bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining Key Features in Patient Perspectives of Hand Aesthetics
Authors: Joo Alex , Phelan Alannah L. , Xu Jing , Gu Garrick , Karpuk John , Qin Baijing , Li Alexander , Chiu David , Rothkopf Douglas M.
Published: March 2023

Background

The hand is highly visible and contributes to an individual's aesthetic image and perceived age. Current perspectives on hand aesthetics are primarily based on expert opinion rather than on lay population perspectives, which are less understood. Our study explores general population perceptions on the features that contribute most to an attractive hand.

Methods

Participants rated the attractiveness of 20 standardized hands as well as the appearance based on each characteristic: freckles, hair presence, skin tone, wrinkles, vein appearance, and soft tissue volume. The relative importance of each feature was assessed by comparison with overall attractiveness scores through multivariate analysis of variance.

Results

A total of 223 participants completed the survey. Soft tissue volume (r = 0.73) was most strongly correlated with overall attractiveness, followed by wrinkles (r = 0.71), skin tone consistency (r = 0.69), veins (r = 0.65), freckles (r = 0.61), and hair (r = 0.47). Female hands were perceived as more attractive, with a mean rating of 4.7 of 10, compared with 4.4 in males (P < 0.001). Participants correctly identified the gender of 90.4% of male hands and 65.0% of female hands. Age was strongly inversely correlated with attractiveness (r = −0.80).

Conclusions

Soft tissue volume is the most important factor in lay perception of hand aesthetics. Female and younger hands were perceived as more attractive. Hand rejuvenation may be optimized by prioritizing soft tissue volume with filler or fat grafting, with secondary priority on resurfacing to address skin tone and wrinkling. An understanding of the factors most important to patients in aesthetic appearance is critical to achieving a pleasing result.
Back Pain According to Roland-Morris Low Back Pain Scale After Abdominoplasty With Plication
Authors: Patel Sneha D. , Joo Alex , Xu Jing , Palic Armin , Wood Jacob J. , Sirls Evan R. , Tomczyk Eleanor G. , Rothkopf Douglas M.
Published: March 2023

Introduction

Chronic back pain is a physically debilitating condition that affects more than 80% of adults in the United States. A recent case series highlighted how abdominoplasty with plication can offer an alternative surgical approach for treating chronic back pain. These results have been corroborated by a large prospective series. However, this study excluded male and nulliparous subjects, who may also benefit from this surgery. Our group aims to investigate the effect of abdominoplasty on back pain in a more diverse patient population.

Methods

Subjects older than 18 years undergoing abdominoplasty with plication were recruited. An initial survey called the Roland-Morris Disability Questionnaire (RMQ) was administered at the preoperative visit. This questionnaire inquiries about and grades the patient's history of back pain and surgery. Demographic, medical, and social history was also obtained. A follow-up survey and RMQ was then given 6 months after surgery.

Results

Thirty subjects were enrolled. Subjects had a mean age of 43.4 ± 14.3 years. Twenty-eight subjects were female and 26 were postpartum. Twenty-one subjects reported initial back pain on the RMQ scale. Of these, 19 reported a decrease in RMQ score after surgery, including male and nulliparous subjects. A significant decrease in mean RMQ score was demonstrated 6 months after surgery (2.94–0.44, P < 0.001). Further subgroup analysis of female subjects demonstrated significantly decreased final RMQ score in parous women, vaginal or cesarean section delivery, and absence of twin gestation.

Conclusions

Abdominoplasty with plication significantly decreases self-reported back pain 6 months after surgery. These results support that abdominoplasty is not purely a cosmetic procedure but can also be applied therapeutically to improve functional symptoms of back pain.
Disinhibition of short-latency but not long-latency afferent inhibition of the lower limb during upper-limb muscle contraction
Authors: Kato Tatsuya , Sasaki Atsushi , Nakazawa Kimitaka
Published: March 2023

Research has demonstrated that motor and sensory functions of the lower limbs can be modulated by upper-limb muscle contractions. However, whether sensorimotor integration of the lower limb can be modulated by upper-limb muscle contractions is still unknown. [AQ: NR Original articles do not require structured abstracts. Hence, abstract subsections have been deleted. Please check.]Human sensorimotor integration has been studied using short- or long-latency afferent inhibition (SAI or LAI, respectively), which refers to inhibition of motor-evoked potentials (MEPs) elicited via transcranial magnetic stimulation by preceding peripheral sensory stimulation. In the present study, we aimed to investigate whether upper-limb muscle contractions could modulate the sensorimotor integration of the lower limbs by examining SAI and LAI. Soleus muscle MEPs following electrical tibial nerve stimulation (TSTN) during rest or voluntary wrist flexion were recorded at inter-stimulus intervals (ISIs) of 30 (i.e. SAI), 100, and 200 ms (i.e. LAI). The soleus Hoffman reflex following TSTN was also measured to identify whether MEP modulation occurred at the cortical or the spinal level. Results showed that lower-limb SAI, but not LAI, was disinhibited during voluntary wrist flexion. Furthermore, the soleus Hoffman reflex following TSTN during voluntary wrist flexion was unchanged when compared with that during the resting state at any ISI. Our findings suggest that upper-limb muscle contractions modulate sensorimotor integration of the lower limbs and that disinhibition of lower-limb SAI during upper-limb muscle contractions is cortically based.
Ginsenoside Rg1 attenuation of neurogenesis disorder and neuronal apoptosis in the rat hippocampus after spinal cord injury may involve brain-derived neurotrophic factor/extracellular signal-regulated kinase signaling
Authors: Xi Bin , Fu Jieping , Wan Dengfeng , Xie Zhiping
Published: March 2023

