bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential targets for the treatment of MI: GRP75-mediated Ca2+transfer in MAM
Authors: Zhang Chenyan , Liu Bowen , Sheng Jiaxing , Wang Jia , Zhu Weijie , Xie Chen , Zhou Xuan , Zhang Yuxin , Meng Qinghai , Li Yu
Published: October 2023

Background

After myocardial infarction (MI), there is a notable disruption in cellular calcium ion homeostasis and mitochondrial function. These alterations are believed to be linked to endoplasmic reticulum (ER) stress, though the specific mechanisms are not fully understood. This research endeavors to elucidate the involvement of glucose regulated protein 75 (GRP75) in post-MI calcium ion homeostasis and mitochondrial function.

Results

Excessive oxidative stress was activated in humans’ post-myocardial infarction, with most differentially expressed genes being enriched in metabolic pathways, especially the calcium signaling pathway. In MI rats, symptoms of myocardial injury were accompanied by an increase in the activation of PERK, ATF6, and IRE1, as well as elevated Binding immunoglobulin protein (Bip) expression. Moreover, in oxygen-glucose deprivation (OGD)-induced cardiomyocytes, it was confirmed that inhibiting PERK exacerbated intracellular Ca2+disruption and cell apoptosis. More importantly, in cardiomyocytes undergoing Tunicamycin-induced ER stress, Ca2+accumulated in both the ER and mitochondria. Concurrently, the co-localization of GRP75 with IP3R and VDAC1 increased under ER stress in cardiomyocytes. In OGD-induced cardiomyocytes, knockdown of GRP75 not only reduced the Ca2+levels in both the ER and mitochondria and improved the ultrastructure of cardiomyocytes, but it also increased the number of contact points between ER and mitochondria, reducing MAM formation, and decreased cell apoptosis. Significantly, knockdown of GRP75 did not affect the protein expression of PERK and hypoxia-inducible factor 1α (HIF-1α). Transcriptome analysis of cardiomyocytes revealed that knockdown of GRP75 mainly influenced the molecular functions of sialyltransferase and IP3R, as well as the biosynthesis of glycosphingolipids and lactate metabolism. In OGD-induced cardiomyocytes, the knockdown of GRP75 lowered the protein expression levels of glucose transporter-1 (Glut1), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), and decreased the metabolic products of glycolysis.

Conclusion

The complex interaction between the ER and mitochondria, driven by the GRP75 and its associated IP3R1-GRP75-VDAC1 complex, is crucial for calcium homeostasis and cardiomyocyte’s adaptive response to ER stress. Modulating GRP75 could offer a strategy to regulate calcium dynamics, diminish glycolysis, and thereby mitigate cardiomyocyte apoptosis.
Observation of electromyogram and electrocardiogram changes with deqi for the development of an objective evaluation index of the occurrence of deqi
Authors: Miyamoto Nao , Sakaue Yusuke , Okada Shima , Shiozawa Naruhiro
Published: October 2023

A unique sensation called “deqi” occurs in acupuncture, which is considered an essential variable in the study of the mechanisms and effects of acupuncture. However, an objective method for evaluating deqi is yet to be established. Therefore, we aimed to create an objective evaluation index for deqi using electromyogram (EMG) and electrocardiogram (ECG), which are expected to present characteristic changes based on the findings of previous studies. This study included 16 healthy adult male subjects. ST36 stimulation was performed three times after a one-week washout (N=48). EMG was used to calculate myopotentials, and ECG was used to calculate the heart rate (HR) immediately after stimulation. The subjects declared whether Deqi occurred, and the characteristic reactions of deqi in EMG and ECG were evaluated. In 48 trials, Deqi occurred 42 times and did not occur 6 times. Myopotentials were significantly higher when deqi occurred than when it did not. Furthermore, a positive correlation was identified between subjective sensation and the rate of change in myopotential. Deqi significantly increased the myopotential levels, indicating that it induced involuntary muscle activity. This involuntary muscle activity may be related to the stretch reflexes and nerve stimulation. For the HR immediately after stimulation, no change with deqi was identified, although a significant decrease in HR was found in cases without deqi. Deqi could induce a transient stress response and inhibit the decrease in the HR caused by acupuncture. The results of this study indicate two characteristics of deqi obtained from EMG and ECG: an increase in myopotential and an inhibition of the decrease in HR expected with acupuncture. These characteristics could provide objective evidence for the occurrence of deqi. Future studies with larger sample sizes are required toto further strengthen the objective assessment of deqi.
Carrageenan-containing nasal spray alleviates allergic symptoms in subjects with grass pollen allergy: A randomized, controlled, crossover clinical trial
Authors: Unger-Manhart Nicole , Morokutti-Kurz Martina , Zieglmayer Petra , Lemell Patrick , Savli Markus , Zieglmayer René , Prieschl-Grassauer Eva
Published: October 2023

Purpose

Nonpharmacological nasal sprays forming a barrier between allergens and the nasal mucosa are used to manage symptoms of allergic rhinitis. We aimed to evaluate the safety and effectiveness of Callergin, a nasal spray containing barrier-forming iota-carrageenan, in the treatment of allergic rhinitis.

