bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of High and Usual Protein Dosing in Critically Ill Patients With Obesity: A Post Hoc Analysis of an International, Pragmatic, Single-Blinded, Randomized Clinical Trial*
Authors: Tweel Lauren E. , Compher Charlene , Bear Danielle E. , Gutierrez-Castrellon Pedro , Leaver Susannah K. , MacEachern Kristen , Ortiz-Reyes Luis , Pooja Lakhani , León Angélica , Wedemire Courtney , Lee Zheng Yii , Day Andrew G. , Heyland Daren K.
Published: November 2023

OBJECTIVES:

Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein.

DESIGN:

A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial.

SETTING:

Eighty-five adult ICUs across 16 countries.

PATIENTS:

Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m2 (n = 425).

INTERVENTIONS:

In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d).

MEASUREMENTS AND MAIN RESULTS:

Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m2. After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58–1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, –5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups.

CONCLUSIONS:

In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk.
The Impact and Burden of Dietary Sugars on the Liver
Authors: Huneault Helaina E. , Ramirez Tovar Ana , Sanchez-Torres Cristian , Welsh Jean A. , Vos Miriam B.
Published: November 2023

NAFLD, or metabolic dysfunction–associated steatotic liver disease, has increased in prevalence hand in hand with the rise in obesity and increased free sugars in the food supply. The causes of NAFLD are genetic in origin combined with environmental drivers of the disease phenotype. Dietary intake of added sugars has been shown to have a major role in the phenotypic onset and progression of the disease. Simple sugars are key drivers of steatosis, likely through fueling de novo lipogenesis, the conversion of excess carbohydrates into fatty acids, but also appear to upregulate lipogenic metabolism and trigger hyperinsulinemia, another driver. NAFLD carries a clinical burden as it is associated with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Patient quality of life is also impacted, and there is an enormous economic burden due to healthcare use, which is likely to increase in the coming years. This review aims to discuss the role of dietary sugar in NAFLD pathogenesis, the health and economic burden, and the promising potential of sugar reduction to improve health outcomes for patients with this chronic liver disease.
Advances in navigating to the nodule and targeting
Authors: Graham Jeffrey , Basist Madeleine , Frye Laura , Agrawal Abhinav , Nasim Faria
Published: November 2023

Purpose of review

The multitude of available platforms and imaging modalities for navigational bronchoscopy, in combination with the various sampling tools that can be used intra-procedurally, is complex. This review seeks to describe the recent developments in peripheral bronchoscopy in regards to navigation, imaging, and sampling target lesions in the pulmonary parenchyma.

Recent findings

Robotic assisted bronchoscopy has improved navigation to the peripheral airways for sampling of peripheral parenchymal lesions. These navigational platforms use innovative technology utilizing electromagnetic navigation and shape-sensing technology for guidance. The greatest improvement has been the stabilization of the robotic scope in the periphery to allow for accurate sampling. Despite improvements in these platforms, limitations of CT to body divergence continue to impact navigation to the lesion and therefore diagnostic yield of the procedure. Advanced intraprocedural imaging with cone beam CT or augmented fluoroscopy has been a recent focus to improve this area. Further, the adoption of newer sampling tools, such as cryobiopsy, offers the possibility of increased diagnostic yield.

The developments in advanced bronchoscopy will impact the role of biopsy in the diagnosis of peripheral pulmonary parenchymal lesions.
Reducing Metabolic Bone Disease Burden in Intestinal Failure Children on Home Parenteral Nutrition
Authors: Tridimas Andreas , Padidela Raja , Bassett John , Wood Rachel , Lawson Maureen , Fagbemi Andrew , Morris Timothy J.
Published: November 2023

Objective:

To determine the prevalence of secondary hyperparathyroidism in a cohort of pediatric patients receiving home parenteral nutrition.

Methods:

For a service review, a population-based cohort of 37 pediatric intestinal failure patients receiving long-term parenteral nutrition that underwent serial biochemical monitoring during a study period of approximately 4 years were examined. Following the production of an algorithm, a follow-up audit was carried out (n = 33) after approximately 6 months.

Results:

Of the 37 patients examined in the initial service review, 22 (59%) were found to have an elevated parathyroid hormone (PTH) during the period of monitoring and 5 (14%) had a persistently elevated PTH. In the follow-up audit following the implementation of an algorithm, the number with elevated PTH reduced to 6 (18%) and no patients had persistently high levels.