Objective

We previously demonstrated that spinal cord injury (SCI) induced hippocampus injury and depression in rodents. Ginsenoside Rg1 effectively prevents neurodegenerative disorders. Here, we investigated the effects of ginsenoside Rg1 on the hippocampus after SCI.

Methods

We used a rat compression SCI model. Western blotting and morphologic assays were used to investigate the protective effects of ginsenoside Rg1 in the hippocampus.

Results

Brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling was altered in the hippocampus at 5 weeks after SCI. SCI attenuated neurogenesis and enhanced the expression of cleaved caspase-3 in the hippocampus; however, ginsenoside Rg1 attenuated cleaved caspase-3 expression and improved neurogenesis and BDNF/ERK signaling in the rat hippocampus. The results suggest that SCI affects BDNF/ERK signaling, and ginsenoside Rg1 can attenuate hippocampal damage after SCI.

Conclusion

We speculate that the protective effects of ginsenoside Rg1 in hippocampal pathophysiology after SCI may involve BDNF/ERK signaling. Ginsenoside Rg1 shows promise as a therapeutic pharmaceutical product when seeking to counter SCI-induced hippocampal damage.
Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin
Authors: Turner A.M. , Li L. , Monk I.R. , Lee J.Y.H. , Ingle D.J. , Portelli S. , Sherry N.L. , Isles N. , Seemann T. , Sharkey L.K. , Walsh C.J. , Reid G.E. , Nie S. , Eijkelkamp B.A. , Holmes N.E. , Collis B. , Vogrin S. , Hiergeist A. , Weber D. , Gessner A. , Holler E. , Ascher D.B. , Duchene S. , Scott N.E. , Stinear T.P. , Kwong J.C. , Gorrie C.L. , Howden B.P. , Carter G.P.
Published: March 2023

Multidrug-resistant bacterial pathogens like vancomycin-resistantEnterococcus faecium(VREfm) are a critical threat to human health. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode-of-action, but for which resistance has surprisingly been widely reported but unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in liver disease patients, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterised operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. Alarmingly, VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered ‘low-risk’ for antibiotic resistance development. Our study shows this assumption is flawed and widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.
Conformations of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoproteins in Detergents and Styrene-Maleic Acid Lipid Particles (SMALPs)
Authors: Zhou Rong , Zhang Shijian , Nguyen Hanh T. , Ding Haitao , Gaffney Althea , Kappes John C. , Smith Amos B. , Sodroski Joseph G.
Published: March 2023

The mature human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer, which consists of non-covalently associated gp120 exterior and gp41 transmembrane subunits, mediates virus entry into cells. The pretriggered (State-1) Env conformation is the major target for broadly neutralizing antibodies (bNAbs), whereas receptor-induced downstream Env conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. To examine the contribution of membrane anchorage to the maintenance of the metastable pretriggered Env conformation, we compared wild-type and State-1-stabilized Envs solubilized in detergents or in styrene-maleic acid (SMA) copolymers. SMA directly incorporates membrane lipids and resident membrane proteins into lipid nanodiscs (SMALPs). The integrity of the Env trimer in SMALPs was maintained at both 4°C and room temperature. By contrast, Envs solubilized in Cymal-5, a non-ionic detergent, were unstable at room temperature, although their stability was improved at 4°C and after incubation with the entry inhibitor BMS-806. Envs solubilized in ionic detergents were relatively unstable at either temperature. Comparison of Envs solubilized in Cymal-5 and SMA at 4°C revealed subtle differences in bNAb binding to the gp41 membrane-proximal external region (MPER), consistent with these distinct modes of Env solubilization. Otherwise, the antigenicity of the Cymal-5- and SMA- solubilized Envs was remarkably similar, both in the absence and presence of BMS-806. However, both solubilized Envs were recognized differently from the mature membrane Env by specific bNAbs and pNAbs. Thus, detergent-based and detergent-free solubilization at 4°C alters the pretriggered membrane Env conformation in consistent ways, indicating that loss of Env association with the membrane results in default state(s).