Methods

In this randomized, controlled, crossover trial, we assigned adults with grass pollen allergy to receive Callergin, VisAlpin and no treatment in a random order for three consecutive periods, separated by a washout period of 7 days. Subjects prophylactically applied one puff of nasal spray to each nostril 5-10 minutes prior to challenge. The primary endpoint was mean change from baseline in ‘total nasal symptom score’ (TNSS) over 3 hours, a sum of rhinorrhea, itching, sneezing, and congestion scores, recorded every 15 minutes during the challenge period.

Results

A total of 42 subjects underwent randomization. Exposure to grass pollen for 3 hours led to a notable TNSS increase from baseline in all subjects at all times. Mean TNSS was lower when subjects received treatment with Callergin compared to no treatment, although the difference did not reach statistical significance (untreated 6.96 ± 2.30; Callergin 6.59 ± 1.93; difference 0.37 points [95% CI -0.17 to 0.91]; p=0.170). In a post-hoc analysis, mean TNSS at 3 hours was significantly reduced with Callergin treatment compared to no treatment (untreated 8.29 ± 2.64; Callergin 7.70 ± 2.56; difference 0.60 points [95% CI -0.10 to 1.29] p=0.028). While all individual nasal symptoms contributed to this effect, rhinorrhea (p=0.013) and congestion (p=0.076) contributed the most. Consistently, nasal secretion weight was slightly reduced with Callergin (p=0.119). VisAlpin improved nasal symptoms, but not significantly in either analysis.

The incidence of adverse events was similar among treatment groups.

Conclusion

Prophylactic treatment with Callergin is safe and alleviates nasal symptoms in adults with grass pollen allergy.

Trial registration

NCT04531358
Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation
Authors: Rödström Karin E.J. , Cloake Alexander , Sörmann Janina , Baronina Agnese , Smith Kathryn H.M. , Pike Ashley C.W. , Ang Jackie , Proks Peter , Schewe Marcus , Holland-Kaye Ingelise , Bushell Simon R. , Elliott Jenna , Pardon Els , Baukrowitz Thomas , Owens Raymond J. , Newstead Simon , Steyaert Jan , Carpenter Elisabeth P. , Tucker Stephen J.
Published: October 2023

Potassium channels of the Two-Pore Domain (K2P) subfamily,KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+channel superfamily. To address the issue of selectivity, we generated camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+channel and identified selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. It also facilitated design of a biparatropic inhibitory nanobody with markedly improved affinity and efficacy. These new tools therefore provide important insights into TREK channel gating and suggest alternative, highly selective approach to modulation of K2P channel activity via their extracellular domains.
VRP Assembler: haplotype-resolvedde novoassembly of diploid and polyploid genomes using quantum computing
Authors: Chen Yibo , Huang Jun-Han , Sun Yuhui , Zhang Yong , Li Yuxiang , Xu Xun
Published: October 2023

Precision medicine’s emphasis on individual genetic variants highlights the importance of haplotype-resolved assembly, a computational challenge in bioinformatics given its combinatorial nature. While classical algorithms have made strides in addressing this issue, the potential of quantum computing remains largely untapped. Here, we present the VRP assembler: a novel approach that transforms this task into a vehicle routing problem, a combinatorial optimization problem solvable on a quantum computer. We demonstrate its potential and feasibility through a proof of concept on short synthetic diploid and triploid genomes using a D-Wave quantum annealer. To tackle larger-scale assembly problems, we integrate the VRP assembler with Google’s OR-Tools, achieving a haplotype-resolved assembly across the human major histocompatibility complex (MHC) region. Our results show encouraging performance compared to hifiasm with the phasing accuracy first approaching the theoretical limit, underscoring the promising future of quantum computing in bioinformatics.
The role of positively charged small biomolecules in the aggregation of hyperphosphorylated tau in Alzheimer’s disease
Authors: Lee Jinmin , Lee Kyubin , Kim Min Soo , Kim Min Wook , Lim Manho , Yoo Jejoong , Lee Sang Hak
Published: October 2023

Tau proteins have recently drawn attention as a possible cause of Alzheimer’s disease (AD)-associated neuronal dementia. Hyperphosphorylated tau proteins detach from microtubules, impairing their stability and leading to neuronal degeneration. The present study focuses on understanding the molecular mechanisms behind the aggregation of hyperphosphorylated tau. Since hyperphosphorylated proteins are highly negatively charged, it is implausible that they create the damaging aggregates in the absence of some counteracting positive charge. This study found such an electrostatic (charge-charge) interaction between tau proteins and polyamines, identifying this interaction as crucial to promoting tau aggregation. In this study, we also directly observed the transition over time from tau protein aggregates to fibril structures. These findings challenge existing theories and offer insights into potential therapeutic targets for AD.
Herb-CMap: Novel Hot Diffusion Algorithm to Identify Bioactive Ingredients from Herbal Medicine Based on Gene Perturbation Profiling
Authors: Wang Yinyin , Sui Yihang , Yao Jiaqi , Hong Jiang , Tian Qimeng , Tang Yun , Tang Jing , Tan Ninghua
Published: October 2023

