bluuebunny/crossref_metadata_2025 huggingface dataset:
Analyzing wav2vec embedding in Parkinson’s disease speech: A study on cross-database classification and regression tasks
Authors: Klempir Ondrej , Krupicka Radim
Published: April 2024

Advancements in deep learning speech representations have facilitated the effective use of extensive datasets comprised of unlabeled speech signals, and have achieved success in modeling tasks associated with Parkinson’s disease (PD) with minimal annotated data. This study focuses on PD non-fine-tuned wav2vec 1.0 architecture. Utilizing features derived from wav2vec embedding, we develop machine learning models tailored for clinically relevant PD speech diagnosis tasks, such as cross-database classification and regression to predict demographic and articulation characteristics, for instance, modeling the subjects’ age and number of characters per second. The primary aim is to conduct feature importance analysis on both classification and regression tasks, investigating whether latent discrete speech representations in PD are shared across models, particularly for related tasks. The proposed wav2vec-based models were evaluated on PD versus healthy controls using three multi-language-task PD datasets. Results indicated that wav2vec accurately detected PD based on speech, outperforming feature extraction using mel-frequency cepstral coefficients in the proposed cross-database scenarios. Furthermore, wav2vec proved effective in regression, modeling various quantitative speech characteristics related to intelligibility and aging. Subsequent analysis of important features, obtained using scikit-learn feature importance built-in tools and the Shapley additive explanations method, examined the presence of significant overlaps between classification and regression models. The feature importance experiments discovered shared features across trained models, with increased sharing for related tasks, further suggesting that wav2vec contributes to improved generalizability. In conclusion, the study proposes wav2vec embedding as a promising step toward a speech-based universal model to assist in the evaluation of PD.
Gastric digestion and changes in serum amino acid concentrations after consumption of casein from cow and goat milk: a randomized crossover trial in healthy men
Authors: van Eijnatten Elise J.M. , Camps Guido , Rombouts Wolf , Pellis Linette , Smeets Paul A.M.
Published: April 2024

Background

In vitrostudies show that goat milk proteins form less compact coagulates in the stomach compared to cow milk proteins, which may facilitate gastric digestion and amino acid (AA) absorption. However, this has not been confirmedin vivoin humans.

Objective

To examine gastric digestion and changes in AA concentrations after cow milk-derived (cow MC) and goat milk-derived casein (goat MC) ingestion.

Methods

In this single-blind randomized cross-over study 18 men (age 23 ± 1.6 years, BMI 23 ± 1.6 kg/m2) consumed 300 ml of a drink containing 30 g of cow MC or goat MC. Participants underwent gastric MRI scans at baseline and every 10 minutes up to 60 minutes postprandially. Blood was drawn at baseline and up to 4 hours postprandially. In addition, participants verbally rated their appetite after each MRI measurement. Primary outcomes were gastric emptying and AA concentrations. Secondary outcome was gastric coagulation as inferred by image texture metrics.

Results

Gastric emptying half-time was 80 ± 25 minutes for goat and 85 ± 24 minutes for cow MC (p = 0.395). In line with this, gastric emptying of the drinks over time was similar (MD 0.77 ml, 95% CI [-6.9, 8.5], p=0.845). Serum essential AA (MD -110 µmol/L, 95% CI [-162, -58]) was higher over time for cow MC (p<0.001). The image texture metric contrast was lower for cow MC (MD 0.010, 95% CI [0.001, 0.020], p=0.036).

Conclusion

Cow MC and goat MC have different coagulating properties, as inferred by AA concentrations and supported by image texture analysis. This did not influence overall gastric emptying or the emptying of the liquid and coagulated fractions, which were similar. This warrants furtherin vivoresearch on casein coagulation in the food matrix to help determine the optimal use for cow and goat milk and their protein fractions.

Financial support: the study was funded by Ausnutria Dairy Corporation Ltd.

Clinical trial registry number: NL8137 (Netherlands Trial Registry), accessible throughhttps://trialsearch.who.int/Trial2.aspx?TrialID=NL-OMON28580
Pregnancy episodes in All of Us: Harnessing multi-source data for pregnancy-related research
Authors: Smith Louisa H. , Wang Wanjiang , Keefe-Oates Brianna
Published: April 2024

Objective

The National Institutes of Health’s All of Us Research Program addresses gaps in biomedical research by collecting health data from diverse populations. Pregnant individuals have historically been underrepresented in biomedical research, and pregnancy-related research is often limited by data availability, sample size, and inadequate representation of the diversity of pregnant people. We aimed to identify pregnancy episodes with high-quality electronic health record (EHR) data in All of Us Research Program data and evaluate the program’s utility for pregnancy-related research.

Materials and Methods

We used an algorithm to identify pregnancy episodes in All of Us EHR data. We described these pregnancies, validated them with additional data, and compared them to national statistics.

Results

Our study identified 18,970 pregnancy episodes from 14,234 participants; other possible pregnancy episodes had low-quality or insufficient data. Validation against people who reported a current pregnancy on an All of Us survey found low false positive and negative rates. Demographics were similar in some respects to national data; however, Asian-Americans were underrepresented, and older, highly educated pregnant people were overrepresented.

