bluuebunny/crossref_metadata_2025 huggingface dataset:
LncRNA-CIR6 Mediates Repair of Infarcted Hearts by Inducing MSCs Differentiation into Cardiogenic Cells through CDK1
Authors: Cui Xiaotian , Dong Hui , Luo Shenghe , Zhuang Bingqi , Li Yansheng , Zhong Chongning , Ma Yuting , Cheng Xianwu , Hong Lan
Published: January 2024

Purpose

This study aims to investigate the induction effect of LncRNA-CIR6 on MSCs differentiation into Cardiogenic Cellsin vitroandin vivo.

Methods

In addition to pretreatment with the Ro-3306 (CDK1 inhibitor), LncRNA-CIR6 was transfected into BMSCs and hUCMSCs using jetPRIME. LncRNA-CIR6 was transfected into C57BL/6 mice heart by 100 μL of AAV9-cTnT-LncRNA-CIR6-ZsGreen i.v. After 3 weeks of transfection followed by AMI surgery, hUCMSCs (5×105/100 μL) were injected by i.v 1 week later. Cardiac function was evaluated using VEVO 2100 and electric mapping 9 days after cell injection. IF, Evans blue-TTC, Masson staining, FACS, and WB were used to determine relevant indicators.

Results

LncRNA-CIR6 induced a significant percentage of differentiation in BMSCs (83.00±0.58)% and hUCMSCs (95.43±2.13)% into cardiogenic cells, as determined by the expression of cTnT. Compared with MI group, cardiac contraction and conduction function in MI heart treated by LncRNA-CIR6 or combined with MSCs injection groups were significantly increased as well as the area of MI and fibrosis were significantly lower. The transcriptional expression region of LncRNA-CIR6 was in Chr17 from 80209290 to 80209536. The functional region of LncRNA-CIR6 was located at nucleotides 0-50/190-255 in the sequence. CDK1 is a protein found to be related to the proliferation and differentiation of cardiomyocytes is which located in the functional region of LncRNA-CIR6 secondary structure (from 0 to 17). Ro-3306 impeded the differentiation of MSCs into cardiogenic cells, while MSCs transfected with LncRNA-CIR6 showed high expression of CDK1. LncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1.

Conclusions

LncRNA-CIR6 mediates repair of infarcted hearts by inducing MSCs differentiation into cardiogenic cells through CDK1.
Bending the course of evolution: how mutualistic interactions affect macroevolutionary dynamics of diversification in mimetic butterflies
Authors: Chazot N. , Pires Braga M. , Aubier T.G. , Llaurens V. , Willmott K. R. , Elias M.
Published: January 2024

Evidence that species interactions can affect macroevolutionary dynamics of trait and species diversification is scarce. Mutualistic Müllerian mimicry is a compelling example of example of ecological interactions that has been shown to drive evolutionary convergence, Here, we test how mutualistic Müllerian mimicry shapes macroevolutionary patterns of diversification in the Ithomiini butterflies. We show that the age of color patterns is the primary determinant of species richness within mimicry rings but not phylogenetic diversity. We find pervasive phylogenetic signal in mimicry rings and in color patterns associated within polymorphic species. Only a small set of mimicry rings show high phylogenetic diversity. We identify patterns of saturation in the accumulation of new mimicry rings and in the number of evolutionary convergences towards the most species-rich mimicry rings. Those saturation patterns are likely caused by niche filling along various ecological dimensions, within and among the mimetic communities living in sympatry. The time-dependent effects detected in our study illustrate how neutral processes and ecological interactions interact and shape species and phenotypic diversification.
Experimental evidence that investment into ejaculation and mating effort impose different life history trade-offs
Authors: Chung Meng-Han Joseph , Fox Rebecca J. , Jennions Michael D.
Published: January 2024

When males compete, sexual selection favors reproductive traits that increase their mating or fertilization success (pre- and post-copulatory sexual selection). It is assumed that males face a trade-off between these two types of sexual traits because they both draw on investment from the same pool of resources. Consequently, investment into mate acquisition or ejaculation should create similar trade-offs with other key life history traits. Tests of these assumptions are exceedingly rare. Males only ejaculate after they mate, and investment into ejaculation is therefore highly correlated with mating effort. Consequently, little is known about how each component of reproductive investment affects a male’s future performance. Here, we ran an experiment using a novel technique to distinguish the life history costs of mating effort and ejaculation for mosquitofish (Gambusia holbrooki). We compared manipulated males (mate without ejaculation), control males (mate and ejaculate) and naïve males (neither mate nor ejaculate) continuously housed with a female and two rival males. We assessed their growth, somatic maintenance, mating and fighting behavior, and sperm traits after 8 and 16 weeks. Past mating effort significantly lowered a male’s future mating effort and growth, but not his sperm production; while past sperm release significantly lowered a male’s future ejaculate quantity, but not his mating effort. These findings challenge the assumption that male reproductive investment draws from a common pool of resources such that, all else being equal, greater mating effort reduces ejaculate investment, andvice versa. Instead, we provide clear evidence that investment in traits under pre- and post-copulatory sexual selection have different trait-specific effects on subsequent male reproductive performance that occur both early and late in life.
Dual-targeting CRISPR-CasRx reducesC9orf72ALS/FTD sense and antisense repeat RNAs in vitro and in vivo
Authors: Kempthorne Liam , Vaizoglu Deniz , Cammack Alexander J. , Carcolé Mireia , Suklai Pacharaporn , Muralidharan Bhavana , Kroll François , Moens Thomas G. , Yshii Lidia , Verschoren Stijn , Hölbling Benedikt V. , Katona Eszter , Mikheenko Alla , Coneys Rachel , de Oliveira Paula , Zhang Yong-Jie , Jansen Karen , Daughrity Lillian M , McGown Alexander , Ramesh Tennore M. , Van Den Bosch Ludo , Rahim Ahad A. , Petrucelli Leonard , Rihel Jason , Isaacs Adrian M.
Published: January 2024

