bluuebunny/crossref_metadata_2025 huggingface dataset:
Aperiodic EEG and 7T MRSI evidence for maturation of E/I balance supporting the development of working memory through adolescence
Authors: McKeon Shane D. , Perica Maria I. , Parr Ashley C. , Calabro Finnegan J. , Foran Will , Hetherington Hoby , Moon Chan-Hong , Luna Beatriz
Published: September 2023

Postmortem animal and human models suggest changes through adolescence in aspects of excitatory glutamatergic and inhibitory GABAergic function (E/I) in prefrontal cortex (PFC) suggestive of critical period plasticity at a time of significant cognitive development. Recently, using high field 7T Magnetic Resonance Spectroscopic Imaging (MRSI), we foundin vivoevidence for increases in PFC glutamate/GABA balance through adolescence into adulthood. We now extend these MRSI findings by investigating, in the same 164 10– 32-year-old participants, its correspondence with EEG aperiodic activity, an independent measure of E/I balance elucidating changes in neural activity. Results showed decreases in PFC aperiodic activity from adolescence to adulthood, that were associated with MRSI measures of glutamate/GABA balance as well as mediating the association between age and EEG aperiodic activity. Further, changes in aperiodic activity predicted performance on a working memory task, indicating a role for E/I based changes in PFC signaling mechanisms in supporting maturation of cognitive control. Taken together, these results suggest that PFC is undergoing critical period plasticity through adolescence evident in both neurotransmitter and neural function that supports cognitive development.
Periodic shifts in viral load increase risk of spillover from bats
Authors: Lunn Tamika J. , Borremans Benny , Jones Devin N. , Kessler Maureen K. , Dale Adrienne S. , Yinda Kwe C. , Ruiz-Aravena Manuel , Falvo Caylee A , Crowley Dan , Lloyd-Smith James O. , Munster Vincent J. , Eby Peggy , McCallum Hamish , Hudson Peter , Restif Olivier , McGuire Liam P. , Smith Ina L. ,   Bat One Health Group, Plowright Raina K. , Peel Alison J.
Published: September 2023

Prediction and management of zoonotic pathogen spillover requires an understanding of infection dynamics within reservoir host populations. Transmission risk is often assessed using prevalence of infected hosts, with infection status based on the presence of genomic material. However, detection of viral genomic material alone does not necessarily indicate the presence of infectious virus, which could decouple prevalence from transmission risk. We undertook a multi-faceted investigation of Hendra virus shedding inPteropusbats, combining insights from virus isolation, viral load proxies, viral prevalence, and longitudinal patterns of shedding, from 6,151 samples. In addition to seasonal and interannual fluctuation in prevalence, we found evidence for periodic shifts in the distribution of viral loads. The proportion of bats shedding high viral loads was higher during peak prevalence periods during which spillover events were observed, and lower during non-peak periods when there were no spillovers. We suggest that prolonged periods of low viral load and low prevalence reflect prolonged shedding of non-infectious RNA, or viral loads that are insufficient or unlikely to overcome dose barriers to spillover infection. These findings show that incorporating viral load (or proxies of viral load) into longitudinal studies of virus excretion will better inform predictions of spillover risk than prevalence alone.

Significance statement

We present a comprehensive analysis of a high-profile bat-virus system (Hendra virus in Australian flying-foxes) to demonstrate that both prevalence and viral loads can shift systematically over time, resulting in concentrated periods of increased spillover risk when prevalence and viral loads are high. We further suggest that prolonged periods of low-prevalence, low-load shedding may not reflect excretion of infectious virus, resolving the outstanding puzzle of why spillovers have not been observed during periods of low off-season prevalence in subtropical Australia, or more frequently in tropical Australia despite consistent low-prevalence shedding. The consideration of viral loads (or proxies of viral load) along with prevalence may improve risk inference from longitudinal surveys of zoonotic viruses across wildlife reservoir hosts.
Topographic Axes of Wiring Space Converge to Genetic Topography in Shaping Human Cortical Layout
Authors: Li Deying , Wang Yufan , Ma Liang , Wang Yaping , Cheng Luqi , Liu Yinan , Shi Weiyang , Lu Yuheng , Wang Haiyan , Gao Chaohong , Erichsen Camilla T. , Zhang Yu , Yang Zhengyi , Eickhoff Simon B , Chen Chi-Hua , Jiang Tianzi , Chu Congying , Fan Lingzhong
Published: September 2023

