bluuebunny/crossref_metadata_2025 huggingface dataset:
The phenotype of SMC6_G514R hinge mutant ofPhyscomitrium patents
Authors: Angelis Karel J. , Holá Marcela , Vágnerová Radka , Vaculíková Jitka , Paleček Jan J.
Published: July 2024

The Structural Maintenance of Chromosomes (SMC) complexes play roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of SMC proteins with a unique structure consisting of an ATPase head, long arm, and hinge. The direct interaction of hinges leads to the formation of SMC heterodimer. A critical SMC6 mutation G551R interrupting the interaction of SMC5 and SMC6 hinges have been previously identified inSchizosaccharomyces pombewithin a conserved motif. Using CRISPR/Cas9 directed oligonucleotide replacement, we have introduced this G to R point mutation in SMC6 ofPhyscomitrium patens(P. patens) at position 514 and also at position 517 of the same hinge domain. It turned out that both mutations are not toxic and do not affect the viability of establishedPpsmc6_G514RandPpsmc6_G517Rlines.

SinceP. patensmutants with entire or partial deletion of theSMC6gene are not viable, we compare hinge mutants with previously established mutant line with attenuated transcription by targeted binding of deactivated Cas9 nuclease (Ppsmc6_dCas). We show that mutation of G to R at position 514 fully prevents the interaction of SMC6 not only with SMC5, but also NSE5 and NSE6. Surprisingly, mutation of close residue 517 has no effect at all. ThePpsmc6_G514Rline has aberrant morphology quite similar toPpsmc6_dCas, though the absence of protonemata branching and formation of gametophores is incomplete. On the contrary, thePpsmc6_G517Rline is morphologically more or less similar to WT. Spontaneous and bleomycin-induced mutagenesis and maintenance of the number of rDNA copies in thePpsmc6_G514Rline is also similar toPpsmc6_dCas, whilePpsmc6_G517Rmore or less mimics WT. The sensitivity of thePpsmc6_G514Rline to bleomycin is not as severe as that ofPpsmc6_dCas, and surprisingly, thePpsmc6_G517Rline is even less sensitive to bleomycin than WT. Moreover, both hinge mutations have no direct effect on the rate of DSB repair in dividing and differentiated cells.

The most unique feature of the hinge mutants is interference with gene targeting (GT). Whilst GT efficiency ofPpsmc6_G517RandPpsmc6_dCaswhen compared to WT is only slightly or moderately reduced, it is completely abolished inPpsmc6_G514R.

Based on these results, we conclude that sufficient amounts of SMC6 and its interactions are necessary for normal moss development and genome stability, such as DNA repair and rDNA maintenance. The reduced levels of SMC6 subunit, and therefore low levels of complete SMC5/6 complex, are insufficient for acute DSB repair, however, the acute DSB repair is not affected by impaired SMC6 interactions inPpsmc6_G514R. In contrast, SMC6 inability to interact with SMC5 and other partners like NSE5 and NSE6 results in abolished GT, while low levels of SMC6 have only mild effect. These data underline importance of different aspects of SMC5/6, such as its levels or interactions.
Chronic Tinnitus is Associated with Aging but not Dementia
Authors: Reisinger Lisa , Weisz Nathan
Published: July 2024

Background

Aging is related to deterioration of bodily and neural functions, leading to various disorders and symptoms, including the development of dementia, hearing loss, or tinnitus. Understanding how these phenomena are intertwined and how aging affects those is crucial for prevention and the future development of interventions.

Methods

We utilized the UK Biobank which includes a total of 502,382 participants between 40 and 70 years old. We used logistic regression models and cox proportional hazard models and compared hazard ratios.

Results

The odds of reporting tinnitus in the older age group (i.e., older than 58 years) were increased by 43.3% and a one decibel increase in the SRT enhanced the odds for tinnitus by 13.5%. For our second analysis regarding hearing loss, the risk of dementia increased by 9.2% with an increase by one decibel in the SRT score. In terms of aging, each additional year increased the risk by 19.2%. Tinnitus alone showed a significant influence with a hazard ratio of 52.1%, however, when adding hearing loss, age and various covariates, the effect vanished.

Conclusion

Findings confirm that tinnitus is indeed related to aging, but presumably independent of the aging processes accompanying the development of dementia. This highlights the urge to further investigate the impact of aging on neural processes that are relevant for alterations in the auditory systems (e.g., leading to the development of tinnitus or hearing loss) as well as for increased vulnerability in terms of neurodegenerative diseases.

Key Points

Question

Aging and hearing loss have been linked to dementia and tinnitus respectively. But is there a direct influence of tinnitus on dementia risk?

Findings

In this case-control study, data derived from the UK Biobank was used to first replicate previous findings establishing aging as a risk factor for tinnitus and hearing loss as a risk factor for dementia. Tinnitus was not found to increase the risk of dementia.