Herbal medicine, especially Traditional Chinese medicine (TCM), is a valuable resource of natural products for drug discovery with obvious therapeutic effects. However, the mechanisms of action (MOAs) of herbal medicine are often unknown due to limited target information and the complexity of multiple ingredients and targets. This study developed a Herb-CMap algorithm to prioritize active ingredients and targets within herbal medicine by integrating transcriptomics- based gene perturbation data with a random walk algorithm. This methodology bridges the gap between gene perturbation of herbal medicine and its therapeutic target. Using the Suhuang antitussive capsule (Suhuang) for treating cough variant asthma (CVA) as a case study, we identify and experimentally verify that quercetin and luteolin directly interact with Il17a, Pik3cb, Pik3cd, Akt1, and Tnf. These interactions inhibit the IL-17 signaling pathway and inactivate PI3K, Akt, and NF- κB, preventing lung inflammation and treating CVA. Our findings demonstrate the potential of the Herb-CMap methodology to provide insights into the molecular MOAs of herbal medicine, thereby advancing drug discovery from herbal medicine.
Screening for links between behaviour and acute hyperthermia and hypoxia resistance in rainbow trout using isogenic lines
Authors: Lagarde H. , Lallias D. , Phocas F. , Goardon L. , Bideau M. , Guyvarc’h F. , Labbé L. , Dupont-Nivet M. , Cousin X.
Published: October 2023

In the context of adaptation to climate change, acute hyperthermia and hypoxia resistance are traits of growing interest in aquaculture. The feasibility of genetic improvement of these resistance traits through selection has been demonstrated in rainbow trout (Oncorhynchus mykiss). The present paper aims to test whether behaviour may be associated with acute hyperthermia and hypoxia resistance to better characterize these resistance phenotypes. For this, six rainbow trout isogenic lines were phenotyped for behaviour variables and for acute hyperthermia and hypoxia resistance, using different individuals for each phenotype. The behaviour variables of the fish were phenotyped using an individual test in a new environment. The experimental design used 150 fish phenotyped per isogenic line for each resistance trait and 18 fish per isogenic line for behavioural traits, distributed in triplicates. Relations between acute hyperthermia and hypoxia resistance phenotypes and behaviour phenotypes were tested at the level of isogenic lines.

Significant differences in behaviour between isogenic lines were found, with some behaviour variables being highly associated with hypoxia resistance and moderately associated with acute hyperthermia resistance. Travelling distance, frequency of change between a risky and a safe zone of the tank and the percentage of time in movement in the behaviour test were strongly positively associated with acute hypoxia resistance. Travelling distance and frequency of change between a risky and a safe zone of the tank in the behaviour test were slightly negatively associated with acute hyperthermia resistance. This previously unstudied link between behaviour and resistance phenotypes also suggests that some behaviour variables could be used as predictors for acute hyperthermia and hypoxia resistance in fish. This result could lead to more ethical acute hyperthermia and hypoxia resistance phenotyping protocols, as the current protocols in use are classified as severe by French ethics committees.
Modulation ofα-Synuclein Aggregation Amid Diverse Environmental Perturbation
Authors: Wasim Abdul , Menon Sneha , Mondal Jagannath
Published: October 2023

Intrinsically disordered proteinα-Synuclein (αS) is implicated in Parkinson’s disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process ofαS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation ofαS in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension ofαS droplet responds differently to crowders (entropy-driven) and salt (enthalpy-driven). Conformational analysis reveals that the IDP chains would adopt extended conformations within aggregates and would maintain mutually perpendicular orientations to minimize inter-chain electrostatic repulsions. The droplet stability is found to stem from a diminished intra-chain interactions in the C-terminal regions ofαS, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifiessmall-world-like networkswithin droplets across environmental conditions, suggesting the prevalence of a consensus interaction patterns among the chains. Together these findings suggest a delicate balance between molecular grammar and environment-dependent nuanced aggregation behaviour ofαS.
Thiolation-Based Protein-Protein Hydrogels for Improved Wound Healing
Authors: Liu Xing , Wang Jie , Guo Zhao , Shen Wenting , Jia Zhenzhen , Jia Shuang , Li Limiao , Wang Jieqi , Wang Liping , Li Jiaqi , Chen Yufang , Sun Yinan , Zhang Min , Bai Jia , Wang Liyao , Li Xinyu
Published: October 2023

The limitations of protein-based hydrogels, including their insufficient mechanical properties and restricted biological functions, arise from the highly specific functions of proteins as natural building blocks. A potential solution to overcome these shortcomings is the development of protein-protein hydrogels, which integrate structural and functional proteins. In this study, we introduce a protein-protein hydrogel formed by crosslinking bovine serum albumin (BSA) and a genetically engineered intrinsically disordered collagen-like protein (CLP) through Ag-S bonding. Our approach involves thiolating lysine residues of BSA and crosslinking CLP with Ag+ions, utilizing thiolation of BSA and the free-cysteines of CLP. The resulting protein-protein hydrogels exhibit exceptional properties, including notable plasticity, inherent self-healing capabilities, and gel-sol transition in response to redox conditions. Furthermore, in comparison to standalone BSA hydrogels, these protein-protein hydrogels demonstrate remarkable antibacterial properties, enhanced cellular viability, and improved cellular migration. In vivo experiments provide conclusive evidence of accelerated wound healing, observed not only in murine models with streptozotocin (Step)-induced diabetes but also in zebrafish models subjected to UV-burn injuries. Detailed mechanistic insights, combined with assessments of pro-inflammatory cytokines and the expression of epidermal differentiation-related proteins, robustly validate the protein-protein hydrogel’s effectiveness in promoting wound repair. This pioneering approach advances the development of protein-protein hydrogels and serves as a reference for the creation of multifunctional protein-based hydrogels.
Mining the heparinome for cryptic antimicrobial peptides that selectively kill gram-negative bacteria
Authors: Sandín Daniel , Valle Javier , Gómez Jordi , Comas Laura , Nieves Larrosa María , González-López Juan José , Jiménez María Ángeles , Andreu David , Torrent Marc
Published: October 2023