Discussion

Our approach demonstrates the capacity of All of Us to support pregnancy research and reveals the diversity of the pregnancy cohort. However, we noted an underrepresentation among some demographics. Other limitations include measurement error in gestational age and limited data on non-live births.

Conclusion

The wide variety of data in the All of Us program, encompassing EHR, survey, genomic, and Fitbit data, offers a valuable resource for studying pregnancy, yet care must be taken to avoid biases.
allofus: An R package to facilitate use of the All of Us Researcher Workbench
Authors: Smith Louisa H. , Cavanaugh Robert
Published: April 2024

Objective

We aimed to increase research and training capacity for the All of Us community through an R package designed to reduce barriers to entry to the Researcher Workbench.

Materials and Methods

We developed the open-source R packageallofus, available on the R package repository CRAN. The package provides functions that address common challenges we encountered while working with All of Us Research Program data. We tested the package with standard R unit tests and in real research projects.

Results

We describe how the package functions allow for an efficient workflow. We demonstrate the package’s utility by creating a cohort of All of Us participants with one year of electronic health record data prior to survey completion and no previous diagnosis of Type 2 diabetes.

Discussion

Despite the program’s easy-to-use tools like the Cohort Builder, using All of Us data for complex research questions requires a relatively high level of technical expertise. We developed an initial set of functions that solve problems we experienced with our own research and in mentoring student projects. In conjunction with the tutorials provided with the package, these tools can reduce the barrier for entry into the All of Us research community. The package will continue to grow and develop with the All of Us Research Program.

Conclusion

TheallofusR package can help build community research capacity by increasing access to the All of Us Research Program data, the efficiency of its use, and the rigor and reproducibility of the resulting research.
Advancing Bloodstream Infection Prediction Using Explanable Artificial Intelligence Framework
Authors: Bopche Rajeev , Gustad Lise Tuset , Afset Jan Egil , Ehrnström Birgitta , Damås Jan Kristian , Nytrø Øystein
Published: April 2024

Bloodstream infections (BSIs) represent a critical public health concern, primarily due to their rapid progression and severe implications such as sepsis and septic shock. This study introduces an innovative Explanable Artificial Intelligence (XAI) framework, leveraging historical electronic health records (EHRs) to enhance BSI prediction. Unlike traditional models that rely heavily on real-time clinical data, our XAI-based approach utilizes a comprehensive dataset incorporating demographic data, laboratory results, and full medical histories from St. Olavs Hospital, Trondheim, Norway, covering 35,591 patients between 2015 and 2020. We developed models to differentiate between high-risk and low-risk BSI cases effectively, optimizing healthcare resource allocation and potentially reducing healthcare costs. Our results demonstrate superior predictive accuracy, particularly the tree-based models, which significantly outperformed contemporary models in both specificity and sensitivity metrics.

Author Summary

In this research, we have developed a new tool that uses artificial intelligence to better predict bloodstream infections, which can lead to serious conditions like sepsis if not quickly identified and treated. It is the first of its kind framework that analyzes past health records and helps identify patients who are at high risk of infection more accurately than existing tools. Unlike existing tools our framework can be implemented at any stage of the patient trajectory and is the only framework to achieve good accuracy without the use of intimate patient features such as vital signs. This ability could enable doctors to prioritize care more pre-emptively, effectively, potentially saving lives and reducing unnecessary medical tests. Our approach is designed to be easily understood and used by both medical professionals and those with little technical expertise, making it a valuable addition to hospital systems.
Facilitators and barriers to contraception access and use for Hispanic American adolescent women: An integrative literature review
Authors: Batek Lindsay M. , Leblanc Natalie M. , Alio Amina P. , Stein Karen F. , McMahon James M.
Published: April 2024

Statement of the Problem

Hispanic American adolescents experience high rates of pregnancy with profound consequences. Compared with White teens, Hispanic teens use contraception less frequently and often choose less effective forms of contraception. Access to contraception is a primary barrier to use which contributes to relatively high and disparate rates of pregnancy in Hispanic teens. This integrative review identifies facilitators and barriers of contraception access and use for Hispanic women, 13-17 years of age, living in the U.S.

Methodology

Following the Whittemore and Knafl (2005) methodology and PRISMA guidelines, peer reviewed studies were retrieved from PUBMED, CINAHL and EMBASE. TheMixed Methods Appraisal Toolwas used to assess the study quality and thematic analysis was used to categorize barriers and facilitators.

Findings

Of 131 studies retrieved, 16 met inclusion criteria. Individual, interpersonal and healthcare provider factors were identified as primary categories of barriers and facilitators with contextual issues comprising an additional barrier category. Individual level barriers were disproportionately represented and further categorized into themes: beliefs/misconceptions, dislike of contraception, pregnancy risk perception, lack of knowledge, and lack of control. The most frequently reported facilitators were perceived parent comfort discussing sexual health and past experience of pregnancy.

Discussion

Limitations in this review may stem from heterogeneity in the acculturation and geography of participants and analysis by a single reviewer. Implications include considering the range of information sources and the influence they have on risk perception and risk mitigation for this population.