IMPORTANCE

The human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) in the viral membrane mediate virus entry into the host cell and are targeted by neutralizing antibodies elicited by natural infection or vaccines. Detailed studies of membrane proteins rely on purification procedures that allow the proteins to maintain their natural conformation. In this study, we show that a styrene-maleic acid (SMA) copolymer can extract HIV-1 Env from a membrane without the use of detergents. The Env in SMA is more stable at room temperature than Env in detergents. The purified Env in SMA maintains many but not all of the characteristics expected of the natural membrane Env. Our results underscore the importance of the membrane environment to the native conformation of HIV-1 Env. Purification methods that bypass the need for detergents could be useful tools for future studies of HIV-1 Env structure and its interaction with receptors and antibodies.
Bivalent booster effectiveness against severe COVID-19 outcomes in Finland, September 2022 – March 2023
Authors: Poukka Eero , Nohynek Hanna , Goebeler Sirkka , Leino Tuija , Baum Ulrike
Published: March 2023

Bivalent COVID-19 vaccines were introduced in 2022 but knowledge of their effectiveness against severe COVID-19 outcomes is currently limited. In Finnish register-based cohort analyses, we compared the risk of severe COVID-19 outcomes among those who received bivalent vaccination (exposed) between September 2022 and March 2023 to those who did not (unexposed). Among elderly aged 65–110 years, bivalent vaccination reduced the risk of hospitalisation and death due to COVID-19 in September–December 2022; the hazard ratios comparing exposed and unexposed ranged from 0.37 to 0.45 during the first 31–60 days since bivalent vaccination. However, in January–March 2023 the effect disappeared possibly indicating immune evasion of new SARS-CoV-2 variants, waning of vaccine effectiveness and increased presence of hybrid immunity. Among the chronically ill aged 18–64 years bivalent vaccination did not reduce the risk of severe COVID-19 outcomes. These results are important for developing COVID-19 vaccines and programmes worldwide.
Noise-robust, physical microscopic deconvolution algorithm enabled by multi-resolution analysis regularization
Authors: Hou Yiwei , Wang Wenyi , Fu Yunzhe , Ge Xichuan , Li Meiqi , Xi Peng
Published: March 2023

Despite the grand advances in fluorescence microscopy, the photon budget of fluorescent molecules remains the fundamental limiting factor for major imaging parameters, such as temporal resolution, duration, contrast, and even spatial resolution. Computational methods can strategically utilize the fluorescence photons against the imaging noise, to break the abovementioned limits. Here, we propose a multi-resolution analysis (MRA) approach to recharacterize and extract the two main characteristics of fluorescence images: (1) high contrast across the edge, and (2) high continuity along the edge. By regularizing the solution using framelet and curvelet domain sparsity, we develop MRA deconvolution algorithm for fluorescence image, which allows fine detail recovery even with negative signal-to-noise-ratio (SNR), and can provide more than 2-fold physical resolution enhancement with conspicuously fewer artifacts than maximum likelihood estimation (MLE) methods. Furthermore, we develop DeepMRA deconvolution algorithm that can provide computational background inhibition through a bias thresholding mechanism while deconvolving a fluorescence image. Compared with conventional background mitigation schemes, this novel deconvolution canonical form can deal with severer background and better preserve the high-frequency and low-intensity details, which are commonly disrupted by other algorithms. We demonstrate that the MRA and DeepMRA deconvolution algorithms can improve the SNR and resolution of biological images in various microscopies, such as wide-field, confocal, spinning-disk confocal (SD-confocal), light-sheet, structured illumination microscopy (SIM), and stimulated excitation depletion (STED) microscopy.
Dynamic Bayesian modeling of the social behavior ofDrosophila melanogaster
Authors: Kalaria Kirtan , Mayekar Harshad , Patel Dhaval , Rajpurohit Subhash
Published: March 2023

Organismal behavior has always been a challenge to understand. Insects are one of the amenable systems used to understand behavior. A striking variety of insect behaviors gain support from genetic and physiological studies.Drosophila, a widely studied model organism due to its known molecular pathways, has also been popular in behavioral studies. Several behavioral traits inDrosophilaincluding mating, locomotion, and oviposition choice have been traced to the neuronal level. Yet, the results of behavioral analyses are equivocal since they often overlook the external milieu, such as social context, which evidentially influences behavior. There have been many attempts to modelDrosophilabehavior, however, all have some fundamental issues like lack of complexity, limitation to isolated organisms, and lack of explainability. Here, we model the behavior of a pair ofDrosophila melanogasterflies using a novel Dynamic Bayesian Network based approach to better understand behavior in a social context. Two models are proposed, each of which is further used as a predictor for predicting the behavior of both the flies in the pair. They are evaluated on an existing dataset and achieve a remarkable performance: 98.22% and 98.32% accuracy on the two models. Our modeling approach could be applied in predicting animal behaviors in a wide variety of contexts to support existing behavioral studies.
Genetic Inactivation of β-Catenin Attenuates and Its Activation Aggravates Desmoplakin Cardiomyopathy
Authors: Olcum Melis , Fan Siyang , Rouhi Leila , Cheedipudi Sirisha , Cathcart Benjamin , Jeong Hyun-Hwan , Zhao Zhongming , Gurha Priyatansh , Marian Ali J.
Published: March 2023

Aim

Mutations in theDSPgene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM). It is typically characterized by biventricular enlargement and dysfunction, severe myocardial fibrosis, cell death, and arrhythmias.

The canonical WNT (cWNT)/β-catenin signaling pathway is implicated in the pathogenesis of ACM. Given that β-catenin, an indispensable co-transcriptional regulator of the cWNT pathway, is also a member of the IDs, we genetically inactivated or activated β-catenin to determine its role in the pathogenesis of the desmoplakin cardiomyopathy.