Conclusion:

Elevated PTH is a common biochemical finding in pediatric intestinal failure patients receiving home parenteral nutrition and its presence should alert clinicians to the need to optimize nutritional parameters such as calcium to phosphate molar ratio and vitamin D status; failure to do so may increase the future burden of metabolic bone disease in such patients. We propose that an algorithm may help in this endeavor.
A biophysically constrained brain connectivity model based on stimulation-evoked potentials
Authors: Schmid William , Danstrom Isabel A. , Echevarria Maria Crespo , Adkinson Joshua , Mattar Layth , Banks Garrett P. , Sheth Sameer A. , Watrous Andrew J. , Heilbronner Sarah R. , Bijanki Kelly R. , Alabastri Alessandro , Bartoli Eleonora
Published: November 2023

Background

Single-pulse electrical stimulation (SPES) is an established technique used to map functional effective connectivity networks in treatment-refractory epilepsy patients undergoing intracranial-electroencephalography monitoring. While the connectivity path between stimulation and recording sites has been explored through the integration of structural connectivity, there are substantial gaps, such that new modeling approaches may advance our understanding of connectivity derived from SPES studies.

New Method

Using intracranial electrophysiology data recorded from a single patient undergoing sEEG evaluation, we employ an automated detection method to identify early response components, C1, from pulse-evoked potentials (PEPs) induced by SPES. C1 components were utilized for a novel topology optimization method, modeling 3D conductivity propagation from stimulation sites. Additionally, PEP features were compared with tractography metrics, and model results were analyzed with respect to anatomical features.

Results

The proposed optimization model resolved conductivity paths with low error. Specific electrode contacts displaying high error correlated with anatomical complexities. The C1 component strongly correlates with additional PEP features and displayed stable, weak correlations with tractography measures.

Comparison with existing methods

Existing methods for estimating conductivity propagation are imaging-based and thus rely on anatomical inferences.

Conclusions

These results demonstrate that informing topology optimization methods with human intracranial SPES data is a feasible method for generating 3D conductivity maps linking electrical pathways with functional neural ensembles. PEP-estimated effective connectivity is correlated with but distinguished from structural connectivity. Modeled conductivity resolves connectivity pathways in the absence of anatomical priors.
Attention and interoception alter perceptual and neural pain signatures
Authors: Niedernhuber Maria , Streicher Joaquim , Lenggenhager Bigna , Bekinschtein Tristan A.
Published: November 2023

Fluctuations of chronic pain levels are determined by a complex interplay of cognitive, emotional and perceptual variables. We introduce a pain tracking platform composed of wearable neurotechnology and a smartphone application to measure and predict chronic pain levels. Our method measures, dynamically, pain strength, phenomenal and neural time series collected with an online tool and low-density EEG. Here we used data from a single participant who performed an attention task at home for a period of 20 days to investigate the role of attention to different bodily systems in chronic pain. Our results show a relationship between emotions and pain strength while allocating attention to the heartbeat, the breathing, the affected or the unaffected limb. We found that pain was maximal when attending to the affected limb, and decreased when the participant focused on his breathing or his heartbeat. These results provide interesting insights regarding the role of attention to interoceptive signals in chronic pain. We found power changes in the delta, theta, alpha and beta (but not in the gamma) band between the four attention conditions. However, there was no reliable association of these changes to pain intensity ratings. Theta power was higher when attention was directed to the unaffected limb compared to the others. Further, the pain ratings, when attending to unaffected limb, were associated with alpha and theta power band changes. Overall, we demonstrate that our neurophysiology and experience tracking platform can capture how body attention allocation alters the dynamics of subjective measures and its neural correlates. This research approach is proof of concept for the development of personalized clinical assessment tools and a testbed for behavioural, subjective and biomarkers characterization.
Transcriptomics and chromatin accessibility in multiple African population samples
Authors: DeGorter Marianne K , Goddard Page C , Karakoc Emre , Kundu Soumya , Yan Stephanie M , Nachun Daniel , Abell Nathan , Aguirre Matthew , Carstensen Tommy , Chen Ziwei , Durrant Matthew , Dwaracherla Vikranth R , Feng Karen , Gloudemans Michael J , Hunter Naiomi , Moorthy Mohana P S , Pomilla Cristina , Rodrigues Kameron B , Smith Courtney J , Smith Kevin S , Ungar Rachel A , Balliu Brunilda , Fellay Jacques , Flicek Paul , McLaren Paul J , Henn Brenna , McCoy Rajiv C , Sugden Lauren , Kundaje Anshul , Sandhu Manjinder S , Gurdasani Deepti , Montgomery Stephen B
Published: November 2023

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.
One gecko’s pain is another gecko’s gain: is the Moorish geckoTarentola mauritanicabecoming invasive in France?
Authors: Renet Julien , Dokhelar Théo , Dubos Nicolas
Published: November 2023