Conclusion & Significance

Adolescents describe many modifiable influences on contraception access and use. Misperceptions related to contraception, stemming from beliefs and perceptions, can be corrected through increased access to reliable sources of sex education, parental support, and direct access to nurses and healthcare providers. Awareness of these influences can inform further research and intervention development to address these health disparities.
Generalizability of Tau and Amyloid Plasma Biomarkers in Alzheimer’s Disease Cohorts of Diverse Genetic Ancestries
Authors: Griswold Anthony J. , Rajabli Farid , Gu Tianjie , Arvizu Jamie , Golightly Charles G. , Whitehead Patrice L. , Hamilton-Nelson Kara L. , Adams Larry D. , Sanchez Jose Javier , Mena Pedro R. , Starks Takiyah D. , Illanes-Manrique Maryenela , Silva Concepcion , Bush William S. , Cuccaro Michael L. , Vance Jeffery M. , Cornejo-Olivas Mario R , Feliciano-Astacio Briseida E. , Byrd Goldie S. , Beecham Gary W. , Haines Jonathan L. , Pericak-Vance Margaret A.
Published: April 2024

Introduction

Plasma phosphorylated threonine-181 of Tau and amyloid beta are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). Given differences in AD risk across diverse populations, generalizability of existing biomarker data is not assured.

Methods

In 2,086 individuals of diverse genetic ancestries (African American, Caribbean Hispanic, and Peruvians) we measured plasma pTau-181 and Aβ42/Aβ40. Differences in biomarkers between cohorts and clinical diagnosis groups and the potential discriminative performance of the two biomarkers were assessed.

Results

pTau-181 and Aβ42/Aβ40 were consistent across cohorts. Higher levels of pTau181 were associated with AD while Aβ42/Aβ40 had minimal differences. Correspondingly, pTau-181 had greater predictive value than Aβ42/Aβ40, however, the area under the curve differed between cohorts.

Discussion

pTau-181 as a plasma biomarker for clinical AD is generalizable across genetic ancestries, but predictive value may differ. Combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses.
Immune-developmental processes contribute to schizophrenia risk: insights from a genetic overlap study with height
Authors: Romero Cato , de Leeuw Christiaan , Schipper Marijn , Maciel Bernardo de A.P.C. , van den Heuvel Martijn P. , Brouwer Rachel M. , Smit August B. , Koopmans Frank , Posthuma Danielle , van der Sluis Sophie
Published: April 2024

Background

Shorter stature has been phenotypically linked to increased prevalence of schizophrenia (SCZ), but the nature of this association is unknown.

Methods

Using genome-wide genetic data, we studied the SCZ-height relationship on a genetic level. Applying novel genetic methods and tools, we analyzed gene-sets, tissue-types, cell-types, local genetic correlation, conditional genetic analyses, and fine-mapping of effector-genes to scrutinize the SCZ-height relationship.

Results

We identified 142 genes statistically associated with both SCZ and height and found enrichment in immune response gene-sets. Genetic annotations implicated the pituitary and specifically mesenchymal stem cells for height and thyrotropic cells for SCZ. While the global SCZ-height genetic correlation was nonsignificant, 9 genomic regions showed robust local genetic correlations (7 negative, 6 in the MHC-region). The shared genetic signal for SCZ and height within the 6 MHC-regions was partially explained by mutual genetic overlap with white blood cell count, particularly lymphocytes. Fine-mapping prioritized 3 shared effector-genes (GIGYF2,HLA-C, andLIN28B) involved in immune response sensitivity and development of immune and pituitary cell-types.

Conclusions

Overall, our findings suggest an involvement during height-development of thyrotropic cells and immune response sensitivity contributing towards risk of SCZ.
Optimal Systolic Blood pressure control after thrombectomy in acute ischemic stroke-a systematic review and meta-analysis
Authors: Panigrahi Baikuntha , Bhatia Rohit , Haldar Partha , Sarkar Risha , Longkumer Imnameren
Published: April 2024

Background and Objectives

Although endovascular thrombectomy(EVT) is the standard of care for acute large vessel occlusions(LVO), optimal systolic blood pressure (SBP) control post procedure has remained elusive. Our study aimed to address the question of whether in adult patients of acute ischemic stroke(AIS) who undergo EVT does an intensive SBP control as compared to a less intensive SBP control/conventional control up to 24 hours post procedure lead to a good functional outcomes defined by modified Rankin score(mRS) of 0-2 at 90days.

Methods

This PRISMA guidelines were followed for this review. Databases(PubMed, SCOPUS, EMBASE, Google Scholar and Web of Science) were searched for English language articles using predefined search terms till Sep 15 2023. The inclusion criteria consisted of randomized controlled trials (RCTs) and observational studies(at least total 20patients) analysing intensive vs conventional SBP control in AIS due to LVO post-EVT up to 24hours. Studies without a separate comparison primary outcome data, comparing SBP control in AIS due to LVO treated only with IV thrombolysis (IVT) without EVT, case series and case reports were excluded. The primary outcome was the rate of functional independence defined by mRS 0-2 at 90days. Risk of bias was assessed using the New Castle Ottawa scale(NOS) for observational studies, and the revised Cochrane risk-of-bias 2 (ROB2) tool for RCTs.

