bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Pelvic Floor Muscle Training on Health-Related Quality of Life in Postmenopausal Women With Genitourinary Syndrome: A Systematic Review and Meta-Analysis
Authors: NGUYEN Tram Thi Bich , HSU Yu-Yun , SARI Yanti Puspita
Published: January 2024

Background

Genitourinary syndrome is commonly reported in postmenopausal women. Kegel's exercise is a noninvasive therapy that improves pelvic floor muscle parameters. However, the effect of Kegel's exercise on health-related quality of life (HRQoL) in postmenopausal women with genitourinary syndrome has not been synthesized or shown.

Purpose

This study was designed to systematically review and analyze the previous literature to determine whether Kegel's exercise enhances HRQoL in postmenopausal women with genitourinary syndrome of menopause.

Methods

A systematic review and meta-analysis of randomized controlled trials was conducted, and six databases were searched, including Embase, MEDLINE, Cochrane, CINAHL, Web of Science, and Scopus, from their dates of inception to November 2021. Eligible studies evaluated the effects of Kegel's exercise on HRQoL in postmenopausal women with urinary, sexual, or genital symptoms. Review Manager software was used to perform the meta-analysis using a random-effects model. Chi-square and I
2 tests were used to evaluate heterogeneity among the studies. Meta-analysis was performed based on the symptoms (i.e., urinary, sexual, and genital) identified in the quality-of-life questionnaires.

Results

This systematic review covered five studies with 268 participants. The research appraisal found most of these studies had a low risk of bias. The intervention periods ranged from 4 to 12 weeks. Compared with non-Kegel's exercise or regular activity, Kegel's exercise was found to significantly improve HRQoL-related urinary symptoms (three studies, standardized mean difference = −0.95, 95% CI [−1.35, −0.54], I
2 = 0%). However, the effect of this exercise on HRQoL-related sexual symptoms did not differ from non-Kegel's exercise or regular activity (two studies, standardized mean difference = 1.11, 95% CI [−0.25, 2.47], I
2 = 94%). None of the covered studies examined the effect of Kegel's exercise on HRQoL-related genital symptoms.

Conclusions/Implications for Practice

Kegel's exercise is an effective intervention for improving HRQoL-related urinary symptoms in postmenopausal women. However, there remains insufficient evidence to assess the effectiveness of Kegel's exercise on HRQoL-related genital symptoms in this population. The results support using Kegel's exercise as a useful intervention to manage urinary symptoms in postmenopausal women.
Pairing Evidence-Based Strategies With Motivational Interviewing to Support Optimal Nutrition and Weight Gain in Pregnancy
Authors: Jevitt Cecilia M. , Ketchum Kiley
Published: January 2024

Objective:

Because eating, nutrition, and weight management patterns adopted during pregnancy may persist beyond the postpartum period, pregnancy provides an opportunity for health education that affects the future health of the pregnant person, the fetus, and the family. This systematic review aimed to find nutrition and weight management behaviors that could be used safely during pregnancy to optimize gestational weight gain.

Methods:

PubMed, MEDLINE, and Web of Science were searched for research or systematic reviews published in English from 2018 to 2023 using terms including gestational weight gain maintenance, weight, management, pregnancy, behavior, strategy, and strategies. Excluded research used pediatric or adolescent populations, restrictive diets such as no carbohydrate or no fat diets, fasting, bariatric surgery, weight loss medications, private industry, or profit-earning programs using food brands or specific diet programs.

Results:

The abstracts reviewed in these areas: excessive gestational weight gain (1019), low-glycemic index diet (640), Mediterranean diet (220), MyPlate diet (2), the Dietary Approaches to Stop Hypertension (DASH) diet (50), portion control (6), home meal preparation (6), mindful eating (13), intuitive eating (10), self-weighing (10), and motivational interviewing during pregnancy (107), were reduced to 102 studies. Studies in those 10 areas were reviewed for nutrition and eating behaviors that are safe to use during pregnancy and could be used along with motivational interviewing.

Conclusion:

Clinicians can discuss these behaviors using motivational interviewing techniques to assist clients in optimizing gestational weight gain. Dialogue examples pairing these strategies with motivational interviewing principles are included.
On the relationship between afterimages and a simple sensorimotor reaction
Authors: Kulakov A.A.
Published: January 2024

Afterimage phenomena (afterimages) are currently widely used in a number of human activities. In this paper, the dynamic properties of afterimages are used and the comparison and relationship with the reaction to light stimulation is investigated. . It is found that the attenuation constant of afterimages and the decay constant of the variable part of the latent time of a simple sensorimotor reaction are in direct linear dependence. In addition, variable light stimulation, which contributes to the rapid attenuation of the afterimage, also accelerates the decline of the variable part of the latent time of a simple sensorimotor reaction, while the constant part increases. Based on these data, we conclude that these two phenomena, the afterimage and a simple sensorimotor reaction are interrelated in the functioning of the reflex chain of excitation transmission from sensors to the motor cortex.
BMP antagonist CHRDL2 enhances the cancer stem cell phenotype and increases chemotherapy resistance in Colorectal Cancer
Authors: Clarkson Eloise , Lewis Annabelle
Published: January 2024

Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression and genomic variants associated with colorectal cancer (CRC) risk. BMP signalling in the normal intestinal epithelium operates in opposition to the WNT signalling pathway, which maintains stem-cells and self-renewal. Elevated WNT signalling leads to expansion of the stem cell compartment and hyperproliferation, defining characteristics of CRC.