The Moorish geckoTarentola mauritanicais currently expanding around the Mediterranean basin as a result of natural dispersal and anthropogenic spread. The species is observed at several sites in sympatry with other gecko species. To date, no impact has been observed on the native species andT. mauritanicais not considered invasive. We present an eight-year survey in southern France, where it lives in sympatry with the European leaf-toed geckoEuleptes europaea. The survey started when the Moorish gecko was rare which enabled us to observe an important increase in abundance. This increase was strongly correlated with a notable decline ofE. europaea, explaining 49% of transect-specific temporal variation in abundance. We suspect that the increase inT. mauritanicadensity is causally related to this decline and recommend intensive monitoring of the species throughout the Mediterranean Basin to determine whether or not the species should be classified as invasive.
Rapid in-EPON CLEM for everyone: Combining fast and efficient labeling of self-labeling enzyme tags with EM-resistant Janelia Fluor dyes
Authors: Franzkoch Rico , Wilkening Sabrina , Liss Viktoria , Holtmannspötter Michael , Kurre Rainer , Psathaki Olympia E. , Hensel Michael
Published: November 2023

Correlative light and electron microscopy (CLEM) allows to link light microscopy (LM) of living cells to ultrastructural analyses by electron microscopy (EM). Pre-embedding CLEM often suffers from inaccurate correlation between the LM and EM modalities due to chemical and physical distortions. Post-embedding CLEM enables precise registration of fluorescent structures directly on thin resin sections. However, in-resin CLEM techniques require fluorescent markers withstanding EM sample preparation. Most fluorescent proteins lose their fluorescence during EM sample preparation. Synthetic dyes present an alternative as their photostability and brightness exceed those of fluorescent proteins. Together with self-labeling enzymes (SLE) as protein tags, these fluorophores can be used to precisely label cellular structures of interest. By applying SLE labelling for post-embedding CLEM, we compared Janelia Fluor dyes and TMR to identify most suitable fluorophores. Epithelial cells expressing HaloTag fusion proteins were stained with various ligand-conjugated dyes, and fluorescence preservation was quantified after conventional room temperature sample preparation with embedding in EPON. The results obtained show that only the red dyes TMR, JF549, JFX549 and JFX554 retain their fluorescence in resin, with JFX549 and JFX554 yielding best signal intensity and signal-to-background ratio during in-resin super-resolution microscopy. Since all red dyes possess an oxygen atom within their xanthene structure, our results indicate that this might be a crucial feature making them more tolerant to sample preparation for electron microscopy. Our work reports a rapid in-resin CLEM approach that combines fast and efficient labeling of SLE tags with EM-compatible fluorophores, and serve as benchmarks for experimental planning and future engineering of fluorophores for CLEM.
A minimal sequence motif drives selective tRNA dihydrouridylation by hDUS2
Authors: Ji Jingwei , Yu Nathan J. , Kleiner Ralph E.
Published: November 2023

The post-transcriptional reduction of uridine to dihydrouridine (D) by dihydrouridine synthase (DUS) enzymes is among the most ubiquitous transformations in RNA biology. D is found at multiple sites in tRNAs and studies in yeast have proposed that each of the four eukaryotic DUS enzymes modifies a different site, however the molecular basis for this exquisite selectivity is unknown and human DUS enzymes have remained largely uncharacterized. Here we investigate the substrate specificity of human dihydrouridine synthase 2 (hDUS2) using mechanism-based crosslinking with 5-bromouridine (5-BrUrd)-modified oligonucleotide probes andin vitrodihydrouridylation assays. We find that hDUS2 modifies U20 in the D loop of diverse tRNA substrates and identify a minimal GU motif within the tRNA tertiary fold required for directing its activity. Further, we use our mechanism-based platform to screen small molecule inhibitors of hDUS2, a potential anti-cancer target. Our work elucidates the principles of substrate modification by a conserved DUS and provides a general platform to studying RNA modifying enzymes with sequence-defined activity-based probes.
MiRGraph: A hybrid deep learning approach to identify microRNA-target interactions by integrating heterogeneous regulatory network and genomic sequences
Authors: Liu Pei , Liu Ying , Luo Jiawei , Li Yue
Published: November 2023