The most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a G4C2repeat expansion in intron 1 of theC9orf72gene. This repeat expansion undergoes bidirectional transcription to produce sense and antisense repeat RNA species. Both sense and antisense-derived repeat RNAs undergo repeat-associated non-AUG translation in all reading frames to generate five distinct dipeptide repeat proteins (DPRs). Importantly, toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs. This suggests targeting both sense and antisense repeat RNA may provide the most effective therapeutic strategy. The RNA-targeting CRISPR-Cas13 systems offer a promising avenue for simultaneous targeting of multiple RNA transcripts, as they mature their own guide arrays, thus allowing targeting of more than one RNA species from a single construct. We show that CRISPR-Cas13d originating fromRuminococcus flavefaciens(CasRx) can successfully reduceC9orf72sense and antisense repeat transcripts and DPRs to background levels in HEK cells overexpressingC9orf72repeats. CRISPR-CasRx also markedly reduced the endogenous sense and antisense repeat RNAs and DPRs in three independentC9orf72patient-derived iPSC-neuron lines, without detectable off-target effects. To determine whether CRISPR-CasRx is effectivein vivo, we treated two distinctC9orf72repeat mouse models using AAV delivery and observed a significant reduction in both sense and antisense repeat-containing transcripts. Taken together this work highlights the potential for RNA-targeting CRISPR systems as therapeutics forC9orf72ALS/FTD.
Revealing the atomic and electronic mechanism of human manganese superoxide dismutase product inhibition
Authors: Azadmanesh Jahaun , Slobodnik Katelyn , Struble Lucas R. , Lutz William E. , Coates Leighton , Weiss Kevin L. , Myles Dean A. A. , Kroll Thomas , Borgstahl Gloria E. O.
Published: January 2024

Human manganese superoxide dismutase (MnSOD) is a crucial oxidoreductase that maintains the vitality of mitochondria by converting O2●-to O2and H2O2with proton-coupled electron transfers (PCETs). Since changes in mitochondrial H2O2concentrations are capable of stimulating apoptotic signaling pathways, human MnSOD has evolutionarily gained the ability to be highly inhibited by its own product, H2O2. A separate set of PCETs is thought to regulate product inhibition, though mechanisms of PCETs are typically unknown due to difficulties in detecting the protonation states of specific residues that coincide with the electronic state of the redox center. To shed light on the underlying mechanism, we combined neutron diffraction and X-ray absorption spectroscopy of the product-bound, trivalent, and divalent states to reveal the all-atom structures and electronic configuration of the metal. The data identifies the product-inhibited complex for the first time and a PCET mechanism of inhibition is constructed.
Oligomeric HIV-1 Integrase Structures Reveal Functional Plasticity for Intasome Assembly and RNA Binding
Authors: Jing Tao , Shan Zelin , Dinh Tung , Biswas Avik , Jang Sooin , Greenwood Juliet , Li Min , Zhang Zeyuan , Gray Gennavieve , Shin Hye Jeong , Zhou Bo , Passos Dario , Aiyer Sriram , Li Zhen , Craigie Robert , Engelman Alan N. , Kvaratskhelia Mamuka , Lyumkis Dmitry
Published: January 2024

Integrase (IN) performs dual essential roles during HIV-1 replication. During ingress, IN functions within an oligomeric “intasome” assembly to catalyze viral DNA integration into host chromatin. During late stages of infection, tetrameric IN binds viral RNA and orchestrates the condensation of ribonucleoprotein complexes into the capsid core. The molecular architectures of HIV-1 IN assemblies that mediate these distinct events remain unknown. Furthermore, the tetramer is an important antiviral target for allosteric IN inhibitors. Here, we determined cryo-EM structures of wildtype HIV-1 IN tetramers and intasome hexadecamers. Our structures unveil a remarkable plasticity that leverages IN C-terminal domains and abutting linkers to assemble functionally distinct oligomeric forms. Alteration of a newly recognized conserved interface revealed that both IN functions track with tetramerizationin vitroand during HIV-1 infection. Collectively, our findings reveal how IN plasticity orchestrates its diverse molecular functions, suggest a working model for IN-viral RNA binding, and provide atomic blueprints for allosteric IN inhibitor development.
Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling
Authors: Bandekar Sumit J. , Garbett Krassimira , Kordon Szymon P. , Dintzner Ethan , Shearer Tanner , Sando Richard C. , Araç Demet
Published: January 2024