Glycosaminoglycan (GAG)-binding proteins regulating essential processes such as cell growth and migration are essential for cell homeostasis. As both GAGs and the lipid A disaccharide core of gram-negative bacteria contain negatively charged disaccharide units, we hypothesized that GAG-binding proteins could also recognize LPS and enclose cryptic antibiotic motifs. Here, we report novel antimicrobial peptides (AMPs) derived from heparin-binding proteins (HBPs), with specific activity against gram-negative bacteria and high LPS binding. We used computational tools to locate antimicrobial regions in 82% of HBPs, most of those colocalizing with putative heparin binding sites. To validate these results, we synthesized five candidates [HBP1-5] that showed remarkable activity against gram-negative bacteria, as well as a strong correlation between heparin and LPS binding. Structural characterization of these AMPs shows that heparin or LPS recognition promotes a conformational arrangement that favors binding. Among all analogs, HBP-5 displayed the highest affinity for both heparin and LPS, with antimicrobial activities against gram-negative bacteria at the nanomolar range. These results suggest that GAG-binding proteins are involved in LPS recognition, which allows them to act also as antimicrobial proteins. Some of the peptides reported here, particularly HBP-5, constitute a new class of AMPs with specific activity against gram-negative bacteria.
Identification of single nucleotide genetic polymorphism sites using machine learning methods
Authors: Yatskou Mikalai M. , Smolyakova Elizabeth V. , Skakun Victor V. , Grinev Vasily V.
Published: October 2023

The paper presents an algorithm for simulation modelling of nucleotide variations in the genomic DNA molecule. To identify single nucleotide genetic polymorphisms, it is proposed to use machine learning methods trained on simulated data. A comparative analysis of the effective classical and machine learning algorithms for identifying single nucleotide polymorphisms was performed on simulated data. The most optimal method for identifying single nucleotide genetic polymorphisms in DNA molecules at various experimental noise levels is the machine learning algorithm CART.
Effects of rumen-bypass protein supplement on growth performance, hepatic mitochondrial protein complexes, and hepatic immune gene expression of beef steers with divergent residual feed intake
Authors: Idowu Modoluwamu , Taiwo Godstime , Sidney Taylor , Treon Emily , Leal Yarahy , Ologunagba Deborah , Eichie Francisca , Pech-Cervantes Andres , Ogunade Ibukun M.
Published: October 2023

We investigated the impact of a rumen-bypass protein supplement on growth performance, plasma and urinary N concentration, hepatic mitochondrial protein complexes, and hepatic mRNA expression of immune genes of beef steers with negative or positive residual feed intake (RFI) phenotype. Forty crossbred beef steers with an average body weight (BW) of 492 ± 36 kg were subjected to a generalized randomized block design over a 42-day experimental period. This study followed a 2 × 2 factorial arrangement of treatments. The factors evaluated were: 1) RFI classification (low-RFI (−2.12 kg/d) vs. high-RFI (2.02 kg/d), and 2) rumen-bypass protein supplement: rumen-bypass protein supplement (RCP; 227 g/steer/d) vs. control diet (CON; 0 g/d), resulting in four distinct treatments: Low-RFI-CON (n = 10), low-RFI-RCP (n = 10), high-RFI-CON (n = 10), and high-RFI-RCP (n = 10). The rumen-bypass protein supplement (84% CP) is a mixture of hydrolyzed feather meal, porcine blood meal, and DL-methionine hydroxy analogue. The beef steers were stratified by BW and randomly assigned to treatments and housed in four pens (1 treatment/pen) equipped with two GrowSafe feed bunks each to measure individual DMI. Body weight was measured every 7 d. Liver tissue samples were collected on d 42 from all the beef steers. These samples were used for mRNA expression analysis of 16 immune-related genes and for evaluating the mitochondrial protein complexes I - V. No significant effects due to RCP supplementation or RFI × RCP interactions (P> 0.05) were observed for ADG and DMI. However, compared to high-RFI steers, low-RFI steers showed a trend towards reduced DMI (12.9 vs. 13.6 kg/d;P= 0.07) but ADG was similar for the two RFI groups. Regardless of RFI status, supplemental RCP increased blood urea nitrogen (BUN) (P= 0.01), with a lower BUN concentration in low-RFI steers compared to high-RFI ones. A tendency for interaction (P= 0.07) between RFI and RCP was detected for urinary N concentrations; feeding RCP diet increased the urinary concentration of urea-N in high-RFI beef steers (209 vs. 124 mM), whereas the concentration was lower than that of the CON group for low-RFI beef steers (86 vs. 131 mM). Interactions of RCP and RFI were observed (P≤ 0.05) for mitochondrial activities of complexes IV, V, and mRNA expressions of some immune genes such asTLR2, TLR3, andIL23A. In conclusion, while RCP supplementation didn’t alter growth performance, its observed effects on hepatic immune gene expression, mitochondrial protein complexes, BUN, and urinary urea nitrogen depended on the beef steers’ RFI phenotype. Further studies are warranted to understand the mechanisms underpinning the interactions between RCP supplementation and RFI status.
Role of the prefrontal cortex in musical and verbal short-term memory: A functional near-infrared spectroscopy study
Authors: Ginzburg Jérémie , Cheylus Anne , Collard Elise , Ferreri Laura , Tillmann Barbara , Moulin Annie , Caclin Anne
Published: October 2023