Here, we explored the impact of CHRDL2 overexpression on CRC cells and normal intestinal organoids to investigate whether CHRDL2’s inhibition of BMP signalling intensified WNT signalling, and enhanced the cancer stem-cell phenotype.

CHRDL2 increased cell survival during chemotherapy and irradiation with associated activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem cell markers and reduced differentiation. RNA-seq analysis revealed that CHRDL2 increased the expression of stem cell markers and well-established cancer-associated pathways. We suggest that CHRDL2 overexpression can augment the stem-cell potential of CRC and normal intestinal cells.

Graphical abstract
Cell Type Specific Responses of the Endoplasmic Reticulum Dynamics to Environmental Stress
Authors: Zhang Yiheng , Liu Jiazheng , Sun Zhengzhe , Guo Jinyue , Yuan Jingbin , Xue Yajun , Qiu Tianbao , Wang Pei , Yin Benfeng , Yang Honglan , Zhai Liting , Han Hua , Li Xiaojuan
Published: January 2024

To overcome the challenge of balancing imaging speecd and resolution, which currently limits the accurate identification of structural and dynamic changes in the study of endoplasmic reticulum (ER) in plant cells. This research employs structured illumination microscopy techniques to achieve super-resolution real-time imaging of the ER in live Arabidopsis materials. Additionally, a self-supervised denoising framework (Blind2Unblind) was optimized to further enhance the signal-to-noise ratio of rapid microscopic imaging. Based on the images with high quality, a method for quantitative analysis of ER structures using time-lapse images is developed. Moreover, detections of changes in ER structures under environmental stress are conducted to verify the effectiveness of the method. Moreover, correlation analyses of various parameters indicate a significant positive correlation between the area and length of tubular ER with the number of growth tips and tricellular junctions, while the area of ER cisternae and bulk flow exhibits a significant negative correlation with the area and length of tubules. The super-resolution imaging and dynamic analysis method developed in this study will provide new technical approaches for further elucidating the function and regulatory mechanisms of the plant ER.
A Bayesian overhaul of thermal tolerance landscape models: Predicting ectotherm lethality buildup and survival amid heatwaves
Authors: Vajedsamiei Jahangir , Warlo Niklas , Meier H. E. Markus , Melzner Frank
Published: January 2024

1. In the face of escalating heatwaves, accurately forecasting ectotherm population mortality is a pressing ecological challenge. Current Thermal Tolerance Landscape (TTL) models, while surpassing single-threshold metrics by incorporating individual survival times, are constrained by frequentist regression parametrization reliant on constant-temperature experiments, omitting probabilistic outcomes.

2. This study addresses these limitations by pioneering the application of Approximate Bayesian Computation-Sequential Monte Carlo (ABC-SMC) to analyze survival data from BalticMytilusmussels subjected to both microcosm (constant temperature) and mesocosm (dynamic temperature) heatwave regimes.

3. The ABC-SMC yields probabilistic predictions of individual lethality buildup and population survival trajectories, closely aligned with observed survival data across both experimental conditions. Informed by more realistic dynamic data, the TTL model predicts local mussel resilience against the most extreme summer heatwaves projected for this century, albeit with considerations for sublethal impacts and potential recruitment declines.

4. Our approach can enhance the predictive accuracy concerning the sensitivity of key marine populations amidst intensifying heatwaves, addressing the urgent need for accurate modeling tools to inform conservation practices and ecosystem management, ultimately aiding in the preservation of marine biodiversity.
The interplay between moult of flight feathers and fuelling conducted on the breeding grounds of the Great SnipeGallinago mediafrom the eastern European, lowland population
Authors: Witkowska Marta , Korniluk Michał , Pinchuk Pavel , Tumiel Tomasz , Karlionova Natalia , Meissner Włodzimierz
Published: January 2024

