bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital outcome measures in pulmonary clinical trials
Authors: Farrand Erica , Swigris Jeffrey J.
Published: May 2023

Purpose of review

We highlight recent advances in the development and use of digital outcome measures in clinical trials, focusing on how to select the appropriate technology, use digital data to define trial endpoints, and glean important lessons from current experiences with digital outcome measures in pulmonary medicine.

Recent findings

A review of emerging literature demonstrates that the use of digital health technologies, particularly pulse oximeters, remote spirometers, accelerometers, and Electronic Patient-Reported Outcomes, has surged in both pulmonary practice and clinical trials. Lessons learned from their use can help researchers to design the next generation of clinical trials leveraging digital outcomes to improve health.

In pulmonary diseases, digital health technologies provide validated, reliable, and usable data on patients in real-world environments. More broadly, digital endpoints have accelerated innovation in clinical trial design, improved clinical trial efficiency, and centered patients. As investigators adopt digital health technologies, it is important to follow a framework informed by both the opportunities and challenges of digitization. Successful use of digital health technologies will transform clinical trials by improving accessibility, efficiency, patient-centricity, and expanding opportunities for personalized medicine.
Heterogeneity of Asthma Care Among Hispanic Subgroups
Authors: Kim Yonsu , Moonie Sheniz , Cochran Chris
Published: May 2023

Background:

Studies found heterogeneity of asthma prevalence among Hispanic subgroups using survey data but addressed under-diagnosis issues due to limited access to health care and diagnosis bias.

Objectives:

To examine heterogeneity by language in health care utilization for asthma among Hispanic subgroups.

Research Design:

A retrospective, longitudinal cohort study of Medi-Cal claims data (2018–2019) using logistic regression to estimate the odds ratio of health care utilization for asthma.

Subjects:

In all, 12,056 (ages 5–64) Hispanics living in Los Angeles were identified as having persistent asthma.

Measures:

Primary language is the predictor variable and outcome measures include ED visits, hospitalizations, and outpatient visits.

Results:

The odds of ED visits among Spanish-speaking Hispanics were lower than English-speaking Hispanics in the subsequent 6 (95% CI=0.65–0.93) and 12 (95% CI=0.66–0.87) months. Spanish-speaking Hispanics were less likely than their English-speaking counterparts to utilize hospitalization in the 6 months (95% CI=0.48–0.98), while they were more likely to utilize outpatient care (95% CI=1.04–1.24). For Hispanics of Mexican origin, the odds of ED visits among Spanish-speaking Hispanics were also lower in the 6 and 12 months (95% CI=0.63–0.93, 95% CI=0.62–0.83), but their odds of outpatient visits were higher for outpatient visits in the 6 months (95% CI=1.04–1.26).

Conclusions:

Spanish-speaking Hispanics with persistent asthma were less likely than English-speaking Hispanics to utilize ED visits and hospitalizations but were more likely to utilize outpatient visits. The findings suggest the reduced burden of asthma among the Spanish-speaking Hispanic subgroup and contribute to explaining the protection effect, specifically among Spanish-speaking Hispanics living in highly segregated communities.
Dill
Authors: Singletary Keith W.
Published: May 2023

Anethum graveolens L. (family Apiaceae) is an important culinary herb commonly called dill in English. This plant is native to southwest Asia and the Mediterranean region and is widely cultivated throughout Asia, Africa, Europe, Southern Russia, and the United States. The leaves, fruit, and essential oil of dill have numerous culinary uses, and the oil is a flavor additive in numerous products in the food industry such as dill pickles, processed meat, cheese, and bread. It is a perfume agent in detergents, soaps, fragrances, cosmetics, and mouthwashes. Dill has a long history of use in traditional medicines dating back thousands of years in China, Greece. and the Roman empire, particularly for relieving pain, indigestion, and anxiety. Recent clinical trials evaluated dill and its extracts for managing risk factors for diabetes and cardiovascular disease, as well as in improving outcomes during labor and delivery. This narrative summarizes these published human studies examining the potential health benefits of dill and highlights potential areas for further research.
Water Fountain Access on University Campuses
Authors: Adams J. D. , Hogan Ashlyn E. , Scarborough Abby , DuBose Kate , Yalden Olivia
Published: May 2023

In this brief review, the focus on university infrastructure and environmental sustainability is apparent, coupled with a review of the tools for success after interventions in children's schools. Given the great overall interest in fluid intake guidelines for public health, higher education campuses should implement policy and infrastructure changes to increase the number of drinking fountains on campus.
“Calvarial Vault Remodeling Technique for Lambdoid Craniosynostosis.”
Authors: Chiang Sarah N , Varagur Kaamya , Skolnick Gary B , Naidoo Sybill D , Smyth Matthew D , Patel Kamlesh B
Published: May 2023

Premature fusion of the lambdoid suture is the most uncommon single suture synostosis. It presents with a classic “windswept” appearance, with a trapezoid-shaped head and significant skull asymmetry notable for an ipsilateral mastoid bulge and contralateral frontal bossing. Due to the rarity of lambdoid synostosis, little is known about optimal techniques for its treatment. In particular, the proximity of the lambdoid suture to critical intracranial structures such as the superior sagittal and transverse sinuses represents a potential for significant intraoperative bleeding. Prior work has shown that parietal asymmetry persists after repair in these cases. Here, we present a technique for the treatment of unilateral lambdoid craniosynostosis along with two representative cases.