Results

Twelve studies(n=5439 patients-eight observational and four RCTs) were included in the final analysis. The primary outcome was not significantly different between both the arms(RR:1.16;95%CI-0.98-1.37;p=0.08).There were no significant differences in the mortality at 90days(RR:0.83;95%CI-0.68-1.02;p=0.08) and the risk of symptomatic intracranial haemorrhage(RR:0.84;95%CI-0.61-1.16;p=0.29). Fewer patients required decompressive surgery in the intensive arm(RR-0.40; 95%CI-0.25-0.66; p=0.0003). A separate analysis for the primary outcome from pooled observational data favoured intensive control(RR-1.34;95%CI-1.20-1.48; p<0.00001) and data from RCTs favoured conventional control(RR-0.82;95%CI-0.72-0.93;p=0.003).

Conclusion

Neither intensive nor conventional SBP control resulted in better functional outcome in the combined analysis of all studies. Although, observational studies favoured intensive control, data from RCTs suggested conventional management as the preferred approach which could currently be a pragmatic strategy. Further ongoing RCTs using homogenous SBP cut-offs will provide more clarity on the ideal SBP target after EVT.
Incidence and Risk of Post-COVID-19 Thromboembolic Disease and the Impact of Aspirin Prescription; Nationwide Observational Cohort at the US Department of Veteran Affairs
Authors: Ware Anna D , Veigulis Zachary P , Hoover Peter J , Blumke Terri L , Ioannou George N , Boyko Edward J , Osborne Thomas F
Published: April 2024

Introduction

COVID-19 triggers prothrombotic and proinflammatory changes, with thrombotic disease prevalent in up to 30% SARS-CoV-2 infected patients. Early work suggests that aspirin could prevent COVID-19 related thromboembolic disorders in some studies but not others. This study leverages data from the largest integrated healthcare system in the United States to better understand this association. Our objective was to evaluate the incidence and risk of COVID-19 associated acute thromboembolic disorders and the potential impact of aspirin.

Methods

This retrospective, observational study utilized national electronic health record data from the Veterans Health Administration. 334,374 Veterans who tested positive for COVID-19 from March 2, 2020, to June 13, 2022, were included, 81,830 of whom had preexisting aspirin prescription prior to their COVID-19 diagnosis. Patients with and without aspirin prescriptions were matched and the odds of post-COVID acute thromboembolic disorders were assessed.

Results

10.1% of Veterans had a documented thromboembolic disorder within 12 months following their COVID-19 diagnosis. Those with specific comorbidities were at greatest risk. Preexisting aspirin prescription was associated with a significant decrease risk of post-COVID-19 thromboembolic disorders, including pulmonary embolism (OR [95% CI]: 0.69 [0.65, 0.74]) and deep vein thrombosis (OR [95% CI]: 0.76 [0.69, 0.83], but an increased risk of acute arterial diseases, including ischemic stroke (OR [95% CI]: 1.54 [1.46, 1.60]) and acute ischemic heart disease (1.33 [1.26, 1.39]).

Conclusions

Findings demonstrated that preexisting aspirin prescription prior to COVID-19 diagnosis was associated with significantly decreased risk of venous thromboembolism and pulmonary embolism but increased risk of acute arterial disease. The risk of arterial disease may be associated with increased COVID-19 prothrombotic effects superimposed on preexisting chronic cardiovascular disease for which aspirin was already prescribed. Prospective clinical trials may help to further assess the efficacy of aspirin use prior to COVID-19 diagnosis for the prevention of post-COVID-19 thromboembolic disorders.
The Immobilization of Hyaluronic Acid in 3D Hydrogel Scaffolds Modulates Macrophage Polarization
Authors: Oates Tiah CL , Boyd Jasmin , Dolan Louise , Kergariou C de , Toye Ash , Perriman Adam W , Boussahel Asme
Published: April 2024

Macrophages are key modulators of immunity, tissue homeostasis and disease development. As our understanding of macrophage biology and their tissue specific behaviors grow the necessity to model macrophages within a 3D biomimetic environment becomes increasingly apparent. Numerous hydrogels have been developed and explored for this purpose, extracellular matrix (ECM) mimicking hydrogels gaining a special interest. In this study, we present the use of such a hydrogel composed of collagen and hyaluronic acid (HA), two of the major ECM components, for the 3D culture of macrophages to model their role in different tissues and diseases. We demonstrate the ability to tailor the mechanical properties of the hydrogel through formulation modulation. Human macrophages retain morphology, viability, and expression of key cell surface markers when 3D cultured within the hydrogel. Interestingly, we demonstrate in this work, that independent of mechanical properties, by adjusting the composition of the hydrogel, specifically HA molecular weight, we can steer macrophage polarization towards either a pro-inflammatory or anti-inflammatory phenotype. This HA-dependent modulation of macrophage behavior is nullified if the HA is chemically crosslinked, shedding light on the impact of one of the most commonly used preparation methods for collagen-HA hydrogels on macrophage behavior.

Graphical abstract

Hyaluronic acid (HA) is an extracellular matrix component, which can modulate the polarization of macrophages. The chemical crosslinking of HA to hydrogel scaffolds counteracts the cell signaling role of this molecule, preventing HA from modulating the immune polarization of macrophages within the model.

Key points

Collagen-HA hydrogels form suitable biomimetic niches for the 3D culture of human macrophages in which hydrogel composition modulates macrophage phenotype, specifically the presence and molecular weight of HA.

