments. Bacteriophages or their components are known to target bacterial cell walls, cell membranes, and lipopolysaccharides (LPS) and hydrolyze them. Bacteriophages being the natural predators of pathogenic bacteria, are inevitably categorized as “human friends”, thus fulfilling the adage that “the enemy of my enemy is my friend”. Leveraging on their lethal capabilities against pathogenic bacteria, researchers are searching for more ways to overcome the current antibiotic resistance challenge. Bacteriophages are considered to be one of the most effective alternative therapies for multidrug resistant bacteria. In this study, we expressed and purified epsilon 34 phage tailspike protein (E34 TSP) from the E34 TSP gene which was previously cloned into a pET30a-LIC vector, then assessed the ability of this bacteriophage protein in the killing of two CBD-resistant strains ofSalmonellaspp. We observed that the combined treatment of CBD-resistant strains ofSalmonellawith CBD and E34 TSP showed poor killing ability whereas the monotreatment with E34 TSP showed considerably higher killing efficiency.
The Human Pangenome’s sequence conservation reveals a landscape of polymorphic structural variations
Authors: Lee HoJoon , Greer Stephanie U. , Pavlichin Dmitri S. , Hughes Christopher R. , Zhou Bo , Weissman Tsachy ,   Human Pangenome Reference Consortium, Ji Hanlee P.
Published: October 2022

The Human Pangenome is a new reference build that addresses many of the limitations of the current reference. The first release is based on 94 high-quality haploid assemblies from individuals with diverse backgrounds. To facilitate the Pangenomes adoption in the wider research community, we conducted a multiple genome comparative analysis against the current GRCh38 reference. We applied a k-mer indexing strategy to identify highly conserved sequences that are omnipresent across all Pangenome assemblies, the reference and CHM13, a reference assembly with telomere-to-telomere chromosomes. Pan-conserved tag segments provided an informative set of universally conserved sequences. Examining the intervals between pairs of these segments defined highly conserved segments of the genome versus ones that have structurally related polymorphisms. We identified a Pangenome landscape of 60,764 polymorphic intervals with unique and geo-ethnic features. Overall, this study of the Pangenome revealed the conserved versus divergent features including the landscape of polymorphic structural variants.
Assessment of the Feasibility of Remote Training, At-Home Testing, and Test-Retest Variability of Clustered Virtual Reality Perimetry
Authors: Chia Zer Keen , Kong Alan W. , Turner Marcus L. , Saifee Murtaza , Damato Bertil E. , Backus Benjamin T. , Blaha James J. , Schuman Joel S. , Deiner Michael , Ou Yvonne
Published: October 2022

Objective

To assess the feasibility of remotely training glaucoma patients to take a ten-session clustered virtual reality (VR) visual field test (VVP-10) at home, analyze results for test-retest variability, and assess correspondence with conventional perimetry.

Design

Cross-sectional study.

Subjects

21 subjects with glaucoma were enrolled and included in the feasibility assessment of remote training. 36 eyes were used for test-retest analysis and determination of concordance with Humphrey Visual Field (HVF) testing.

Methods

Subjects were provided with a mobile VR headset containing the VVP-10 test software and trained remotely via video conferencing. Subjects were instructed to complete ten sessions over a 14-day period.

Main Outcome Measures

Feasibility was determined by the number of subjects who were able to independently complete VVP-10 over the 14-day period after one remote training session. Intraclass correlation coefficient (ICC) of average fraction seen across ten sessions and standard error (SE) for the mean were primary outcome measures for assessing test-retest variability. Correlation with HVF mean sensitivity (MS) across eyes, was a secondary outcome measure.

Results

20 subjects (95%) successfully completed the VVP-10 test series after one training session. ICC of VVP-10 was 0.95 (95% CI [0.92, 0.97]). Mean SE in units of fraction seen was 0.012. The Spearman correlations of VVP-10 average fraction seen versus HVF MS were 0.88 (95% CI [0.66, 0.99]) for moderate to advanced glaucoma eyes, and decreased to 0.68 (95% CI [0.29, 0.94]) when all eyes were included.