This calvarial vault remodeling technique requires the removal of both ipsilateral and contralateral parietal bones. These are moved across hemispheres and re-inset on opposite sides to help correct the parietal asymmetry. Obliquely orientated barrel stave osteotomies are performed to provide a safe mechanism for correction of occipital flattening. Our early results show improvement in correction of volume asymmetry one year post-operatively relative to patients treated with prior calvarial vault remodeling techniques. We believe the technique presented here corrects the windswept appearance in patients with lambdoid craniosynostosis while also reducing the potential for complications. Further work will be necessary to confirm this technique’s long-term efficacy in a larger cohort.
Less Is Better: Full-Incision Double-Eyelid Blepharoplasty with Rapid Recovery
Authors: Zhang Yi , Li Mengjuan , Lei Shaorong , Long Jianhong , Qi Min
Published: May 2023

Full-incision double-eyelid blepharoplasty is effective, but postoperative complications, such as local trauma and persistent tissue swelling, are major concerns. Because tissue swelling is caused by the obstruction of blood and lymphatic flow, the authors modified the conventional full-incision method to minimize the trauma as much as possible. Twenty-five patients underwent the modified procedure. There was minor swelling immediately after the surgery, which subsided 1 to 5 days after the surgery. No patient reported loss of the double eyelid crease. Only 2 patients underwent a second operation because of a low crease. Satisfactory results were obtained in 92% of patients (23 of 25). According to our understanding of this technique, less trauma is the key to obtaining better results under certain conditions.
Integrated Approaches for Reconstruction of Facial Paralysis
Authors: Chen Shihheng , Chen Hung-Chi , Tang Yueh-Bih
Published: May 2023

Background

Facial paralysis can affect periorbital muscles, oral competence, and facial expressions with significant facial deformities, which could occur in either children or adults with variable severity, duration, and degree of recovery.

Objective

The present study was aimed to delineate treatment plans for facial paralysis with different clinical scenarios and to report the results of these patients.

Methods

Patients were grouped according to different presentations as follows: (1) facial paralysis with incomplete recovery; (2) young patients of facial paralysis without recovery; (3) senile patients of facial palsy without recovery; (4) combined facial palsy with mandibular deficiency, vascularized bone reconstruction for mandible with (a) subsequent muscle transfer or (b) simultaneous sling operation or (c) simultaneous facial nerve exploration and cross nerve grafting; (5) palsy of frontal branch of facial nerve; (6) palsy of zygomatic-buccal branch of facial nerve; (7) palsy of marginal mandibular branch of facial nerve; (8) partial recovery with dyskinesia; and (9) facial paralysis with dynamic asymmetry and muscle atrophy. According to clinical scenarios, different treatment plans were provided, and clinical outcomes were evaluated and presented.

Results

All patient groups achieved fair or satisfactory outcomes. Revisions using sling procedures, botulinum toxin injection, and filler or fat graft as supplement further refined the ultimate outcomes.

Conclusions

For reconstruction of facial paralysis, individualized integrated treatment plans are mandatory according to the presentation and condition of the patient. Comprehensive considerations and strategic solutions for the existing disabilities have been appreciated by the patients. The least numbers of operations with considerate correction of asymmetry were the major concerns of the patients.
The Promise of Precision Nutrition for Modulation of the Gut Microbiota as a Novel Therapeutic Approach to Acute Graft-versus-host Disease
Authors: Lakshmanan Arun Prasath , Deola Sara , Terranegra Annalisa
Published: May 2023

Acute graft-versus-host disease (aGVHD) is a severe side effect of allogeneic hematopoietic stem cell transplantation (aHSCT) that has complex phenotypes and often unpredictable outcomes. The current management is not always able to prevent aGVHD. A neglected actor in the management of aGVHD is the gut microbiota. Gut microbiota dysbiosis after aHSCT is caused by many factors and may contribute to the development of aGVHD. Diet and nutritional status modify the gut microbiota and a wide range of products are now available to manipulate the gut microbiota (pro-, pre-, and postbiotics). New investigations are testing the effect of probiotics and nutritional supplements in both animal models and human studies, with encouraging results. In this review, we summarize the most recent literature about the probiotics and nutritional factors able to modulate the gut microbiota and we discuss the future perspective in developing new integrative therapeutic approaches to reducing the risk of graft-versus-host disease in patients undergoing aHSCT.
Leucobacter allii sp. nov. and Leucobacter rhizosphaerae sp. nov., isolated from rhizospheres of onion and garlic, respectively
Authors: Kim Seunghwan , Asano Tomomi , Naito Hanako , Hamada Moriyuki , Weon Hang-Yeon , Kwon Soon-Wo , Heo Jun
Published: May 2023

Three bacterial strains, H21R-40T and H21R-36 from garlic (Allium sativum) and H25R-14T from onion (Allium cepa), were isolated from plant rhizospheres sampled in the Republic of Korea. Results of 16S rRNA gene sequence analysis revealed the highest sequence similarity of strain H21R-40T to