Genetic information is involved in the gradual emergence of cortical areas since the neural tube begins to form, shaping the heterogeneous functions of neural circuits in the human brain. Informed by invasive tract-tracing measurements, the cortex exhibits marked interareal variation in connectivity profiles to reveal the heterogeneity across cortical areas. However, it remains unclear about the organizing principles possibly shared by genetics and cortical wiring to manifest the spatial heterogeneity across the cortex. Instead of considering a complex one-to-one mapping between genetic coding and interareal connectivity, we hypothesized the existence of a more efficient way that the organizing principles are embedded in genetic profiles to underpin the cortical wiring space. Leveraging on the vertex-wise tractography in diffusion-weighted MRI, we derived the global connectopies to reliably index the organizing principles of interareal connectivity variation in a low-dimensional space, which specifically captured three dominant topographic patterns along the dorsoventral, rostrocaudal, and mediolateral axes of the cortex. More importantly, we demonstrated that the global connectopies converge to the gradients of vertex-by-vertex genetic correlation matrix on the phenotype of cortical morphology and the cortex-wide spatiomolecular gradients. By diving into the genetic profiles, we found the critical role of genes scaffolding the global connectopies were related to brain morphogenesis and enriched in radial glial cells before birth and excitatory neurons after birth. Taken together, our findings demonstrated the existence of a genetically determined space to encode the interareal connectivity variation, which may give new insights into the links between cortical connections and arealization.
Effects of Savoring Meditation on Positive Emotions and Pain-Related Brain Function: A Mechanistic Randomized Controlled Trial in People With Rheumatoid Arthritis
Authors: Finan Patrick H. , Hunt Carly , Keaser Michael L. , Smith Katie , Lerman Sheera , Bingham Clifton O. , Barrett Frederick , Garland Eric L. , Zeidan Fadel , Seminowicz David A.
Published: September 2023

Positive emotions are a promising target for intervention in chronic pain, but mixed findings across trials to date suggest that existing interventions may not be optimized to efficiently engage the target. The aim of the current mechanistic randomized controlled trial was to test the effects of a single skill positive emotion-enhancing intervention called Savoring Meditation on pain-related neural and behavioral targets in patients with rheumatoid arthritis (RA). Participants included 44 patients with a physician-confirmed diagnosis of RA (n=29 included in fMRI analyses), who were randomized to either Savoring Meditation or a Slow Breathing control. Both meditation interventions were brief (four 20-minute sessions). Self-report measures were collected pre- and post-intervention. An fMRI task was conducted at post-intervention, during which participants practiced the meditation technique on which they had been trained while exposed to non-painful and painful thermal stimuli. Relative to Slow Breathing, Savoring significantly reduced experimental pain intensity ratings relative to rest (p<.001), increased cerebral blood flow in the ventromedial prefrontal cortex (vmPFC) and increased connectivity between the vmPFC and caudate during noxious thermal stimulation (z=2.3 voxelwise, FDR cluster corrected p=0.05). Participants in the Savoring condition also reported significantly increased positive emotions (ps<.05) and reduced anhedonic symptoms (p<.01) from pre-to post-intervention. These findings suggest that that Savoring recruits reward-enhancing corticostriatal circuits in the face of pain, and future work should extend these findings to evaluate if these mechanisms of Savoring are associated with improved clinical pain outcomes in diverse patient populations.
Stereotypic persistent B cell receptor clonotypes in Alzheimer’s Disease
Authors: Yang Hyunji , Kim Namphil , Lee Yonghee , Yoo Duck Kyun , Choi Jinny , Kim Ki Woong , Bae Jong Bin , Han Ji Won , Kwon Sunghoon , Chung Junho
Published: September 2023

We constructed B cell receptor (BCR) repertoiresin silicousing peripheral blood (PB) samples collected from 44 Alzheimer’s Disease (AD) patients at baseline and 37 patients at follow-up. For the control group (CG), we used BCR repertoire data from the chronologically collected PB samples of 55 healthy volunteers vaccinated with SARS-CoV-2 mRNA. The AD patients shared 3,983 stereotypic non-naïve BCR clonotypes not found in CG, and their degree of overlap between patient pairs were significantly higher than that of CG pairs, even with the SARS-CoV-2 spike protein triggering a concerted BCR response. Twenty stereotypic non-naïve AD patient-specific BCR clonotypes co-existed in more than four patients and persisted throughout two sampling points. One of these BCR clonotypes encoded an antibody reactive to the Aβ42 peptide. Our findings strongly suggest that AD patients are exposed to common (auto)antigens associated with disease pathology, and their BCR repertoires show unique signatures with diagnostic potential.
Predictive Models and Impact of Interfacial Contacts and Amino Acids on Protein-protein Binding Affinity
Authors: Yi Carey Huang , Taylor Mitchell Lee , Ziebarth Jesse , Wang Yongmei
Published: September 2023

Protein-protein interactions (PPIs) play a central role in nearly all cellular processes and that require proteins interact with sufficient binding affinity (BA) to form stable or transient complexes. Despite advancements in our understanding of protein-protein binding, much remains unknown about the interfacial region and its association with BA. Here we investigate the correlation of residue and atomic contacts of different types with BA and reveal the impact of the specific amino acids at the binding interface on BA. We create a series of linear regression (LR) models incorporating different contact features at both residue and atomic levels and examine how different methods of identifying and characterizing these properties impact the performance of these models. Particularly, we introduce a new and simple approach to predict BA based on the quantities of specific amino acids in contacts at the protein-protein interface. We show that the interfacial numbers of amino acids can be used to produce models with consistently good performance across different datasets, indicating the importance of the identities of interfacial amino acids in underlying the strength of BA. When trained on a diverse set of 141 complexes from two benchmark datasets, the best performing BA model (Pearson correlation coefficient R=0.68) was generated with an explicit linear equation involving six amino acids (tyrosine, glycine, serine, arginine, valine, and isoleucine). Tyrosine, in particular, was identified as the key amino acid in the quantitative link between specific amino acids and BA, as it had the strongest correlation with BA and was consistently identified as the most important amino acid in feature importance studies. Glycine, serine, and arginine were identified as the next three most important amino acids in predicting BA. The results from this study further our understanding of the importance of specific amino acids in PPIs and can be used to make improved predictions of BA, giving them implications for drug design and screening in the pharmaceutical industry.
Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI
Authors: Schwaderlapp Niels , Paschen Enya , LeVan Pierre , von Elverfeldt Dominik , Haas Carola
Published: September 2023

