bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of a Multidimensional Short Version Zarit Burden Interview (ZBI-9) for Caregivers of Persons With Cognitive Impairment
Authors: Zhi-Xiang Lim , Lim Wee Shiong , Chan Ee-Yuee
Published: January 2023

Background:

There is a lack of appreciation of the full dimensionality of the original 22-item Zarit Burden Interview (ZBI) in the development of short versions. Existing short versions are premised upon a 1-factor or 2-factor structure or statistical techniques for item selection. Thus, there is a need for ZBI short versions that considers the multidimensional constructs of role strain, personal strain, and worry about performance (WaP) during item selection to provide a more holistic and comprehensive evaluation.

Purpose:

To develop and validate a short version of ZBI through a combined quantitative and qualitative approach that incorporates the validated 4-factor structure of role strain demands; role strain-control; personal strain, and WaP.

Patients:

We studied 202 caregivers of patients with dementia (84.2%) or mild cognitive impairment (15.8%) attending a memory clinic in Singapore.

Methods:

Confirmatory factor analysis and qualitative considerations from expert consensus were used for item selection. Confirmatory factor analysis fit statistics support the 4-factor structure. The 9-item ZBI-9 showed good internal consistency (Cronbach’s α=0.87) and convergent validity with anxiety and depression (Pearson correlation: Hospital Anxiety and Depression sub-scales, r≥0.56, P<0.001; ZBI- 22, r=0.95, P<0.001). Using a cut-off score of ≥13, ZBI-9 displayed good discriminatory ability for depressive symptoms (area under curve=0.79, P<0.001; sensitivity=70%, specificity=75%). The ZBI-9 also displayed comparable performance to the 22-item full version and three 12-item short versions.

Conclusion:

The ZBI-9 is a multidimensional short-version assessment tool for caregivers of persons with dementia and mild cognitive impairment that is reliable, valid, and discriminates depressive symptoms.
Sodium chloride inhibits effective bubbly drag reduction in turbulent bubbly Taylor–Couette flows
Authors: Blaauw Luuk J. , Lohse Detlef , Huisman Sander G.
Published: January 2023

Using the Taylor–Couette geometry we experimentally investigate the effect of salt on drag reduction caused by bubbles present in the flow. We combine torque measurements with optical high-speed imaging to relate the bubble size to the drag experienced by the flow. Previous studies have shown that a small percentage of air (4%) can lead to dramatic drag reduction (40%). In contrast to previous laboratory experiments, which mainly used fresh water, we will vary the salinity from that of fresh water to the average salinity of ocean water. We find that the drag reduction is increasingly more inhibited for increasing salt concentrations, going from 40% for fresh water to just 15% for sea water. Salts present in the working fluid inhibit coalescence events, resulting in smaller bubbles in the flow and, with that, a decrease in the drag reduction. Above a critical salinity, increasing the salinity has no further effect on the size of bubbles in the flow and thus the drag experienced by the flow. Our new findings demonstrate the importance of sodium chloride on the bubbly drag reduction mechanism, and will further challenge naval architects to implement promising air lubrication systems on marine vessels.

This article is part of the theme issue ‘Taylor–Couette and related flows on the centennial of Taylor’s seminal
Philosophical Transactions
paper (part 1)’.
Observing a dynamical skeleton of turbulence in Taylor–Couette flow experiments
Authors: Crowley C. J. , Pughe-Sanford J. L. , Toler W. , Grigoriev R. O. , Schatz M. F.
Published: January 2023

Recent work shows that recurrent solutions of the equations governing fluid flow play an important role in structuring the dynamics of turbulence. Here, an improved version of an earlier method (Krygier
et al.
2021
J. Fluid. Mech.
923
, A7 and Crowley
et al.
2022
Proc. Natl Acad. Sci. USA
119
, e2120665119) is used for detecting and analyzing intervals of time when turbulence ‘shadows’ (spatially and temporally mimics) recurrent solutions in both numerical simulations and laboratory experiments. We find that all the recurrent solutions shadowed in numerics are also shadowed in experiment, and the corresponding statistics of shadowing agree. Our results set the stage for experimentally grounded dynamical descriptions of turbulence in a variety of wall-bounded shear flows, enabling applications to forecasting and control.