The Great Snipe as a long-distant migrant wintering in Africa, faces the challenge of accumulating sufficient energy reserves before the departure from European breeding grounds. Despite possible trade-offs in resource allocation, this species additionally initiates moult of flight feathers before southward migration. Here we discuss the strategy of flight feather moult and fuelling, exploring their scheduling, constrained by the timing of breeding and departure for female and male Great Snipes from the European lowland population. We found significant intrasexual differences in both moult initiation date and moult duration. Males start flight feather replacement more than two weeks earlier and moult faster compared to females. However, neither sex completed this process on breeding grounds before the migration, as late in the season all males and half of the females had suspended their primary moult, with the remaining females not moulting at all. Moult of secondaries occurred exceptionally in the studied population. We observed a non-linear energetic stores gain in the studied period, where both sexes maintained a stable and low body condition until the end of July, coinciding with the primary moulting period. Subsequently, there was an increase in body condition, of approximately 1% of the lean body mass per day, indicating a shift towards fuelling for migratory flight. The overlap between stages of maintaining a stable and low body condition and moulting suggests a resource allocation towards feather growth before initiating fuelling. Our study describes moult strategy in Great Snipe conducted on their breeding grounds, highlighting the intrasexual differences, likely resulting from different parental duties of males and females of this lekking species.
Robust Evaluation of Deep Learning-based Representation Methods for Survival and Gene Essentiality Prediction on Bulk RNA-seq Data
Authors: Gross Baptiste , Dauvin Antonin , Cabeli Vincent , Kmetzsch Virgilio , Khoury Jean El , Dissez Gaëtan , Ouardini Khalil , Grouard Simon , Davi Alec , Loeb Regis , Esposito Christian , Hulot Louis , Ghermi Ridouane , Blum Michael , Darhi Yannis , Durand Eric Y. , Romagnoni Alberto
Published: January 2024

Deep learning (DL) has shown potential to provide powerful representations of bulk RNA-seq data in cancer research. However, there is no consensus regarding the impact of design choices of DL approaches on the performance of the learned representation, including the model architecture, the training methodology and the various hyperparameters. To address this problem, we evaluate the performance of various design choices of DL representation learning methods using TCGA and DepMap pan-cancer datasets, and assess their predictive power for survival and gene essentiality predictions. We demonstrate that non DL-based baseline methods achieve comparable or superior performance compared to more complex models on survival predictions tasks. DL representation methods, however, are the most efficient to predict the gene essentiality of cell lines. We show that auto-encoders (AE) are consistently improved by techniques such as masking and multi-head training. Our results suggest that the impact of DL representations and of pre-training are highly task- and architecture-dependent, highlighting the need for adopting rigorous evaluation guidelines. These guidelines for robust evaluation are implemented in a pipeline made available to the research community.
Measurement of solubility product in a model condensate reveals the interplay of small oligomerization and self-association
Authors: Chattaraj Aniruddha , Baltaci Zeynep , Mayer Bruce J. , Loew Leslie M. , Ditlev Jonathon A.
Published: January 2024

Cellular condensates often consist of 10s to 100s of distinct interacting molecular species. Because of the complexity of these interactions, predicting the point at which they will undergo phase separation into discrete compartments is daunting. Using experiments and computation, we therefore studied a simple model system consisting of 2 proteins, polySH3 and polyPRM, designed for pentavalent heterotypic binding. We tested whether the peak solubility product, the product of dilute phase monomer concentrations, is a predictive parameter for the onset of phase separation. Titrating up equal total concentrations of each component showed that the maximum solubility product does approximately coincide with the threshold for phase separation in both the experiments and models. However, we found that measurements of dilute phase concentration include contributions from small oligomers, not just monomers; therefore, a quantitative comparison of the experiments and models required inclusion of small oligomers in the model analysis. We also examined full phase diagrams where the model results were almost symmetric along the diagonal, but the experimental results were highly asymmetric. This led us to perform dynamic light scattering experiments, where we discovered a weak homotypic interaction for polyPRM; when this was added to the computational model, it was able to recapitulate the experimentally observed asymmetry. Thus, comparing experiments to simulation reveals that the solubility product can be predictive of phase separation, even if small oligomers and low affinity homotypic interactions preclude experimental measurement of monomer concentration.
Divergent mechanisms of steroid inhibition in the human ρ1 GABAAreceptor
Authors: Fan Chen , Cowgill John , Howard Rebecca J. , Lindahl Erik
Published: January 2024

ρ-type γ-aminobutyric acid-A (GABAA) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABAAreceptors, but their inhibitory mechanisms are not clear. By combining four new cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABAAreceptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design.
Functional studies of deafness-associated pendrin and prestin variants
Authors: Takahashi Satoe , Kojima Takashi , Wasano Koichiro , Homma Kazuaki
Published: January 2024

Pendrin and prestin are evolutionary conserved membrane proteins that are essential for normal hearing. Pendrin is an anion transporter required for normal development and maintenance of ion homeostasis in the inner ear, while prestin is a voltage-dependent motor responsible for cochlear amplification essential for high sensitivity and frequency selectivity of mammalian hearing. Dysfunction of these proteins result in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here we report results from our ongoing efforts in experimentally characterizing pendrin and prestin variants usingin vitrofunctional assays, providing invaluable information regarding their pathogenicity.
ATP-Binding Cassette Family C member 1 constrains metabolic responses to high-fat diet in male mice
Authors: Villalobos Elisa , Miguelez-Crespo Allende , Morgan Ruth A. , Ivatt Lisa , Kurian Dominic , Aguilar Judit , Kline Rachel A. , Wishart Thomas M. , Morton Nicholas , Stimson Roland H. , Andrew Ruth , Walker Brian R. , Nixon Mark
Published: January 2024

Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intra-cellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-Binding Cassette Family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact ofAbcc1deficiency on glucocorticoid action and high fat-diet (HFD)-induced obesity. In lean mice, deficiency ofAbcc1increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast,Abcc1-deficient mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing in adipose tissue and skeletal muscle revealed thatAbcc1deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue. Moreover, theAbcc1deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.
TimberTracer: A Comprehensive Framework for the Evaluation of Carbon Sequestration by Forest Management and Substitution of Harvested Wood Products
Authors: Boukhris I. , Collalti A. , Lahssini S. , Dalmonech D. , Nakhle F. , Testolin R. , Chiriacò M. V. , Santini M. , Valentini R.
Published: January 2024

Background

Harvested wood products (HWPs) have a pivotal role in climate change mitigation, a recognition solidified in many Nationally Determined Contributions (NDCs) under the Paris Agreement. Integrating HWPs’ greenhouse gas (GHG) emissions and removals into accounting requirements relies on typical decision-oriented tools known as wood product models (WPMs). The study introduces the ‘TimberTracer’ (TT) framework, designed to simulate HWP carbon stock, substitution effects, and emissions from wood decay and bioenergy.

Results

Coupled with the 3D-CMCC-FEM forest growth model,TimberTracerwas applied to Laricio Pine (Pinus nigrasubsp.laricio) in Italy’s Bonis watershed, evaluating three forest management practices (clearcut, selective thinning, and shelterwood) and four wood-use scenarios (business as usual, increased recycling rate, extended average lifespan, and a simultaneous increase in both the recycling rate and the average lifespan) over a 140-year planning horizon, to assess the overall carbon balance of HWPs. Furthermore, this study evaluates the consequences of disregarding landfill methane emissions and relying on static substitution factors, assessing their impact on the mitigation potential of various options. This investigation, covering HWPs stock, carbon (C) emissions, and the substitution effect, revealed that selective thinning emerged as the optimal forest management scenario. Furthermore, a simultaneous 10% increase in both the recycling rate and half-life, under the so-called “sustainability” scenario, proved to be the optimal wood-use strategy. Finally, the analysis shows that failing to account for landfill methane emissions and the use of dynamic substitution can significantly overestimate the mitigation potential of various forest management and wood-use options, which underscores the critical importance of a comprehensive accounting in climate mitigation strategies involving HWPs.

Conclusion

Our study highlights the critical role of harvested wood products (HWPs) in climate change mitigation, as endorsed by multiple Nationally Determined Contributions (NDCs) under the Paris Agreement. Utilizing the ‘TimberTracer’ framework coupled with the 3D-CMCC-FEM forest growth model, we identified selective thinning as the optimal forest management practice. Additionally, enhancing recycling rates and extending product lifespans effectively bolstered the carbon balance. Moreover, this study emphasizes the necessity of accounting for landfill methane emissions and dynamic product substitution, as failing to do so may significantly overestimate the mitigation potential of implemented projects. These findings offer actionable insights to optimize forest management strategies and advance climate change mitigation efforts.
Context-dependent effects ofCDKN2Aand other 9p21 gene losses during the evolution of oesophageal cancer
Authors: Ganguli Piyali , Basanta Celia C. , Acha-Sagredo Amelia , Misetic Hrvoje , Armero Maria , Mendez Akram , Zahra Aeman , Devonshire Ginny , Kelly Gavin , Freeman Adam , Green Mary , Nye Emma , Bichisecchi Anita , Bonfanti Paola , Clinical Oesophageal Cancer ,   Molecular Stratification (OCCAMS) Consortium, Rodriguez-Justo Manuel , Spencer Jo , Fitzgerald Rebecca C. , Ciccarelli Francesca D.
Published: January 2024

CDKN2Ais a tumour suppressor located in chromosome 9p21 and frequently lost in Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). HowCDKN2Aand other 9p21 gene co-deletions affect OAC evolution remains understudied. We explored the effects of 9p21 loss in OACs and cancer progressor and non-progressor BOs with matched genomic, transcriptomic, and clinical data. Despite its cancer driver role,CDKN2Aloss in BO prevents OAC initiation by counter-selecting subsequentTP53alterations. 9p21 gene co-deletions predict poor patient survival in OAC but not BO through context-dependent effects on cell cycle, oxidative phosphorylation, and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed thatIFNEloss reduces immune infiltration in BO but not OAC. Mechanistically,CDKN2Aloss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.
ER-located PIN5 transporter generates potent auxin sinks driven by the IAA decarboxylation pathway
Authors: Čovanová Milada , Müller Karel , Klierová Nikoleta , Abdollahi Sisi Nayyer , Skůpa Petr , Smetana Ondřej , Dobrev Petre Ivanov , Růžička Kamil , Petrášek Jan
Published: January 2024