Meaning

Aging is related to tinnitus, however, since tinnitus does not influence the risk of dementia, we conclude that the aging processes that determine tinnitus are independent of neural processes facilitating the development of dementia.
Therapy Without Borders: A Systematic Review on Telehealth’s Role in Expanding Mental Health Access
Authors: Swint Jennifer , Fischer Margaret , Zhang Wei , Zhang Xi
Published: July 2024

Background

The COVID-19 pandemic has accelerated the adoption of telehealth services in mental healthcare. This systematic review aims to evaluate the effectiveness of telehealth interventions for mental health conditions compared to traditional face-to-face treatment.

Methods

We searched major electronic databases (PubMed, PsycINFO, CINAHL, and Cochrane Library) for randomized controlled trials published between 2010 and 2023. Studies comparing telehealth interventions to face-to-face treatment for adults with mental health disorders were included. Two independent reviewers assessed study quality and extracted data. Meta-analyses were conducted where appropriate.

Results

Thirty-five studies met the inclusion criteria, encompassing 4,827 participants across various mental health conditions. Telehealth interventions demonstrated non-inferiority to face-to-face treatment for depression (standardized mean difference [SMD] = -0.03, 95% CI [-0.15, 0.09]) and anxiety disorders (SMD = -0.06, 95% CI [-0.19, 0.07]). For post-traumatic stress disorder, telehealth showed a small but significant advantage (SMD = -0.21, 95% CI [-0.37, -0.05]). Patient satisfaction and therapeutic alliance were comparable between telehealth and face-to-face interventions. However, dropout rates were slightly higher in telehealth conditions (risk ratio = 1.27, 95% CI [1.11, 1.46]).

Conclusion

This review suggests that telehealth interventions are generally as effective as face-to-face treatment for common mental health disorders. While promising, these findings should be interpreted cautiously due to heterogeneity in study designs and interventions. Future research should focus on long-term outcomes, cost-effectiveness, and strategies to improve engagement in telehealth settings.
Anisotropic Articular Cartilage Biofabrication based on Decellularized Extracellular Matrix
Authors: Puiggalí-Jou Anna , Hui Isabel , Baldi Lucrezia , Frischknecht Rea , Asadikorayem Maryam , Janiak Jakub , Chansoria Parth , McCabe Maxwell C. , Stoddart Martin J. , Hansen Kirk C. , Christman Karen L. , Zenobi-Wong Marcy
Published: July 2024

Tissue-engineered grafts that mimic articular cartilage show promise for treating cartilage injuries. However, engineering cartilage cell-based therapies to match zonal architecture and biochemical composition remains challenging. Decellularized articular cartilage extracellular matrix (dECM) has gained attention for its chondro-inductive properties, yet dECM-based bioinks have limitations in mechanical stability and printability. This study proposes a rapid light-based bioprinting method using a tyrosine-based crosslinking mechanism, which does not require chemical modifications of dECM and thereby preserves its structure and bioactivity. Combining this resin with Filamented Light (FLight) biofabrication enables the creation of cellular, porous, and anisotropic dECM scaffolds composed of aligned microfilaments. Specifically, we investigate the effects of various biopolymer compositions (i.e., hyaluronic acid, collagen I, and dECM) and inner architecture (i.e., bulk light vs FLight) on immune response and cell morphology, and we investigate their influence on nascent ECM production and long-term tissue maturation. Our findings highlight the importance of FLight scaffolds in directing collagen deposition resembling articular cartilage structure and promoting construct maturation, and they emphasize the superiority of biological-rich dECM over single-component materials for engineering articular cartilage, thereby offering new avenues for the development of effective cartilage tissue engineering strategies.
Event-marked Windowed Communication: Inferring activity propagation from neural time series
Authors: Madan Mohan Varun , Varley Thomas F , Cash Robin , Seguin Caio , Zalesky Andrew
Published: July 2024

Tracking signal propagation in nervous systems is crucial to our understanding of brain function and information processing. Current methods for inferring neural communication track patterns of sustained co-activation over time, making them unsuitable to detect discrete instances of signal transmission. Here, we propose Event-marked Windowed Communication (EWC), a new analytical framework to infer functional interactions arising from discrete signalling events between neural elements, in otherwise continuous time series data. In contrast to conventional measures of functional connectivity, our method utilises an event-based subsampling of neural time series, which allows it to capture the statistical analogue of activity propagation. We test EWC on simulations of neural dynamics and show that it is capable of retrieving ground truth motifs of directional signalling, over a range of model configurations. Critically, we demonstrate that EWC's subsampling approach affords profound reductions in computation times, compared to established network inference methods such as transfer entropy. Lastly, we showcase the utility of EWC to infer whole-brain functional networks from MEG recordings. Networks computed using EWC and transfer entropy were highly correlated (median r=0.821 across subjects), but EWC inference was approximately 6.5 times faster per epoch. In summary, our work presents a new method to infer signalling from time series of neural activity at low computational costs. Our framework is flexible and can be applied to activity time series captured by diverse functional neuroimaging modalities, opening up new avenues for the study of neural communication.
Bacteria combine polar- and dispersed-growth to power cell elongation and wall width dynamics
Authors: Zambri Matthew P. , Baglio Christine R. , Irazoki Oihane , Jones Stephanie E. , Garner Ethan C. , Cava Felipe , Elliot Marie A.
Published: July 2024