Polarization of macrophage phenotype by HA is nullified if HA is chemically cross-linked within the hydrogel.
Loading of extracellular vesicles with nucleic acids via hybridization with sponge-like lipid nanoparticles
Authors: Bader Johannes , Rüedi Pascal , Mantella Valeria , Geisshüsler Silvana , Brigger Finn , Qureshi Bilal M. , Arroyo Jaime Ortega , Montanari Elita , Leroux Jean-Christophe
Published: April 2024

The translation of cell-derived extracellular vesicles (EVs) into biogenic gene delivery systems is limited by relatively inefficient loading strategies. In this work, we describe the loading of various nucleic acids into small EVsviatheir spontaneous hybridization with preloaded non-lamellar liquid crystalline lipid nanoparticles (LCNPs) under physiological conditions, forming hybrid EVs (HEVs). We correlate LCNPs’ topological characteristics with their propensity to fuse/aggregate with EVs and found that sponge (L3) phases at pH 7.4 were particularly suitable to induce a controlled hybridization process. State-of-the-art single-particle analysis techniques revealed that L3-based LCNPs interact with various EV subpopulations and that around 40% of HEVs were loaded with the genetic cargo. Importantly, this study demonstrates that EV membrane proteins remain accessible on HEV surfaces, with their intrinsic enzymatic activity unaffected after the hybridization process. Finally, HEVs showedin vitroimproved transfection efficiencies compared to unhybridized LCNPs. In summary, this versatile platform holds potential for loading various nucleic acid molecules into native EVs and may help developing EV-based therapeutics.

Teaser

Topology of lipid nanoparticles influences their hybridization behavior with extracellular vesicles and produces novel biogenic gene delivery systems.
Unexpectedly dense colonization of soil pore space by microbes
Authors: Schmidt Hannes , Schlüter Steffen , Raynaud Xavier , Felde Vincent J.M.N.L. , Zeller-Plumhoff Berit , Richter Andreas , Nunan Naoise
Published: April 2024

Pore surfaces in soil are considered to be sparsely colonised, dispersed only with isolated cells or colonies of bacteria and archaea. Here, we question this ‘empty space’-concept by combining microstructure analysis with molecular biology and provide a data-driven update on habitable surface areas (HSA) in soil. Our unique approach allowed us to provide 1) evidence that microbial densities in soil have been underestimated for decades and 2) two-dimensional simulations of their potential distribution within the soil pore space. Our results demonstrate the need for a new perspective on how densely soil is colonised, with implications for how we think of basic ecological processes such as microbial motility or predation, and how microbial processes, including organic matter dynamics, are ultimately modelled.
On Human Motor Coordination: The Synergy Expansion Hypothesis
Authors: Tessari Federico , West A. Michael , Hogan Neville
Published: April 2024

The search for an answer to Bernstein's degrees of freedom problem has propelled a large portion of research studies in human motor control over the past six decades. Different theories have been developed to explain how humans might use their incredibly complex neuro-musculo-skeletal system with astonishing ease. Among these theories, motor synergies appeared as one possible explanation. In this work, the authors investigate the nature and role of synergies and propose a new theoretical framework, namely the 'expansion hypothesis', to answer Bernstein's problem. The expansion hypothesis is articulated in three propositions: mechanical, developmental, and behavioral. Each proposition addresses a different question on the nature of synergies: (i) How many synergies can humans have? (ii) How do we learn and develop synergies? (iii) How do we use synergies? An example numerical simulation is presented and analyzed to clarify the hypothesis propositions. The expansion hypothesis is contextualized with respect to the existing literature on motor synergies both in healthy and impaired individuals, as well as other prominent theories in human motor control and development. The expansion hypothesis provides a novel framework to better comprehend and explain the nature, use and evolution of human motor skills.
The role of FraI in cell-cell communication and differentiation in the hormogonia-forming cyanobacterium Nostoc punctiforme
Authors: Janović Ana , Maldener Iris , Menzel Claudia , Parrett Gabriel A. , Risser Douglas D.
Published: April 2024

Multicellular cyanobacteria, likeNostoc punctiforme, rely on septal junctions for cell-cell communication, which is crucial for coordinating various physiological processes including differentiation of N2-fixing heterocysts, spore-like akinetes and hormogonia - short, motile filaments important for dispersal. In this study we functionally characterize a protein, encoded by geneNpF4142, which in a random mutagenesis approach, initially showed a motility-related function. The reconstructedNpF4142knockout mutant exhibits further distinct phenotypic traits, including altered hormogonia formation with significant reduced motility, inability to differentiate heterocysts and filament fragmentation. For that reason, we named the protein FraI (fragmentation phenotype). The mutant displays severely impaired cell-cell communication, due to almost complete absence of the nanopore array in the septal cell wall, which is an essential part of the septal junctions. Despite lack of communication, hormogonia in the ΔfraImutant maintain motility and phototactic behaviour, even though less pronounced than the wild type. This suggests an alternative mechanism for coordinated movement beyond septal junctions. Our study underscores the significance of FraI in nanopore formation and cell differentiation and provides additional evidence for the importance of septal junction formation and communication in various differentiation traits of cyanobacteria. The findings contribute to a deeper understanding of the regulatory networks governing multicellular cyanobacterial behaviour, with implications for broader insights into microbial multicellularity.