Methods and Results

TheDspgene was conditionally deleted in cardiac myocytes concomitant with the genetic inactivation or activation of β-catenin using the tamoxifen-inducible MerCreMer mice. Inactivation and activation of β-catenin were achieved upon deletion of its transcriptional domain and degrons, respectively. Analysis of cardiac myocytes transcripts and proteins showed marked dysregulation of the cWNT/β-catenin pathway in the DSP-deficient mouse cardiac myocytes (Myh6-McmTam:DspF/F), as indicated by increased expression of cWNT/β-catenin targets along with its inhibitors and isoforms of its key co-effectors. Genetic inactivation of β-catenin in theMyh6-McmTam:DspF/Fmice prolonged survival, improved cardiac function, reduced cardiac arrhythmias, and attenuated myocardial fibrosis, and cell death caused by apoptosis, necroptosis, pyroptosis, i.e., PANoptosis, whereas its activation had the opposite effects. Inactivation of β-catenin was associated with partial restoration of the suppressed genes involved in OXPHOS, whereas its activation has the opposite effect. The beneficial effects were independent of the changes in the transcript levels of the cWNT target genes.

Conclusion

The cWNT/β-catenin was markedly dysregulated in the cardiac myocytes from a mouse model of DC. Inactivation of β-catenin attenuated the phenotype partly through the recovery of OXPHOS genes whereas its activation had deleterious effects. The findings suggest suppression of β-catenin might be beneficial in desmoplakin-cardiomyopathy.

Genetic inactivation of β-catenin improved desmoplakin cardiomyopathy, in part through the restoration of expression of genes involved in oxidative phosphorylation, whereas its activation was deleterious.
Type I interferon dynamics determines memory B cell epigenetic identity in chronic viral infection
Authors: Cooper Lucy , Xu Hui , Polmear Jack , Szeto Christopher , Pang Ee Shan , Gupta Mansi , Taylor Justin J , Jackson Katherine J L , Nguyen Angela , Gruta Nicole La , Martelotto Luciano , Parish Ian A , O’Keeffe Meredith , Scharer Christopher D , Gras Stephanie , Good-Jacobson Kim L
Published: March 2023

Memory B cells are key providers of long-lived immunity against infectious disease, yet in chronic viral infection they do not produce effective protection. How chronic viral infection disrupts memory B cell development, and whether such changes are reversible, remains unknown. Here, we uncover type-I interferon (IFN-I) dynamics as a key determinant in shaping chronic memory B cell development. Through single-cell (sc)ATAC-sequencing and scRNA-sequencing, we identified a unique memory subset enriched for IFN-stimulated genes (ISGs) during chronic lymphocytic choriomeningitis virus infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic memory B cells, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing a phenotypic change in the dominating memory B cell subset. However, timing was critical, with memory B cells resistant to intervention after 4 weeks post-infection. Together, our research identifies a key mechanism to instruct memory B cell identity during viral infection.

One Sentence Summary:IFN dynamics in chronic versus acute viral infection determines memory B cell development.
Neuronal wiring receptors Dprs and DIPs are GPI anchored and this modification contributes to their cell surface organization
Authors: Lobb-Rabe Meike , Nawrocka Wioletta I. , Carrillo Robert A. , Özkan Engin
Published: March 2023

TheDrosophilaDpr and DIP proteins belong to the immunoglobulin superfamily of cell surface proteins (CSPs). Their hetero- and homophilic interactions have been implicated in a variety of neuronal functions, including synaptic connectivity, cell survival, and axon fasciculation. However, the signaling pathways underlying these diverse functions are unknown. To gain insight into Dpr–DIP signaling, we sought to examine how these CSPs are associated with the membrane. Specifically, we asked whether Dprs and DIPs are integral membrane proteins or membrane anchored through the addition of glycosylphosphatidylinositol (GPI) linkage. We demonstrate that Dprs and DIPs are GPI anchored to the membrane of insect cells and validate these findings for some family members in vivo usingDrosophilalarvae, where GPI anchor cleavage results in loss of surface labeling. Additionally, we show that GPI cleavage abrogates aggregation of insect cells expressing cognate Dpr–DIP partners. To test if the GPI anchor affects Dpr–DIP localization, we replaced it with a transmembrane domain and observed perturbation of sub-cellular localization on motor neurons and muscles. These data suggest that membrane anchoring of Dprs and DIPs through GPI linkage is required for localization and that Dpr–DIP intracellular signaling likely requires transmembrane co-receptors.
Transcript Isoform Diversity of Ampliconic Genes on the Y Chromosome of Great Apes
Authors: Tomaszkiewicz Marta , Sahlin Kristoffer , Medvedev Paul , Makova Kateryna D.
Published: March 2023