The cell wall is a complex structure. For most bacteria, peptidoglycan is an essential component of their cell wall, with different bacteria having evolved distinct biosynthetic strategies. The mechanisms driving bacterial growth can be divided into three, mutually-exclusive categories: (i) dispersed growth, mediated by MreB and employed by many rod-shaped bacteria; (ii) polar growth, driven by distinct proteins in the actinobacteria and rhizobiales; and (iii) septal growth, fueled by FtsZ in many coccoid bacteria. Here, we show that under conditions of rapid growth, the actinobacterial representativeStreptomyces venezuelaetranscends these categories, simultaneously employing both canonical polar growth, and MreB-mediated dispersed growth. Our results indicate that MreB is essential for cell wall integrity and culture viability under these growth conditions, promotes dynamic cell wall changes over the course of a growth cycle, and contributes to a wall that is structurally distinct from that of conventionally growing streptomycetes.
Id2 levels determine the development of effector vs. exhausted tissue-resident memory CD8+T cells during CNS chronic infection
Authors: Coulibaly Aboubacar Sidiki K. , Nozeran Lucie , Thomann Céline , Alis Marine , Bassot Emilie , Hassan Ali , Porte Rémi , Belloy Marcy , Blanchard Nicolas , Masson Frederick
Published: July 2024

Tissue-resident memory T cells (Trm) are essential for regional immunity in non-lymphoid tissues. Although single-cell transcriptomics have revealed Trm heterogeneity in various diseases, the molecular mechanisms behind this diversity are unclear. To investigate this, we usedToxoplasma gondii(T. gondii) infection, which persists in the central nervous system (CNS) and is controlled by brain CD8+Trm. Our single-cell transcriptomic analysis of brain CD8+T cells fromT. gondii-infected mice showed heterogeneous expression of the transcriptional regulator Id2, correlating with different functional states. Using mixed bone marrow chimeras, we found that Id2-deficiency in T cells caused parasite-specific Trm to develop an altered phenotype with diminished effector functions and reduced expression of CD49a. Furthermore, loss of Id2 in brain-infiltrating CD8+T cells led to the accumulation of exhausted PD1+Tox+CD8+Trm cells, while Id2 overexpression repressed T cell exhaustion. Overall, our study shows that Id2 levels dictate the acquisition of effectorvs.exhausted phenotypes in CD8+Trm during chronic CNS infection.

One sentence Summary

Id2 expression level regulates the functional heterogeneity of brain Trm during CNS chronic infection
Rapid neutralizing assay for circulating H5N1 influenza virus in dairy cows
Authors: Miyakawa Kei , Ota Makoto , Sano Kaori , Momose Fumitaka , Okura Takashi , Kishida Noriko , Arita Tomoko , Suzuki Yasushi , Shirakura Masayuki , Asanuma Hideki , Watanabe Shinji , Ryo Akihide , Hasegawa Hideki
Published: July 2024

A rapid and safe neutralization assay is required for emerging highly pathogenic avian influenza viruses, including the H5N1 subtype, which was recently found in cows. Herein, we report a novel neutralization assay using HiBiT-tagged virus-like particles (hiVLPs). Our hiVLP-based neutralization test demonstrated a higher quantitative value and shorter assay time than conventional methods. We used this assay to evaluate whether the neutralizing antibodies induced by the candidate vaccine virus (NIID-002) were cross-reactive with cow-derived H5N1. Our results suggest that the circulating H5N1 virus in cows shares antigenic characteristics with NIID-002, providing significant implications for the development and preparation of vaccines.
MIND WANDERING DURING IMPLICIT LEARNING IS ASSOCIATED WITH INCREASED PERIODIC EEG ACTIVITY AND IMPROVED EXTRACTION OF HIDDEN PROBABILISTIC PATTERNS
Authors: Simor Peter , Vekony Teodora , Farkas Bence Csaba , Szalardy Orsolya , Bogdany Tamas , Brezoczki Bianka , Csifcsak Gabor , Nemeth Dezso
Published: July 2024