This article is part of the theme issue ‘Taylor–Couette and related flows on the centennial of Taylor’s seminal
Philosophical Transactions
paper (part 1)’.
Impact of vaccination and risk factors on COVID-19 mortality amid delta wave in Libya: a single centre cohort study
Authors: Alhudiri Inas , Abusrewil Zakarya , Dakhil Omran , Zwaik Mosab Ali , Awn Mohammed Ammar , Jallul Mwada , Ahmed Aimen Ibrahim , Abughrara Rasha , Elzaghied Adam
Published: January 2023

Background

The Delta variant has led to a surge in COVID-19 cases in Libya, making it crucial to investigate the impact of vaccination on mortality rates among hospitalized patients and critically ill.

Aims

To study risk factors and COVID-19 mortality rates among unvaccinated and vaccinated adults during delta wave at a single COVID-19 care centre in Tripoli, Libya.

Methods

The study involved two independent cohorts (n=341). One cohort was collected retrospectively from May 2021-August 2021 and the second cohort was prospectively collected from August 2021-October 2021 and most of them were during the Delta wave. The two cohorts were merged and analysed as one group.

Results

Most patients were male (60.5%) and 53.3% were >60 years. The vast majority of admitted patients did not have previous COVID-19 infection (98.9%) and were unvaccinated (90.3%). Among vaccinated, 30 patients had one dose and only 3 had two doses. Among patients who received one dose, 58.1% (18/31) died and 41.9% (13/31) survived. Most patients (72.2%) had a pre-existing medical condition. Multivariable prediction model showed that age >60 years was significantly associated with death (odds ratio=2.328, CI 1.456-3.724, p-value=<0.0001).

Conclusion

Previous infection or full vaccination against COVID-19 significantly reduces hospitalization and death, as most admitted patients were unvaccinated and not previously infected. However, a single vaccine dose may not be adequate, especially for older individuals and those with underlying medical conditions. High-risk older patients with comorbidities should be fully vaccinated and offered up to date bivalent COVID-19 booster doses.
Limited evidence for validity and reliability of non-navigated low and high frequency rTMS over the motor cortex
Authors: Prei Kilian , Kanig Carolina , Osnabrügge Mirja , Langguth Berthold , Mack Wolfgang , Abdelnaim Mohamed , Schecklmann Martin , Schoisswohl Stefan
Published: January 2023

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) are often described as inhibiting for low frequency and facilitating for high frequency protocols, leading to the lofi-hife heuristic. However, the data basis for this is inconsistent and reliability of rTMS is barely evaluated. The present study examines the validity of this lofi-hife heuristic at group and single subject level and the reliability of rTMS in a non-navigated setting close to clinical application. In 30 healthy participants, 1 Hz and 20 Hz rTMS were each administered twice over the left motor cortex resulting in four sessions/participant. Motor evoked potentials (MEPs) were measured before and after each session. Reliability measures were intraclass and Pearson’s correlation coefficient (ICC andr). The heuristic was not evident at group level. At single-subject level four participants responded with heuristic-conform changes, i.e., concomitant decreases for 1 Hz and increases for 20 Hz sessions. ICCs andrwere low to moderate. Within subgroups of less confounded measures, we found goodrvalues for 20 Hz rTMS. Results demonstrate high inter- and intraindividual variability of rTMS questioning the lofi-hife heuristic. Methodological improvements for the usage of rTMS might help to increase validity and reliability of non-invasive brain stimulation.
Clinical Trial of a Probiotic and Herbal Supplement for Lung and Gut Health
Authors: Wenger Nancy M. , Qiao Luhua , Nicola Teodora , Nizami Zoha , Martin Isaac , Halloran Brian A. , Tanaka Kosuke , Evans Michael , Xu Xin , Dinan Timothy G. , Kakilla Charles , DunnGalvin Gillian , Ambalavanan Namasivayam , Willis Kent A. , Gaggar Amit , Lal Charitharth Vivek
Published: January 2023