Y-chromosomal Ampliconic Genes (YAGs) are important for male fertility, as they encode proteins functioning in spermatogenesis. The variation in copy number and expression levels of these multicopy gene families has been recently studied in great apes, however, the diversity of splicing variants remains unexplored. Here we deciphered the sequences of polyadenylated transcripts of all nine YAG families (BPY2,CDY,DAZ,HSFY,PRY,RBMY,TSPY,VCY, andXKRY) from testis samples of six great ape species (human, chimpanzee, bonobo, gorilla, Bornean orangutan, and Sumatran orangutan). To achieve this, we enriched YAG transcripts with capture-probe hybridization and sequenced them with long (Pacific Biosciences) reads. Our analysis of this dataset resulted in several findings. First, we uncovered a high diversity of YAG transcripts across great apes. Second, we observed evolutionarily conserved alternative splicing patterns for most YAG families except forBPY2andPRY. Our results suggest thatBPY2transcripts and predicted proteins in several great ape species (bonobo and the two orangutans) have independent evolutionary origins and are not homologous to human reference transcripts and proteins. In contrast, our results suggest that thePRYgene family, having the highest representation of transcripts without open reading frames, has been undergoing pseudogenization. Third, even though we have identified many species-specific protein-coding YAG transcripts, we have not detected any signatures of positive selection. Overall, our work illuminates the YAG isoform landscape and its evolutionary history, and provides a genomic resource for future functional studies focusing on infertility phenotypes in humans and critically endangered great apes.
Non-contrast-Enhanced Functional Lung MRI to evaluate treatment response of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis: a pilot study
Authors: Benlala Ilyes , Klaar Rabea , Gaass Thomas , Macey Julie , Bui Stéphanie , Berger Patrick , Laurent François , Dournes Gael , Dinkel Julien
Published: March 2023

Background

Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up the response to treatment of ABPA in CF.

Purpose

To evaluate whether Fourier decomposition (FD) functional lung MRI can detect the response to treatment of ABPA in CF patients.

Study type

Retrospective longitudinal.

Population

A total of 12 CF patients.

Field strength/sequence

2D balanced steady-state free precession (bSSFP) sequence with Fourier decomposition (FD) at 1.5T scanner.

Assessment

Ventilation weighted (V) and perfusion weighted (Q) maps were obtained after FD processing of the 2D coronal bSSFP time resolved images before and after treatment of ABPA. Defects extent was assessed on the functional maps using a visual semi quantitative score. Mean and coefficient of variation (cv) of the ventilation signal intensity (VSI) and the perfusion signal intensity (QSI) were calculated. Measurements were performed independently by two readers and averaged. The reproducibility of the measurements was also assessed. Pulmonary function tests (PFTs) were performed as markers of the airflow limitation severity.

Statistical tests

Comparisons of medians were assessed using paired Wilcoxon test. Reproducibility was assessed using the intraclass correlation coefficient (ICC). Correlations were assessed using Spearman test. A p value <0.05 was considered as significant.

Results

Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (p<0.01). VSI_mean was significantly increased after treatment (p<0.01). Visual analyses reproducibility showed an ICC >0.93. ICC of the quantitative measurements was almost perfect (>0.99). VSI_cv and QSI_cv variations correlated inversely with the variation of obstructive parameters of PFTs (rho = -0.68, p=0.01).

Data conclusion

Non-contrast enhanced FD lung MRI appears to be able to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFTs’ obstructive parameters.
Somatic mutations in chronic lung disease are associated with reduced lung function
Authors: Yun Jeong H. , Khan M.A. Wasay , Ghosh Auyon , Hobbs Brian D. , Castaldi Peter J. , Hersh Craig P. , Miller Peter G. , Cool Carlyne D. , Sciurba Frank , Barwick Lucas , Limper Andrew H. , Flaherty Kevin , Criner Gerard J. , Brown Kevin , Wise Robert , Martinez Fernando , Silverman Edwin K. , Demeo Dawn , Cho Michael H. , Bick Alexander G.
Published: March 2023

Among human organs, the lung harbors one of the highest rates of somatic mutations. However, the relationship of these mutations to lung disease and function is not known. We analyzed the somatic mutational pattern from 1,251 samples of normal and diseased non-cancerous lung tissue from the Lung Tissue Research Consortium using RNA-seq. In two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD, 29%) and idiopathic pulmonary fibrosis (IPF, 13%), we found a significantly increased burden of somatic mutations compared to normal. Using deconvoluted cell type proportions, we found that a major predictor of somatic mutations was the airway to alveolar cell proportion and pathogenic cell types. We also found that mutational burden was associated with reduced lung function. This relationship remained even after adjustment for age, sex, smoking, and cell type proportion and in COPD and IPF. Our identification of an increased prevalence of somatic mutation in diseased lung that correlates with cell type proportion and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.
Quality of Drug Prescription and Dispensing Practices in a Teaching Hospital in a developing country
Authors: Samuel Owhondah King , Zorte Zite , Samuel Ogaji Daprim
Published: March 2023

Background

The World Health Organization recommends rational drug usage to protect patient health and quality of life. Study assessed the quality of drug prescription and dispensing in a tertiary hospital.

Methods

Cross-sectional study with retrospective and prospective data collection underpinned by the WHO core prescribing indicators. A cluster sample of 10 clinical units and their attached pharmacies in the hospital. Six hundred prescriptions from the pharmacy over six months were randomly selected to evaluate the prescription indicators, 330 patient encounters observed for patient care indicators, and 48 randomly selected doctors to evaluate factors influencing their prescribing practices across the 10 clinics. Descriptive analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 25 and comparison done across all indicators of rational drug use.