Background

Electrical neurostimulation is a potentially effective therapy in epilepsy but the optimal approach is not yet clear. The parameter space is wide and the effects of different stimulations are not immediately obvious. Functional MRI (fMRI) can reveal which brain areas are affected by stimulation and help understand the induced effects. However, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. Preclinical stimulation-fMRI studies can provide predictive value and help identify optimal neurostimulation parameters.

Objective

To systematically investigate the brain-wide responses to hippocampal electrical stimulations in a mouse model of mesial temporal lobe epilepsy (mTLE) using fMRI.

Methods

We applied electrical stimulation in the intrahippocampal kainate mouse model of mTLE and assessed the effect of different stimulation amplitudes (80-230 µA) and frequencies (1-100 Hz). In addition, the effect of prolonged 1 Hz stimulation was explored. Saline-injected mice served as controls.

Results

Varying the stimulation amplitudes had little effect on the resulting activation patterns. Low frequency stimulation led to a local response at the stimulation site only, whereas high frequency resulted in a spread of activation from the hippocampal formation into cortical and frontal areas. Prolonged low frequency stimulation reduced excitability.

Conclusions

While the amplitude parameter offers little opportunity to vary the outcome, the frequency represented the key parameter and determined whether the induced activation remained local or spread across the brain. This is in line with the few DBS-fMRI results obtained in epilepsy patients demonstrating the translational value of fMRI.
Learning site-invariant features of connectomes to harmonize complex network measures
Authors: Newlin Nancy R. , Kanakaraj Praitayini , Li Thomas , Pechman Kimberly , Archer Derek , Jefferson Angela ,   The BIOCARD Study Team, Landman Bennett , Moyer Daniel
Published: September 2023

Multi-site diffusion MRI data is often acquired on different scanners and with distinct protocols. Differences in hardware and acquisition result in data that contains site dependent information, which confounds connectome analyses aiming to combine such multi-site data. We propose a data-driven solution that isolates site-invariant information whilst maintaining relevant features of the connectome. We construct a latent space that is uncorrelated with the imaging site and highly correlated with patient age and a connectome summary measure. Here, we focus on network modularity. The proposed model is a conditional, variational autoencoder with three additional prediction tasks: one for patient age, and two for modularity trained exclusively on data from each site. This model enables us to 1) isolate site-invariant biological features, learn site context, and 3) re-inject site context and project biological features to desired site domains. We tested these hypotheses by projecting 77 connectomes from two studies and protocols (Vanderbilt Memory and Aging Project (VMAP) and Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) to a common site. We find that the resulting dataset of modularity has statistically similar means (p-value <0.05) across sites. In addition, we fit a linear model to the joint dataset and find that positive correlations between age and modularity were preserved.
An efficient peptide ligase engineered from a bamboo asparaginyl endopeptidase
Authors: Wang Xin-Bo , Zhang Cong-Hui , Zhang Teng , Li Hao-Zheng , Liu Ya-Li , Xu Zeng-Guang , Lei Gang , Cai Chun-Ju , Guo Zhan-Yun
Published: September 2023

In recent years, a few asparaginyl endopeptidases (AEPs) from certain higher plants have been identified as efficient peptide ligases with wide applications in protein labeling and cyclic peptide synthesis. Recently, we developed a NanoLuc Binary Technology (NanoBiT)-based peptide ligase activity assay to identify more AEP-type peptide ligases. Herein, we screened 61 bamboo species from 16 genera using this assay and detected AEP-type peptide ligase activity in the crude extract of all tested bamboo leaves. From a popular bamboo species,Bambusa multiplex, we identified a full-length AEP-type peptide ligase candidate (BmAEP1) via transcriptomic sequencing. After its zymogen was overexpressed inEscherichia coliand self-activatedin vitro, BmAEP1 displayed high peptide ligase activity, but with considerable hydrolysis activity. After site-directed mutagenesis of its ligase activity determinants, the mutant zymogen of [G238V]BmAEP1 was normally overexpressed inE. coli, but failed to activate itself. To solve this problem, we developed a novel protease-assisted activation approach in which trypsin was used to cleave the mutant zymogen and was then conveniently removed via an ion-exchange chromatography. After the non-covalently bound cap domain was dissociated from the catalytic core domain under acidic conditions, the recombinant [G238V]BmAEP1 displayed high peptide ligase activity with much lower hydrolysis activity, and could efficiently catalyze inter-molecular protein ligation and intra-molecular peptide cyclization. Thus, the engineered bamboo-derived peptide ligase represents a novel tool for protein labeling and cyclic peptide synthesis.
Body Maps of Uncertainty and Surprise in Musical Chord Progression and its individual differences in Depression and Body Perception Sensitivity
Authors: Daikoku Tatsuya , Tanaka Masaki , Yamawaki Shigeto
Published: September 2023