MicroRNAs (miRNAs) mediates gene expression regulation by targeting specific messenger RNAs (mRNAs) in the cytoplasm. They can function as both tumor suppressors and oncogenes depending on the specific miRNA and its target genes. Detecting miRNA-target interactions (MTIs) is critical for unraveling the complex mechanisms of gene regulation and promising towards RNA therapy for cancer. There is currently a lack of MTIs prediction methods that simultaneously perform feature learning from heterogeneous gene regulatory network (GRN) and genomic sequences. To improve the prediction performance of MTIs, we present a novel transformer-based multiview feature learning method – MiRGraph, which consists of two main modules for learning the sequence-based and GRN-based feature embedding. For the former, we utilize the mature miRNA sequences and the complete 3’UTR sequence of the target mRNAs to encode sequence features using a hybrid transformer and convolutional neural network (CNN) (TransCNN) architecture. For the latter, we utilize a heterogeneous graph transformer (HGT) module to extract the relational and structural information from the GRN consisting of miRNA-miRNA, gene-gene and miRNA-target interactions. The TransCNN and HGT modules can be learned end-to-end to predict experimentally validated MTIs from MiRTarBase. MiRGraph outperforms existing methods in not only recapitulating the true MTIs but also in predicting strength of the MTIs based on thein-vitromeasurements of miRNA transfections. In a case study on breast cancer, we identified plausible target genes of an oncomir.
FICTURE:Scalable segmentation-free analysis of submicron resolution spatial transcriptomics
Authors: Si Yichen , Lee ChangHee , Hwang Yongha , Yun Jeong H. , Cheng Weiqiu , Cho Chun-Seok , Quiros Miguel , Nusrat Asma , Zhang Weizhou , Jun Goo , Zöllner Sebastian , Lee Jun Hee , Kang Hyun Min
Published: November 2023

Spatial transcriptomics (ST) technologies have advanced to enable transcriptome-wide gene expression analysis at submicron resolution over large areas. Analysis of high-resolution ST data relies heavily on image-based cell segmentation or gridding, which often fails in complex tissues due to diversity and irregularity of cell size and shape. Existing segmentation-free analysis methods scale only to small regions and a small number of genes, limiting their utility in high-throughput studies. Here we present FICTURE, a segmentation-free spatial factorization method that can handle transcriptome-wide data labeled with billions of submicron resolution spatial coordinates. FICTURE is orders of magnitude more efficient than existing methods and it is compatible with both sequencing- and imaging-based ST data. FICTURE reveals the microscopic ST architecture for challenging tissues, such as vascular, fibrotic, muscular, and lipid-laden areas in real data where previous methods failed. FICTURE’s cross-platform generality, scalability, and precision make it a powerful tool for exploring high-resolution ST.
Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility and Aging (SOMMA)
Authors: Tranah Gregory J , Barnes Haley N , Cawthon Peggy M , Coen Paul M , Esser Karyn A , Hepple Russell T , Huo Zhiguang , Kramer Philip A , Toledo Frederico G. S. , Evans Daniel S , Cummings Steven R
Published: November 2023

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility and Aging. Expression levels of twenty-one protein coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including: maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2peak, 400m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteinsSOD2,TRX2,PRX3,PRX5, andGRX2were associated with higher levels of mitochondrial respiration and VO2peak. In addition, greaterSOD2, PRX3,andGRX2expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.
Machine Learning Model to Predict Allocation of Patients with Chronic Back Pain for Integrated Practice Units in a System of Value-based Health Care
Authors: Barbosa Vitor Pereira , Said dos Reis João Lucas Maehara , von Zuben de Valega Negrão Cyro , Barboza Victor Rossetto , Simoes Marcondes Keli Cristina Betto , Rezende Elton Pereira , Neto Pereira Cerize Natália , de Paula Guirado Vinicius Monteiro
Published: November 2023

Chronic pain incurs substantial global healthcare costs, requiring long-term specialized care. However, the variability in treatment approaches hampers the feasibility of value-based healthcare. To advance management and prevention efforts, data science tools like supervised and unsupervised machine learning algorithms offer promising solutions. This study employed data from six questionnaires to evaluate pain conditions in patients. Correlation techniques were applied to determine the questions most strongly correlated with low back pain, back pain, and leg pain. Five machine learning algorithms predicted the presence or absence of pain in the low back region. Seven variables were identified as input for the prediction models, with the XBoost Classifier demonstrating the highest accuracy, precision, recall, and F1-Score (0.8 accuracy, precision, recall; 0.78 F1-Score). By incorporating the machine learning model, it predicts the allocation of chronic back pain patients to integrated practice in a value-based healthcare system. Finally, our findings show that data science methods, such as machine learning, improve chronic pain management, expedite surveys, and improve value-based healthcare through efficient allocation.

Graphical abstract

Highlights

Correlation analysis identified pain-related questions (back, leg, chronic low back).

7 characteristics used by ML algorithms to forecast chronic low back pain occurrence.

XBoost algorithm and neural network achieved best performance (Precision, Recall ∼0.8).

Outcomes aid patient allocation, screening, and reducing costs in value-based healthcare.