Leucobacter celer

subsp.

astrifaciens

CBX151T (97.3 %) and

Leucobacter triazinivorans

JW-1T (97.2 %), and strain H25R-14T to

Leucobacter insecticola

HDW9BT (98.8 %) and

Leucobacter humi

Re6T (98.4 %), while the sequence similarity between strains H21R-40T and H21R-36 was 99.8 %. According to the phylogenomic tree, strains H21R-40T with H21R-36 formed an independent clade separable from other

Leucobacter

species within the genus

Leucobacter

and strain H25R-14T clustered with

Leucobacter insecticola

HDW9BT,

Leucobacter coleopterorum

HDW9AT and

Leucobacter viscericola

HDW9CT. Strains H21R-40T and H21R-36 had orthologous average nucleotide identity (OrthoANI) and digital DNA–DNA hybridization (dDDH) values (98.1 % and 86.9 %, respectively) higher than the threshold ranges for species delineation (95–96 % and 70 %, respectively). The OrthoANI and dDDH values between two strains (H21R-40T and H25R-14T) and the type strains of species of the genus

Leucobacter

were lower than 81 and 24 %, respectively. The peptidoglycan type of three strains was type B1. The major menaquinones and major polar lipids of the strains were MK-11 and MK-10, and diphosphatidylglycerol, phatidylglycerol and an unidentified glycolipid, respectively. The major fatty acids (more than 10 % of the total fatty acids) of strains H21R-40T and H21R-36 were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0, and those of strain H25R-14T were anteiso-C15 : 0 and iso-C16 : 0. The phenotypic, chemotaxonomic and genotypic data obtained in this study showed that the strains represent two novel species of the genus

Leucobacter

, named Leucobacter allii sp. nov. (H21R-40T and H21R-36) and Leucobacter rhizosphaerae sp. nov. (H25R-14T). The respective type strains are H21R-40T (=DSM 114348T=JCM 35241T=KACC 21839T=NBRC 115481T) and H25R-14T (=DSM 114346T=JCM 35239T=KACC 21837T=NBRC 115479T).
Systematic review search strategies are poorly described and not reproducible: a cross-sectional meta-research study
Authors: Rethlefsen Melissa L. , Brigham Tara J. , Price Carrie , Moher David , Bouter Lex M. , Kirkham Jamie J. , Schroter Sara , Zeegers Maurice P.
Published: May 2023

Objective

To determine the reproducibility of biomedical systematic review search strategies.

Design

Cross-sectional meta-research study.

Population

Random sample of 100 systematic reviews indexed in MEDLINE in November 2021.

Main Outcome Measures

The primary outcome measure is the percentage of systematic reviews for which all database searches can be reproduced. This was operationalized as fulfilling six key PRISMA-S reporting guideline items (database name, multi-database searching, full search strategies, limits and restrictions, date(s) of searches, and total records) and having all database searches reproduced within 10% of the number of original results.

Results

The 100 systematic review articles contained 453 database searches. Of those, 214 (47.2%) provided complete database information (named the database and platform; PRISMA-S item 1). Only 22 (4.9%) database searches reported all six PRISMA-S items. Forty-seven (10.4%) database searches could be reproduced within 10% of the number of results from the original search; 6 searches differed by more than 1000% between the originally reported number of results and the reproduction. Only one systematic review article provided the necessary details for all database searches to be fully reproducible.

Conclusion

Systematic review search reporting is poor. As systematic reviews and clinical practice guidelines based upon them continue to proliferate, so does research waste. To correct this will require a multi-faceted response from systematic review authors, peer reviewers, journal editors, and database providers.
PREVALENCE OF MYOPIA AMONG PUBLIC SCHOOL CHILDREN IN SOUTHERN BRAZIL
Authors: Gus Patrícia Ioschpe , de Maman Raquel Silveira , Lengler Arthur Dementshuk , Martins Antônia Stumpf , Torres Arteche Maria Antônia , Pieta Marina Puerari , Leivas Gabriel , Carloto Rafael , Marinho Diane , Tartarella Márcia Beatriz , Pakter Helena , Fabris Caroline , Castro Terla , Kronbauer Fernando , Colossi Carina , Jong Monica , Resnikoff Serge
Published: May 2023

Purpose

Myopia has been considered a public health issue by the World Health Organization since 2015. The growing incidence of myopia worldwide, called the myopia epidemic, and its potential blinding complications in adulthood like cataract, glaucoma, retinal detachment and maculopathy, have been extensively published and discussed in peer review papers. Nonetheless, little information about Latin America is available. This study aims to detect the prevalence of myopia in southern Brazil, the biggest country of South America.

Methods

A prospective cross sectional study recruited 330 public school children between 2019 and 2021, aged 5 to 20 years old. All children underwent a comprehensive eye examination and detailed lifestyle questionnaire. The Pearson correlation coefficient, Kruskal Wallys and the Chi-Square Test were used to assess simple correlations and associations between myopia and medical conditions, use of medications, ophthalmic history and family history of ocular conditions, besides demographics and lifestyle focused on screen time/day. Associations between the results of the ophthalmologic evaluation and all factors included in the questionnaire were analyzed using the Generalized Estimating Equation model (GEE). The prevalence of hyperopia and astigmatism were also assessed.