Auditory short-term memory (STM) is a key process in auditory cognition, with evidence for partly distinct networks subtending musical and verbal STM. The delayed matching-to-sample task (DMST) paradigm has been found suitable for comparing musical and verbal STM and for manipulating memory load. In this study, musical and verbal DMSTs were investigated with measures of activity in frontal areas with functional near-infrared spectroscopy (fNIRS): Experiment 1 compared musical and verbal DMSTs with a low-level perception task (that does not entail encoding, retention, or retrieval of information), to identify frontal regions involved in memory processes. Experiment 2 manipulated memory load for musical and verbal materials to uncover frontal brain regions showing parametric changes in activity with load and their potential differences between musical and verbal materials. A FIR model was used to deconvolute fNIRS signals across successive trials without making assumptions with respect to the shape of the hemodynamic response in a DMST. Results revealed the involvement of the dorso-lateral prefrontal cortex (dlPFC) and inferior frontal gyri (IFG), but not of the superior frontal gyri (SFG) in both experiments, in keeping with previously reported neuroimaging data (including fMRI). Experiment 2 demonstrated a parametric variation of activity with memory load in bilateral IFGs during the maintenance period, with opposite directions for musical and verbal materials. Activity in the IFGs increased with memory load for verbal sound sequences, in keeping with previous results with n-back tasks. The decreased activity with memory load observed with musical sequences is discussed in relation to previous research on auditory STM rehearsal strategies. This study highlights fNIRS as a promising tool for investigating musical and verbal STM not only for typical populations, but also for populations with developmental language disorders associated with functional alterations in auditory STM.
Uncoupling protein 1-driven Cre (Ucp1-Cre) is expressed in the epithelial cells of mammary glands and various non-adipose tissues
Authors: Kim Kyungchan , Wann Jamie , Kim Hyeong-Geug , So Jisun , Rosen Evan D. , Roh Hyun Cheol
Published: October 2023

Objective

Uncoupling protein 1 (UCP1), a mitochondrial protein responsible for nonshivering thermogenesis in adipose tissue, serves as a distinct marker for thermogenic brown and beige adipocytes.Ucp1-Cremice are thus widely used to genetically manipulate these thermogenic adipocytes. However, evidence suggests that UCP1 may also be expressed in non-adipocyte cell types. In this study, we investigated the presence of UCP1 expression in different mouse tissues that have not been previously reported.

Methods

We employedUcp1-Cremice crossed with Cre-inducible transgenic reporter Nuclear tagging and Translating Ribosome Affinity Purification (NuTRAP) mice, to investigateUcp1-Creexpression in various tissues of adult female mice and developing embryos. Tamoxifen-inducibleUcp1-CreERT2mice crossed with NuTRAP mice were used to assess active UCP1 expression. Immunostaining, RNA analysis, and single-cell/nucleus RNA-seq (sc/snRNA-seq) data analysis were performed to determine the expression of endogenous UCP1 andUcp1-Cre-driven reporter expression. We also investigated the impact of UCP1 deficiency on mammary gland development and function usingUcp1-knockout (KO) mice.

Results

Ucp1-Creexpression was observed in the mammary glands within the inguinal white adipose tissue of femaleUcp1-Cre; NuTRAP mice. However, endogenousUcp1was not actively expressed asUcp1-CreERT2failed to induce the reporter expression in the mammary glands.Ucp1-Crewas activated during embryonic development in various tissues, including mammary glands, as well as in the brain, kidneys, eyes, and ears, specifically in epithelial cells in these organs. While sc/snRNA-seq data suggest potential expression of UCP1 in mammary epithelial cells in adult mice and humans,Ucp1-KO female mice displayed normal mammary gland development and function.

Conclusions

Our findings reveal widespreadUcp1-Creexpression in various non-adipose tissue types, starting during early development. These results highlight the importance of exercising caution when interpreting data and devising experiments involvingUcp1-Cremice.
Directional predictions of HIV transmission with optimised genomics in cohorts of serodiscordant couples
Authors: Zhao Lele , Hall Matthew , Wymant Chris , Abeler-Dörner Lucie , Otecko Newton , MacIntyre-Cockett George , Chaudron Sandra E. , Thomson Laura , Golubchik Tanya , Lingappa Jairam , Ferretti Luca , Lythgoe Katrina , Fraser Christophe , Herbeck Joshua , Bonsall David ,   the PANGEA consortium
Published: October 2023