Streamlining surveys boosts response rates and enables larger datasets for improved modeling.
A community-based mentoring scheme for pregnant and parenting adolescents in Sierra Leone: protocol for a hybrid pilot cluster randomised controlled trial
Authors: Fernandez Turienzo C , Kamara M , November L , Kamara P , Kingsford AM , Ridout A , Thomas S , Seed PT , Shennan AH , Sandall J , Williams PT
Published: November 2023

Background

Sierra Leone has a very high maternal mortality rate, and this burden falls heavily on adolescents, a particularly vulnerable group; this is usually driven by poverty, lack of education and employment opportunities. In 2017, a local grassroots organisation, Lifeline Nehemiah Projects, developed a community-based mentoring intervention ‘2YoungLives’ (2YLs) for adolescent girls in Eastern Freetown. We aim to formally assess the feasibility and implementation of the 2YL mentorship scheme in new communities in Sierra Leone.

Methods

A hybrid type 2 pilot cluster randomised controlled trial of the 2YL mentoring scheme in urban and rural communities living around twelve peripheral health units (PHU) across five districts in Sierra Leone. Clusters will be matched into pairs and randomisation will be determined by computer-generated random numbers via a secure web-based system hosted by MedSciNet. All under-eighteen adolescents identified as pregnant in the community and/or the PHU are included. Feasibility (recruitment, retention, and attrition rates; data collection and completeness; sample calculation) and primary clinical outcome data (composite of maternal deaths, stillbirths, neonatal deaths) will be collected. A mixed-methods process evaluation will explore implementation outcomes, mechanisms of change, contextual factors, experiences of care, and health and wellbeing. A concurrent cost-consequence analysis will be undertaken. Main trial analysis will be pragmatic, by intention to treat, and a complementary per protocol analysis will also be included.

Discussion

Improving health and wellbeing for adolescent girls (including sexual and reproductive health) remains a top priority in Sierra Leone indicated by several government policies targeted to this group, in which maternal and infant mortality are still persistently high. Supporting these girls and facilitating their wellbeing is imperative, along with sensitisation of communities, strengthening of youth friendly services and collaboration with stakeholders at all levels (government, regional, community, family). We believe 2YL supports the global holistic agenda to integrate and implement interventions across health, education, and social systems in order to protect, nurture, and support the health and development potential of every adolescent girl, and thus become a model of good practice for adolescent pregnancy, to be adopted more widely in Sierra Leone and elsewhere.

Trial registration

ISRCTN registryISRCTN32414369. Prospectively registered on 14/03/2022.
Associations of Objective and Self-Reported Physical Activity and Sedentary Behavior with Skeletal Muscle Energetics: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Qiao Yujia (Susanna) , Blackwell Terri L. , Cawthon Peggy M. , Coen Paul M. , Cummings Steven R. , Distefano Giovanna , Farsijani Samaneh , Forman Daniel E. , Goodpaster Bret H. , Kritchevsky Stephen B. , Mau Theresa , Toledo Frederico G.S. , Newman Anne B. , Glynn Nancy W.
Published: November 2023

Background

Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to counteract these declines in older adults. Yet, many studies were based on self-reported PA or structured exercise interventions. We examined the associations of objective daily PA and sedentary behavior (SB) with skeletal muscle energetics and also compared with self-reported PA and SB. We also explored the extent to which PA would attenuate the associations of age with muscle energetics.

Methods

Among the Study of Muscle, Mobility and Aging (SOMMA) enrolled older adults, 810 (mean age=76±5, 58% women) had maximal muscle oxidative capacity measuredex vivovia high-resolution respirometry of permeabilized myofibers (maxOXPHOS) andin vivoby31Phosphorus magnetic resonance spectroscopy (ATPmax). Objective PA was measured using the wrist-worn ActiGraph GT9X over 7-days to capture sedentary behavior (SB), light, and moderate-to-vigorous PA (MVPA). Self-reported SB, MVPA, and all exercise-related PA were assessed with The Community Healthy Activities Model Program for Seniors questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations between SB, PA and muscle energetics, and the attenuation of the age / muscle energetic association by PA.

Results

Every 30 minutes more objective MVPA was associated with 0.65 pmol/s*mg higher maxOXPHOS and 0.012 mM/sec higher ATPmax, after adjustment for age, site/technician and sex. More time spent in objective light+MVPA was significantly associated with higher ATPmax, but not maxOXPHOS. In contrast, every 30 minutes spent in objective SB was associated with 0.43 pmol/s*mg lower maxOXPHOS and 0.004 mM/sec lower ATPmax. Only associations with ATPmaxheld after further adjusting for socioeconomic status, body mass index, lifestyle factors and multimorbidities. Self-reported MVPA and all exercise-related activities, but not SB, yielded similar associations with maxOXPHOS and ATPmax. Lastly, age was only significantly associated with muscle energetics in men. Adjusting for objective time spent in MVPA attenuated the age association with ATPmaxby nearly 60% in men.