Mind wandering, occupying 30-50% of our waking time, remains an enigmatic phenomenon in cognitive neuroscience. Predominantly viewed negatively, mind wandering is often associated with detrimental impacts on attention-demanding (model-based) tasks in both natural settings and laboratory conditions. Mind wandering however, might not be detrimental for all cognitive domains. We proposed that mind wandering may facilitate model-free processes, such as probabilistic learning, which relies on the automatic acquisition of statistical regularities with minimal attentional demands. We administered a well-established implicit probabilistic learning task combined with mind wandering thought probes in healthy adults (N = 37, 30 females). To explore the neural correlates of mind wandering and probabilistic learning, participants were fitted with high-density electroencephalography. Our findings indicate that probabilistic learning was not only immune to periods of mind wandering, but was positively associated with it. Spontaneous, as opposed to deliberate mind wandering, was particularly beneficial for extracting the probabilistic patterns hidden in the visual stream. Additionally, cortical oscillatory activity in the low-frequency (slow and delta) range, indicative of covert sleep-like states, was associated with both mind wandering and improved probabilistic learning, particularly in the early stages of the task. Given the importance of probabilistic implicit learning in predictive processing, our findings provide novel insights into the potential cognitive benefits of task-unrelated thoughts in addition to shedding light on its neural mechanisms. This surprising benefit challenges the predominant view of mind wandering as solely detrimental and highlights its complex role in human cognition, especially in memory consolidation.
Regulatory Subfunctionalization drives OXPHOS evolution in teleosts
Authors: Tsipourlianos A , Cardoso JCR , Angelakopoulos R , Kotoula A , Power DM , Mamuris Z , Moutou KA
Published: July 2024

Oxidative phosphorylation (OXPHOS) supplies over 90% of the cellular ATP requirements through the orchestrated function of five multiprotein complexes located in the inner mitochondrial membrane. The study explores how the evolutionary constraints imposed by the indispensable function of OXPHOS guide the outcome of Whole Genome Duplication (WGD) events. Two teleosts, the gilthead seabream (Sparus aurata) and the European seabass (Dicentrarchus labrax), which have undergone three rounds of WGDs were used as models and OXPHOS gene expression was assessed during the highly plastic and energy-demanding period of early development. Fish ontogeny is a unique period in fish life marked with dramatic changes in morphology, physiology, metabolism and behavior. The tightly regulated landscape of cell divisions, migrations and differentiation driving these dramatic changes demands high energy supplies. The discovery of 24 and 22 OXPHOS gene families in gilthead seabream and European seabass genome, respectively, and the subsequent phylogenetic analysis showed in most cases divergence from a common ancestor at the base of the teleost lineage, a process attributed to teleost-specific WGD. Overall results indicate that the WGD events have resulted in early retention of OXPHOS paralogue genes and subsequent species- or lineage-specific losses. OXPHOS paralogue gene expression levels were compared following RNA sequencing within and between distinct developmental stages in gilthead seabream and European seabass. Different expression patterns between paralogs were revealed; some were in dosage balance, others were expressed only in particular stage(s) and a lot of them were differentially expressed between stages. Differences in both the number and location of SNPs were revealed between paralogs, after merging the RNA sequencing data with whole genome sequencing data. A considerable number of mutations were mapped in the UTRs and mostly synonymous substitutions were identified in the CDS. The ratio of non-synonymous to synonymous substitutions when comparing the CDS variants revealed neutral positions while others are subject to purifying selection, safeguarding protein structural integrity and/or function. Overall, regulatory subfunctionalization of OXPHOS paralogs appeared as the evolutionary mechanism behind the retention of the paralogs in gilthead seabream and European seabass genomes in favor of ontogenetic plasticity.
Charting Taxa inAmanitaSectionAmidella(Basidiomycota:Amanitaceae)
Authors: Oliveira Paulo , Arraiano-Castilho Ricardo
Published: July 2024

Species determination in theAmidellaclade is notoriously difficult, because of the relative dearth of diagnostic characters and the rather common occurrence of homoplasies. This results in a substantial number of misnamed and unnamed collections, a misapprehension of the geographic range of known species, and a gross underestimation of the number of species it contains. To assess the diversity that should be considered as part ofAmidella, DNA sequences available for this group were retrieved in public nucleotide databases, using a combination of approaches to achieve a comprehensive representation. Phylogenetic analysis based on the aligned ITS sequences, consistently with the results from other molecular markers (ncLSU,RPB2,TEF1,BTUB), suggests five major clades: one containing the type speciesAmanita volvata, another forAmanita ponderosaand allies, a third one (roughly half of all species) withAmanita lepiotoides, and two others without valid species yet. At species level, around 81 clades were delimited, of which only 16–17 can be assigned a valid name, with a few more corresponding to provisional taxa listed in the amanitaceae.org website. Up to three further species without assigned sequences might correspond to the proposed clades. The current evidence suggests a rather narrow geographic range for most of these clades. This study provides a phylogeny-arranged outlook of the worldwide distribution ofAmidellaspecies, and an infrasectional framework for optimizing taxonomic sampling and designing clade-specific molecular markers to assist in identification.
Single cell data enables dissecting cell types present in bulk transcriptome data
Authors: Wruck Wasco , Adjaye James
Published: July 2024