Viral genetic information from people living with HIV can deepen our understanding of the infection’s epidemiology at many scales. To better understand the potentials and limits of tools that utilise such information, we show the performance of two representative tools (HIV-TRACEandphyloscanner) in describing HIV transmission dynamics, with different types of genetic data, and compare with previous findings. The samples were collected from three cohort studies in Sub-Saharan Africa and were deep sequenced to produce both short Illumina reads and long PacBio reads. By comparingphyloscanner’s performance with short and long reads, we show that long reads provide improved phylogenetic resolution for the classic transmission topology in joint within-host trees. Our pipeline accurately predicted the direction of transmission 88%-92% of the time. We also show that the timing of sample collection plays an important role in the reconstruction of directionality using deep sequencing data. Consensus sequences were also generated and used asHIV-TRACEinput to show different patterns of clustering sensitivity and specificity for data from different genomic regions or the entire genome. Finally, we discuss adjusting expectations about sensitivity and specificity of different types of sequence data, considering rapid pathogen evolution, and highlight the potentials of high within-host phylogenetic resolution in HIV. In conclusion, viral genetic data collected and presented differently could greatly influence our ability to describe the underlying dynamics. Methods for source attribution analysis have reached levels of superior accuracy. However, residual uncertainty emphasizes sequence analysis alone cannot conclusively prove linkage at the individual level.

Importance

Understanding HIV transmission dynamics is key to designing effective HIV testing and prevention strategies. By using different sequencing techniques on well-characterised cohorts, we were able to evaluate the effect of genetic data resolution on the accuracy of identifying likely transmission pairs and the direction of transmission within pairs. We find that the longer reads generated by PacBio sequencing are more suitable for transmission analyses.
Bilateral Intracortical Inhibition during Unilateral Motor Preparation and Sequence Learning
Authors: Hamel R. , Waltzing B. M. , Hinder M.R. , McAllister C. , Jenkinson N. , Galea J.M
Published: October 2023

Motor sequence learning gradually quickens reaction time, suggesting that sequence learning alters motor preparation processes. Interestingly, evidence has shown that preparing sequence movements decreases short intracortical inhibition (SICI) in the contralateral motor cortex (M1), but also that sequence learning alters motor preparation processes in both the contralateral and ipsilateral M1s. Therefore, one possibility is that sequence learning alters the SICI decreases occurring during motor preparation in bilateral M1s. To examine this, two novel hypotheses were tested: unilateral sequence preparation would decrease SICI in bilateral M1s, and sequence learning would alter such bilateral SICI responses. Paired-pulse transcranial magnetic stimulation was delivered over the contralateral and ipsilateral M1s to assess SICI in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. In the absence of sequence learning, SICI decreased in both the contralateral and ipsilateral M1s during the preparation of sequences initiated by the right index finger, suggesting that SICI decreases in bilateral M1s during unilateral motor preparation. As sequence learning progressed, SICI decreased in the contralateral M1 whilst it increased in the ipsilateral M1. Moreover, these bilateral SICI responses were observed at the onset of motor preparation, suggesting that sequence learning altered baseline SICI levels rather than the SICI decreases occurring during motor preparationper se. Altogether, these results suggest that SICI responses in bilateral M1s reflect two motor processes: an acute decrease of inhibition during motor preparation, and a cooperative but bidirectional shift of baseline inhibition levels as sequence learning progresses.
Load modulation affects pediatric lower limb joint moments during a step-up task
Authors: Goyal Vatsala , Gordon Keith E. , Sukal-Moulton Theresa
Published: October 2023

Performance in a single step has been suggested to be sensitive measure of movement quality in pediatric clinical populations. Although there is less information available in children with typical development, researchers have postulated the importance of analyzing the effect of body weight modulation on the initiation of stair ascent, especially during single limb stance where upright stability is most critical. The purpose of this study was to investigate the effect of load modulation from -20% to +15% of body weight on typical pediatric lower limb joint moments during a step-up task. Fourteen participants between 5-21 years with no known history of neurological or musculoskeletal concerns were recruited to perform multiple step-up trials. Peak extensor support and hip abduction moments were identified during the push-off and pull-up stance phases. Linear regressions were used to determine the relationship between peak moments and load. Mixed effects models were used to estimate the effect of load on hip, knee, and ankle percent contributions to peak support moments. There was a positive linear relationship between peak support moments and load in both stance phases, where these moments scaled with load. There was no relationship between peak hip abduction moments and load. While the ankle and knee were the primary contributors to the support moments, the hip contributed more than expected in the pull-up phase. Clinicians can use these results to contextualize movement differences in pediatric clinical populations including cerebral palsy and highlight potential target areas for rehabilitation for populations such as adolescent athletes.
Perceptions and responses to COVID-19 through wastewater surveillance information and online search behavior: A randomized controlled trial
Authors: Murakami Michio , Nomura Shuhei , Ando Hiroki , Kitajima Masaaki
Published: October 2023