Results

Total prevalence of myopia was 17.4% (CI 13.8 – 21.7%). Low myopia (-0.50D to -5.75D) comprised 15.2% (CI 11.9 – 19.3%) and high myopia (-6,00D or worse) was 2.1% (CI 1.1 – 4.1%). Relative risk of myopia for females was 1.6 (CI 1.00 – 2.57%) and each additional hour of screen time increased a child’s chance of having myopia by 6.5%. The prevalence of hyperopia was 7,7% (CI 5.4 -10.9%) and of astigmatism, either myopic or hyperopic, was 25.6% (CI 21.4 – 30.2%).

Conclusions

Brazil has always been considered a hyperopic country. These are the highest reported prevalences of myopia under cycloplegia and the first paper to present myopia as a more prevalent refractive error than hyperopia among Brazilian school children to date.
Distinct Neurocognitive Profiles and Clinical Phenotypes Associated with Copy Number Variation at the 22q11.2 Locus
Authors: O’Hora Kathleen P. , Kushan-Wells Leila , Hoftman Gil D. , Jalbrzikowski Maria , Gur Raquel C. , Gur Ruben , Bearden Carrie E.
Published: May 2023

Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene-brain-behavior relationships relevant to autism. Copy number variation at the 22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn-CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (MAge=19.2 years, 49.1% male), 30 22qDup carriers (MAge=17.3 years, 53.3 % male), and 41 typically developing (TD) subjects (MAge=17.3 years, 39.0 % male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (Episodic Memory, Executive Function, Complex Cognition, Social Cognition, and Sensorimotor Speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in Episodic Memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 CNV carriers failed to show age-associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.
Associations of rest-activity rhythm disturbances with stroke risk and post-stroke adverse outcomes
Authors: Gao Lei , Zheng Xi , Baker Sarah N. , Li Peng , Scheer Frank A.J.L. , Nogueira Ricardo C , Hu Kun
Published: May 2023

Background

Almost all biological and disease processes are influenced by circadian clocks and display ∼24-hour rhythms. Disruption of these rhythms may be an important novel risk factor for stroke. We evaluated the association between 24-h rest-activity rhythm measures, stroke risk, and major post-stroke adverse outcomes.

Methods

In this cohort study, we examined ∼100,000 participants in the UK Biobank (44-79 years old; ∼57% females) who underwent an actigraphy (6-7 days) and 5-year median follow-up. We derived: (1) most active 10 hours activity counts (M10) across the 24-h cycle and the timing of its midpoint (M10 midpoint); (2) the least active 5 hours counts (L5) and its midpoint timing (L5 midpoint); (3) relative amplitude (RA) - (M10-L5)/(M10+L5); (4)interdaily stability(IS): stability and (5)intradaily variability(IV), fragmentation of the rhythm. Cox proportional hazard models were constructed for time to (i) incident stroke (n=1,652); and (ii) post-stroke adverse outcomes (dementia, depression, disability, or death).

Results

Suppressed RA (lower M10 and higher L5) was associated with stroke risk after adjusting for demographics; the risk was highest in the lowest quartile [Q1] for RA (HR=1.62; 95% CI:1.36-1.93,p<0.001) compared to the top quartile [Q4]. Participants withlaterM10 midpoint timing (14:00-15:26, HR=1.26, CI:1.07-1.49,p=0.007) also had a higher risk for stroke thanearlier(12:17-13:10) participants. A fragmented rhythm (IV) was also associated with a higher risk for stroke (Q4 vs. Q1; HR=1.27; CI:1.06-1.50,p=0.008), but differences in the stability of rhythms (IS) were not. Suppressed RA was associated with an increased risk of unfavorable post-stroke outcomes (Q1 vs. Q4; 1.78 [1.29-2.47];p<0.001). All the associations were independent of age, sex, race, obesity, sleep disorders, cardiovascular diseases or risks, and other morbidity burdens.

Conclusion

Suppressed 24-h rest-activity rhythm may be a risk factor for stroke and an early indicator of major post-stroke adverse outcomes.
Effects of age and sex on patient-reported outcomes following total knee arthroplasty with a rotating bearing tibial platform design: A single-surgeon practice registry study
Authors: Fatima Manaal , Scholes Corey , Ireland John
Published: May 2023

Withdrawal statement

The authors have withdrawn their manuscript owing to a manufacturer’s recall notice for the implant reported. The results reported here may have been impacted by a higher than expected rate of implant revision, which cannot be verified in the available data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Identification of neuropathology-based subgroups in multiple sclerosis using a data-driven approach
Authors: de Boer Alyse , van den Bosch Aletta M.R. , Mekkes Nienke J. , Fransen Nina , Hoekstra Eric , Smolders Joost , Hamann Jörg , Huitinga Inge , Holtman Inge R.
Published: May 2023

Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pathophysiology. Stratification into biologically distinct subgroups could enhance prognostication and efficacious allocation to disease-modifying therapies. In this study, we identified MS subgroups by performing a clustering analysis on neuropathology data collected for MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The input dataset contained detailed information on white matter lesion load, the proportion of active, mixed active/inactive, inactive and remyelinating lesions, microglia morphology in these lesions, and the presence of microglial nodules, perivascular cuffs and cortical lesions for 228 donors. A factor analysis was performed to reduce noise and redundancy prior to hierarchical clustering with K-means consolidation. Four subgroups with distinct patterns of white matter lesions were identified. These were subsequently validated with additional clinical, neuropathological and genetic data. The subgroups differed with regards to disease progression and duration, the timing of motor, sensory and other relevant signs and symptoms, patterns of cortical lesions and the presence of B cells. Age at MS onset and sex, previously associated with milder forms of MS, did not differ between the subgroups; the subgroups could also not be distinguished based on the manifestation of clinical signs and symptoms. The available genetic data was used to calculate MS polygenic risk scores (PRSs) for donors included in the NBB cohort. The MS PRS did not differ between the subgroups, but was significantly correlated with the first and second dimension of the factor analysis, the latter lending genetic support to our subdivision. Taken together, these findings suggest a complex relationship between neuropathological subgroups and clinical characteristics, indicating that post-mortem cohort studies are critical to better stratify patients and understand underlying neuropathophysiological mechanisms, in order to ultimately achieve personalised medicine in MS.
CHIR99021 causes inactivation of Tyrosine Hydroxylase and depletion of dopamine in rat brain striatum
Authors: Hamdon Sally , Fernandez-Gonzalez Pol , Omar Muhammad Yusof , González-Sepúlveda Marta , Ortiz Jordi , Gil Carles
Published: May 2023

CHIR99021, also known as laduviglusib or CT99021, is a Glycogen-synthase kinase 3β (GSK3β) inhibitor, which has been reported as a promising drug for cardiomyocyte regeneration or treatment of sensorial hearing loss. Since the activation of dopamine (DA) receptors regulates dopamine synthesis and they can signal through the β-arrestin pathway and GSK3β, we decided to check the effect of GSK3β inhibitors (CHIR99021, SB216763 and lithium ion) in the control of DA synthesis. Usingex vivoexperiments with minces from rat brain striatum, we observed that CHIR99021, but not SB216763 nor lithium, causes a complete abrogation of DA synthesis and accumulation at low µM concentrations, pointing to off-target effects of CHIR99021. This decrease can be attributed to tyrosine hydroxylase (TH) inhibition since the accumulation of L-DOPA in the presence of a DOPA decarboxylase inhibitor was similarly decreased. On the other hand, CHIR99021 caused a dramatic increase in the DOPAC / DA ratio, an indicator of DA metabolization, and hindered DA incorporation into striatum tissue to the same extent as tetrabenazine, thus pointing to some effect on DA storage that triggers DA feedback inhibition of TH. In addition, CHIR99021 or SB216763, but not lithium, decreased TH phosphorylation in Ser19, but not in Ser31 or Ser40. These results demonstrate that CHIR99021 can lead to TH inactivation and DA depletion in brain striatum, opening the possibility of its use in DA-related disorders, and shows effects to be considered in future clinical trials.
Major changes in domain arrangements are associated with the evolution of termite castes
Authors: Mikhailova Alina A. , Dohmen Elias , Harrison Mark C.
Published: May 2023

Domains as functional protein units and their rearrangements along the phylogeny can shed light on the functional changes of proteomes associated with the evolution of complex traits like eusociality. This complex trait is associated with sterile soldiers and workers, and long-lived, highly fecund reproductives. Unlike in Hymenotpera (ants, bees, and wasps), the evolution of eusociality within Blattodea, where termites evolved from within cockroaches, was accompanied by a reduction in proteome size, raising the question of whether functional novelty was achieved with existing rather than novel proteins. To address this, we investigated the role of domain rearrangements during the evolution of termite eusociality. Analysing domain rearrangements in the proteomes of three solitary cockroaches and five eusocial termites, we inferred more than 5000 rearrangements over the phylogeny of Blattodea. The 90 novel domain arrangements that emerged at the origin of termites were enriched for several functions related to longevity, such as protein homeostasis, DNA repair, mitochondrial activity, and nutrient sensing. Many domain rearrangements were related to changes in developmental pathways, important for the emergence of novel castes. Along with the elaboration of social complexity, including permanently sterile workers and larger, foraging colonies, we found 110 further domain arrangements with functions related to protein glycosylation and ion transport. We found an enrichment of caste-biased expression and splicing within rearranged genes, highlighting their importance for the evolution of castes. Furthermore, we found increased levels of DNA methylation among rearranged compared to non-rearranged genes suggesting fundamental differences in their regulation. Our findings indicate an importance of domain rearrangements in the generation of functional novelty necessary for termite eusociality to evolve.
Identification and Integration of Key-Metabolic Reactions from Untargeted Metabolomics
Authors: Köhler Nikolai , Würf Vivian , Rose Tim D. , Pauling Josch K.
Published: May 2023