Conclusion

More time spent in daily PA, especially MVPA, were associated with higher muscle energetics. Interventions that increase higher intensity activity might offer potential therapeutic interventions to slow the age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.
Modeling the START transition in the budding yeast cell cycle
Authors: Ravi Janani , Samart Kewalin , Zwolak Jason
Published: November 2023

Budding yeast,Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5’s nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling all known regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on all established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ∼150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer. All wildtype and mutant simulations of our START-BYCC model are available atsbmlsimulator.org/simulator/by-start, and the supporting data is available on GitHub:github.com/jravilab/start-bycc.
Polycomb Repressive Complex 2 is critical for mouse cortical glutamatergic neuron development
Authors: Currey Laura , Mitchell Benjamin , Al-Kahlily Majd , McElnea Sarah-Jayne , Harkins Danyon , Pelenyi Alexandra , Kurniawan Nyoman D. , Burne Thomas H. , Harris Lachlan , Thor Stefan , Piper Michael
Published: November 2023

The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet the consequences of mutations to this epigenetic modifier in the mature brain are poorly defined. Importantly, PRC2 core genes are haploinsufficient and causative for several human neurodevelopmental disorders. To address the role of PRC2 in mature cortical structure and function, we conditionally mutated the PRC2 geneEedin the developing mouse telencephalon. Adult homozygotes displayed smaller forebrain structures. Single-nucleus transcriptomics revealed glutamatergic neurons were particularly affected, exhibiting dysregulation of cortical layer-specific profiles, accompanied by aberrations in neuronal morphology and connectivity. Incredibly, homozygous mice performed well on challenging cognitive tasks. In contrast, heterozygous mice did not exhibit anatomical or behavioral phenotypes but displayed dysregulation of neuronal genes and altered neuronal morphology that was strikingly different from homozygous phenotypes. Collectively, we demonstrate how alterations to PRC2 function shape the mature brain and reveal a dose-specific role for PRC2 in determining glutamatergic neuron identity.
The Host-specific Microbiota is Required for Diet-Specific Metabolic Homeostasis
Authors: Fei Na , Xie Bingqing , Long Tyler J. , StGeorge Marissa , Tan Alan , Manzoor Sumeed , Sidebottom Ashley M. , Spedale Melanie , Theriault Betty R , Sulakhe Dinanath , Chang Eugene B.
Published: November 2023

In complex mammals, the importance and host-specificity of microbial communities have been demonstrated through their positive effects on host immune fitness or performance. However, whether host metabolic physiology homeostasis depends on a specific bacterial community exclusive to the host remains unclear. Here, we show that the coevolved host-specific microbiota is required to maintain diet-specific flexible and sufficient metabolic homeostasis through a high colonization rate, modulating gut metabolites, and related targets. Using germ-free (GF) mice, we tested whether the fitness benefiting the host metabolic phenotype of microbiota was host-specific. We demonstrated that GF mice associated with exogenous microbiota (human microbiota (HM)), which exhibited different and reduced gut microbial species diversity, significantly elevated metabolic rate, and exhibited metabolic insufficiency, all characteristics of GF mice. Strikingly, the absence of the host-specific microbiome attenuated high-fat diet-specific metabolism features. Different diets caused different metabolic changes in only host-specific microbiota-associated mice, not the host-microbiota mismatched mice. While RNA sequencing revealed subtle changes in the expression of genes in the liver, GF mice and HM mice showed considerably altered expression of genes associated with metabolic physiology compared to GF mice associated with host-specific microbiota. The effect of diet outweighed microbiota in the liver transcriptome. These changes occurred in the setting of decreased luminal short-chain fatty acids (SCFAs) and the secondary bile acid (BAs) pool and downstream gut signaling targets in HM and GF mice, which affects whole-body metabolism. These data indicate that a foreign microbial community provides little metabolic benefit to the host when compared to a host-specific microbiome, due to the colonization selection pressure and microbiota-derived metabolites dysfunction. Overall, microbiome fitness effects on the host metabolic phenotype were host-specific. Understanding the impact of the host-specificity of the microbiome on metabolic homeostasis may provide important insights for building a better probiotic.

Highlights

Microbiome fitness effects on the host metabolic phenotype were host-specific in mammals.

Human microbiota-associated mice exhibited lower host metabolic fitness or performance, and similar functional costs in GF mice.