Wastewater surveillance is anticipated to be a representative and timely method to assess infectious disease status; however, its influence on public perception and behavior remains unclear. Therefore, in this study, we used a randomized controlled trial to analyze the influence of wastewater surveillance-based information on understanding of, interest in, relief regarding, preventive behavioral intention against, and subsequent online search behavior related to coronavirus disease 2019 (COVID-19). Valid responses were obtained from 1,000 individuals in both control and intervention groups from Yahoo crowdsourcing users aged ≥18 years in Japan. This survey was conducted from August 4 to August 7, 2023, just before the common Japanese tradition of returning to hometowns. The questionnaire not only collected personal attributes but also gauged responses to COVID-19 information. This information highlighted the early detection capabilities and representativeness of wastewater surveillance compared with sentinel surveillance at medical institutions. At one-week post-survey, we obtained the survey participants’ online search history for key words such as “bullet train,” “highway,” “airplane,” and “wastewater.” The findings showed no significant differences between the two groups in terms of COVID-19 interest or preventive behavior before information provision, verifying the effectiveness of participant randomization. Wastewater surveillance-based information did not notably elevate understanding or specific intentions regarding COVID-19, such as wearing masks and receiving vaccination. However, it significantly increased interest in, relief concerning the infection status, and general preventive behavioral intentions. Heightened interest and general preventive intentions did not depend on prior interest or behavior. However, those who previously engaged in preventive behavior or who were less interested in COVID-19 exhibited more relief after exposure to wastewater surveillance-based information. Furthermore, this information could slightly influence online searches related to return travel modes, such as highways. In conclusion, information from wastewater surveillance effectively shapes individual perceptions of and responses to infections.
Changing patterns of cigarette and ENDS transitions in the USA: a multistate transition analysis of adults in the PATH Study in 2017–2019 vs 2019–2021
Authors: Brouwer Andrew F. , Jeon Jihyoun , Jimenez-Mendoza Evelyn , Land Stephanie R. , Holford Theodore R. , Friedman Abigail S. , Tam Jamie , Mistry Ritesh , Levy David T. , Meza Rafael
Published: October 2023

Introduction

The use of cigarettes and electronic nicotine delivery system (ENDS) has likely changed since 2019 with the rise of pods and disposables, the outbreak of lung injuries related to vaping THC, flavor bans, and the COVID pandemic. We analyzed patterns of initiation, cessation, and transitions between cigarettes, ENDS, and dual use before and after 2019.

Methods

Using the Population Assessment of Tobacco and Health (PATH) Study, we applied a multistate transition model to 28,061 adults in Waves 4–5 (2017–19) and 24,751 adults in Waves 5–6 (2019–21), estimating transition rates for initiation, cessation, and switching products for each period overall and by age group.

Results

Cigarette initiation among adults who never used either product decreased from 2017–19 to 2019–21, but ENDS initiation did not significantly change. Persistence of ENDS-only use remained high, with 75–80% still using ENDS only after 1 year. Cigarette-only use transitions remained similar, with about 88% remaining, 7% transitioning to non-current use, and 5% transitioning to dual or ENDS-only use. In contrast, dual use to ENDS-only transitions increased from 9.5% (95%CI: 7.3–11.7%) to 20.1% (95%CI: 17.5–22.7%) per year from 2017–19 to 2019–21, decreasing the persistence of dual use. The dual use to cigarette-only transition remained at about 25%. These changes were qualitatively similar across adult age groups, though adults ages 18–24 years exhibited the highest probability of switching from cigarette-only use to dual use and from dual use to ENDS-only use.

Conclusions

Persistence of ENDS use among adults remained high in 2019–21, but a larger fraction of dual users transitioned to ENDS-only use compared to 2017–19. Because the fraction of cigarette-only users switching to dual use remained low, the public health implications of the increased dual use to ENDS-only transition are minimal.
How does the proportion of never treatment influence the success of mass drug administration programmes for the elimination of lymphatic filariasis?
Authors: Kura Klodeta , Stolk Wilma A. , Basáñez Maria-Gloria , Collyer Benjamin S. , de Vlas Sake J. , Diggle Peter J , Gass Katherine , Graham Matthew , Hollingsworth T. Déirdre , King Jonathan D. , Krentel Alison , Anderson Roy M. , Coffeng Luc E.
Published: October 2023

Background

Mass drug administration (MDA) is the cornerstone for the elimination of lymphatic filariasis (LF). The proportion of the population that is never treated (NT) is a crucial determinant of whether this goal is achieved within reasonable timeframes.

Methods

Using two individual-based stochastic LF transmission models, we assess the maximum permissible level of NT for which the 1% mf prevalence threshold can be achieved (with 90% probability) within 10 years under different scenarios of annual MDA coverage, drug combination and transmission setting.

Results

ForAnopheles-transmission settings, we find that treating 80% of the eligible population annually with ivermectin+albendazole (IA) can achieve the 1% mf prevalence threshold within 10 years of annual treatment when baseline mf prevalence is 10%, as long as NT <10%. Higher proportions of NT are acceptable when more efficacious treatment regimens are used. ForCulex-transmission settings with a low (5%) baseline mf prevalence and Diethylcarbamazine+Albendazole (DA) or Ivermectin+Diethylcarbamazine+Albendazole (IDA) treatment, elimination can be reached if treatment coverage among eligibles is 80% or higher. For 10% baseline mf prevalence, the target can be achieved when the annual coverage is 80% and NT ≤15%. Higher infection prevalence or levels of NT would make achieving the target more difficult.

Conclusions

The proportion of people never treated in MDA programmes for LF can strongly influence the achievement of elimination and the impact of NT is greater in high transmission areas. This study provides a starting point for further development of criteria for the evaluation of NT.
Sex differences in ADHD diagnosis and clinical care: A national study of population healthcare records in Wales
Authors: Martin Joanna , Langley Kate , Cooper Miriam , Rouquette Olivier Y. , John Ann , Sayal Kapil , Ford Tamsin , Thapar Anita
Published: October 2023

Background

Population-based studies have observed sex biases in the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD). Females are less likely to be diagnosed or prescribed ADHD medication. This study uses national healthcare records, to investigate sex differences in diagnosis and clinical care in young people with ADHD, particularly regarding recognition and treatment of other mental health conditions.