Music has profoundly shaped the human experience across diverse cultures and generations, yet the mechanisms that it influences our minds and bodies remain elusive. This study examined how the perception of music chords elicits bodily sensations and emotions through predictive processing of the brain. By deploying body-mapping tests and emotional evaluations on 527 participants exposed to chord progressions, we unveil the intricate interplay between musical uncertainty, prediction error, and temporal dynamics in eliciting specific bodily sensations and emotions. Our results demonstrated that the chord progressions characterized by low uncertainty coupled with high surprise or predictability evoke bodily sensations closely associated with interoception including the cardiac and abdominal regions. Notably, these sensations are associated with aesthetic appreciation, with the intensity of cardiac sensations being positively correlated with valence in chord progressions with low uncertainty and high surprise. These results highlight the pivotal role of uncertainty and prediction error in shaping emotional responses and also suggest a hypothesis for emotion generation through predictive processing and sound embodiment. This study offers a tantalizing glimpse into the potential nexus between interoception by music and mental well-being, underscoring the importance of recognizing diverse forms of musical pleasure and their unique effects on our minds and bodies.
Cisplatin promotes pyroptosis of gastric cancer cells by activating GSDME
Authors: Jiang Xianglai , Wang Yongfeng , Wang Chenyu , Ma Haizhong , Yu Miao , Cai Hui
Published: September 2023

According to studies, numerous chemotherapeutic drugs can facilitate programmed cell death via pyroptosis. Clarifying the mechanism by which cisplatin kills gastric cancer cells is crucial for enhancing gastric cancer’s sensitivity to chemotherapy and elucidating the mechanism of drug resistance in gastric cancer. The differentially expressed genes following cisplatin treatment were identified using second-generation sequencing technology. Bioinformatics was used to investigate the functional enrichment of differentially expressed genes and core genes in tumor cells killed by cisplatin. Cox regression analyses were used to examine the pyroptosis core genes that worked as independent prognostic factors for patients with gastric cancer. The expression of core genes in gastric cancer cells was silenced by siRNA, and the changes in the proliferation of gastric cancer cells were observed. The expression of related genes and the survival of gastric cancer cells after the addition of cisplatin were observed. The second-generation sequencing, RT-PCR and Western blotting showed that the pyroptosis core gene was significantly highly expressed after cisplatin treatment. The results of differential gene enrichment of cisplatin-treated gastric cancer cells showed that differential genes were mainly concentrated in biological processes and signaling pathways related to pyroptosis. GSDME protein is highly expressed after cisplatin treatment, and it is also a poor prognostic factor for gastric cancer patients and an independent prognostic factor. After the same dose of cisplatin treatment, the survival rate of siGSDME gastric cancer cells was significantly higher than that of GSDME regular expression gastric cancer cells. After acting on gastric cancer cells, cisplatin triggers pyroptosis by stimulating the activation of genes such as GSDME, resulting in the death of gastric cancer cells. GSDME is an independent prognostic factor for gastric cancer patients and is significantly linked with a shorter OS. In gastric cancer cells, silencing GSDME can substantially reduce cisplatin’s cytotoxicity.
Prognostic models predicting transition to psychotic disorder using blood-based biomarkers: a systematic review and critical appraisal
Authors: Byrne Jonah F. , Mongan David , Murphy Jennifer , Healy Colm , Fӧcking Melanie , Cannon Mary , Cotter David R.
Published: September 2023

Background

Accumulating evidence suggests individuals with psychotic disorder show abnormalities in metabolic and inflammatory processes. Recently, several studies have employed blood-based predictors in models predicting transition to psychotic disorder in risk-enriched populations. A systematic review of the performance and methodology of prognostic models using blood-based biomarkers in the prediction of psychotic disorder from risk-enriched populations is warranted.

Methods

Databases (PubMed, EMBASE and PsycINFO) were searched for eligible texts from 1998 to 15/05/2023 which detailed model development or validation studies. The checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) was used to guide data extraction from eligible texts and the Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess risk of bias and applicability of the studies. A narrative synthesis of included studies was performed.

Results

17 eligible studies were identified: 16 eligible model development studies and one eligible model validation study. A wide range of biomarkers were assessed including nucleic acids, proteins, metabolites and lipids. The range of C-index (area under the curve) estimates reported for the models was 0.67-1.00. No studies assessed model calibration. According to PROBAST criteria, all studies were at high risk of bias in the analysis domain.