Cadherin EGF Laminin G seven-pass G-type receptors (CELSRs or ADGRCs) are conserved adhesion G protein-coupled receptors which are essential for animal development. CELSRs have extracellular regions (ECRs) containing 23 adhesion domains which couple adhesion to intracellular signaling. However, molecular-level insight into CELSR function is sparsely available. We report the 4.3 Å cryo-EM reconstruction of the mCELSR1 ECR with 13 domains resolved in the structure. These domains form a compact module mediated by interdomain interactions with contact between the N- and C-terminal domains. We show the mCELSR1 ECR forms an extended species in the presence of Ca2+, which we propose represents the antiparallel cadherin repeat dimer. Using assays for adhesion and G protein-coupling, we assign the N-terminal CADH1-8 module as necessary for cell adhesion and we show the C-terminal CAHD9-GAIN module regulates signaling. Our work provides important molecular context to the literature on CELSR function and opens the door towards further mechanistic studies.
Transcriptional and phenotypic heterogeneity underpinning venetoclax resistance in AML
Authors: Mohanty Vakul , Baran Natalia , Huang Yuefan , Ramage Cassandra L , Cooper Laurie M , He Shan , Iqbal Ramiz , Daher May ,   CTD2 Research Network, Tyner Jeffrey W. , Mills Gordon B. , Konopleva Marina , Chen Ken
Published: January 2024

The venetoclax BCL2 inhibitor in combination with hypomethylating agents represents a cornerstone of induction therapy for older AML patients, unfit for intensive chemotherapy. Like other targeted therapies, venetoclax-based therapies suffer from innate and acquired resistance. While several mechanisms of resistance have been identified, the heterogeneity of resistance mechanism across patient populations is poorly understood. Here we utilized integrative analysis of transcriptomic andex-vivodrug response data in AML patients to identify four transcriptionally distinct VEN resistant clusters (VR_C1-4), with distinct phenotypic, genetic and drug response patterns. VR_C1 was characterized by enrichment for differentiated monocytic- and cDC-like blasts, transcriptional activation of PI3K-AKT-mTOR signaling axis, and energy metabolism pathways. They showed sensitivity to mTOR and CDK inhibition. VR_C2 was enriched forNRASmutations and associated with distinctive transcriptional suppression ofHOXexpression. VR_C3 was characterized by enrichment forTP53mutations and higher infiltration by cytotoxic T cells. This cluster showed transcriptional expression of erythroid markers, suggesting tumor cells mimicking erythroid differentiation, activation of JAK-STAT signaling, and sensitivity to JAK inhibition, which in a subset of cases synergized with venetoclax. VR_C4 shared transcriptional similarities with venetoclax-sensitive patients, with modest over-expression of interferon signaling. They were also characterized by high rates ofDNMT3Amutations. Finally, we projected venetoclax-resistance states onto single cells profiled from a patient who relapsed under venetoclax therapy capturing multiple resistance states in the tumor and shifts in their abundance under venetoclax selection, suggesting that single tumors may consist of cells mimicking multiple VR_Cs contributing to intra-tumor heterogeneity. Taken together, our results provide a strategy to evaluate inter- and intra-tumor heterogeneity of venetoclax resistance mechanisms and provide insights into approaches to navigate further management of patients who failed therapy with BCL2 inhibitors.
Approximate Nearest Neighbor Graph Provides Fast and Efficient Embedding with Applications in Large-scale Biological Data
Authors: Zhao Jianshu , Pierre-Both Jean , Konstantinidis Konstantinos T.
Published: January 2024

Dimension reduction (or embedding), as a popular way to visualize data, has been a fundamental technique in many applications. Non-linear dimension reduction such as t-SNE and UMAP has been widely used in visualizing single cell RNA sequencing data and metagenomic binning and thus receive many attentions in bioinformatics and computational biology. Here in this paper, we further improve UMAP-like non-linear dimension reduction algorithms by updating the graph- based nearest neighbor search algorithm (e.g. we use Hierarchical Navigable Small World Graph, or HNSW instead of K-graph) and combine several aspects of t-SNE and UMAP to create a new non-linear dimension reduction algorithm. We also provide several additional features including computation of LID (Local Intrinsic Dimension) and hubness, which can reflect structures and properties of the underlying data that strongly affect nearest neighbor search algorithm in traditional UMAP-like algorithms and thus the quality of embeddings. We also combined the improved non-linear dimension reduction algorithm with probabilistic data structures such as MinHash-likes ones (e.g., ProbMinHash et.al.) for large-scale biological sequence data visualization. Our library is called annembed and it was implemented and fully parallelized in Rust. We benchmark it against popular tools mentioned above using standard testing datasets and it showed competitive accuracy. Additionally, we apply our library in three real-world problems: visualizing large-scale microbial genomic database, visualizing single cell RNA sequencing data and metagenomic binning, to showcase the performance, scalability and efficiency of the library when distance computation is expensive or when the number of data points is large (e.g. millions or billions). Annembed can be found here:https://github.com/jean-pierreBoth/annembed
Sustaining healthy long-term host-microbiome interactions in a physiologically relevant dynamic gingival tissue model
Authors: Adelfio M. , Callen G. E. , Diaz A. R. , Paster B J. , He X. , Hasturk H. , Ghezzi C. E.
Published: January 2024

Host-oral microbiome interactions are known to be critical in maintaining local and systemic health of the human body, although they are difficult to study in both clinical andin vitroapplications. Despite efforts, recapitulation of gingival architecture and physiological characteristics of the periodontal niche cannot be achieved by traditional tissue engineering strategies. Here, we advanced our humanized three-dimensional gingival model by co-culturing it with a healthy patient-derived microbiomes for seven days within an oral bioreactor that mimics native salivary dynamics. Our results indicated long-term host and microbiome viability, host barrier integrity and physiological response, and preservation of healthy microbial populations and interbacterial dialogues. The model has proven useful in successfully mimicking tissue homeostasis at the interface of the periodontal niche and suitable for the introduction of immune cells. Future studies will focus on using the model as a comparator of periodontal inflammation and identifying biomarkers associated with eubiotic/dysbiotic profiles.