Rationale: Dysbiosis of the gut microbiome may augment lung disease via the gut-lung axis. Proteobacteria may increase MMP-9 release and contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic lung disease. Trial Design: We sought to determine if a probiotic and herbal blend was safe and well-tolerated in healthy volunteers and asthmatic patients. Methods: We conducted a 1-month randomized, open-label clinical trial in Cork, Ireland with healthy and asthmatic patients who took the blend twice a day. The primary endpoint was safety with secondary endpoints including quality of life, lung function, gut microbiome ecology, and inflammatory biomarkers. Results: All subjects tolerated the blend without adverse events. Asthmatic subjects who took the blend showed significant improvements in lung function and serum short chain fatty acid levels from baseline to Week 4. The gut microbiome of asthmatic subjects differed significantly from controls, with the most prominent difference in the relative abundance of the proteobacteria Escherichia coli. Administration of the probiotic maintained overall microbial community architecture with the only significant difference being an increase in absolute abundance of the probiotic strains measured by strain-specific PCR. Conclusions: This study supports the safety and efficacy potential of oral probiotic administration of the probiotic and herbal to act on the gut-lung axis.
serosim: an R package for simulating serological survey data arising from vaccination, epidemiological and antibody kinetics processes
Authors: Menezes Arthur , Takahashi Saki , Routledge Isobel , Metcalf C. Jessica E. , Graham Andrea L. , Hay James A.
Published: January 2023

serosimis an open source R package designed to aid inference of serological surveys, by simulating data arising from user-specified vaccine and infection-generated antibody kinetics processes using a random effects model. Serological surveys are used to assess population immunity by directly measuring individuals’ antibody titers. They uncover locations and/or populations which are susceptible and provide evidence of past infection or vaccination to help inform public health measures and surveillance. Both serological surveys and new analytical techniques used to interpret them are increasingly widespread. This expansion creates a need for tools to simulate serological surveys and the processes underlying the observed titer values, as this will enable researchers to identify best practices for serological survey design, and provide a standardized framework to evaluate the performance of different inference methods.serosimallows users to specify and adjust model inputs representing underlying processes responsible for generating the observed titer values like time-varying patterns of infection and vaccination, population demography, immunity and antibody kinetics, and serological survey sampling design in order to best represent the population and disease system(s) of interest. This package will be useful for planning sampling design of future serological surveys, understanding determinants of observed serological data, and validating the accuracy and power of new statistical methods.

Author Summary

Public health researchers use serological surveys to obtain serum samples from individuals and measure antibody levels against one or more pathogens. When paired with appropriate analytical methods, these surveys can be used to determine whether individuals have been previously infected with or vaccinated against those pathogens. However, there is currently a lack of tools to simulate realistic serological survey data from the processes determining these observed antibody levels. We developedserosim, an open source R package which enables users to simulate serological survey data matching their disease system(s) of interest. This package allows users to specify and modify model inputs responsible for generating an individual’s antibody level at various levels, from the within-host processes to the observation process.serosimwill be useful for designing more informative serological surveys, better understanding the processes behind observed serological data, and assessing new serological survey analytical methods.
Effectiveness of a chatbot in improving the mental wellbeing of health workers in Malawi during the COVID-19 pandemic: A randomized, controlled trial
Authors: Kleinau Eckhard F. , Lamba Tilinao , Jaskiewicz Wanda , Gorentz Katy , Hungerbuehler Ines , Rahimi Donya , Kokota Demoubly , Maliwichi Limbika , Jamu Edister S. , Zumazuma Alex , Negrão Mariana , Mota Raphael , Khouri Yasmine , Kapps Michael
Published: January 2023

We conducted a randomized, controlled trial (RCT) to investigate our hypothesis that the interactive chatbot, Vitalk, is more effective in improving mental wellbeing and resilience outcomes of health workers in Malawi than the passive use of Internet resources.

For our 2-arm, 8-week, parallel RCT (ISRCTN Registry: trial IDISRCTN16378480), we recruited participants from 8 professional cadres from public and private healthcare facilities. The treatment arm used Vitalk; the control arm received links to Internet resources. The research team was blinded to the assignment. Of 1,584 participants randomly assigned to the treatment and control arms, 215 participants in the treatment and 296 in the control group completed baseline and endline anxiety assessments. Six assessments provided outcome measures for: anxiety (GAD-7); depression (PHQ-9); burnout (OLBI); loneliness (ULCA); resilience (RS-14); and resilience-building activities. We analyzed effectiveness using mixed-effects linear models, effect size estimates, and reliable change in risk levels.