Discussion

While a wide range of potentially predictive biomarkers were identified in the included studies, most studies did not account for overfitting in model performance estimates, no studies assessed calibration, and all models were at high risk of bias according to PROBAST criteria. External validation of the models is needed to provide more accurate estimates of their performance. Future studies which follow the latest available methodological and reporting guidelines and adopt strategies to accommodate required sample sizes for model development or validation will clarify the value of including blood-based biomarkers in models predicting psychosis.
Prevalence and predictors of self-medication for COVID-19 among slum dwellers in Jinja City, Uganda
Authors: Nakito Prossy , Kisakye Angela N. , Walekhwa Abel Wilson , Tumukunde Gloria , Mutesi Charity , Muhumuza Nicholas , Nyamor Carolyne , Musoke David , Musinguzi Geofrey , Byonanebye Dathan M.
Published: September 2023

Introduction

Self-medication is a serious public health concern globally and is more prevalent in underserved populations, especially in resource limited settings. The lack of effective treatment for COVID-19 and poor access to healthcare were drivers of self-medication. We investigated the prevalence and associated factors with self-medication for COVID-19 among slum dwellers in a Ugandan slum.

Methods and materials

We conducted a cross-sectional study using randomly selected respondents from slums in Jinja city, Uganda. Households were proportionately selected from the slums and one participant with confirmed or self-reported COVID-19 during 2021 was recruited. Poisson regression with robust standard errors was used to determine the crude (CPR) and adjusted prevalence ratios (APR) (95% CI) of factors associated with self-medication. Variables were selected apriori and backward elimination approach used to fit the final multivariate model in which variables with aP≤ 0.05 were included.

Results

Overall, 517 respondents were recruited, median age (years) was 31 (26-40), and 59% were male. The prevalence of self-medication for COVID-19 was 87.23% (451/517), 95% CI: [84.00%-90.00%] and 56% knew that self-medication was dangerous. Age≥50 years, compared to 20-29 years [APR: 1.12, 95% CI:1.05, 1.20], being female [APR: 1.07, 95% CI: 1.02, 1.13], minor [APR: 1.62, 95% CI: 1.25, 2.11], and severe symptoms [APR: 1.51, 95% CI: 1.16, 1.96], access to internet [APR: 1.13, 95% CI: 1.07, 1.20]. Having medical insurance [APR: 0.63, 95% CI: 0.46, 0.87] and awareness about laws against self-medication [APR: 0.89, 95% CI: 0.81, 0.97] were associated with a lower risk of self-medication.

Conclusion

The prevalence of self-medication in slum dwellers in Uganda was high despite high awareness about its dangers. Self-medication was common in those with severe symptoms and those access to internet. There is need to control infodemia and improve health insurance cover in informal settlements within Uganda.
Local G-quadruplexes are not a major determinant of altered gene expression in BLM-deficient cells
Authors: Lobo Thamar Jessurun , Lansdorp Peter M , Guryev Victor
Published: September 2023

Mutations in theBlmgene can cause Bloom Syndrome, a genetic disorder characterized by genome instability and cancer predisposition.Blmencodes a helicase which was reported to resolve G-quadruplex DNA structuresin vitro. The G-quadruplex resolving activity of the BLM helicase has been previously implicated in altering gene expression. However, the exact mechanisms of how G-quadruplex structures may affect gene expression remain to be elucidated. We employed experimentally defined G-quadruplex forming DNA sequences and generated transcriptomes for several Bloom Syndrome patient-derived cell lines and BLM-deficient mouse embryonic stem cells to further investigate the effect of G-quadruplexes on gene expression. Our results do not support the previous findings that G-quadruplexes located within a gene play a major role in altering its expression in BLM-deficient cells. We found concerted large-scale changes in transcript abundance, splicing, nucleosome occupancy, and phasing, that cannot be linked to the local presence of G-quadruplex sequences in either gene bodies or promotors. The investigation of genomic features associated with large-scale differences in nucleosome density highlights the rDNA locus and active enhancers as the most strongly affected regions. We hypothesize that global changes in chromatin structure rather than local G4s might mediate the transcriptome changes in the absence of BLM.
NSUN5 is essential for proper Hippo signaling in mouse preimplantation development
Authors: Liu Dan , Yamamoto Takuto , Minami Naojiro , Honda Shinnosuke , Ikeda Shuntaro
Published: September 2023