Graphical Abstract

Created partially in biorender.com.
Crossover Interference Mediates Multiscale Patterning Along Meiotic Chromosomes
Authors: White Martin A. , Weiner Beth , Chu Lingluo , Lim Gyubum , Kleckner Nancy E.
Published: January 2024

The classical phenomenon of crossover interference is a one-dimensional spatial patterning process that produces evenly spaced crossovers during meiosis. Quantitative analysis of diagnostic molecules along budding yeast chromosomes reveals that this process also sets up a second, interdigitated pattern of related but longer periodicity, in a “two-tiered” patterning process. The second tier corresponds to a previously mysterious minority set of crossovers. Thus,in toto, the two tiers account for all detected crossover events. Both tiers of patterning set up spatially clustered assemblies of three types of molecules (“triads”) representing the three major components of meiotic chromosomes (crossover recombination complexes and chromosome axis and synaptonemal complex components), and give focal and domainal signals, respectively. Roles are suggested. All observed effects are economically and synthetically explained if crossover patterning is mediated by mechanical forces along prophase chromosomes. Intensity levels of domainal triad components are further modulated, dynamically, by the conserved protein remodeler Pch2/TRIP13.
Unravelling the ageing-reversal potency of stem cell-derived extracellular vesicles in a rat model of premature cardiac senescence
Authors: Gómez-Cid L , Campo-Fonseca A , Cervera-Negueruela M , Ocampo A , Pinto A , Gil-Jaurena JM , Suárez-Sancho S , Fernández-Avilés F , Bermejo J , Grigorian-Shamagian L
Published: January 2024

Cardiosphere-derived cells (CDCs) and the extracellular vesicles they release (CDC-EVs) have demonstrated to induce rejuvenation and to improve cardiac structure and function, but their efficacy may vary among donors and there is still a lack of adequate potency assays. We aimed to identify parameters that could easily predict the ageing-reversal potency of CDC-EVs. CDCs derived from cardiac tissue of 34 human donors (age range: 3-months to 81-years old) were characterized in terms of their phenotypical and biological properties. The anti-senescent activity of the CDC-EVs was assessedin vitrousing a predesigned matrix assay with several ageing-related markers. We found that while CDC-donor’s chronological age was not determinant, the degree of CDC senescence in culture showed a strong correlation to most CDĆs bioactive properties. However, CDC senescence alone was insufficient to predict CDC-EVin vitropotency. Thus, we scored the potency of the CDC-EVs based on their performance in the newly designedin vitromatrix assay and classified them as more-(P-EVs) and less-potent (NP-EVs). We then tested P- and NP-EVs in a rat model of premature cardiac ageing and found that only the P-EVs reduced senescence-associatedGLB1gene expression in the heart and tended to protect it from hypertrophy development and fibrosis. On the contrary, NP-EVs failed to induce any improvements and negatively affected cardiac hypertrophy, fibrosis, and perfusion. In conclusion, despite CDC-EV anti-ageing potency cannot be predicted by the chronological age of the donors or CDC senescence as surrogate markers, we propose anin vitropotency assay that could be used to evaluate allogenic EV suitability before its use in the treatment of cardiac ageing.
Familial risk of myocardial infarction with non-obstructive and obstructive coronary arteries-A nation-wide cohort study
Authors: Hakansson Felicia HK , Svensson Per , Pettersson Hans J , Ehrenborg Ewa , Spaak Jonas , Nordenskjold Anna M , Eggers Kai M , Tornvall Per
Published: January 2024

Background

The familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings.

Objectives

To investigate familial risk of MI without and with obstructive coronary arteries.

Methods

A register-based cohort study with a total of 15,462 MINOCA cases, 204,424 MI-CAD cases, 38,220 control subjects without MI and with non-obstructive coronary arteries. First-degree relatives were identified 1995-2020. Cox proportional hazard regression models were used to compare familial risk in MINOCA and MI-CAD with control subjects.

Results

During a mean follow-up of 8.1 ± 4.2 years, MINOCA occurred in 1.0% of first-degree relatives with MINOCA whereas MI-CAD occurred in 9.7% of first-degree relatives of MINOCA. The age- and sex-adjusted hazard ratio (HR) for a MINOCA-relative experiencing MINOCA and MI-CAD, compared to control subjects, was 0.99 (95% confidence interval [CI] 0.80-1.23) and 1.10 (95% CI 1.03-1.18), respectively. During a mean follow-up of 8.5 ±4.8 years, MI-CAD occurred in 12.2% of first-degree relatives with MI-CAD with age- and sex-adjusted HR 1.43 (95% CI 1.37-1.49).

Conclusions

No increased familial risk of MINOCA was observed for MINOCA-patients whereas there was an increased familial risk for MI-CAD when compared to control subjects. These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA, thus MI-CAD and MINOCA could share underlying mechanisms.