Metabolomics has become increasingly popular in biological and biomedical research, especially for multi-omics studies, due to the many associations of metabolism with diseases. This development is driven by improvements in metabolite identification and generating large amounts of data, increasing the need for computational solutions for data interpretation. In particular, only few computational approaches directly generating mechanistic hypotheses exist, making the biochemical interpretation of metabolomics data difficult. We presentmantra, an approach to estimate how metabolic reactions change their activity between biological conditions without requiring absolute quantification of metabolites. Starting with a data-specific metabolic network we utilize linear models between substrates and products of a metabolic reaction to approximate deviations in activity. The obtained estimates can subsequently be used for network enrichment and integration with other omics data. By applyingmantrato untargeted metabolomics measurements of Triple-Negative Breast Cancer biopsies, we show that it can accurately pinpoint biomarkers. On a dataset of stool metabolomics from Inflammatory Bowel Disease patients, we demonstrate that predictions on our proposed reaction metric generalize to an independent validation cohort and that it can be used for multi-omics network integration. By allowing mechanistic interpretation we facilitate knowledge extraction from metabolomics experiments.
In situ Quantification of Biomolecular Concentration of Cytoplasmic Membraneless Organelles in a Living Cell
Authors: Shibuya Ren , Kajimoto Shinji , Yaginuma Hideyuki , Ariyoshi Tetsuro , Okada Yasushi , Nakabayashi Takakazu
Published: May 2023

Liquid droplets formed via intracellular Liquid–liquid phase separation (LLPS) are called membraneless organelles and provide enzymatic reaction fields for maintaining cellular homeostasis, while they can be sources of protein aggregates and fibrils, causing neurodegenerative diseases. To understand the nature of intracellular liquid droplets, it is essential to quantify liquid droplets inside a living cell. Here, we performed near-IR fluorescence and Raman imaging to quantify chemical components inside stress granules (SGs) formed via LLPS in living cells under oxidative stress. The Raman images of stressed cells indicate the concentration of nucleic acids in the SGs was 20% higher than surrounding cytoplasm, while the lipid concentration was lower. The intensity of biomolecular C–H bands relative to the water band shows the net concentration of biomolecules was almost the same inside and outside the SGs, indicating intracellular droplets are not highly condensed, but the crowding environments are similar to the surroundings.

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Diffusion Tensor Imaging: Influence of segmentation on fiber tracking in the supraspinatus muscle – an inter-operator reliability analysis
Authors: Vetter Sebastian , Köhler Hans-Peter , Hepp Pierre , Steinke Hanno , Schleifenbaum Stefan , Theopold Jan , Kiem Simon , Witt Maren , Henkelmann Jeanette , Roth Christian
Published: May 2023

The ability of muscle to generate force depends on its architecture and quality. MR-based diffusion tensor imaging of muscle (mDTI) is an innovative approach for showing the fiber arrangement for the whole muscle volume. For accurate calculations of fiber metrics, muscle segmentation prior to tractography seems mandatory. Since segmentation is known to be operator dependent, it is important to understand how segmentation affects tractography. The aim of this study was to compare the results of deterministic fiber tracking based on muscle models generated by two independent operators. In addition, this study compares the results with a segmentation-free approach. Fifteen subjects underwent mDTI of the right shoulder. The results showed that mDTI can be successfully applied to complex joints such as the human shoulder. Furthermore, operators segmentation did not influence the results of fiber tracking and showed excellent intraclass correlation estimates (≥ 0.975). As an exploratory approach, the segmentation-free fiber tracking showed significant differences in terms of mean fascicle length. Based on these findings, we assume that tractography does not require a detailed muscle segmentation. Furthermore, it implies that mDTI and automatic segmentation approaches or even a segmentation-free analysis can be considered for evaluation of muscle changes.
Spectral consistency in sound sequence affects perceptual accuracy in discriminating subdivided rhythmic patterns
Authors: Nitta Jun , Kondoh Sotaro , Okanoya Kazuo , Tachibana Ryosuke O.
Published: May 2023

Musical compositions are distinguished by their unique rhythmic patterns, determined by subtle differences in how regular beats are subdivided. Precise perception of these subdivisions is essential for discerning nuances in rhythmic patterns. While musical rhythm typically comprises sound elements with a variety of timbres or spectral cues, the impact of such spectral variations on the perception of rhythmic patterns remains unclear. Here, we show that consistency in spectral cues affects perceptual accuracy in discriminating subdivided rhythmic patterns. We conducted online experiments using rhythmic sound sequences consisting of band-passed noise bursts to measure discrimination accuracy. Participants were asked to discriminate between a swing-like rhythm sequence, characterized by a 2:1 interval ratio, and its more or less exaggerated version. This task was also performed under two additional rhythm conditions: inversed-swing rhythm (1:2 ratio) and regular subdivision (1:1 ratio). The center frequency of the band noises was either held constant or alternated between two values. Our results revealed a significant decrease in discrimination accuracy when the center frequency was alternated, irrespective of the rhythm ratio condition. This suggests that rhythm perception is not only shaped by temporal structure but also affected by spectral properties.
Direct detection of deformation modes on varying length scales in active biopolymer networks
Authors: Stam Samantha , Gardel Margaret L. , Weirich Kimberly
Published: May 2023