Auxin is an essential and well-investigated regulator of plant development. Still, many aspects determining its (sub-)cellular distribution, as well as its metabolic turnover, are obscure. PIN5 is a transporter that resides on the endoplasmic reticulum and is presumed to influence internal auxin homeostasis by direct sequestration and subsequent degradation. Due to its distinct expression pattern and incomplete metabolomics analyses, the exact role of PIN5 protein and the identity of downstream auxin degradation products show significant gaps. To this end, we utilized morphologically homogeneous tobacco BY-2 cell cultures. We show that the expression ofArabidopsis thaliana AtPIN5in the BY-2 system phenocopies so-called auxin starvation defects. Moreover, we reveal that the activity ofAtPIN5 leads, in extreme cases, to the broad range of processes accompanying programmed cell death (PCD). Notably, based on the recently updated knowledge on auxin metabolism, we also show that a significant part of auxin metabolites downstream of theAtPIN5 activity are part of the re-emerging auxin decarboxylation pathway. Taking together, we report the direct induction of PCD by auxin stimulus and propose the physiological framework of the auxin decarboxylation route.
Diversity and structure of the deep-sea sponge microbiome in the equatorial Atlantic Ocean
Authors: Williams Sam E. , Varliero Gilda , Lurgi Miguel , Stach Jem , Race Paul R. , Curnow Paul
Published: January 2024

Sponges (phylum Porifera) harbour specific microbial communities that drive the ecology and evolution of the host. Understanding the structure and dynamics of these communities is emerging as a primary focus in marine microbial ecology research. Much of the work to date has focused on sponges from warm and shallow coastal waters, while sponges from the deep ocean remain less well-studied. Here, we present a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges. We identify a high abundance of archaea relative to bacteria across these communities, with certain sponge microbiomes comprising more than 90% archaea. Specifically, the archaeal familyNitrosopumilaceaeare prolific, comprising over 99% of all archaeal reads. Our analysis revealed sponge microbial communities mirror the host sponge phylogeny, indicating a key role for host taxonomy in defining microbiome composition. Our work confirms the contribution of both evolutionary and environmental processes to the composition of microbial communities in deep-sea sponges.

Importance

The deep ocean is the largest biome on Earth, accounting for >90% of the planet’s marine environment. Despite this it remains a largely unexplored ecosystem, with less than 0.01% of the deep seafloor having been quantitatively sampled. Deep-sea sponges are ancient metazoans which harbour complex microbial communities and much still remains to be learned about the composition and diversity of these unique microbiomes. In an effort to address this, here we report a metataxonomic analysis of the microbial consortia associated with 23 deep-sea sponges from the equatorial Atlantic Ocean. Our findings reveal intricate, species-specific microbial communities dominated by ammonia-oxidizing archaea. This study highlights the significant role sponges play in shaping microbial consortia, providing new insights into deep-sea ecosystem dynamics. Importantly, our findings provide a scientific basis for understanding the evolutionary relationships between sponges and their symbiotic microorganisms.
Interictal epileptic network hubs as a biomarker for automatic localization of the epileptogenic zone: a connectivity and machine learning based analysis of stereo-EEG
Authors: Susi G. , Gozzo F. , Di Giacomo R. , Panzica F. , Duran D. , Spreafico R. , Tassi L. , Varotto G.
Published: January 2024

Objective

The study was aimed at developing an automatic system, based on complex network analysis and machine learning, to identify interictal network-based biomarkers in patients with drug-resistant focal epilepsy and no visible anatomical lesions candidate for surgery, able to support the localization of the Epileptogenic Zone (EZ) and to further disclose properties of the interictal epileptogenic network.

Methods

3 min of interictal SEEG signals, recorded in 18 patients with drug-resistant epilepsy, different EZ localization, negative MRI, were analysed. Patients were divided into seizure-free (SF) and non-seizure free (NSF) groups, according to their post-surgical outcome. After a first step of effective connectivity estimation, hubs were defined through the combination of nine graph theory-based indices of centrality. The values of centrality indices related to these hubs were used as input of an ensemble subspace discriminant classifier.

Results

The proposed procedure was able to automatically localise the EZ with 98% sensitivity and 59% specificity for SF patients. Moreover, our results showed a clear difference between SF and NSF patients, mainly in terms of false positive rate (i.e., the percentage of NEZ leads classified as EZ), which resulted significantly higher in NSF patients. Lastly, the centrality indexes confirmed a different role of the Propagation Zone in NSF and SF groups.