Condensed Abstract

In this register-based nation-wide cohort study including 15,462 MINOCA cases, 204,424 MI-CAD cases, and 38,220 control subjects, studied between 1995-2020, we show that there is an increased familial risk for MINOCA having a first-degree relative with MI-CAD, without an increased familial risk of MINOCA having a first-degree relative with MINOCA compared to controls. Age- and sex-adjusted hazard ratio (HR) for MICAD was 1.10 (95% confidence interval 1.03-1.18), and for MINOCA 0.99 (95% confidence interval 0.80-1.23). These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA.
Sex Disparity in Referral for Catheter Ablation for Atrial Fibrillation at a Single Integrated Health System
Authors: Gangadharan Arati A. , Muhammad Lutfiyya N. , Song Jing , Knight Bradley , Passman Rod
Published: January 2024

Background

Catheter ablation for atrial fibrillation (AFCA) is indicated for select patients with atrial fibrillation (AF) and has been shown to reduce AF burden and improve quality of life. Earlier studies demonstrated that women are less likely to undergo AFCA despite having more AF symptoms. We investigated whether an association exists between referral patterns and this sex disparity.

Methods and Results

A retrospective cohort study was conducted of outpatients with newly diagnosed AF using the electronic medical record at Northwestern. Of 5,445 patients analyzed, 2,108 were women, and 3,337 were men. Characteristics including race, insurance status, comorbidities, and prior AF treatment were compared by sex. Logistic regression models adjusted for socioeconomic and clinical factors were constructed to determine associations between sex and binary dependent variables including referrals to and visits with general cardiology and electrophysiology (EP) and utilization of AFCA. There were no significant differences in odds of referral to (aOR, 1.17 [0.92-1.48], P=0.20) or visits with (aOR, 1.03 [0.82-1.30], P=0.79) general cardiologists between women and men. There were no significant differences in odds of referral to (aOR, 0.83 [0.68-1.01], P=0.06) or visits with (aOR, 0.87 [0.72-1.05], P=0.15) electrophysiologists between women and men. Finally, no significant difference was found in likelihood to undergo AFCA between women and men (aOR, 1.08 [0.83-1.40], P=0.56).

Conclusions

Our study demonstrates no significant differences in referral patterns to specialists or rates of AFCA between women and men. Encouraging equitable referral to specialists and access to AFCA is essential in ensuring appropriate care for all patients.
Development and Validation of a Bedside Scale for Assessing Upper Limb Function Following Stroke: A Methodological Study. [version 1; peer review: awaiting peer review]
Authors: Pawani Dhaval , Joshua Abraham M. , Nayak Akshatha , Palaniswamy Vijayakumar , Mithra Prasanna , Prabhakar Ashish John , Amaravadi Sampath Kumar
Published: January 2024

Background

Numerous tools are available for evaluation of upper limb (UL) functions among stroke survivors. Despite the excellent psychometric properties, many require considerable amount of time, are resource-intensive, and often impractical for bedside evaluation.

Objectives

To develop and concurrently validate a simple, resource-efficient, and time-efficient bedside tool for evaluating UL function in stroke survivors.

Methods

Relevant literature review was carried out to conceptualize and define the theoretical framework of day-to-day UL movement tasks. Subsequently, an item pool of 18 UL movements was developed. A mini-Delphi method was employed to verify content validity. During the iterative rounds, 18-items were revised and refined to a 12-items scale. The final bedside upper limb evaluation tool (BUFET) scale underwent concurrent validation by correlating the scores with Wolf Motor Function Test (WMFT) scores using Spearman’s correlation coefficient. Internal consistency was evaluated through Cronbach’s alpha.

Results

Concurrent validity and internal consistency of the scale were supported by a high correlation coefficient (r = 0.937; p<0.001) with WMFT and high Cronbach’s alpha (0.948).

Conclusions

Newly developed BUFET was found to be a valid and reliable bedside tool in the evaluation of upper limb functions and can be administered in a resource and time-efficient manner.
Slow running benefits: Boosts in mood and facilitation of prefrontal cognition even at very light intensity
Authors: Damrongthai Chorphaka , Kuwamizu Ryuta , Yamazaki Yudai , Aoike Naoki , Lee Dongmin , Byun Kyeongho , Torma Ferenc , Churdchomjan Worachat , Yassa Michal A. , Adachi Kazutaka , Soya Hideaki
Published: January 2024

Although running upright has been reported to have positive effects on both physical and mental health, the minimum running intensity/speed that would benefit mood and prefrontal cognition is not yet clear. For this reason, we aimed to investigate the acute effect of very slow running, which is classified as a very light intensity exercise, on mood, executive function (EF), and their neural substrates in the prefrontal cortex (PFC). Twenty-four healthy participants completed a 10-minute very slow running session on a treadmill at 35%and a resting control session in randomized order. EF was measured using the Stroop task and the mood state was measured using the Two-Dimensional Mood Scale (TDMS) before and after both sessions. Cortical hemodynamic changes while performing the task were monitored using functional near-infrared spectroscopy (fNIRS). The results show that ten minutes of very slow running significantly enhanced mood, reduced Stroop interference time (i.e., enhanced EF), and elicited left lateral PFC activation. Moreover, head acceleration, the magnitude of up-and-down oscillations, was measured during running, and a significant positive correlation with pleasant mood was found. Head acceleration is a remarkable characteristic of running and may be one of the factors related to a pleasant mood induced by very slow running. In conclusion, the current study reveals that a single bout of running, even at very slow speed, elicits a pleasant mood and improved executive function with enhancing activation in prefrontal subregions. This shed light on the slow running benefits to brain health.
Postharvest partial dehydration of blueberries enhanced blueberry wine aroma via upregulating phenylalanine metabolism and terpene biosynthesis
Authors: Wang Yu , Zhang Qi , Yang Qin , Bian Chen , Huang Shu-Qin , Zhao Lu-Lu , Huang Ya-Qiong , Shen Shan-Shan , Chen Qi , Zhang Hai-Wei , Gao Xue-Ling
Published: January 2024