NOL1/NOP2/Sun domain family, member 5 (NSUN5) is an enzyme belonging to the 5-methylcytosine (m5C) writer family that modifies rRNA and mRNA. By re-analyzing published RNA-sequencing data, we found thatNsun5expression was increased at the 2-cell stage during mouse preimplantation development. It has been reported that m5C regulates the stability of rRNA and mRNA. Therefore, NSUN5 may affect the expression of genes required for the development and differentiation of early mouse embryos via its role in modifying RNA. The Hippo signaling pathway has been identified as a critical regulator of the segregation of inner cell mass and trophectoderm lineages during mouse embryogenesis. According to these findings, we hypothesized that NSUN5 controls cell differentiation by regulating the expression of components of the Hippo signaling pathway in mouse early embryos. UsingNsun5-specific small interfering RNAs, we efficiently knocked downNsun5expression in mouse preimplantation embryos, resulting in impairments in early development, including reduced blastocyst formation, smaller size, and impaired hatching from the zona pellucida.Nsun5depletion also led to decreased cell numbers, suggesting impaired cell proliferation. Furthermore,Nsun5knockdown embryos exhibited reduced yes-associated protein 1 (YAP1) nuclear translocation during the morula stage, potentially affecting cell differentiation. The imbalance in pluripotent and trophectoderm lineages was evident with a significant reduction in the ratio of CDX2-positive cells to OCT4-positive cells.Nsun5depletion impacted the Hippo signaling pathway, increasing the expression of the key genesLats1andLats2during the morula stage. Our findings underscore the essential role ofNsun5in early embryonic development by affecting cell proliferation, YAP1 nuclear translocation, and the Hippo pathway. Understanding the roles ofNsun5in mouse early embryos will provide insights into complex regulatory networks in development, with implications for reproductive medicine and fertility research.
Thermal and Nutrient Stress Drove Permian-Triassic Marine Extinctions
Authors: Foster William J. , Frank Anja B. , Li Qijan , Danise Silvia , Wang Xia , Peckmann Jörn
Published: September 2023

The Permian-Triassic mass extinction coincides with extensive environmental changes (i.e., thermal stress, deoxygenation and potentially ocean acidification), but the primary drivers of extinction in them marine realm are currently unknown. To understand which factors caused extinctions, we quantitatively investigated the relationship between geochemical proxies and fossil record at the most intensively-studied locality for this event, the Meishan section, China. We found that δ18Oapatite(paleotemperature proxy) and δ114Cd (primary productivity proxy) best explain changes in species diversity and composition at Meishan’s paleoequatorial setting. These findings suggest that the physiological stresses induced by ocean warming and nutrient availability played a predominant role in driving equatorial marine extinctions during the Permian-Triassic event. This research enhances our understanding of the interplay between environmental changes and extinction dynamics during a past climate crisis.

One-Sentence Summary

Ocean warming and nutrient availability were key drivers of equatorial marine extinctions during the Permian-Triassic mass extinction.
CCG-1423-derived compounds reduce global RNA synthesis and inhibit transcriptional responses
Authors: Prajapati Bina , Sokolova Maria , Sidorenko Ekaterina , Kyriacou Mikael , Kyheröinen Salla , Vihervaara Anniina , Vartiainen Maria K.
Published: September 2023

Myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF), and thereby regulate cytoskeletal gene expression in response to actin dynamics. MRTFs have also been implicated in heat shock protein (hsp) transcription in fly ovaries, but the mechanisms remain unclear. Here we demonstrate that in mammalian cells, MRTFs are dispensable forhspgene induction. However, the widely used small molecule inhibitors of MRTF/SRF transcription pathway, derived from CCG-1423, efficiently inhibithspgene transcription in both fly and mammalian cells also in absence of MRTFs. Quantifying RNA synthesis and RNA polymerase distribution demonstrates that CCG-1423-derived compounds have a genome-wide effect on transcription. Indeed, tracking nascent transcription at nucleotide resolution reveals that CCG-1423-derived compounds reduce RNA polymerase II elongation, and severely dampen the transcriptional response to heat shock. The effects of CCG-1423-derived compounds therefore extend beyond the MRTF/SRF pathway into nascent transcription, opening novel opportunities for their use in transcription research.
Molecular control of cellulosic fin morphogenesis in ascidians
Authors: LANOIZELET Maxence , ELKHOURY YOUHANNA Christel , DARRAS SébasBen
Published: September 2023

The tunicates form a group of filter-feeding marine animals closely related to vertebrates. They share with them a number of features such as a notochord and a dorsal neural tube in the tadpole larvae of ascidians, one of the three groups that make tunicates. However, a number of typical chordate characters have been lost in different branches of tunicates, a diverse and fast-evolving phylum. Consequently, the tunic, a sort of exoskeleton made of extracellular material including cellulose secreted by the epidermis, is the unifying character defining the tunicate phylum. In the larva of ascidians, the tunic differenBates in the tail into a median fin (with dorsal and ventral extended blades) and a caudal fin. Here we have performed experiments in the ascidianPhallusia mammillatato address the molecular control of tunic 3D morphogenesis. We have demonstrated that the tail epidermis medio-lateral paaerning essenBal for peripheral nervous system specificaBon also controls tunic elongaBon into fins. More specifically, when tail epidermis midline idenBty was abolished by BMP signaling inhibiBon, or CRISPR/Cas9 inacBvaBon of the transcripBon factor coding genesMsxorKlf1/2/4/17, median fin did not form. We postulated that this geneBc program should regulate effectors of tunic secreBon. We thus analyzed the expression and regulaBon in different ascidian species of two genes acquired by horizontal gene transfer (HGT) from bacteria,CesAcoding for a cellulose synthase andGh6coding for a cellulase. Although we have uncovered an unexpected dynamic history of these genes in tunicates, and high levels of variability in gene expression and regulaBon among ascidians, we showed thatGh6has a regionalized expression in the epidermis, and that it is a regulator of caudal fin formaBon. Our study consBtutes an important step in the study of the integraBon of HGT-acquired genes into developmental networks, and a cellulose-based morphogenesis of extracellular material in animals.
Proteome partitioning constraints on long-term laboratory evolution
Authors: Mori Matteo , Patsalo Vadim , Williamson James R. , Scott Matthew
Published: September 2023