Significance

Results pointed out that network centrality plays a key role in interictal epileptogenic network, even in case of the absence of anatomical alterations and SEEG epileptic abnormalities, and that the combination of connectivity, graph theory, and machine learning analysis can efficiently support interictal EZ localization. These findings also suggest that poorer post-surgical prognosis can be associated with larger connectivity alteration, with wider “hubs”, and with a different involvement of the PZ, thus making this approach a promising biomarker for surgical outcome.

Impact statement

The correct localization of the epileptogenic zone is still an unsolved question, mainly based on visual and subjective analysis of electrophysiological recordings, and highly time-consuming due to the needing of ictal recording. This issue is even more critical in patients with negative MRI and extra-temporal EZ localization. The approach proposed in this study represents an innovative and effective tool to reveal interictal epileptogenic network abnormalities, able to support and improve the EZ presurgical identification and to capture differences between poor and good post-surgical outcome
Multifaceted Roles of Histone Lysine Lactylation in Meiotic Gene Dynamics and Recombination
Authors: Zhang Xiaoyu , Liu Yan , Wang Ning
Published: January 2024

Male germ cells, which are responsible for producing millions of genetically diverse sperm through meiosis in the testis, rely on lactate as their central energy metabolite. Recent study has revealed that lactate induces epigenetic modification in cells through histone lactylation, a post-translational modification involving the addition of lactyl groups to lysine residues on histones. Here we report dynamic histone lactylation at histone H4-lysine 5 (K5), -K8, and -K12 during meiosis prophase I in mouse spermatogenesis. By profiling genome-wide occupancy of histone H4-K8 lactylation (H4K8la), which peaks at zygotene, our data show that H4K8la mark is observed at the promoters of genes exhibiting active expression with Gene Ontology (GO) functions enriched for meiosis. Notably, our data also demonstrate that H4K8la is closely associated with recombination hotspots, where machinery involved in the processing DNA double-stranded breaks (DSBs), such as SPO11, DMC1, RAD51, and RPA2, is engaged. In addition, H4K8la was also detected at the meiosis-specific cohesion sites (marked by RAD21L and REC8) flanking the recombination hotspots. Collectively, our findings suggest that histone lactylation serves as a novel mechanism through which lactate regulates germ cell meiosis.
Improving Nitrofurantoin Resistance Prediction inEscherichia colifrom Whole Genome Sequence by Integrating NfsA/B Enzyme Assays
Authors: Dulyayangkul Punyawee , Sealey Jordan E , Lee Winnie WY , Satapoomin Naphat , Reding Carlos , Heesom Kate J. , Williams Philip B , Avison Matthew B
Published: January 2024

Nitrofurantoin resistance inEscherichia coliis primarily caused by mutations damaging two enzymes, NfsA and NfsB. Studies based on small isolate collections with defined nitrofurantoin MICs have found significant random genetic drift innfsAandnfsBmaking it extremely difficult to predict nitrofurantoin resistance from whole genome sequence (WGS) where both genes are not obviously disrupted by nonsense or frameshift mutations or insertional inactivation. Here we report a WGS survey of 200E. colifrom community urine samples, of which 34 were nitrofurantoin resistant. We characterised individual non-synonymous mutations seen innfsAandnfsBamong this collection using complementation cloning and assays of NfsA/B enzyme activity in cell extracts. We definitively identified R203C, H11Y, W212R, A112E, A112T and A122T in NfsA and R121C, Q142H, F84S, P163H, W46R, K57E and V191G in NfsB as amino acid substitutions that reduce enzyme activity sufficiently to cause resistance. In contrast, E58D, I117T, K141E, L157F, A172S, G187D and A188V in NfsA and G66D, M75I, V93A and A174E in NfsB, are functionally silent in this context. We identified that 9/166 (5.4%) of nitrofurantoin susceptible isolates were “pre-resistant”, defined as having loss of function mutations innfsAornfsB. Finally, using NfsA/B enzyme activity assay and proteomics we demonstrated that 9/34 (26.5%) of nitrofurantoin resistant isolates carried functionally wild-typenfsBornfsB/nfsA. In these cases, enzyme activity was reduced through downregulated gene expression. Our biological understanding of nitrofurantoin resistance is greatly improved by this analysis, but is still insufficient to allow its reliable prediction from WGS data.
Resolution of ribosomal stalling by ABCF ATPases YfmR and YkpA/YbiT
Authors: Takada Hiraku , Fujiwara Keigo , Atkinson Gemma C. , Shinobu Chiba , Hauryliuk Vasili
Published: January 2024