Postharvest partial dehydration of blueberries can enhance blueberry wine aroma, while the underlying mechanisms remain unclear. In this study, the key odor-active volatiles in blueberry wines fermented from dehydrated blueberries (30% weight loss) were identified via aroma extract dilution analysis. Results showed that increased levels of phenylalanine-derived compounds such as phenylethanol, and terpenes such as linalool and geraniol, primarily led to the enhancement of sweet, floral and fruity aromas of blueberry wines. Postharvest partial dehydration increased the contents of these compounds, which could be linked to the upregulation ofVcGOT2andVcPARinvolved in phenylalanine metabolism, and the upregulation ofVcDXS,VcHDRandVcTPSinvolved in terpene biosynthesis. Notably, the upregulatedVcTPSencoded a monoterpene synthase responsible for producing linalool. These findings provided insight into the impact of postharvest dehydration on phenylalanine and terpene metabolism in blueberries, offering a reference for improving blueberry wine aroma through postharvest partial dehydration techniques.
Intolerance of uncertainty does not significantly predict decisions about delayed, probabilistic rewards
Authors: Cobos Pedro L. , Quintero María J. , López Francisco J. , Luque David , Ciria Luis F. , Morís y Joaquín
Published: January 2024

Intolerance of Uncertainty (IU) is thought to lead to maladaptive behaviours and dysfunctional decision making, both in the clinical and healthy population. The seminal study reported by Luhmann and collaborators in 2011 showed that IU was negatively associated with choosing a delayed, but more certain and valuable, reward over choosing an immediate, but less certain and valuable, reward. These findings have been widely disseminated across the field of personality and individual differences because of their relevance to understand the role of IU in maladaptive behaviours in anxiety-related disorders. We conducted a study to replicate and extend Luhmann et al.’s results with a sample of 313 participants, which exceeded the size necessary (N = 266) to largely improve the statistical power of the original study by using thesmall telescopes approach. The results of our well powered study strongly suggest that the relationship between IU and the tendency to prefer an immediate, but less certain and less valuable reward is virtually negligible. Consequently, although this relationship cannot be definitely discarded, we conclude that it cannot be detected with Luhmann et al.’s (2011) decision-making task.
Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through multiple mechanisms
Authors: Liu Pan , Yue Can , Meng Bo , Xiao Tianhe , Yang Sijie , Liu Shuo , Jian Fanchong , Zhu Qianhui , Yu Yuanling , Ren Yanyan , Wang Peng , Li Yixin , Wang Jinyue , Mao Xin , Shao Fei , Wang Youchun , Gupta Ravindra Kumar , Cao Yunlong , Wang Xiangxi
Published: January 2024

Selective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course of the COVID-19 pandemic. Recently evolved variants differ from ancestors in additional glycosylation within the spike protein receptor-binding domain (RBD). Details of how the acquisition of glycosylation impacts viral fitness and human adaptation are not clearly understood. Here, we dissected the role of N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as a RBD conformational control element in attenuating viral infectivity. The reduced infectivity could be recovered in the presence of heparin sulfate, which targets the “N354 pocket” to ease restrictions of conformational transition resulting in a “RBD-up” state, thereby conferring an adjustable infectivity. Furthermore, N354 glycosylation improved spike cleavage and cell-cell fusion, and in particular escaped one subset of ADCC antibodies. Together with reduced immunogenicity in hybrid immunity background, these indicate a single spike amino acid glycosylation event provides selective advantage in humans through multiple mechanisms.

HIGHLIGHTS

N354 glycosylation acts as a conformational control element to modulate infectivity Reduced infectivity could be recovered by altered binding mode of heparin sulfate N354 glycosylation improved fusogenicity and conferred escape from ADCC antibodies N354 glycosylation reduced immunogenicity and conferred immune evasion
Imaging Aβ aggregation by liquid-phase transmission electron microscopy
Authors: Ing Gabriel , Acosta-Gutiérrez Silvia , Vendruscolo Michele , Battaglia Giuseppe , Ruiz-Pérez Lorena
Published: January 2024

The amyloid beta peptide (Aβ) readily aggregates into amyloid fibrils. This process has been the subject of intense investigations since it is associated with Alzheimer’s disease. However, it has been highly challenging to observe the microscopic steps in the aggregation reaction directly and to characterize the oligomeric assemblies formed as intermediates. To achieve this goal, we apply liquid-phase transmission electron microscopy (LTEM) in combination with all-atom molecular dynamics simulations. Our results offer an initial visualization of the dynamics of Aβ oligomers, the formation of Aβ protofibrils, and the presence of Aβ oligomers on the surface of Aβ fibrils. This work illustrates how the application of LTEM to the study of protein aggregation in solution enables the imaging of key molecular events in the aggregation process of Aβ.
Body temperature regulates glucose metabolism and torpid behavior
Authors: Lee Ming-Liang , Chang Ching-Pu , Toda Chitoku , Nemoto Tomomi , Enoki Ryosuke
Published: January 2024