Different diets cause different metabolic changes only in host-specific microbiota-associated mice, not the host-microbiota mismatched mice.

The defective gut microbiota in host-specific microbiota, microbial metabolites and related targets likely drive the metabolic homeostasis.

Graphical Abstract
The Arabidopsiskatamari2Mutant Exhibits a Hypersensitive Seedling Arrest Response at the Phase Transition from Heterotrophic to Autotrophic Growth
Authors: Hosokawa Chika , Yagi Hiroki , Segami Shoji , Nagano Atsushi J. , Koumoto Yasuko , Tamura Kentaro , Oka Yoshito , Matsushita Tomonao , Shimada Tomoo
Published: November 2023

Young seedlings use nutrients stored in the seeds to grow and acquire photosynthetic potential. This process, called seedling establishment, involves a developmental phase transition from heterotrophic to autotrophic growth. Some membrane-trafficking mutants ofArabidopsis thaliana(Arabidopsis), such as thekatamari2(kam2) mutant, exhibit growth arrest during seedling development, with a portion of individuals failing to develop true leaves on sucrose-free solid medium. However, the reason for this seedling arrest is unclear. In this study, we show that seedling arrest is a temporal growth arrest response that occurs not only inkam2but also in wild-type Arabidopsis; however, the threshold for this response is lower inkam2than in the wild type. A subset of the arrestedkam2seedlings resumed growth after transfer to fresh sucrose-free medium. Growth arrest inkam2on sucrose-free medium was restored by increasing the gel concentration of the medium or covering the surface of the medium with a perforated plastic sheet. Wild-type Arabidopsis seedlings were also arrested when the gel concentration of sucrose-free medium was reduced. RNA sequencing revealed that transcriptomic changes associated with the rate of seedling establishment were observed as early as 4 days after sowing. Our results suggest that the growth arrest of bothkam2and wild-type seedlings is an adaptive stress response and is not simply caused by the lack of a carbon source in the medium. This study provides a new perspective on an environmental stress response under unfavorable conditions during the phase transition from heterotrophic to autotrophic growth in Arabidopsis.
Bioenergetic mapping of ‘healthy microbiomes’ via compound processing potential imprinted in gut and soil metagenomes
Authors: Liddicoat Craig , Edwards Robert A. , Roach Michael , Robinson Jake M. , Wallace Kiri Joy , Barnes Andrew D. , Brame Joel , Heintz-Buschart Anna , Cavagnaro Timothy R. , Dinsdale Elizabeth A. , Doane Michael P. , Eisenhauer Nico , Mitchell Grace , Rai Bibishan , Ramesh Sunita , Breed Martin F.
Published: November 2023

Despite mounting evidence of their importance in human health and ecosystem functioning, the definition and measurement of ‘healthy microbiomes’ remain unclear. More advanced knowledge exists on health associations for compounds used or produced by microbes. Environmental microbiome exposures (especially via soils) also help shape, and may supplement, the functional capacity of human microbiomes. Given the synchronous interaction between microbes, their feedstocks, and micro-environments, with functional genes facilitating chemical transformations, there exists an intriguing opportunity to examine microbiomes in terms of their capacity to process compounds relevant to human health. Here we integrate functional genomics and biochemistry frameworks to derive new quantitative measures of the potential for human gut and environmental soil metagenomes to process major compound classes (e.g., lipids, carbohydrates) and selected biomolecules (e.g., vitamins, short-chain fatty acids) linked to human health. Metagenome functional potential profile data were translated into a universal compound mapping ‘landscape’ based on bioenergetic van Krevelen mapping of function-level meta-compounds and corresponding functional relative abundances, reflecting imprinted genetic capacity of microbiomes to metabolize an array of different compounds. We show that measures of ‘compound processing potential’ associated with human health and disease (examining atherosclerotic cardiovascular disease, colorectal cancer, type 2 diabetes and anxious-depressive behavior case studies), and displayed seemingly predictable shifts along gradients of ecological disturbance in plant-soil ecosystems (three case studies). Ecosystem quality explained 60–92% of variation in soil metagenome compound processing potential measures in a post-mining restoration case study dataset. With growing knowledge of the varying proficiency of environmental microbiota to process human health associated compounds, we might design environmental interventions or nature prescriptions to modulate our exposures, thereby advancing microbiota-oriented approaches to human health. Compound processing potential offers a simplified, integrative approach for applying metagenomics in ongoing efforts to understand and quantify the role and linkages of microbiota in environmental- and human-health.
Multi-night EEG reveals positive association between sleep efficiency and hippocampal subfield volumes in healthy aging
Authors: Keresztes Attila , Bankó Éva , Báthori Noémi , Tomacsek Vivien , Varga Virág Anna , Nárai Ádám , Nemecz Zsuzsanna , Dénes Ádám , Gál Viktor , Hermann Petra , Simor Péter , Vidnyánszky Zoltán
Published: November 2023