Efficiency of protein synthesis on the ribosome is strongly affected by the amino acid composition of the assembled amino acid chain. Challenging sequences include proline-rich motifs as well as highly positively and negatively charged amino acid stretches. Members of the F subfamily of ABC ATPases (ABCFs) have been long hypothesised to promote translation of such problematic motifs. In this study we have applied genetics and reporter-based assays to characterise the four housekeeping ABCF ATPases ofBacillus subtilis: YdiF, YfmM, YfmR/Uup and YkpA/YbiT. We show that YfmR cooperates with the translation factor EF-P that promotes translation of Pro-rich motifs. Simultaneous loss of both YfmR and EF-P results in a dramatic growth defect. Surprisingly, this growth defect can be largely suppressed though overexpression of an EF-P variant lacking the otherwise crucial 5-amino-pentanolylated residue K32. Usingin vivoreporter assays, we show that overexpression of YfmR can alleviate ribosomal stalling on Asp-Pro motifs. Finally, we demonstrate that YkpA/YbiT promotes translation of positively and negatively charged motifs but is inactive in resolving ribosomal stalls on proline-rich stretches. Collectively, our results provide insights into the function of ABCF translation factors in modulating protein synthesis inB. subtilis.
Apnea, Intermittent Hypoxemia, and Bradycardia Events Predict Late-Onset Sepsis in Extremely Preterm Infants
Authors: Kausch Sherry L. , Lake Douglas E. , Di Fiore Juliann M. , Weese-Mayer Debra E. , Claure Nelson , Ambalavanan Namasivayam , Vesoulis Zachary A. , Fairchild Karen D. , Dennery Phyllis A. , Hibbs Anna Maria , Martin Richard J. , Indic Premananda , Travers Colm P. , Bancalari Eduardo , Hamvas Aaron , Kemp James S. , Carroll John L. , Moorman J. Randall , Sullivan Brynne A. ,   The Prematurity-Related Ventilatory Control (Pre-Vent) Investigators
Published: January 2024

Objectives

Detection of changes in cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, may facilitate earlier detection of sepsis. Our objective was to examine the association of cardiorespiratory events with late-onset sepsis for extremely preterm infants (<29 weeks’ gestational age (GA)) on versus off invasive mechanical ventilation.

Study Design

Retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.govidentifierNCT03174301), an observational study in five level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean GA 26.4w, SD 1.71). Monitoring data were available and analyzed for 719 infants (47,512 patient-days), of whom 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72h after birth and ≥ 5d antibiotics).

Results

For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer IH80 events and more bradycardia events before sepsis. IH events were associated with higher sepsis risk, but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model predicted sepsis with an AUC of 0.783.

Conclusion

We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.
A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver
Authors: Perry Andrew S. , Hadad Niran , Chatterjee Emeli , Ramos Maria Jimenez , Farber-Eger Eric , Roshani Rashedeh , Stolze Lindsay K. , Zhao Shilin , Martens Liesbet , Kendall Timothy J. , Thone Tinne , Amancherla Kaushik , Bailin Samuel , Gabriel Curtis L. , Koethe John , Carr J. Jeffrey , Terry James Greg , Freedman Jane , Tanriverdi Kahraman , Alsop Eric , Keuren-Jensen Kendall Van , Sauld John F.K. , Mahajan Gautam , Khan Sadiya , Colangelo Laura , Nayor Matthew , Fisher-Hoch Susan , McCormick Joseph , North Kari E. , Below Jennifer , Wells Quinn , Abel Dale , Kalhan Ravi , Scott Charlotte , Guilliams Martin , Fallowfield Jonathan A. , Banovich Nicholas E. , Das Saumya , Shah Ravi
Published: January 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized “liver-on-a-chip” model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic “liquid biopsy” of human liver relevant to clinical biomarker and mechanistic applications.
Prognostic value of echocardiographic velocity time integral ratio post transcatheter edge-to-edge mitral valve repair
Authors: Scalia Isabel G. , Farina Juan M. , Wraith Rachel , Brown Lisa , Abbas Mohammed Tiseer , Pereyra Milagros , Allam Mohamed , Mahmoud Ahmed K. , Kamel Moaz A. , Barry Timothy , Fortuin F. David , Lester Steven J. , Sweeney John , Sell-Dottin Kristen A. , Alkhouli Mohamad , Holmes David R. , Chao Chieh-Ju , Alsidawi Said , Ayoub Chadi , Arsanjani Reza
Published: January 2024

Objective

Residual mitral regurgitation (MR) is frequent after transcatheter edge-to-edge repair (TEER). There is controversy regarding the clinical impact of residual MR and its quantitative assessment by transthoracic echocardiography (TTE), which is often challenging with multiple eccentric jets and artifact from the clip. The utility of the velocity time integral (VTI) ratio between the mitral valve (MV) and left ventricular outflow tract (LVOT), (VTIMV/LVOT), a simple Doppler measurement that increases with MR, has not been assessed post TEER.

Methods

Baseline characteristics, clinical outcomes, and TTE data from patients who underwent TEER between 2014 and 2021 across three academic centers were analyzed. Post-procedure TTEs were evaluated for VTIMV/LVOTin the first three months after TEER. One-year outcomes including all-cause and cardiac mortality, major adverse cardiac events, and MV reintervention were compared between patients with high VTIMV/LVOT(≥ 2.5) and low (< 2.5).