Conclusions

Remote training of patients at home is feasible and subsequent remote clustered visual field testing using VVP-10 by patients on their own without any further interactions with caregivers or study staff was possible. At-home VVP-10 results demonstrated low test-retest variability. Future studies must be conducted to determine if VVP-10, taken at home as convenient for the patient, may be a viable supplement to provide equivalent or complementary results to that of standard in-clinic assessment of visual function in glaucoma.
Gut microbiota modulates distal symmetric polyneuropathy in diabetic patients
Authors: Yang Junpeng , Yang Xueli , Wu Guojun , Huang Fenglian , Shi Xiaoyang , Wei Wei , Zhang Yingchao , Zhang Haihui , Cheng Lina , Yu Lu , Shang Jing , Lv Yinghua , Wang Xiaobing , Zhai Rui , Li Pan , Cui Bota , Fang Yuanyuan , Deng Xinru , Tang Shasha , Wang Limin , Yuan Qian , Zhao Liping , Zhang Faming , Zhang Chenhong , Yuan Huijuan
Published: October 2022

The contribution of the gut microbiota to distal symmetric polyneuropathy (DSPN) in diabetic patients remains elusive. We found that the gut microbiota from DSPN patients induced more severe peripheral neuropathy in db/db mice. Gut microbiota from healthy donors significantly alleviated DSPN independent from glycaemic control in patients in a randomized, double-blind and placebo-controlled trial. The gut bacterial genomes correlated with Toronto Clinical Scoring System score were organized in two competing guilds. Increased Guild 1 that had higher capacity in butyrate production and decreased Guild 2 that harbored more genes in synthetic pathway of endotoxin were associated with improved gut barrier integrity and decreased proinflammatory cytokine levels. Moreover, matched enterotype between transplants and recipients showed better therapeutic efficacy with more enriched Guild 1 and suppressed Guild 2. Thus, the two competing guilds may mediate the causative role of the gut microbiota in DSPN and have the potential to be an effective target for treatment.
Clinical Trial Registration ID #: ChiCTR1800017257.
Body Composition, Cardiometabolic Risk Factors and Comorbidities in Psoriasis and the Effect ofHLA-C*06:02Status: The HUNT Study, Norway
Authors: Solvin Åshild Ø. , Bjarkø Vera V. , Thomas Laurent F. , Berrospi Patricia , Hveem Kristian , Saunes Marit , Åsvold Bjørn O. , Løset Mari
Published: October 2022

Psoriasis has been associated with increased adiposity measures driving systemic inflammation, which may lead to metabolic dysfunction and comorbidities. In this population-based, cross-sectional study, we used data from 56 042 individuals in the fourth wave of the Trøndelag Health Study (HUNT4), to investigate the associations between psoriasis and body composition measures assessed using bioelectrical impedance analysis, cardiometabolic risk factors, and comorbidities. Further, we investigated the associations betweenHLA-C*06:02status, a potential clinical biomarker for a distinct psoriasis endotype, and these outcomes. Psoriasis was associated with increased adiposity measures, including increased body and visceral fat, and lower levels of skeletal muscle and soft lean mass, as well as higher prevalence of cardiovascular, respiratory and endocrine disorders.HLA-C*06:02-positive individuals with psoriasis had lower levels of hsCRP, increased prevalence of atrial fibrillation and decreased prevalence of migraine. Our results point to altered body composition in psoriasis with increased levels of fat, and particularly metabolically active visceral fat, and provide support for a broad clinical approach to psoriatic patients in a general population.
BamQuery: a proteogenomic tool for the genome-wide exploration of the immunopeptidome
Authors: Ruiz Cuevas Maria Virginia , Hardy Marie-Pierre , Larouche Jean-David , Apavaloaei Anca , Kina Eralda , Vincent Krystel , Gendron Patrick , Laverdure Jean-Philippe , Durette Chantal , Thibault Pierre , Lemieux Sébastien , Perreault Claude , Ehx Grégory
Published: October 2022

MHC-I-associated peptides (MAPs) derive from selective yet highly diverse genomic regions, including allegedly non-protein-coding sequences, such as endogenous retroelements (EREs). Quantifying canonical (exonic) and non-canonical MAPs-encoding RNA expression in malignant and benign cells is critical for identifying tumor antigens (TAs) but represents a challenge for immunologists. We present BamQuery, a computational tool attributing an exhaustive RNA expression to MAPs of any origin (exon, intron, UTR, intergenic) from bulk and single-cell RNA-sequencing data. We show that non-canonical MAPs (including TAs) can derive from multiple different genomic regions (up to 35,343 for EREs), abundantly expressed in normal tissues. We also show that supposedly tumor-specific mutated MAPs, viral MAPs, and MAPs derived from proteasomal splicing can arise from different unmutated non-canonical genomic regions. The genome-wide approach of BamQuery allows comprehensive mapping of all MAPs in healthy and cancer tissues. BamQuery can also help predict MAP immunogenicity and identify safe and actionable TAs.
Fast burst fraction transients convey information independent of the firing rate
Authors: Naud Richard , Wang Xingyun , Friedenberger Zachary , Payeur Alexandre , Shin Jiyun N , Beique Jean-Claude , Richards Blake , Drüke Moritz , Larkum Matthew , Doron Guy
Published: October 2022