abstract

Age-related atrophy of the human hippocampus and the enthorinal cortex starts accelerating at around age 60. Due to the contributions of these regions to many cognitive functions seamlessly used in everyday life, this can heavily impact the lives of elderly people. The hippocampus is not a unitary structure and mechanisms of its age-related decline appear to differentially affect its subfields. Human and animal studies have suggested that altered sleep is associated with hippocampal atrophy. Yet, we know little about subfield specific effects of altered sleep in healthy aging and their effect on cognition. Here, in a sample of 118 older adults (Mage= 63.25 years), we examined the association between highly reliable hippocampal subfield volumetry, sleep measures derived from multi-night recordings of portable electroencephalography and episodic memory. Objective sleep efficiency – but not self-report measures of sleep – was associated with entorhinal cortex volume when controlling for age. Age-related differences in subfield volumes were associated with objective sleep efficiency, but not with self-report measures of sleep. Moreover, older adults characterized by a common multivariate pattern of subfield volumes that contributed to positive sleep– subfield volume associations, showed lower rates of forgetting. Our results showcase the benefit of objective sleep measures in identifying potential contributors of age-related differences in brain-behavior couplings.
Exploring the perceptions and experiences of community rehabilitation for Long COVID from the perspectives of Scottish General Practitioners’ and people living with Long COVID: a qualitative study
Authors: Cooper Kay , Duncan Edward , Hart-Winks Erin , Cowie Julie , Shim Joanna , Stage Emma , Tooman Tricia , Alexander Lyndsay , Love Alison , Morris Jacqui , Ormerod Jane , Preston Jenny , Swinton Paul Alan
Published: November 2023

Objectives

To explore the experience of accessing Long COVID community rehabilitation from the perspectives of people with Long COVID and General Practitioners (GPs).

Design

Qualitative descriptive study employing one-to-one semi-structured virtual interviews analysed using the framework method.

Setting

Four NHS Scotland territorial health boards.

Participants

Eleven people with Long COVID (1 male, 10 female; aged 40-65 [mean 53], and 13 GPs (5 male, 8 female).

Results

Four key themes were identified: i) The lived experience of Long COVID; ii) The challenges of an emergent and complex chronic condition; iii) Systemic challenges for Long COVID service delivery, and iv) Perceptions and experiences of Long COVID and its management, including rehabilitation.

Conclusions

There are several patient, GP, and service-level barriers to accessing community rehabilitation for Long COVID. There is a need for greater understanding by the public, GPs, and other potential referrers of the role of community rehabilitation professionals in the management of Long COVID. There is also a need for community rehabilitation services to be well promoted and accessible to the people with Long COVID for whom they may be appropriate. Service providers need to consider availability and accessibility of Long COVID rehabilitation and ensure adequate interprofessional communication and collaboration to enhance the experience for people with Long COVID.

Strengths and limitations of this study

This is the first study to explore the issue of accessing Long COVID community rehabilitation from the perspectives of potential service users and referrers in the Scottish context.

One researcher conducted all interviews, ensuring consistency in their conduct

Data were analysed and interpreted by multiple researchers, including people with Long COVID

The small sample size, largely drawn from health boards with a similar approach to Long COVID rehabilitation, limits generalisability
Effectiveness and safety of drugs in pregnancy: evidence from drug target Mendelian randomization
Authors: Barry Ciarrah-Jane S , Walker Venexia M , Burden Christy , Havdahl Alexandra , Davies Neil M
Published: November 2023

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended foetal harm. We investigate genetically proxied intrauterine antihypertensive exposure on offspring outcomes, including gestational age and birthweight, using two-sample multivariable Mendelian randomization. Higher levels of maternal protein targets for calcium channel blockers increased gestational age by 3.99 days (95%CI: 0.02, 7.96) per 10mmHg decrease in SBP. Genetically proxied maternal protein targets for beta-adrenoceptor blocking drugs, vasodilator antihypertensive drugs on the KNCJ11 gene, potassium-sparing diuretics and aldosterone antagonists demonstrated little evidence of increased risk to offspring. Both parental genetic protein targets for vasodilator antihypertensive drugs demonstrated similar effects on birthweight, suggesting detrimental offspring effects due to genetic perturbation of these pathways is unlikely. Little evidence for increased risk of adverse offspring outcomes due to maternal antihypertensive drug target perturbation was found. Triangulation of these findings with existing evidence may guide physicians and mothers during pregnancy.