Glucose is a significant energy resource for maintaining physiological activities, including body temperature homeostasis, and glucose homeostasis is tightly regulated in mammals. Although ambient temperature tunes glucose metabolism to maintain euthermia, the significance of body temperature in metabolic regulation remains unclear owing to strict thermoregulation. Activation of Qrfp neurons in the preoptic area induced a harmless hypothermic state known as Q-neuron-induced hypothermia and hypometabolism (QIH), which is suitable for studying glucose metabolism under hypothermia. In this study, we first observed that QIH mice had hyperinsulinemia and insulin resistance. This glucose hypometabolic state was abolished by increasing the body temperature to euthermia. Moreover, QIH-mediated inappetence and locomotor inactivity were recovered in euthermia QIH mice. These results indicate that body temperature is considerably more powerful than ambient temperature in regulating glucose metabolism and behavior, and hypometabolism in QIH is secondary to hypothermia rather than modulated by Qrfp neurons.

Highlights

QIH reorganizes glucose homeostasis which is unchanged by fasting.

QIH mice exhibit glucose hypometabolism with hyperinsuliemia and insulin resistance.

Increased body temperature abolishes QIH-mediated hypometabolism and torpid behaviors.

Body temperature is a strong factor in controlling metabolism and behavior.

Body temperature-mediated glucose metabolism is reversible.
The interplay between peptides and RNA is critical for protoribosome compartmentalization and stability
Authors: Codispoti Simone , Yamaguchi Tomoko , Makarov Mikhail , Giacobelli Valerio G. , Mašek Martin , Kolář Michal H. , Sanchez Rocha Alma Carolina , Fujishima Kosuke , Zanchetta Giuliano , Hlouchová Klára
Published: January 2024

The ribosome, owing to its exceptional conservation and biological importance, harbours a remarkable molecular fossil known as the protoribosome. It surrounds the peptidyl transferase center (PTC), responsible for peptide bond formation. While previous studies have demonstrated the PTC activity in RNA alone, our investigation reveals the intricate roles of the ribosomal protein fragments (rPeptides) within the ribosomal core.

This research highlights the significance of rPeptides in stability and coacervation of two distinct protoribosomal evolutionary stages. The 617nt “big” protoribosome model which associates with rPeptides specifically, exhibits a structurally defined and rigid nature, further stabilised by the peptides. In contrast, the 136nt “small” model, previously linked to peptidyltransferase activity, displays greater structural flexibility. While this construct interacts with rPeptides with lower specificity, they induce coacervation of the “small” protoribosome across a wide concentration range, which is concomitantly dependent on the RNA sequence and structure. Moreover, these conditions protect RNA from degradation. This phenomenon suggests a significant evolutionary advantage in the RNA-protein interaction at the early stages of ribosome evolution.

The distinct properties of the two protoribosomal stages suggest that rPeptides initially provided compartmentalization and prevented RNA degradation, preceding the emergence of specific RNA-protein interactions crucial for the ribosomal structural integrity.

3

keypoints

- The most ancient fragments of ribosomal peptides trigger coacervation of protoribosome

- The protoribosome coacervation provides protection against RNA degradation

- Coacervation is more profound with a smaller and more flexible model of the protoribosome
Rewriting endogenous human transcripts withtrans-splicing
Authors: Chandrasekaran Sita S. , Tau Cyrus , Nemeth Matthew , Pawluk April , Konermann Silvana , Hsu Patrick D.
Published: January 2024

Splicing bridges the gap between static DNA sequence and the diverse and dynamic set of protein products that execute a gene’s biological functions. While exon skipping technologies enable influence over splice site selection, many desired perturbations to the transcriptome require replacement or addition of exogenous exons to target mRNAs: for example, to replace disease-causing exons, repair truncated proteins, or engineer protein fusions. Here, we report the development ofRNA-guidedtrans-splicing withCaseditor (RESPLICE), inspired by the rare, natural process of trans-splicing that joins exons from two distinct primary transcripts. RESPLICE uses two orthogonal RNA-targeting CRISPR effectors to co-localize a trans-splicing pre-mRNA and to inhibit the cis-splicing reaction, respectively. We demonstrate efficient, specific, and programmable trans-splicing of multi-kilobase RNA cargo into nine endogenous transcripts across two human cell types, achieving up to 45% trans-splicing efficiency in bulk, or 90% when sorting for high effector expression. Our results present RESPLICE as a new mode of RNA editing for fine-tuned and transient control of cellular programs without permanent alterations to the genetic code.
Multiplex PCR reveals population structure in an inbred communal bird
Authors: Babaei Sarah , Grieves Leanne A. , Evans Ben , Quinn James S.
Published: January 2024