Theories of attention and learning have hypothesized a central role for high-frequency bursting in cognitive functions, but experimental reports of burst-mediated representations \emph{in vivo} have been limited. Here we used a novel demultiplexing approach by considering a conjunctive burst code. We studied this code \emph{in vivo} while animals learned to report direct electrical stimulation of the somatosensory cortex and found two acquired yet independent representations. One code, the event rate, showed a sparse and succint stiumulus representation and a small modulation upon detection errors. The other code, the burst fraction, correlated more globally with stimulation and more promptly responded to detection errors. Potent and fast modulations of the burst fraction were seen even in cells that were considered unresponsive based on the firing rate. During the later stages of training, this modulation in bursting happened earlier, gradually aligning temporally with the representation in event rate. The alignment of bursting and event rate modulation sharpened the firing rate response, and was strongly associated with behavioral accuracy. Thus a fine-grained separation of spike timing patterns reveals two signals that accompany stimulus representations: an error signal that can be essential to guide learning and a sharpening signal that could implement attention mechanisms.
Pixelated microfluidics for drug screening on tumour spheroids and ex vivo microdissected primary tissue
Authors: Dorrigiv Dina , Goyette Pierre-Alexandre , St-Georges-Robillard Amélie , Mes-Masson Anne-Marie , Gervais Thomas
Published: October 2022

Anti-cancer drugs have the lowest success rate of approval in drug development programs. Thus, preclinical assays that closely predict the clinical responses to drugs are of utmost importance in both clinical oncology and pharmaceutical research. 3D tumour models preserve the tumoural architecture and are cost-, labour-, and time-efficient. However, the short-term longevity, limited throughput, and limitations to live imaging of these models have so far driven researchers towards simpler, less realistic tumour models such as monolayer cell cultures. Here, we present a static open-space microfluidic drug screening platform that enables the formation, culture, and multiplexed delivery of several reagents to various 3D tumour models, namely cancer cell line spheroids and ex vivo primary tumour fragments. Our platform utilizes an open-space microfluidic technology, a pixelated chemical display, which creates fluidic “pixels” of biochemical reagents that stream over tumour models in a contact-free fashion. Up to 9 different treatment conditions can be tested over 144 samples in a single experiment. We provide a proof-of-concept application by staining fixed and live tumour models with multiple cellular dyes. Furthermore, we demonstrate that the various responses of the tumour models to biological stimuli can be assessed using the proposed drug screening platform. The platform is amenable to various 3D tumour models, such as tumour organoids. Upscaling of the microfluidic platform to larger areas can lead to higher throughputs, and thus will have a significant impact on developing treatments for cancer.
Widespread chromatin context-dependencies of DNA double-strand break repair proteins
Authors: Vergara Xabier , Manjón Anna G. , Morris Ben , Schep Ruben , Leemans Christ , Sanders Mathijs A. , Beijersbergen Roderick L. , Medema René H. , van Steensel Bas
Published: October 2022

DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. BRCA2 is an example of the former, which is corroborated by chromatin-dependent shifts in mutation patterns of BRCA2-/- cancer genomes. These results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner.

ONE SENTENCE SUMMARY

A multiplexed screen reveals how dozens of proteins sense the local chromatin context to tune the balance between two DNA repair pathways.
Nitrate leaching and its implication for Fe and As mobility in a Southeast Asian aquifer
Authors: Glodowska Martyna , Ma Yinxiao , Smith Garrett , Kappler Andreas , Jetten Mike , Welte Cornelia U.
Published: October 2022