Importance

The filament-forming cyanobacteriumNostoc punctiformeserves as a valuable model for studying cell differentiation, including the formation of nitrogen-fixing heterocysts and hormogonia. Hormogonia filaments play a crucial role in dispersal and plant colonization, providing a nitrogen source through atmospheric nitrogen fixation, thus holding promise for fertilizer-free agriculture. The coordination among the hormogonia cells enabling uniform movement towards the positive signal remains poorly understood. This study investigates the role of septal junction-mediated communication in hormogonia differentiation and motility, by studying a ΔfraImutant with significantly impaired communication. Surprisingly, impaired communication does not abolish synchronized filament movement, suggesting an alternative coordination mechanism. These findings deepen our understanding of cyanobacterial biology and have broader implications for multicellular behavior in prokaryotes.
Mechanically Sheared Axially Swept Light-Sheet Microscopy
Authors: Lin Jinlong , Mehra Dushyant , Marin Zach , Wang Xiaoding , Borges Hazel M. , Shen Qionghua , Gałecki Seweryn , Haug John , Dean Kevin M.
Published: April 2024

We present a mechanically sheared image acquisition format for upright and open-top light-sheet microscopes that automatically places data in its proper spatial context. This approach, which reduces computational post-processing and eliminates unnecessary interpolation or duplication of the data, is demonstrated on an upright variant of Axially Swept Light-Sheet Microscopy (ASLM) that achieves a field of view, measuring 774 x 435 microns, that is 3.2-fold larger than previous models and a raw and isotropic resolution of ∼420 nm. Combined, we demonstrate the power of this approach by imaging sub-diffraction beads, cleared biological tissues, and expanded specimens.
Diffusion tractography predicts Deep Brain Stimulation evoked potential amplitude and delay
Authors: Abe Sumiko , Vidmark Jessica , Hernandez-Martin Estefania , Kasiri Maral , Sorouhmojdehi Rahil , Seyyed Mousavi S. Alireza , Sanger Terence D.
Published: April 2024

Objective

This study investigated the relationship between DBS evoked potentials (EPs) and diffusion tensor imaging (DTI) in a group of patients with dystonia who underwent DBS treatment. EPs and DTI are both useful methods for studying neural connectivity in the brain but measure different aspects of brain function. EPs provide information on electrical connectivity, while DTI provides information on anatomical pathways connecting regions.

Methods

This study focused on the pallidum and motor thalamus nuclei, which are common targets for DBS in dystonia. Prior to DBS implantation, DTI images were acquired for each patient, and were processed to obtain DTI coefficients such as length (L), volume (V), and fractional anisotropy (FA) of the fiber tracts. The relationship between the fiber tracts and electrophysiology was examined using a generalized linear model (GLM).

Results

We showed that the amplitude of EPs correlated with FA and tract volume, while delay correlated with tract length. These findings suggest that DBS signals travel across tracts to affect both local and distant brain regions, and the magnitude of the effect of DBS is determined by the integrity of the white matter tract, while DBS signal delay is affected by the tract length. Our results further suggest that the magnitude and delay of the spread of the DBS signal may be predicted by the DTI connectivity. This provides strong supporting evidence for other studies that have assumed, but have been unable to test, such a relationship.

Conclusion

Overall, this study suggests that the electrical effects of DBS can be at least partially predicted by noninvasive DTI imaging in patients with dystonia. By combining EPs with DTI, we could investigate the propagation of stimulation pulses through brain regions. While this relationship has been previously hypothesized by the neuroscience community, this is the first study in humans to demonstrate this relationship between DBS EPs and DTI, thereby advancing the field of human brain mapping and enhancing the precision of neurosurgical targeting.
Understanding emotional and health indicators underlying the burnout risk of healthcare workers
Authors: Güveyi Elçin , Elvin Garry , Kennedy Angela , Kurt Zeyneb , Sice Petia , Patel Paras , Dubruel Antoinette , Heckels Drummond
Published: April 2024

Background

Burnout of healthcare workers is of increasing concern as workload pressures mount. Burnout is usually conceptualised as resulting from external pressures rather than internal resilience and although is not a diagnosable condition, it is related to help seeking for its psychological sequelae.

Objective

To understand how staff support services can intervene with staff heading for burnout, it is important to understand what other intrapsychic factors that are related to it.

Methods

A diary tool was used by staff in a region of England to self monitor their wellbeing over time. The tool explores many areas of mental health and wellbeing and enabled regression analysis to predict which of the various factors predicted scores on the burnout item.

Findings

Burnout can be best explained with independent variables includingdepression, receptiveness, mental wellbeing, andconnectedness(p<0.05) using a multiple linear regression model. It was also shown that 71% of the variance present in the response variable, i.e. burnout, explained by independent variables. There is no evidence found for multicollinearity in our regression models confirmed by both the Spearman Rank Correlation and the Variance Inflation Factor methods.

Conclusion

We showed how burnout can be explained using a handful number of factors including emotional and mental health indicators.