Adaptive laboratory evolution experiments provide a controlled context in which the dynamics of selection and adaptation can be followed in real-time at the single-nucleotide level1. And yet this precision introduces hundreds of degrees-of-freedom as genetic changes accrue in parallel lineages over generations2. On short timescales, physiological constraints have been leveraged to provide a coarse-grained view of bacterial gene expression characterized by a small set of phenomenological parameters3–5. Here, we ask whether this same framework, operating at a level between genotype and fitness, informs physiological changes that occur on evolutionary timescales. Using Lenski’s Ara-1 lineage adapted to growth in glucose minimal medium6, we find that the proteome is substantially remodeled over 40 000 generations. We apply our existing quantitative proteomics analysis to partition hundreds of expressed proteins into six sectors with shared metabolic function and physiological response4. To accommodate the increased growth rates in the evolved strains, expression of metabolic enzymes undergoes sector-specific adaptation to enable increased fluxes. We find that catabolic proteins adapt by increasing the total enzyme abundance, whereas anabolic and glycolytic proteins exhibit decreased free-enzyme pools. We propose that flux-dependent regulation7and substrate saturation8can account for the sector-specific remodeling.
In-vitroreconstitution of Herpes Simplex Virus 1 fusion identifies low pH as a fusion co-trigger
Authors: Ramirez J. Martin , Calderon-Zavala Ariana , Balaram Ariane , Heldwein Ekaterina E.
Published: September 2023

Membrane fusion mediated by Herpes Simplex virus 1 (HSV-1) is a complex, multi-protein process that is receptor-triggered and can occur both at the cell surface and in endosomes. To deconvolute this complexity, we reconstituted HSV-1 fusion with synthetic lipid vesiclesin vitro. Using this simplified, controllable system, we discovered that HSV-1 fusion required not only a cognate host receptor but also low pH. On the target membrane side, efficient fusion required cholesterol, negatively charged lipids found in the endosomal membranes, and an optimal balance of lipid order and disorder. On the virion side, the four HSV-1 entry glycoproteins gB, gD, gH, and gL were sufficient for fusion. We propose that low pH is a biologically relevant co-trigger for HSV-1 fusion. The dependence of fusion on low pH and endosomal lipids could explain why HSV-1 enters most cell types by endocytosis. We hypothesize that under neutral pH conditions, other, yet undefined, cellular factors may serve as fusion co-triggers. Thein-vitrofusion system established here can be employed to systematically investigate HSV-1-mediated membrane fusion.

IMPORTANCE

Herpes simplex virus 1 (HSV-1) causes life-long, incurable infections and diseases ranging from mucocutaneous lesions to fatal encephalitis. Fusion of viral and host membranes is a critical step in HSV-1 infection of target cells that requires multiple factors on both the viral and host sides. Due to this complexity, many fundamental questions remain unanswered, such as the viral and host factors that are necessary and sufficient for HSV-1-mediated membrane fusion and the nature of the fusion trigger. Here, we developed a simplifiedin-vitrofusion assay to examine the fusion requirements and identified low pH as a co-trigger for virus-mediated fusionin vitro.We hypothesize that low pH has a critical role in cell entry and, potentially, pathogenesis.
A cell atlas of the larvalAedes aegyptiventral nerve cord
Authors: Yin Chang , Morita Takeshi , Parrish Jay Z.
Published: September 2023

Mosquito-borne diseases account for nearly one million human deaths annually, yet we have a limited understanding of developmental events that influence host-seeking behavior and pathogen transmission in mosquitoes. Mosquito-borne pathogens are transmitted during blood meals, hence adult mosquito behavior and physiology have been intensely studied. However, events during larval development shape adult traits, larvae respond to many of the same sensory cues as adults, and larvae are susceptible to infection by many of the same disease-causing agents as adults. Hence, a better understanding of larval physiology will directly inform our understanding of physiological processes in adults. Here, we use single cell RNA sequencing (scRNA-seq) to provide a comprehensive view of cellular composition in theAedes aegyptilarval ventral nerve cord (VNC), a central hub of sensory inputs and motor outputs which additionally controls multiple aspects of larval physiology. We identify more than 35 VNC cell types defined in part by neurotransmitter and neuropeptide expression. We also explore diversity among monoaminergic and peptidergic neurons that likely control key elements of larval physiology and developmental timing, and identify neuroblasts and immature neurons, providing a view of neuronal differentiation in the VNC. Finally, we find that larval cell composition, number, and position are preserved in the adult abdominal VNC, suggesting studies of larval VNC form and function will likely directly inform our understanding adult mosquito physiology. Altogether, these studies provide a framework for targeted analysis of VNC development and neuronal function inAedeslarvae.
Peripheral insulin resistance attenuates cerebral glucose metabolism and impairs working memory in healthy adults
Authors: Deery Hamish A. , Liang Emma , Di Paolo Robert , Voigt Katharina , Murray Gerard , Siddiqui M. Navyaan , Egan Gary F. , Moran Chris , Jamadar Sharna D.
Published: September 2023