Correlated flows and forces that emerge from active matter orchestrate complex processes such as shape regulation and deformations in biological cells and tissues. The active materials central to cellular mechanics are cytoskeletal networks, where molecular motor activity drives deformations and remodeling. Here, we investigate deformation modes in contractile actin networks driven by the molecular motor myosin II through quantitative fluorescence microscopy. We examine the deformation anisotropy at different length scales in networks of sparsely cross-linked and bundled actin. In sparsely cross-linked networks, we find myosin-dependent biaxial buckling modes across length scales. Interestingly, both long and short-wavelength buckling may contribute to network contractility. In cross-linked bundled networks, uniaxial contraction predominates on long length scales, while the uniaxial or biaxial nature of the deformation depends on bundle microstructure at shorter length scales. The anisotropy of deformations may provide insight to the mechanical origins of contractility in actin networks and regulation of collective behavior in a variety of active materials.
Sorting receptor SORCS2 facilitates a protective stress response in pancreatic islets
Authors: Kalnytska Oleksandra , Qvist Per , Kunz Séverine , Conrad Thomas , Willnow Thomas E. , Schmidt Vanessa
Published: May 2023

Objective

SORCS2 is an intracellular sorting receptor genetically associated with body mass index (BMI) in humans, yet its mode of action remains unknown. Elucidating the receptor function that defines its role in metabolic health is the objective of this work.

Methods

Combiningin vivometabolic studies in SORCS2-deficient mouse models withex vivostructural and functional analyses as well as single-cell transcriptomics of murine pancreatic tissues, we studied the pathophysiological consequences of receptor dysfunction for metabolism.

Results

Our studies identified an important role for SORCS2 in islet stress response essential to sustain glucose-stimulated insulin release. In detail, we show that SORCS2 is predominantly expressed in islet alpha cells. Loss of receptor expression coincides with the inability of these cells to produce osteopontin, a secreted factor that facilitates insulin release from beta cells under stress. In line with diminished osteopontin levels, beta cells in SORCS2- deficient islets show changes in gene expression patterns related to aggravated ER stress, protein misfolding, as well as mitochondrial dysfunction; and they exhibit defects in insulin granule maturation and a blunted response to glucose stimulationin vivoandex vivo. Impaired glucose tolerance in receptor mutant mice coincides with alterations in body weight and composition.

Conclusion

Our data identified a novel concept in protective islet stress response involving the alpha cell receptor SORCS2 and provide experimental support for association ofSORCS2with metabolic control in humans.
Intra-host quasispecies reconstructions resemble inter-host variability of transmitted chronic hepatitis B virus strains
Authors: Le Clercq Louis S , Bowyer Sheila M , Mayaphi Simnikiwe H
Published: May 2023

The hepatitis B virus is a partially double stranded DNA virus in the Hepadnaviridae family of viruses that infect the liver cells of vertebrates including humans. The virus replicates through the reverse transcription of an RNA intermediate by a viral polymerase, akin to retroviruses. The viral polymerase has high replication capacity but low fidelity and no proofreading activity resulting in a high mutation rate. This contributes to the emergence of a cloud of mutants or quasispecies within host systems during infection. Several host and viral factors have been identified that contribute to mutations and mutation frequency in shaping viral evolution, however, because the dynamics of viral evolution cannot be understood from the fittest strain alone, the need exists to sequence and reconstruct intra-host diversity, recently made possible through next generation sequencing. Due to the extensive pipeline of bioinformatic analyses associated with next generation sequencing studies are needed to ascertain if quasispecies reconstruction methods and diversity measures accurately model known diversity. Here, next generation sequencing and various quasispecies reconstruction methods are used to model the natural evolution of viral populations across the full genome of hepatitis B virus strains from South Africa. This study illustrates that (i) different methods of quasispecies reconstruction reconstruct the same amount of diversity, (ii) intra-host diversity derived from full quasispecies analyses resembles diversity measures obtained from previous methods, (iii) inter-host diversity resembles the diversity between closely related quasispecies variants, (iv) diversity is increased in HIV-negative individuals, and (v) corroborate that seroconversion of HBV biomarkers increases mutation rates.
New Curcuphenol Analogues Possess Anti-Metastatic Biological Activity
Authors: Ellis Samantha L.S. , Nohara Lilian L. , Dada Sarah , Saranchova Iryna , Munro Lonna , Choi Kyung Bok , Garrovillas Emmanuel , Pfeifer Cheryl G. , Williams David E. , Cheng Ping , Andersen Raymond J. , Jefferies Wilfred A.
Published: May 2023

For eons, turmeric and curcumin have been used as culinary spices and as traditional medicines and as vogue dietary supplements for a growing list of disorders, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression and cancer. The activities of these spices are commonly attributed to curcuminoids; however, the medical applications of this class of compounds has been limited due to the low water solubility, chemical instability, acid lability, poor absorption, rapid catabolism by enzymes of the diverse curcuminoids contained in turmeric and curcumin extracts. Furthermore, identifying the bio-active curcuminoids with unique molecular entities responsible for specific medicinal benefit is at its infancy. To overcome these many issues and substantially advance this area of inquiry, we created a water-soluble achiral curcuphenol analogue and a water-soluble racemic analogue that have enhanced chemical characteristics and biological performance, and we subsequently demonstrated their ability to reverse the immune-escape phenotype, a process that enables tumours to hide from host immune responses and thereby provides tumours a significant growth advantage to metastatic tumours. The discovery that curcuphenols can reverse tumour immune-escape mechanisms and thereby reduce tumour growth, provides a rationale for the development of advanced dissecting nutraceuticals and bioceuticals for unique chemical entities as therapeutic building blocks to synthesize analogues with optimal chemical characteristics capable of harnessing the power of the immune system to extinguish metastatic cancers and beyond.
The transcription factor DksA exerts opposing effects on cell division depending on the presence of ppGpp
Authors: Anderson Sarah E. , Vadia Stephen E. , McKelvy Jane , Levin Petra Anne
Published: May 2023