Clinical implications

The findings suggest a simple set of items can predict burnout and could be used for screening. The data suggests attention to four factors around social safeness, grounding and care in the self, hope and meaning and having sufficient energy could form the basis of attention in weelbeing programs.
Differences in sleep spindle wave density between patients with diabetes mellitus and matched controls: implications for sensing and regulation of peripheral blood glucose
Authors: Yeung Deryck , Talukder Amlan , Shi Min , Umbach David M. , Li Yuanyuan , Motsinger-Reif Alison , Fan Zheng , Li Leping
Published: April 2024

Background

Brain waves during sleep are involved in sensing and regulating peripheral glucose level. Whether brain waves in patients with diabetes differ from those of healthy subjects is unknown. We examined the hypothesis that patients with diabetes have reduced sleep spindle waves, a form of brain wave implicated in periphery glucose regulation during sleep.

Methods

From a retrospective analysis of polysomnography (PSG) studies on patients who underwent sleep apnea evaluation, we identified 1,214 studies of patients with diabetes mellitus (>66% type 2) and included a sex- and age-matched control subject for each within the scope of our analysis. We similarly identified 376 patients with prediabetes and their matched controls. We extracted spindle characteristics from artifact-removed PSG electroencephalograms and other patient data from records. We used rank-based statistical methods to test hypotheses. We validated our finding on an external PSG dataset.

Results

Patients with diabetes mellitus exhibited on average about half the spindle density (median=0.38 spindles/min) during sleep as their matched control subjects (median=0.70 spindles/min) (P<2.2e-16). Compared to controls, spindle loss was more pronounced in female patients than in male patients in the frontal regions of the brain (P=0.04). Patients with prediabetes also exhibited signs of lower spindle density compared to matched controls (P=0.01-0.04).

Conclusions

Patients with diabetes have fewer spindle waves that are implicated in glucose regulation than matched controls during sleep. Besides offering a possible explanation for neurological complications from diabetes, our findings open the possibility that reversing/reducing spindle loss could improve the overall health of patients with diabetes mellitus.

Funding

This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (ZIA ES101765).
Differential Serum Levels of CACNA1C, Circadian Rhythm and Stress Response Molecules in Subjects with Bipolar Disorder: Associations with Genetic and Clinical Factors
Authors: Allen Obie , Coombes Brandon J. , Pazdernik Vanessa , Gisabella Barbara , Hartley Joshua , Biernacka Joanna M. , Frye Mark A. , Markota Matej , Pantazopoulos Harry
Published: April 2024

Background

Many patients with bipolar disorder (BD) do not respond to or have difficulties tolerating lithium and/or other mood stabilizing agents. There is a need for personalized treatments based on biomarkers in guiding treatment options. The calcium voltage-gated channel CACNA1C is a promising candidate for developing personalized treatments. CACNA1C is implicated in BD by genome-wide association studies and several lines of evidence suggest that targeting L-type calcium channels could be an effective treatment strategy. However, before such individualized treatments can be pursued, biomarkers predicting treatment response need to be developed.

Methods

As a first step in testing the hypothesis that CACNA1C genotype is associated with serum levels of CACNA1C, we conducted ELISA measures on serum samples from 100 subjects with BD and 100 control subjects.

Results

We observed significantly higher CACNA1C (p<0.01) protein levels in subjects with BD. The risk SNP (rs11062170) showed functional significance as subjects homozygous for the risk allele (CC) had significantly greater CACNA1C protein levels compared to subjects with one (p=0.013) or no copies (p=0.009). We observed higher somatostatin (SST) (p<0.003) protein levels and lower levels of the clock protein ARTNL (p<0.03) and stress signaling factor corticotrophin releasing hormone (CRH) (p<0.001) in BD. SST and PER2 protein levels were associated with both alcohol dependence and lithium response.

Conclusions

Our findings represent the first evidence for increased serum levels of CACNA1C in BD. Along with altered levels of SST, ARNTL, and CRH our findings suggest CACNA1C is associated with circadian rhythm and stress response disturbances in BD.
Improving the detection and management of non-communicable diseases among the adult population of the catchment areas of a rural primary healthcare unit in Sidama National Regional State, Ethiopia: A study protocol
Authors: Likka Melaku Haile , Areru Hiwot Abera , Birhanu Betelihem Eshetu , Hibistu Desalegn Tsegaw , Lindtjørn Bernt
Published: April 2024

Background

The World Health Organization has designed a package of essential non-communicable diseases (PEN) strategy to improve the detection and management of NCDs. However, the implementation of the PEN in Ethiopia is at an early stage and the readiness of rural primary healthcare units (PHCUs) to implement the strategy is unknown. We, therefore, propose to apply the strategy in the catchment areas of Dobe-Toga Health Center, a rural PHCU in Sidama National Regional State (SNRS), Ethiopia, and improve the NCDs care among adults aged≥45 years.

Aim

We aim to determine the prevalence of undiagnosed hypertension, pre-T2DM mellitus, T2DM, and comorbidity of hypertension and T2DM among the older adults in the study areas, apply the WHO-PEN- based care model for the participants diagnosed with T2DM and/or hypertension and evaluate its effectiveness in controlling blood glucose and/or pressure. The readiness of PHCUs to implement the WHO-PEN approach in the region will also be determined. Additionally, we examine the influence of diagnosis with hypertension and/or T2DM on the willingness of the study participants to join and/or renew membership in community-based health insurance (CBHI).