The quality of organoid models can be assessed by single-cell-RNA-sequencing (scRNA-seq) but often only bulk transcriptome data is available. Here we present a pipeline for the analysis of scRNA-seq data and subsequent “deconvolution”, which is a method for estimating cell type fractions in bulk transcriptome data based on expression profiles and cell types found in scRNA-seq data derived from biopsies. We applied this pipeline on bulk iPSC-derived kidney and brain organoid transcriptome data to identify cell types employing two scRNA-seq kidney datasets and one brain dataset. Relevant cells present in kidney (eg. proximal tubules, distal convoluted tubules and podocytes) and brain (eg. neurons, astrocytes, oligodendrocytes and microglia) with obligatory endothelial and immune-related cells were identified. We anticipate that this pipeline will also enable estimation of cell type fractions in organoids of other tissues.
Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues
Authors: Zhang Xiao , Majumdar Anurag , Kim Clara , Kleiboeker Brian , Magee Kristann L , Learman Brian S , Thomas Steven A , Lodhi Irfan J , MacDougald Ormond A , Scheller Erica L
Published: July 2024

Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitorsAcvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potentin vivoneurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
Embryological insights into the evolution of genome regulation using haploid and diploid whiteflies,Bemisia tabaci
Authors: Shelby Emily A. , McKinney Elizabeth C. , Simmons Alvin M. , Moore Allen J. , Moore Patricia J.
Published: July 2024

The whitefly,Bemisia tabaci, is a hemipteran with a haplodiploid sex determination system, which provides a natural experiment for examining genome function in haploid and diploid embryos. Yet the embryogenesis ofB. tabaciremains understudied. Our previous work has established a possible role ofDNA methyltransferase 1(Dnmt1) in genome stability. In this study we used maternal RNA interference (RNAi) and immunohistochemistry to study the complex dynamics between DNMT1 and ploidy during embryogenesis. We found that both haploid and diploidB. tabacihave a similar developmental timeline to other holometabolous insects. We also found that, like other obligatory haploid insects, ploidy does not affect developmental timing, suggesting that maternal factors play a greater role than ploidy in developmental timing. For embryos with reduced expression ofDnmt1, we found that the loss of DNMT1 disrupts blastoderm development and affects nuclei morphology in both haploid and diploid embryos. Our results suggest that DNMT1 is required for blastoderm development.
A computational model of altered neuronal activity in altered gravity
Authors: Gontier Camille , Kalinski Laura , Striebel Johannes , Sturm Maximilian , Meerholz Zoe , Schunk Sarah , Lichterfeld Yannick , Liemersdorf Christian
Published: July 2024

Electrophysiological experiments have shown that neuronal activity changes upon exposure to altered gravity. More specifically, the firing rate increases during microgravity and decreases during centrifugal-induced hypergravity. However, the mechanism by which altered gravity impacts neuronal activity is still unknown. Different explanations have been proposed: a first hypothesis states that microgravity increases the fluidity of the cell membrane and modifies the properties of the neurons’ ion channels. Another hypothesis suggests the role of mechano-gated (MG) ion channels depolarizing the cells during microgravity exposure. Although intuitive, these models have not been backed by quantitative analyses nor simulations. Here, we developed computational models of the impact of altered gravity, both on single cell activity and on population dynamics. Firstly, in line with previous electrophysiological experiments, we suggest that microgravity could be modelled as an increase of the voltage-dependent channel transition rates, which are assumed to be the result of higher membrane fluidity and can be readily implemented into the Hodgkin-Huxley model. Using in-silico simulations of single neurons, we show that this model of the influence of gravity on neuronal activity allows to reproduce the increased firing and burst rates observed in microgravity. Secondly, we explore the role of MG ion channels on population activity. We show that recordings can be fitted by a network of connected excitatory neurons, whose activity is balanced by firing rate adaptation. Adding a small depolarizing current to account for the activation of mechano-gated channels also reproduces the observed increased firing and burst rates. Overall, our results fill an important gap in the literature, by providing a computational link between altered gravity and neuronal activity.
Scaling and Merging Time-Resolved Laue Data with Variational Inference
Authors: Zielinski Kara A. , Dolamore Cole , Wang Harrison K. , Henning Robert W. , Wilson Mark A. , Pollack Lois , Srajer Vukica , Hekstra Doeke R. , Dalton Kevin M.
Published: July 2024

Time-resolved X-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data.
Cell-type-specific striatal modulation of amygdalar acetylcholine in salience assignment
Authors: Chen Aixiao , Li Yunjing , Zhu Hangfei , Gu Hanmei , Weng Yanhong , Ye Qinyong , Guan Wuqiang , Sun Qingtao , Li Bo , Xu Fuqiang , Deng Hanfei , Xiao Xiong
Published: July 2024