People with insulin resistance are at increased risk for cognitive decline. Insulin resistance has previously been considered primarily a condition of ageing but it is increasingly seen in younger adults. Here, we explore the question that changes in insulin function in early adulthood have both proximal effects, and moderate or even accelerate changes in cerebral metabolism in ageing. Thirty-six younger (mean 27.8 years) and 43 older (mean 75.5) participants completed a battery of tests, including blood sampling, cognitive assessment and a simultaneous PET/MR scan. Cortical thickness and cerebral metabolic rate of glucose were derived for 100 regions and 17 functional networks. Older adults had lower rates of regional cerebral glucose metabolism than younger adults across the brain even after adjusting for lower cortical thickness in older adults. In younger adults, higher insulin resistance was associated with attenuated rates of regional cerebral glucose metabolism, but this was not seen in older adults. The largest effects of insulin resistance in younger adults were in prefrontal, parietal and temporal regions; and in the control, salience ventral attention, default and somatomotor networks. Higher rates of network glucose metabolism were associated with lower reaction time and psychomotor speed. Higher levels of insulin resistance were associated with lower working memory. Our results underscore the importance of insulin sensitivity to brain health and cognitive function across the adult lifespan, even in early adulthood.

Significance Statement

We show that preventing insulin resistance in early adulthood is important for ensuring efficient fuel supply for the brain and the maintenance of cognitive health across the adult lifespan. Glucose is the primary source of energy for the brain. Decreased glucose metabolism in the brain due to clinically significant levels of insulin resistance is associated with cognitive impairment. Although sub-clinical levels of insulin resistance have also been associated with brain changes, their impact on cerebral metabolism in healthy individuals is unclear. We showed for the first time that – while older adults have lower rates of cerebral metabolism - peripheral insulin resistance attenuates cerebral metabolism more so in healthy younger than healthy older adults, and impairs working memory.
Person knowledge is independently encoded by allocentric and egocentric reference frames within separate brain systems
Authors: Chavez Robert S. , Guthrie Taylor D. , Kapustka Jack M.
Published: September 2023

Humans spontaneously infer information about others to perceive the similarity in behaviors and traits among people in our social environments. However, evaluating the similarity among people can be achieved through multiple frames of reference: other-to-other differences (allocentric similarity) or self-to-other differences (egocentric similarity), which are difficult to dissociate with behavioral measures alone. Here, we use functional magnetic resonance imaging to test whether the similarity of brain response patterns when thinking of others and the self is predicted by models of allocentric and egocentric similarity in the trait-judgments of well-acquainted peers from 20 independent groups of people (total N = 108; within-subject design). Results show that both allocentric and egocentric similarity during person representation are reflected in brain response similarity patterns when thinking of others but do so differentially and in non-overlapping brain systems. Specifically, allocentric similarity was positively related to brain similarity patterns in distributed regions involved in social cognition as well as in regions involved in general non-social spatial reference frame encoding. Egocentric similarity was inversely related to brain response similarity but only within dorsal regions of the medial prefrontal cortex and anterior cingulate, suggesting that activation within this region is important for dissociating selfrepresentation from that of similar others. These results suggest that the brain processes both kinds of reference frames independently to encode trait information about conspecifics that we use to represent person knowledge about other people within realworld social networks.
Medical students' perceptions of introducing medical terms in Arabic within a curriculum taught in English: a descriptive study
Authors: Tayem Yasin I. , Almarabheh Amer J.
Published: September 2023

Purpose

All colleges of medicine in the Gulf Cooperation Council (GCC) adopt English as a language of instructions. This study aimed to examine medical students' views on introducing medical terminology in Arabic within an English-based curriculum.

Design/methodology/approach

This descriptive study targeted preclinical second- and fourth-year students in the College of Medicine and Medical Sciences at the Arabian Gulf University, during the academic year 2022–2023 (n = 407). Within the pharmacology teaching material in unit I (second year) and unit VIII (fourth year), which are taught in English, students were provided with medical terms in Arabic. At the end of these two units, students' views were sought by using a self-administered questionnaire.

Findings

The number of respondents was 263 (response rate 64.1%: 22.2% males, 77.8% females). Most participants received their school education mainly in Arabic (78.8%). A significant percentage of students believed that providing Arabic terms helped their learning (79.8%). If pharmacology is taught exclusively in English, majority of the students anticipated to face difficulties when explaining drug treatment to their patients in the future (71.3%). Most respondents expected this intervention to help them communicate with patients (86.7%), and preferred to include it in the clinical skills training (82.2%). The second-year students and those whose school education was mainly in Arabic were more likely to agree to the intervention (p < 0.05 for both).

Originality/value

The introduction of medical terms in Arabic is an acceptable alternative to complete Arabization, and is believed to help students in their learning and communication with their patients.