We sampled communally breeding pūkeko (Porphyrio melanotus melanotus, family Rallidae) populations on the North (Tāwharanui Park) and South (Otokia Reserve) Islands of New Zealand that differ in climate and ecology. North Island populations have year-round territories, philopatry, and form kin groups, resulting in inbreeding. South Island populations have seasonal territories, high dispersal rates, and form non-kin groups, leading to outbreeding. Given behavioural evidence of inbreeding we predicted that the North Island population would exhibit lower heterozygosity and higher inbreeding coefficients than the South Island population. We hypothesized that the South Island population originated via a range expansion from the north and predicted that South Island birds would have lower allelic diversity due to founder effects. To test these predictions, we developed microsatellite primers, optimized multiplex PCRs, and genotyped breeding groups from the North and South Island. Breeding groups from North Island were genetically differentiated, whereas population structure was not detected in the South Island birds. North Island birds had higher inbreeding coefficients and levels of within group kinship, but not allelic diversity, compared to South Island birds. Our results are thus inconclusive about whether the South Island population originated via a range expansion from the north. This pilot study validated microsatellite markers and PCR methods and is the first genetic analysis of population structure and relatedness within communal breeding pūkeko groups. These genetic tools will be used for larger-scale studies to help resolve the origins of the South Island population and provide further insights into the effects of ecology and behaviour on inbreeding, reproductive success, and population demographics in this species. Pūkeko may provide an excellent model for experimental analyses of inbreeding effects on wild avian populations without the attendant concerns that come with small, endangered populations. This work may thus inform conservation efforts, including translocations of endangered species.
Variant calling and genotyping accuracy of ddRAD-seq: comparison with 20X WGS in layers
Authors: Doublet Mathilde , Degalez Fabien , Lagarrigue Sandrine , Lagoutte Laetitia , Gueret Elise , Allais Sophie , Lecerf Frédéric
Published: January 2024

Whole Genome Sequencing (WGS) remains a costly or unsuitable method for routine genotyping of laying hens methods, thus alternatives have been developed. Among these, reduced representation sequencing approaches can offer both sequencing quality and cost-effectiveness by reducing the genomic regions covered by sequencing. The aim of this study was to evaluate the ability ofdouble digested Restriction site Associated DNA sequencing(ddRAD-seq) to identify and genotype SNPs in laying hens, by comparison with a presumed reliable WGS approach. Firstly, the sensitivity and precision of variant calling and the genotyping reliability of ddRADseq were determined. Next, the SNP Call Rate (CRSNP) and mean depth of sequencing per SNP (DPSNP) were compared between both methods. Finally, the effect of multiple combinations of thresholds for these parameters on genotyping reliability and amount of remaining SNPs in ddRAD-seq was studied. In raw form, the ddRAD-seq identified 349,497 SNPs evenly distributed on the genome with a CRSNPof 0.55, a DPSNPof 11X and a mean genotyping reliability rate per SNP of 80%. Considering genomic regions covered by expected enzymatic fragments (EFs), the sensitivity of the ddRAD-seq was estimated at 32.4% and its precision at 96.4%. The low CRSNPand DPSNPvalues were explained by the detection of SNPs outside the EFs theoretically generated by the ddRAD-seq protocol. Indeed, SNPs outside the EFs had significantly lower CRSNP(0.25) and DPSNP(1X) values than SNPs within the EFs (0.7 and 17X, resp.). The study demonstrated the relationship between CRSNP, DPSNP, genotyping reliability and the number of SNPs retained, to provide a decision-support tool for defining filtration thresholds. Severe quality control over ddRAD-seq data allowed to retain a minimum of 40% of the SNPs with a CcR of 98%. Then, ddRAD-seq was defined as a suitable method for variant calling and genotyping in layers.
West Nile virus is transmitted within mosquito populations through infectious mosquito excreta
Authors: Hamel Rodolphe , Narpon Quentin , Serrato-Pomar Idalba , Gauliard Camille , Berthomieu Arnaud , Wichit Sineewanlaya , Missé Dorothée , Sofonea Mircea T. , Pompon Julien
Published: January 2024

Understanding transmission routes of arboviruses is key to control their epidemiology and global health burden. Using West Nile virus andCulexmosquitoes, we tested whether arboviruses are transmitted through mosquito excreta. First, we determined the presence of infectious virions in excreta and quantified a high concentration of infectious units per excreta. Second, we showed that virion excretion starts early after oral infection and remains constant for a long period, regardless of mosquito infection level. These results highlight the infectiousness of excreta from infected mosquitoes. Third, we found that both larvae and pupae were susceptible to infection, although pupae were highly permissive. Forth, we established the proof-of-concept that immature mosqui-toes can be infected by infectious excreta, demonstrating a new excreta-mediated mode of transmission. Finally, by mathematically modelling excreta-mediated transmission in the field, we demonstrated its potential impact on arbovirus epidemiology. Our study uncovers a new route of transmission for arboviruses, unveiling mechanisms of viral maintenance in mosquito reservoirs and of vector species shift that contribute to zoonotic emergence.
Cost-benefit analysis of cryogenic electron tomography subtomogram averaging of chaperonin MmCpn at near atomic resolution
Authors: Zhao Yanyan , Schmid Michael F. , Chiu Wah
Published: January 2024

Cryogenic electron microscopy single particle reconstruction (cryoEM-SPR) has evolved into a routine approach for determining macromolecule structures to near-atomic resolution. Cryogenic electron tomography subtomogram averaging (cryoET-STA) towards similar resolution, in contrast, is still under active development. CryoET can capture the 3D snapshot of individual macromolecules by stage tilting, offering multiple angular views per particle than the single particle reconstruction approach. Here we use the archaea chaperonin MmCpn as a model macromolecule to investigate the resolution limiting factors of cryoET-STA in terms of cumulative electron dose, ice thickness, subtomogram numbers and tilt angle ranges. By quantitative analysis of these factors against the STA reconstruction resolution, we delineate the feasibility of attaining high resolution structure determination with cryoET-STA. This study provides biophysical guidance for the application of cryoET-STA towards high resolution and the cost against benefit of using cryoET-STA to achieve an efficient outcome at the desired resolution.