Bacterial cell size is a multifactorial trait that is influenced by variables including nutritional availability and the timing of cell division. Prior work revealed a negative correlation between the alarmone (p)ppGpp (ppGpp) and cell length inEscherichia coli, suggesting that ppGpp may promote assembly of the division machinery (divisome) and cytokinesis in this organism. To clarify this counterintuitive connection between a starvation induced stress response effector and cell proliferation, we undertook a systematic analysis of growth and division inE. colicells defective in ppGpp synthesis and/or engineered to overproduce the alarmone. Our data indicate that ppGpp acts indirectly on divisome assembly through its role as a global mediator of transcription. Loss of either ppGpp (ppGpp0) or the ppGpp-associated transcription factor DksA led to increased average length, with ppGpp0mutants also exhibiting a high frequency of extremely long filamentous cells. Using heat-sensitive division mutants and fluorescently labeled division proteins, we confirmed that ppGpp and DksA are cell division activators. We found that ppGpp and DksA regulate division through their effects on transcription, although the lack of known division genes or regulators in available transcriptomics data strongly suggests that this regulation is indirect. Surprisingly, we also found that DksA inhibits division in ppGpp0cells, contrary to its role in a wild-type background. We propose that the ability of ppGpp to switch DksA from a division inhibitor to a division activator helps tune cell length across different concentrations of ppGpp.

Importance

Cell division is a key step in the bacterial lifecycle that must be appropriately regulated to ensure survival. This work identifies the alarmone ppGpp as a general regulator of cell division, extending our understanding of the role of ppGpp beyond a signal for starvation and other stress. Even in nutrient replete conditions, basal levels of ppGpp are essential for division to occur appropriately and for cell size to be maintained. This study establishes ppGpp as a “switch” that controls whether the transcription factor DksA behaves as a division activator or inhibitor. This unexpected finding enhances our understanding of the complex regulatory mechanisms employed by bacteria to coordinate division with diverse aspects of cell growth and stress response. Because division is an essential process, a better understanding the mechanisms governing assembly and activation of the division machinery could contribute to the development of novel therapeutics to treat bacterial infections.
Stability Oracle: A Structure-Based Graph-Transformer for Identifying Stabilizing Mutations
Authors: Diaz Daniel J. , Gong Chengyue , Ouyang-Zhang Jeffrey , Loy James M. , Wells Jordan , Yang David , Ellington Andrew D. , Dimakis Alex , Klivans Adam R.
Published: May 2023

Stabilizing proteins is a fundamental challenge in protein engineering and is almost always a prerequisite for the development of industrial and pharmaceutical biotechnologies. Here we present Stability Oracle: a structure-based graph-transformer framework that achieves state-of-the-art performance on predicting the effect of a point mutation on a protein’s thermodynamic stability (ΔΔG). A strength of our model is its ability to identifystabilizingmutations, which often make up a small fraction of a protein’s mutational landscape. Our framework introduces several data and machine learning innovations to overcome well-known challenges in data scarcity and bias, generalization, and computation time. Stability Oracle is first pretrained on over 2M masked microenvironments and then fine-tuned using a novel data augmentation technique, Thermodynamic Permutations (TP), applied to a ∼120K curated subset of the mega-scale cDNA display proteolysis dataset. This technique increases the original 120K mutations to over 2M thermodynamically valid ΔΔG measurements to generate the first structure training set that samples and balances all 380 mutation types. By using the masked microenvironment paradigm, Stability Oracle does not require a second mutant structure and instead uses amino acid structural embeddings to represent a mutation. This architectural design accelerates training and inference times: we can both train on 2M instances with just 119 structures and generate deep mutational scan (DMS) predictions from only the wildtype structure. We benchmark Stability Oracle with both experimental and AlphaFold structures of all proteins on T2837, a test set that aggregates the common test sets (SSym, S669, p53, and Myoglobin) with all additional experimental data from proteins with over a 30% sequence similarity overlap. We used TP augmented T2837 to evaluate performance for engineering protein stability: Stability Oracle correctly identifies 48% of stabilizing mutations (ΔΔG < −0.5 kcal/mol) and 74% of its stabilizing predictions are indeed stabilizing (18% and 8% of predictions were neutral and destabilizing, respectively). For a fair comparison between sequence and structure-based fine-tuned deep learning models, we build on the Prostata framework and fine-tune the sequence embeddings of ESM2 on our training set (Prostata-IFML). A head-to-head comparison demonstrates that Stability Oracle outperforms Prostata-IFML on regression and classification even though the model is 548 times smaller and is pretrained with 4000 times fewer proteins, highlighting the advantages of learning from structures.