Results

Average drugs per encounter was 3.4 ± 1.9 drugs. Antibiotics and injections were prescribed in 40.2% and 24.8% encounters respectively. Generic names were used in 43.6% and 97.1% of prescription were from the essential medicine list. Average time for consultation was 17.5 ± 8.0 minutes, dispensing time was 7.7 ± 3.8 minutes, 99.8% of medications were properly labelled, and 82% of patients understood the drug doses. The pharmacies stocked 93.3% of key drugs but no consultation room had the essential drug list. Only 43.7% of physicians demonstrated accurate understanding of rational drug use.

Conclusion

Findings on the WHO core drug indicators showed poor quality of drug prescription. Brand prescription, polypharmacy, and antibiotic overuse observed requires intensifying training and monitoring on rational drug use.
Estimation of Life’s Essential 8 Score with Incomplete Data of Individual Metrics
Authors: Zheng Yi , Huang Tianyi , Guasch-Ferre Marta , Hart Jaime , Laden Francine , Chavarro Jorge , Rimm Eric , Coull Brent , Hu Hui
Published: March 2023

Background

The American Heart Association’s Life’s Essential 8 (LE8) is an updated construct of cardiovascular health (CVH), including blood pressure, lipids, glucose, body mass index, nicotine exposure, diet, physical activity, and sleep health. It is challenging to simultaneously measure all eight metrics at multiple time points in most research and clinical settings, hindering the use of LE8 to assess individuals’ overall CVH trajectories over time.

Methods and Results

We obtained data from 5,588 participants in the Nurses’ Health Studies (NHS, NHSII) and Health Professional’s Follow-up Study (HPFS), and 27,194 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) with all eight metrics available. Individuals’ overall cardiovascular health (CVH) was determined by LE8 score (0-100). CVH-related factors that are routinely collected in many settings (i.e., demographics, BMI, smoking, hypertension, hypercholesterolemia, and diabetes) were included as predictors in the base models of LE8 score, and subsequent models further included less frequently measured factors (i.e., physical activity, diet, blood pressure, and sleep health). Gradient boosting decision trees were trained with hyper-parameters tuned by cross-validations. The base models trained using NHS, NHSII, and HPFS had validated root mean squared errors (RMSEs) of 8.06 (internal) and 16.72 (external). Models with additional predictors further improved performance. Consistent results were observed in models trained using NHANES. The predicted CVH scores can generate consistent effect estimates in associational studies as the observed CVH scores.

Conclusions

CVH-related factors routinely measured in many settings can be used to accurately estimate individuals’ overall CVH when LE8 metrics are incomplete.

Clinical Perspective

What Is New?

Life’s Essential 8 (LE8) has great potential to assess and promote cardiovascular health (CVH) across life course, however, it is challenging to simultaneously collect all eight metrics at multiple time points in most research and clinical settings.

We demonstrated that CVH-related factors routinely collected in many research and clinical settings can be used to accurately estimate individuals’ overall CVH across time even when LE8 metrics are incomplete.

What Are the Clinical Implications?

The approach introduced in this study provides a cost-effective and feasible way to estimate individuals’ overall CVH.

It can be used to track individuals’ CVH trajectories in clinical settings.
Possible biological control of ash dieback using the parasitic Hymenoscyphus fraxineus mitovirus 2?
Authors: Shamsi Wajeeha , Mittelstrass Jana , Kondo Hideki , Ulrich Sven , Rigling Daniel , Prospero Simone
Published: March 2023

Invasive fungal diseases represent a major threat to forest ecosystems worldwide. As fungicides are often unfeasible and not a sustainable solution, only a few other control options are available, including biological control. In this context, the use of parasitic mycoviruses as biocontrol agents of fungal pathogens has recently gained particular attention. Since the 1990s, the Asian fungusHymenoscyphus fraxineushas been causing lethal ash dieback across Europe. In the present study, we investigated the biocontrol potential of the mitovirus Hymenoscyphus fraxineus mitovirus 2 (HfMV2) previously identified in Japanese populations of the pathogen. HfMV2 could be successfully introduced via co-culturing into 16 out of 105 virus-free isolates. A virus infection had contrasting effects on fungal growthin vitro, from cryptic to detrimental or beneficial. Virus-infectedH. fraxineusisolates whose growth was reduced by HfMV2 showed a lower virulence on ash (Fraxinus excelsior) saplings compared to their isogenic virus-free isolates. The results suggest that mycoviruses exist in the native populations ofH. fraxineusin Asia that have the potential for biological control of ash dieback in Europe.
Within-host density and duration of colonization of multidrug-resistant Enterobacterales acquired during travel to the tropics
Authors: Cotto Olivier , Armand-Lefèvre Laurence , Matheron Sophie , Ruppé Etienne , Blanquart François
Published: March 2023