The drinking water quality of millions of people in South and Southeast Asia is at risk due to arsenic (As) contamination of groundwater and insufficient access to water treatment facilities. Intensive use of nitrogen (N) fertilizer increases the possibility of nitrate (NO3-) leaching into aquifers, yet very little is known about how the N cycle will interact with and affect the iron (Fe) and As mobility in aquifers. We hypothesized that input of NO3- into highly methanogenic aquifers can stimulate nitrate-dependent anaerobic methane oxidation (N-DAMO) and subsequently help to remove NO3- and decrease CH4 emission. We, therefore, investigated the effects of N input into aquifers and its effect on Fe and As mobility, by running a set of microcosm experiments using aquifer sediment from Van Phuc, Vietnam supplemented with 15NO3- and 13CH4. Additionally, we assessed the effect of N-DAMO by inoculating the sediment with two different N-DAMO enrichment cultures (N-DAMO(O) and N-DAMO(V)). We found that native microbial communities and both N-DAMO enrichments could efficiently consume nearly 5 mM NO3- in 5 days. In an uninoculated setup, NO3- was preferentially used over Fe(III) as electron acceptor and consequently inhibited Fe(III) reduction and As mobilization. The addition of N-DAMO(O) and N-DAMO(V) enrichment cultures led to substantial Fe(III) reduction followed by the release of Fe2+ (0.190±0.002 mM and 0.350±0.007 mM, respectively) and buildup of sedimentary Fe(II) (11.20±0.20 mM and 10.91±0.47 mM, respectively) at the end of the experiment (day 64). Only in the N-DAMO(O) inoculated setup, As was mobilized (27.1±10.8 μg/L), while in the setup inoculated with N-DAMO(V) a significant amount of Mn (24.15±0.41 mg/L) was released to the water. Methane oxidation and 13CO2 formation were observed only in the inoculated setups, suggesting that the native microbial community did not have sufficient potential for N-DAMO. An increase of NH4+ implied that dissimilatory nitrate reduction to ammonium (DNRA) took place in both inoculated setups. The archaeal community in all treatments was dominated by Ca. Methanoperedens while the bacterial community consisted largely of various denitrifiers. Overall, our results suggest that input of N fertilizers to the aquifer decreases As mobility and that CH4 cannot serve as an electron donor for the native NO3- reducing community.

Graphical abstract
A general theory for the dynamics of social populations: Within-group density dependence and between-group processes
Authors: Lerch Brian A. , Abbott Karen C.
Published: October 2022

Despite the importance of population structures throughout ecology, relatively little theoretical attention has been paid to understanding the implications of social groups for population dynamics. The dynamics of socially structured populations differ substantially from those of unstructured or metapopulation-structured populations, because social groups themselves may split, fuse, and compete. These “between-group processes” have been suggested to be important drivers of the dynamics of socially-structured populations, but no general theoretical framework exists that can handle various density-dependent between-group processes within a single model. Here, we develop a general framework for the dynamics of socially-structured populations that considers births, deaths, migration, group extinction, fissions, fusions, and between-group competition within a single model. Both logistic growth and an Allee effect are considered for within-group density dependence. We show that the effect of various between-group processes is mediated by their influence on the stable distribution of group sizes, with the ultimate impact on the population determined by the interaction between the altered group size distribution and within-group density dependence. The group level is important to the dynamics of the entire population, since it drives extinction risk, impacts population growth rates, and leads to the emergence of population-level density dependence (even if birth and death rates depend only on group size and not population size). We conclude with a series of case studies that illustrate different ways that age, sex, and class structure impact the dynamics of social populations. In sum, our results make clear the importance of within-group density dependence, between-group dynamics, and the interactions between them for the population dynamics of social species and provide a general, flexible framework for modeling social populations.
Multiscale model of the different modes of cancer cell invasion
Authors: Ruscone Marco , Montagud Arnau , Chavrier Philippe , Destaing Olivier , Bonnet Isabelle , Zinovyev Andrei , Barillot Emmanuel , Noël Vincent , Calzone Laurence
Published: October 2022

Mathematical models of biological processes implicated in cancer are built using the knowledge of complex networks of signaling pathways, describing the molecular regulations inside different cell types, such as tumor cells, immune and other stromal cells. If these models mainly focus on intracellular information, they often omit a description of the spatial organization among cells and their interactions, and with the tumoral microenvironment. We present here a model of tumor cell invasion simulated with PhysiBoSS, a multiscale framework which combines agent-based modeling and continuous time Markov processes applied on Boolean network models. With this model, we aim to study the different modes of cell migration by considering both spatial information obtained from the agent-based simulation and intracellular regulation obtained from the Boolean model. Our multiscale model integrates the impact of gene mutations with the perturbation of the environmental conditions and allows the visualization of the results with 2D and 3D representations. The model successfully reproduces single and collective migration processes and is validated on published experiments on cell invasion.In silicoexperiments are suggested to search for possible targets that can block the more invasive tumoral phenotypes.