Results

In total, 372 patients were included (mean age 78.7 ± 8.8 years, 68% male, mean pre-TEER ejection fraction of 50.5 ± 14.7%). Follow up TTEs were performed at a median of 37.5 (IQR 30 - 48) days post-procedure. Patients with high VTIMV/LVOThad significantly higher all-cause mortality (HR 2.10, p = 0.003), cardiac mortality (HR 3.03, p = 0.004) and heart failure admissions (HR 2.28, p < 0.001) at one-year post-procedure. There was no association between raised VTIMV/LVOTand subsequent MV reintervention.

Conclusion

High VTIMV/LVOThas clinically significant prognostic value at one year post TEER. This tool could be used to select patients for consideration of repeat intervention.

What is already known on this topic

Residual mitral valve dysfunction after transcatheter edge-to-edge repair (TEER) is common and associated with poorer clinical outcomes. Quantification and subsequent prognostication are complex and challenging.

What this study adds

The ratio of velocity time integral of the mitral valve to left ventricular outflow tract on echocardiography (VTIMV/LVOT) independently predicts risk of all-cause and cardiac mortality and heart failure admissions at one year following TEER.

How this study might affect research, practice or policy

These findings may allow for early identification of a high-risk cohort post TEER that may benefit from closer surveillance and more aggressive intervention.
New insights into the domain of unknown function DUF of EccC5, the pivotal ATPase providing the secretion driving force to the ESX5 secretion system
Authors: Ceballos-Zúñiga Fernando , Menéndez Margarita , Pérez-Dorado Inmaculada
Published: January 2024

Type VII secretion (T7S) systems, also referred to as ESAT6 secretion (ESX) systems, are molecular machines that have gained great attention due to their implication in cell homeostasis and host pathogen interactions in mycobacteria. The latter include important human pathogens such asMycobacterium tuberculosis(Mtb), the etiological cause of human tuberculosis and a pandemic accounting for more than 1 million deaths every year. The ESX5 system is exclusively found in slow-growing pathogenic mycobacteria, where it mediates the secretion of a large family of virulence factors, the PE and PPE proteins. The secretion driving force is provided by EccC5, a multidomain ATPase operating through four globular cytosolic domains, an N-terminal domain of unknown function (EccCDUF) and three FtsK/SpoIIIE ATPase domains. Recent structural and functional studies of ESX3 and ESX5 systems have revealed EccCDUFas an ATPase-like fold domain with potential ATPase activity, and whose functionality is essential for secretion. Here we report the crystal structure ofMtbEccC5DUFdomain at 2.05 Å resolution, which unveils a nucleotide-free structure with degeneratedcis-acting andtrans-acting elements involved in ATP-binding and hydrolysis. Our crystallographic study, together with a biophysical assessment ofMtbEccC5DUFinteraction with ATP/Mg2+, supports the absence of ATPase activity proposed for this domain. We show that this degeneration is also present in DUF domains of other ESX and ESX-like systems, which are likely to exhibit poor or null ATPase activity. Moreover, and based on anin-silicomodel ofMtbEccC5N-terminal region, we propose thatMtbEccC5DUFis a degenerated ATPase domain that may have retained the ability to hexamerise. Observations that call the attention on DUF domains as structural elements with potential implications in the opening and closure of the membrane pore during the secretion process.
Fragmented micro-growth habitats present opportunities for alternative competitive outcomes
Authors: Batsch Maxime , Guex Isaline , Todorov Helena , Heiman Clara M. , Vacheron Jordan , Vorholt Julia A. , Keel Christoph , van der Meer Jan Roelof
Published: January 2024

Bacteria in nature often proliferate in highly patchy environments, such as soil pores, particles, plant roots or leaves. The resulting spatial fragmentation leads to cells being constrained to smaller habitats, shared with potentially fewer other species. The effects of microhabitats on the emergence of bacterial interspecific interactions are poorly understood, but potentially important for the maintenance of diversity at a larger scale. To study this more in-depth, we contrasted paired species-growth in picoliter droplets at low population census with that in large (macro) population liquid suspended cultures. Four interaction scenarios were imposed by using different bacterial strain combinations and media: substrate competition, substrate independence, growth inhibition, and cell killing by tailocins. In contrast to macro-level culturing, we observed that fragmented growth in picoliter droplets in all cases yielded more variable outcomes, and even reversing the macro-level assumed interaction type in a small proportion of droplet habitats. Timelapse imaging and mathematical simulations indicated that the variable and alternative interaction outcomes are a consequence of founder cell phenotypic variation and small founder population sizes. Simulations further suggested that increased growth kinetic variation may be a crucial selectable property for slower-growing bacterial species to survive competition. Our results thus demonstrate how microhabitat fragmentation enables the proliferation of alternative interaction trajectories and contributes to the maintenance of higher species diversity under substrate competition.