Although it seems obvious that antibiotic use promotes antibiotic resistance, the processes underlying the changes in prevalence of MRE in European communities are still poorly understood. Information on how the within-host bacterial density varies after acquisition of a resistant strain and in the absence of antibiotic selection is key to our ability to further understand, model and manage resistance in the community. Empirical studies on the within-host dynamics following colonization by MRE are very scarce. Here, we study the within-host strain dynamics in healthy travelers colonized with MRE upon their return from tropical regions. Densities of both sensitive and resistant strains are stable for a few months, until resistant strains are abruptly cleared. Multivariate survival analysis further revealed that MRE acquired from Asia and carried at larger densities persist for longer. These dynamics do not support the classically assumed slow competitive exclusion of MRE. Rather, MRE and sensitive strains coexist in apparent equilibrium for months, with MRE representing about 0.1% of total Enterobacterales, before MRE are abruptly cleared. These results inform potential therapeutic strategies to clear MRE and epidemiological models of antibiotic resistance.
Maned wolves (Chrysocyon brachyurus) in the Ecological Station of Itirapina-Brazil: temporal and spatial distribution based on long-distance vocalizations recordings
Authors: da Costa Angélica Felício , Padovese Linilson
Published: March 2023

The maned wolf (Chrysocyon brachyurus; Illiger, 1815) is considered the largest canid in South America, it has crepuscular nocturnal behavior, solitary and skittish habits. Its vocalization has different classifications, one of them called roar-barks, which helps in long-distance communication, being ideal for passive acoustic monitoring. For the study of the vocalizations of C. brachyurus in the Ecological Station of Itirapina in Brazil, were implanted 6 autonomous recorders called EcoPods. The locations of the station with the highest detection of vocalizations, their characteristics, temporal distribution in relation to sunset and moon phases were studied. The point with the highest concentration of roar-barks is the same as the point with the litter’s vocalization, indicating the importance of vocalizations in parental care. Passive acoustic monitoring allows a less invasive study and helps to understand the behavior of the maned wolf for its preservation.
Re-engineering of TNFα-NF-κB signalling dynamics in cancer cells using pathogenicE. colieffectors
Authors: Zhong Qiyun , Butera Francesca , Frankel Gad , Bakal Chris
Published: March 2023

Re-engineering NF-κB signalling towards enhancing beneficial outcomes such as tumour cell elimination, while minimising inflammatory damage, is a potential therapeutic avenue. In this study, we explored the ability of bacterial effectors injected into host cells by the type III secretion system to regulate NF-κB translocation dynamics. We used the enteropathogenicEscherichia colieffectors Tir (NF-κB activator), NleC (NF-κB protease) and NleE (TAB2/3 methyltransferase), to manipulate NF-κB translocation and cancer cell survival. We discovered that while these effectors have either limited or no cytotoxicity alone, they greatly enhanced caspase-8-dependent pancreatic cancer cell death in the presence of TNFα. Single cell analysis revealed that the sub-population of cells showing high NF-κB activation is less susceptible to cell death caused by NleC or NleE but instead is more susceptible to Tir. A combination of Tir, NleE and TNFα eliminated 95% cancer cells with limited NF-κB activation, potentially due to NleE-dependent blockage of the immediate pro-survival NF-κB activation without inhibiting Tir’s long-term NF-κB activation that promotes cell death. This work demonstrates that effector combinations could be used to re-engineer stress responses towards favourable outcomes.
Distinct horizontal transfer mechanisms for type I and type V CRISPR-associated transposons
Authors: Hu Kuang , Chou Chia-Wei , Wilke Claus O. , Finkelstein Ilya J.
Published: March 2023

CRISPR-associated transposons (CASTs) co-opt CRISPR-Cas proteins and Tn7-family transposons for RNA-guided vertical and horizontal transmission. CASTs encode minimal CRISPR arrays but can’t acquire new spacers. Here, we show that CASTs instead co-opt defense-associated CRISPR arrays for horizontal transmission. A bioinformatic analysis shows that all CAST sub-types co-occur with defense-associated CRISPR-Cas systems. Using anE. coliquantitative transposition assay, we show that CASTs use CRISPR RNAs (crRNAs) from these defense systems for horizontal gene transfer. A high-resolution structure of the type I-F CAST-Cascade in complex with a type III-B crRNA reveals that Cas6 recognizes direct repeats via sequence-independentπ − πinteractions. In addition to using heterologous CRISPR arrays, type V CASTs can also transpose via a crRNA-independent unguided mechanism, even when the S15 co-factor is over-expressed. Over-expressing S15 and the trans-activating CRISPR RNA (tracrRNA) or a single guide RNA (sgRNA) reduces, but does not abrogate, off-target integration for type V CASTs. Exploiting new spacers in defense-associated CRISPR arrays explains how CASTs horizontally transfer to new hosts. More broadly, this work will guide further efforts to engineer the activity and specificity of CASTs for gene editing applications.
Conformational entropy of intrinsically disordered proteins bars intruders from biomolecular condensates
Authors: Grigorev Vladimir , Wingreen Ned S. , Zhang Yaojun
Published: March 2023