The salience assignment is pivotal for both natural and artificial intelligence. Pioneering studies established that basal forebrain cholinergic neurons process behaviorally relevant salient information. However, the neural circuit mechanism underlying salience assignment remains poorly understood. Here we show that the acetylcholine (ACh) level in the basolateral amygdala (BLA) dynamically represented behavioral salience. Distinct neuronal subpopulations in the nucleus accumbens (NAc), D1- and D2-expressing medium spiny neurons (MSNs), antagonistically and specifically promote and suppress ACh release in the BLA, but not the cortex and hippocampus. These striatal D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the basal forebrain subregion substantia innominata (SI), respectively. Optogenetic manipulations of the pathway from striatal D1 and D2 MSNs to the SI opposingly affect associative learning. Our findings uncover an unconventional role of striatal MSNs in salience assignment via regulating the salience-representing amygdalar ACh activity.
AncFlow: An Ancestral Sequence Reconstruction Approach for Determining Novel Protein Structural
Authors: Rouzbehani Ryin , Kelley Scott T.
Published: July 2024

The rapid growth of sequence data from high-throughput sequencing technologies has unveiled a vast number of previously unknown proteins, presenting a significant challenge in their functional characterization. Ancestral sequence reconstruction (ASR) has emerged as a powerful tool to elucidate the evolutionary history of protein families and identify sequence determinants of protein function. Here, we present AncFlow, an automated software pipeline that integrates phylogenetic analysis, subfamily identification, and ASR to generate ancestral protein sequences for structural prediction using state-of-the-art tools like AlphaFold. AncFlow streamlines the process of ASR by combining multiple sequence alignment, phylogenetic tree inference, subfamily identification, and ancestral sequence reconstruction from unaligned protein sequences. The reconstructed ancestral sequences are then subjected to structural prediction using AlphaFold, enabling the investigation of the structural basis of functional divergence within protein families. We validated AncFlow using two well-characterized protein families: acyltransferases and dehydrogenases. The pipeline successfully reconstructed ancestral sequences for multiple internal nodes of the phylogenetic trees, and their predicted structures were compared with those of extant proteins. By analyzing the structural similarities and differences between ancestral and extant proteins, we gained insights into the evolutionary mechanisms underpinning the functional diversification within these families. AncFlow demonstrates the potential of integrating ASR and structural prediction to unravel the structural basis of functional divergence in protein families. The insights gained from this approach can guide protein engineering efforts, facilitating the design of proteins with desired functions. As the amount of sequence data continues to grow, AncFlow provides a valuable tool for exploring the evolutionary landscape of proteins and accelerating the discovery of novel protein functions.
Annotation Vocabulary (Might Be) All You Need
Authors: Hallee Logan , Rafailidis Niko , Horger Colin , Hong David , Gleghorn Jason P.
Published: July 2024

Protein Language Models (pLMs) have revolutionized the computational modeling of protein systems, building numerical embeddings that are centered around structural features. To enhance the breadth of biochemically relevant properties available in protein embeddings, we engineered theAnnotation Vocabulary, a transformer readable language of protein properties defined by structured ontologies. We trainedAnnotation Transformers(AT) from the ground up to recover masked protein property inputs without reference to amino acid sequences, building a new numerical feature space on protein descriptions alone. We leverage AT representations in various model architectures, for both protein representation and generation. To showcase the merit of Annotation Vocabulary integration, we performed 515 diverse downstream experiments. Using a novel loss function and only $3 in commercial compute, our premier representation model CAMP produces state-of-the-art embeddings for five out of 15 common datasets with competitive performance on the rest; highlighting the computational efficiency of latent space curation with Annotation Vocabulary. To standardize the comparison ofde novogenerated protein sequences, we suggest a new sequence alignment-based score that is more flexible and biologically relevant than traditional language modeling metrics. Our generative model, GSM, produces high alignment scores from annotation-only prompts with a BERT-like generation scheme. Of particular note, many GSM hallucinations return statistically significant BLAST hits, where enrichment analysis shows properties matching the annotation prompt even when the ground truth haslowsequence identity to theentiretraining set. Overall, the Annotation Vocabulary toolbox presents a promising pathway to replace traditional tokens with members of ontologies and knowledge graphs, enhancing transformer models in specific domains. The concise, accurate, and efficient descriptions of proteins by the Annotation Vocabulary offers a novel way to build numerical representations of proteins for protein annotation and design.
MRI signatures of cortical microstructure in human development align with oligodendrocyte cell-type expression
Authors: Genc Sila , Ball Gareth , Chamberland Maxime , Raven Erika P , Tax Chantal MW , Ward Isobel , Yang Joseph Yuan-Mou , Palombo Marco , Jones Derek K
Published: July 2024

Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss with age. However, the underlying cellular mechanisms remain elusive with conventional neuroimaging. Recent advances in MRI hardware and new biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. This study used ultra-strong gradient MRI to obtain high-resolution, in vivo estimates of cortical neurite and soma microstructure in sample of typically developing children and adolescents. Cortical neurite signal fraction, attributed to neuronal and glial processes, increased with age (mean R2fneurite=.53, p<3.3e-11, 11.91% increase over age), while apparent soma radius decreased (mean R2Rsoma=.48, p<4.4e-10, 1% decrease over age) across domain-specific networks. To complement these findings, developmental patterns of cortical gene expression in two independent post-mortem databases were analysed. This revealed increased expression of genes expressed in oligodendrocytes, and excitatory neurons, alongside a relative decrease in expression of genes expressed in astrocyte, microglia and endothelial cell-types. Age-related genes were significantly enriched in cortical oligodendrocytes, oligodendrocyte progenitors and Layer 5-6 neurons (pFDR<.001) and prominently expressed in adolescence and young adulthood. The spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes suggest that ongoing cortical myelination processes contribute to adolescent cortical development. These findings highlight the role of intra-cortical myelination in cortical maturation during adolescence and into adulthood.
Temperature drives seagrass recovery across the Western North Atlantic
Authors: Smulders Fee O. H. , Campbell Justin E. , Altieri Andrew H. , Armitage Anna R. , Bakker Elisabeth S. , Barry Savanna C. , Becker S. Tatiana , Bethel Enrique , Douglass James G. , van Duijnhoven Hannah J. , de Fouw Jimmy , Frazer Thomas K. , Glazner Rachael , Goeke Janelle A. , Gort Gerrit , Heck Kenneth L. , Kramer Olivier A. A. , van de Leemput Ingrid A. , Manuel Sarah A. , Martin Charles W. , Martinez López Isis G. , McDonald Ashley M. , Munson Calvin J. , O’Shea Owen R. , Paul Valerie J. , Reynolds Laura K. , Rhoades O. Kennedy , Rodriguez Bravo Lucia M. , Sang Amanda , Sawall Yvonne , Smith Khalil , Thompson Jamie E. , van Tussenbroek Brigitta , Wied William L. , Christianen Marjolijn J. A.
Published: July 2024

Climate-driven shifts in herbivores, temperature and nutrient runoff threaten coastal ecosystem resilience. However, our understanding of ecological resilience, particularly for foundation species, remains limited due to a rarity of field experiments that are conducted across appropriate spatial and temporal scales and that investigate multiple stressors. This study aimed to evaluate the resilience of a widespread tropical marine plant (turtlegrass) to disturbances across its geographic range and how this is impacted by environmental gradients in (a)biotic factors. We assessed the resilience (i.e. recovery) of turtlegrass to a simulated disturbance (complete above- and belowground biomass removal) over a year. Contrary to temperate studies, higher temperature generally enhanced seagrass recovery. While nutrients and light availability had minimal impact, combined high levels of nutrients and herbivore grazing (meso and megaherbivore) reduced aboveground recovery. Our results suggest that the resilience of some tropical species, especially in cooler subtropical waters, may initially increase with warming.
A lipid nanoparticle-mRNA vaccine provides potent immunogenicity and protection againstMycobacterium tuberculosis
Authors: Lukeman Hannah , Al-Wassiti Hareth , Fabb Stewart A. , Lim Leonard , Wang Trixie , Britton Warwick J. , Steain Megan , Pouton Colin W. , Triccas James A. , Counoupas Claudio
Published: July 2024

Mycobacterium tuberculosisremains the largest infectious cause of mortality worldwide, even with over a century of widespread administration of the only licensed tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG). mRNA technology remains an underexplored approach for combating chronic bacterial infections such as TB. We have developed a lipid nanoparticle (LNP)-mRNA vaccine encoding for a fusion protein of two immunogenic TB antigens, termed mRNACV2. In C57BL/6 mice intramuscularly vaccinated with mRNACV2, high frequencies of polyfunctional, antigen-specific Th1 CD4+T cells were observed in the blood and lungs, which was associated with the rapid recruitment of both innate and adaptive immune cells to lymph nodes draining the site of immunisation. mRNACV2vaccination provided significant pulmonary protection inM. tuberculosis-infected mice, reducing bacterial load and inflammatory infiltration in the lungs. As BCG is widely administered in infants in TB endemic countries, new TB vaccines should be able to boost the effects of BCG. Importantly, mRNACV2enhanced immune responses and long-term protection when used to boost BCG-primed mice. These findings, which provide the first report of a highly protective LNP-mRNA vaccine for TB, highlight the potential of the LNP-mRNA platform for TB control and support further research to facilitate translation to humans.
Development of an Organ-on-a-Chip for Correlative Microscopy: Visualizing Early Osteogenesis in 3D with High Resolution
Authors: Schaart Judith M. , Wasserberg Dorothee , Eufrásio Cruz Marcos A. , Lindert Mariska Kea-te , van der Meijden Robin H.M. , Roverts Rona , Debera Nataliya D. , Lu Minh Phu , Rouwkema Jeroen , Nijhuis Wouter H. , van der Meer Andries D. , Jonkheijm Pascal , Sommerdijk Nico , Akiva Anat
Published: July 2024

Organs-on-a-chip are of increasing interest for studying tissue development in health and disease. In the past years, platforms have been developed to analyze developmental biological processes by light microscopy and biochemical assays. While these show great potential for pharmaceutical applications, retrieving ultrastructural information about microtissues remains challenging. In this study, an organ-on-a-chip is presented that is suitable for analysis by correlative light and electron microscopy. Using osteogenic cultures in which the cells and deposited collagen matrix align between pillars, the applicability of this platform for high-resolution, longitudinal monitoring of the microtissue development during multiple weeks with 3D live fluorescence microscopy is shown. The analysis of complete microtissues showed the development of two distinct actin patterns during differentiation. Furthermore, intact microtissues were extracted and cryo-fixed by high-pressure freezing, to enable processing for volume electron microscopy. The region of interest for electron microscopy was selected based on the fluorescence images and the resulting FIB/SEM image stack shows ultrastructural information about the cellular organization, collagen alignment, and mineralization in the cultures. The platform developed in this study shows great potential for increasing our understanding of processes underlying structural organization of tissues in health and disease, by allowing ultrastructural analysis of tissues during development.