Method

The cohort included individuals diagnosed with ADHD, born between 1989 and 2013 and living in Wales between 2000 and 2019. Routine primary and secondary healthcare record data were used to derive diagnoses of ADHD and other neurodevelopmental and mental health conditions, as well as ADHD and antidepressant medications. Demographic variables included ethnicity, socioeconomic deprivation, and contact with social services.

Results

There were 16,458 individuals diagnosed with ADHD (20.3% females, ages 3–30 years), with a male-to-female ratio of 3.9:1. Higher ratios (4.8:1) were seen in individuals diagnosed younger (<12 years), with the lowest ratio (1.9:1) in those diagnosed as adults (>18). Males were younger at first recorded ADHD diagnosis (mean=10.9 vs 12.6 years), more likely to be prescribed ADHD medication, and younger at diagnosis of co-occurring neurodevelopmental conditions. In contrast, females were more likely to receive a diagnosis of anxiety, depression, or another mental health condition and to be prescribed antidepressant medications, prior to ADHD diagnosis. These sex differences were largely stable across demographic groups.

Conclusion

This study adds to the evidence base that females with ADHD are experiencing later recognition and treatment of ADHD. The results indicate that this may be partly because of diagnostic over-shadowing from other mental health conditions, such as anxiety and depression, or initial misdiagnosis. Further research and dissemination of findings to the public are needed to improve awareness, timely diagnosis, and treatment of ADHD in females.
Postacute Sequelae SARS-CoV-2 Infection by Vaccination Status: A Six-Month Latent Class Analysis
Authors: Sun Xiaowu , DeShazo Jonathan P. , Anatale-Tardiff Laura , Fusco Manuela Di , Allen Kristen E. , Porter Thomas M. , Coetzer Henriette , Lopez Santiago M.C , Puzniak Laura , Cappelleri Joseph C.
Published: October 2023

Symptoms post-SARS-CoV-2 infection may persist for months and cause significant impairment and impact to quality of life. Acute symptoms of SARS-CoV-2 infection are well studied, yet data on clusters of symptoms over time, or postacute sequelae of SARS-CoV-2 infection (PASC), are limited. We aim to characterize PASC phenotypes by identifying symptom clusters over a six-month period following infection in individuals vaccinated (boosted and not) and those unvaccinated.

Subjects with ≥1 self-reported symptom and positive RT-PCR for SARS-CoV-2 at CVS Health US test sites were recruited between January and April 2022. Patient-reported outcomes symptoms, heath-related quality of life (QoL), work productivity and activity impairment (WPAI) were captured at 1 month, 3 months, and 6 months post-acute infection.

Logistic regression and latent class analysis (LCA) were performed on 20 symptoms using baseline socio-demographic, clinical characteristics, and vaccination status as well as EQ-5and WPAI results as covariables. Subjects with more symptoms were associated with lower health-related quality of life, and worse WPAI scores.

LCA identified three phenotypes that are primarily differentiated by number of symptoms. These three phenotypes remained consistent across time periods. Vaccinated individuals were more likely to be in the low symptom burden latent classes at all time points compared to unvaccinated individuals.
Spatial mapping of rheumatoid arthritis synovial niches reveals specific macrophage networks associated with response to therapy
Authors: De Lima Julien , Boutet Marie-Astrid , Bortolotti Olivier , Chépeaux Laure-Agnès , Glasson Yaël , Dumé Anne-Sophie , Le Pluart Adrien , Nerviani Alessandra , Fossati-Jimack Liliane , Michaud Henri-Alexandre , Guicheux Jérôme , Goff Benoit Le , Pitzalis Costantino , Courties Gabriel , Apparailly Florence , Blanchard Frederic
Published: October 2023

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting peripheral joints and for which approximately 40% of the patients respond insufficiently to the available synthetic or biologic disease modifying anti-rheumatic drugs (DMARDs). The infiltration of the synovial membrane by lymphocytes and monocytes profoundly alters its homeostatic functions, leading to chronic joint inflammation and bone destruction. A better understanding of how DMARDs impact the complex synovial cell social network in relationship to response/ non-response remains an unmet need to design more targeted and active therapeutic strategies. Here, we used imaging mass cytometry (IMC) to comparatively profile more than 115,000 cells in the synovial tissue of healthy, low inflammatory osteoarthritis and matched active early treatment-naïve RA patients at baseline and at 6 months after starting DMARDs treatment. We notably highlighted that tissue resident macrophages (LYVE1+CD206+) in perivascular synovial niches encompassing specific subsets of vascular cells, fibroblasts and immune cells vanished in active RA but were recovered in response to DMARDs treatment. Combined ligand-receptor analysis of single-cell RNA sequencing datasets identified that IL10, C-type lectin or TAM (TYRO3, AXL and MERTK) receptors were particularly involved in the restoration of these spatial cell interactions in the context of clinical remission. In addition to providing an unprecedented synovial spatial mapping, our work uncovered novel potential cellular and molecular targets for the development of therapies for RA.

One Sentence Summary

Single-cell spatial profiling of rheumatoid arthritis synovium identifies specific cell states linked to treatment response