Methods

The study will be conducted in catchment areas of Dobe-Toga Health Center from April to November 2024. A cross-sectional survey of 41 health centers and 4 primary hospitals, triangulated with qualitative data, will be employed to assess the readiness of the PHCUs to implement the WHO-PEN interventions while the qualitative data for this study has not been collected yet, the quantitative data was collected through observation checklist of inputs. The remaining studies will be conducted in two phases. In Phase 1, cross- sectional surveys will be conducted to determine the prevalence of undiagnosed hypertension, T2DM, pre- T2DM, and comorbidity of T2DM and hypertension in a randomly selected sample of 3301 older adults. Additionally, the participants’ willingness to pay (WTP) for HbA1c tests will be assessed, and CBHI-related surveys will be conducted. In the second phase, the cohorts will be linked to the health center and will receive the WHO-PEN-based care model. In phase 2, the effects of the care model in controlling blood pressure and glucose will be examined. Furthermore, the adherence to self-care practices of the cohorts will be determined.
Cardiovascular symptoms of PASC are associated with trace-level cytokines that affect the function of human pluripotent stem cell derived cardiomyocytes
Authors: Sinclair Jane E. , Vedelago Courtney , Ryan Feargal J. , Carney Meagan , Lynn Miriam A. , Grubor-Bauk Branka , Cao Yuanzhao , Henders Anjali K. , Chew Keng Yih , Gilroy Deborah , Greaves Kim , Labzin Larisa , Ziser Laura , Ronacher Katharina , Wallace Leanne M. , Zhang Yiwen , Macauslane Kyle , Ellis Daniel J. , Rao Sudha , Burr Lucy , Bain Amanda , Schulz Benjamin L. , Li Junrong , Lynn David J. , Palpant Nathan , Wuethrich Alain , Trau Matt , Short Kirsty R.
Published: April 2024

Globally, over 65 million individuals are estimated to suffer from post-acute sequelae of COVID-19 (PASC). A large number of individuals living with PASC experience cardiovascular symptoms (i.e. chest pain and heart palpitations) (PASC-CVS). The role of chronic inflammation in these symptoms, in particular in individuals with symptoms persisting for >1 year after SARS-CoV-2 infection, remains to be clearly defined. In this cross-sectional study, blood samples were obtained from three different sites in Australia from individuals with i) a resolved SARS-CoV-2 infection (and no persistent symptoms i.e. ‘Recovered’), ii) individuals with prolonged PASC-CVS and iii) SARS-CoV-2 negative individuals. Individuals with PASC-CVS, relative to Recovered individuals, had a blood transcriptomic signature associated with inflammation. This was accompanied by elevated levels of pro-inflammatory cytokines (IL-12, IL-1β, MCP-1 and IL-6) at approximately 18 months post-infection. These cytokines were present in trace amounts, such that they could only be detected with the use of novel nanotechnology. Importantly, these trace-level cytokines had a direct effect on the functionality of pluripotent stem cell derived cardiomyocytesin vitro. This effect was not observed in the presence of dexamethasone. Plasma proteomics demonstrated further differences between PASC-CVS and Recovered patients at approximately 18 months post-infection including enrichment of complement and coagulation associated proteins in those with prolonged cardiovascular symptoms. Together, these data provide a new insight into the role of chronic inflammation in PASC-CVS and present nanotechnology as a possible novel diagnostic approach for the condition.
Molecular architecture of synaptic vesicles
Authors: Kravcenko Uljana , Ruwolt Max , Kroll Jana , Yushkevich Artsemi , Zenkner Martina , Ruta Julia , Lotfy Rowaa , Wanker Erich E. , Rosenmund Christian , Liu Fan , Kudryashev Mikhail
Published: April 2024

Synaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins and excess membrane are recycled via endocytosis, and new SVs are formed in a clathrin-dependent manner. This process maintains the morphology and complex molecular composition of SVs through multiple recycling rounds. Previous studies explored the molecular composition of SVs through proteomic analysis and fluorescent microscopy, proposing a model for an average SV1,2. However, the structural heterogeneity and molecular architecture of individual SVs are not well described. Here we used cryo-electron tomography to visualize morphological and molecular details of SVs isolated from mouse brains and inside cultured neurons. We describe several classes of small proteins on the SV surface and long proteinaceous densities inside SVs. We identified V-ATPases, determined a structure using subtomogram average, and showed them forming a complex with the membrane-embedded protein synaptophysin. Our bioluminescence assay revealed pairwise interactions between VAMP2 and synaptophysin and V-ATPase Voe1 domains. Interestingly, V-ATPases were randomly distributed on the surface of SVs irrespective of vesicle sizes. A subpopulation of isolated vesicles and vesicles inside neurons contained a partially assembled clathrin coat with a soccer-ball symmetry. We observed a V-ATPase under clathrin cage in several isolated clathrin-coated vesicles. Additionally, from isolated SV preparations and within hippocampal neurons we identified clathrin baskets without vesicles. We determined their preferential location in proximity to the cell membrane. Our analysis advances the understanding of individual SVs’ diversity and their molecular architecture.