It has recently been discovered that eukaryotic cells are host to a multiplicity of biomolecular condensates. These condensates typically contain protein and/or RNA components with intrinsically disordered regions (IDRs). While IDRs have been proposed and demonstrated to play many roles in condensate biology, we suggest here an additional crucial role of IDRs, which is to exclude unwanted “intruders” from condensates. This exclusion effect arises from the large conformational entropy of IDRs, i.e., there is a high free-energy cost to occupying space that would otherwise be available to the IDRs. By combining polymer theory with sticker-spacer simulations, we show that the relevant insertion free energy increases with the concentration of IDRs in the condensate as well as with intruder size, attaining a linear scaling with surface area for large intruders. We find that at realistic IDR concentrations, particles as small as the size of an average protein (4 nm in diameter) can be more than 97% excluded from condensates. To overcome this entropic barrier, molecules must interact favorably with condensate components to be recruited as clients into condensates. Application of the developed size-exclusion theory to biological condensates suggests that condensate IDRs may play a generic exclusionary role across organisms and types of condensates.
JAMS - A framework for the taxonomic and functional exploration of microbiological genomic data
Authors: McCulloch John A. , Badger Jonathan H. , Cannon Nikki , Rodrigues Richard R. , Valencia Michael , Barb Jennifer J. , Fernandes Miriam R. , Balaji Ascharya , Crowson Lisa , O’hUigin Colm , Dzutsev Amiran , Trinchieri Giorgio
Published: March 2023

Shotgun microbiome sequencing analysis presents several challenges to accurately and consistently depict sample composition and functional potential. Here we present a two-part framework – JAMS (Just a Microbiology System) – whereby with raw fastq files and metadata as input, meaningful analysis within a sample and between a sample can be performed with ease for either shotgun or 16S sequences. JAMS is the first package to provide seamless deconvolution of functions into their taxonomic contributors. We validated our JAMS framework on two human gut shotgun metagenome test datasets against the popular tool MetaPhlAn 4. We further demonstrate the application of the JAMS package, particularly the plotting functions, on a mouse shotgun dataset.
A Flexible Transgene Integration ‘Landing-Pad’ Toolkit in Human Induced Pluripotent Stem Cells Enables Facile Cellular Engineering, Gene Zygosity Control, and Parallel Transgene Integration
Authors: Rosenstein Aaron H. , Nguyen Maria , Al-Attar Rasha , Serra Danielle , Gulati Nitya , Yin Ting , Gilbert Penney M. , Garton Michael
Published: March 2023

Development of a repeatable method for delivering transgene payloads to human induced pluripotent stem cells (hiPSCs) without risking unintended off-target effects is not fully realized. Yet, such methods are indispensable to fully unlocking the potential for applying synthetic biological approaches to regenerative medicine, delivering quantum impacts to cell-based therapeutics development. Here we present a toolkit for engineering hiPSCs centred on the development of two core ‘landing-pad’ cell-lines, facilitating rapid high-efficiency delivery of transgenes to theAAVS1safe-harbour locus using the Bxb1 large-serine recombinase. We developed two landing-pad cell lines expressing green and red fluorescent reporters respectively, both retaining stemness whilst fully capable of differentiation into all three germ layers. A fully selected hiPSC population can be isolated within 1-2 weeks after landing-pad recombinase-mediated cassette exchange. We demonstrate the capability for investigator-controlled homozygous or heterozygous transgene configurations in these cells. As such, the toolkit of vectors and protocols associated with this landing-pad hiPSC system has the potential to accelerate engineering workflows for researchers in a variety of disciplines.
Computational Scoring and Experimental Evaluation of Enzymes Generated by Neural Networks
Authors: Johnson Sean R. , Fu Xiaozhi , Viknander Sandra , Goldin Clara , Monaco Sarah , Zelezniak Aleksej , Yang Kevin K.
Published: March 2023

In recent years, generative protein sequence models have been developed to sample novel sequences. However, predicting whether generated proteins will fold and function remains challenging. We evaluate computational metrics to assess the quality of enzyme sequences produced by three contrasting generative models: ancestral sequence reconstruction, a generative adversarial network, and a protein language model. Focusing on two enzyme families, we expressed and purified over 440 natural and generated sequences with 70-90% identity to the most similar natural sequences to benchmark computational metrics for predictingin vitroenzyme activity. Over three rounds of experiments, we developed a computational filter that improved experimental success rates by 44-100%. Surprisingly, neither sequence identity to natural sequences nor AlphaFold2 residue-confidence scores were predictive of enzyme activity. The proposed metrics and models will drive protein engineering research by serving as a benchmark for generative protein sequence models and helping to select active variants to test experimentally.
SUNi mutagenesis: scalable and uniform nicking for efficient generation of variant libraries
Authors: Mighell Taylor L. , Toledano Ignasi , Lehner Ben
Published: March 2023

Multiplexed assays of variant effects (MAVEs) have made possible the functional assessment of all possible mutations to genes and regulatory sequences. A core pillar of the approach is generation of variant libraries, but current methods are either difficult to scale or not uniform enough to enable MAVEs at the scale of gene families or beyond. We present an improved method called Scalable and Uniform Nicking (SUNi) mutagenesis that combines massive scalability with high uniformity to enable cost-effective MAVEs of gene families and eventually genomes.