Table of Contents

An organ-on-a-chip is presented that is suitable for high-resolution fluorescence microscopy over multiple weeks and from which intact samples can be extracted for analysis by volume electron microscopy. A case-study with osteogenically differentiated microtissues showed the development of two types of actin patterns during differentiation. Subsequent electron microscopy showed the presence of aligned cells and collagen, as well as mineral deposition.
Flavor-independent yield of high-
pT
hadrons from nuclear collisions
Authors: Kopeliovich B. Z. , Nemchik J.
Published: July 2024

Data on high-pT hadron production in heavy ion collisions at Feynman xF=0 indicate at universality of the observed nuclear suppression. Our analysis of the production mechanisms demonstrates important role of the color transparency effects which make the survival probability of a quark-antiquark dipole independent of the quark flavor, provided that the hadron wave function is formed outside the medium. The latter condition imposes restrictions on the range of pT, which should be sufficiently high to make the nuclear suppression universal. We also found that the in-medium broadening rate q^ (frequently called transport coefficient) significantly depends on the quark flavor, diminishing for heavy quarks.

Published by the American Physical Society
2024
General backreaction force of cosmological bubble expansion
Authors: Wang Jun-Chen , Yuwen Zi-Yan , Hao Yu-Shi , Wang Shao-Jiang
Published: July 2024

The gravitational-wave energy-density spectra from cosmological first-order phase transitions crucially depend on the terminal wall velocity of asymptotic bubble expansion when the driving force from the effective potential difference is gradually balanced by the backreaction force from the thermal plasma. Much attention has previously focused on the backreaction force acting on the bubble wall alone but overlooked the backreaction forces on the sound shell and shock-wave front, if any, which have been both numerically and analytically accomplished in our previous studies but only for a bag equation of state. In this paper, we will generalize the backreaction force on bubble expansion beyond the simple bag model.

Published by the American Physical Society
2024
Using a research-based assessment instrument to explore undergraduate students’ proficiencies around measurement uncertainty in physics lab contexts
Authors: Geschwind Gayle , Vignal Michael , Caballero Marcos D. , Lewandowski H. J.
Published: July 2024

Concepts and practices surrounding measurement uncertainty are vital knowledge for physicists and are often emphasized in undergraduate physics laboratory courses. We have previously developed a research-based assessment instrument—the Survey of Physics Reasoning on Uncertainty Concepts in Experiments (SPRUCE)—to examine student proficiency with measurement uncertainty along a variety of axes, including sources of uncertainty, handling of uncertainty, and distributions and repeated measurements. We present here initial results from the assessment representing over 1500 students from 20 institutions. We analyze students’ performance pre- and postinstruction in lab courses and examine how instruction impacts students with different majors and gender. We find that students typically excel in certain areas, such as reporting the mean of a distribution as their result, while they struggle in other areas, such as comparing measurements with uncertainty and correctly propagating errors using formulas. Additionally, we find that the importance that an instructor places in certain areas of measurement uncertainty is uncorrelated with student performance in those areas.

Published by the American Physical Society
2024
Provably Trainable Rotationally Equivariant Quantum Machine Learning
Authors: West Maxwell T. , Heredge Jamie , Sevior Martin , Usman Muhammad
Published: July 2024

Exploiting the power of quantum computation to realize superior machine learning algorithms has been a major research focus of recent years, but the prospects of quantum machine learning (QML) remain dampened by considerable technical challenges. A particularly significant issue is that generic QML models suffer from so-called barren plateaus in their training landscapes—large regions where cost function gradients vanish exponentially in the number of qubits employed, rendering large models effectively untrainable. A leading strategy for combating this effect is to build problem-specific models that take into account the symmetries of their data in order to focus on a smaller, relevant subset of Hilbert space. In this work, we introduce a family of rotationally equivariant QML models built upon the quantum Fourier transform, and leverage recent insights from the Lie-algebraic study of QML models to prove that (a subset of) our models do not exhibit barren plateaus. In addition to our analytical results we numerically test our rotationally equivariant models on a dataset of simulated scanning tunneling microscope images of phosphorus impurities in silicon, where rotational symmetry naturally arises, and find that they dramatically outperform their generic counterparts in practice.

Published by the American Physical Society
2024