Results support our hypothesis. Difference-in-differences estimators showed that Vitalk reduced: depression (−0.68 [95% CI −1.15 to −0.21]); anxiety (−0.44 [95% CI −0.88 to 0.01]); and burnout (−0.58 [95% CI −1.32 to 0.15]). Changes in resilience (1.47 [95% CI 0.05 to 2.88]) and resilience-building activities (1.22 [95% CI 0.56 to 1.87]) were significantly greater in the treatment group. Our RCT produced a medium effect size for the treatment and a small effect size for the control group.

This is the first RCT of a mental health app for healthcare workers during the COVID-19 pandemic in Southern Africa combining multiple mental wellbeing outcomes and measuring resilience and resilience-building activities. A substantial number of participants could have benefited from mental health support (1 in 8 reported anxiety and depression; 3 in 4 suffered burnout; and 1 in 4 had low resilience). Such help is not readily available in Malawi. Vitalk has the potential to fill this gap.
Relationship of mild to moderate impairment of left ventricular ejection fraction with fatal ventricular arrhythmic events in cardiac sarcoidosis
Authors: Akama Yuka , Fujimoto Yudai , Matsue Yuya , Maeda Daichi , Yoshioka Kenji , Dotare Taishi , Sunayama Tsutomu , Nabeta Takeru , Naruse Yoshihisa , Kitai Takeshi , Taniguchi Tatsunori , Tanaka Hidekazu , Okumura Takahiro , Baba Yuichi , Minamino Tohru
Published: January 2023

Background

Current guidelines recommend placing an implantable cardiac defibrillator for patients with cardiac sarcoidosis (CS) and severely impaired left ventricular ejection fraction (LVEF) of ≤35%. In this study, we aimed to explore the association between mild or moderate LVEF impairment and fatal ventricular arrhythmic event (FVAE).

Methods

Here, 401 patients with CS without sustained ventricular arrhythmia at diagnosis were retrospectively analyzed. The primary endpoint was an FVAE, which was defined as the combined endpoint of documented ventricular tachycardia or ventricular fibrillation and sudden cardiac death. Two cut-off points for LVEF were used; sex-specific lower threshold of normal range of LVEF, 52% for men and 54% for women, and LVEF of 35% which is used in the current guidelines.

Results

During a median follow-up of 3.2 years, 58 FVAEs were observed, and the 5- and 10-year estimated incidences of FVAE were 16.8% and 23.0%, respectively. All patients were classified into three groups according to LVEF: impaired LVEF group, mild to moderate impairment of LVEF group, and maintained LVEF group. Multivariable competing risk analysis showed that both the impaired LVEF group (HR: 3.02, 95% CI: 1.25–7.32) and the mild to moderate impairment of LVEF group (HR: 2.12, 95% CI: 1.02–4.40) were associated with a higher incidence of FVAE than the maintained LVEF group after adjustment for covariates.

Conclusions

Patients with CS are at a high risk of FVAEs, regardless of documented ventricular arrhythmia at the time of diagnosis. In patients with CS, even mild to moderate impairment of LVEF is associated with FVAEs.

Clinical Perspective

What is Known

Patients with cardiac sarcoidosis (CS) are at a higher risk of fatal ventricular arrhythmic event (FVAE).

Current guidelines adopt left ventricular ejection fraction (LVEF) ≤35% as a cut-off value for Class I indication for implantable cardioverter defibrillators (ICD) implantation.

What the Study Adds

Cumulative incidence curves showed that the 5-year FVAE risk in patients with CS with preserved LVEF was 7%, which was as high as that of non-ischemic cardiomyopathy with reduced LVEF.

For risk stratification of future fatal ventricular arrhythmic events, even milder left ventricular ejection fraction impairment, compared to that currently suggested by guidelines, needs to be considered as a risk factor in patients with cardiac sarcoidosis.

Preventive strategies for fatal ventricular arrhythmic events and sudden cardiac death using an implantable cardiac defibrillator according to individualized risk stratification need to be developed and evaluated in clinical studies of patients with cardiac sarcoidosis.
Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimer’s Disease
Authors: Fan Peihao , Zeng Lang , Ding Ying , Kofler Julia , Silverstein Jonathan , Krivinko Joshua , Sweet Robert A , Wang Lirong
Published: January 2023

Background

Psychotic symptoms are reported as one of the most common complications of Alzheimer’s disease (AD), affecting approximately half of AD patients, in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in AD patients with psychosis (AD+P) and themselves increase mortality. A recent genome-wide meta-analysis and early clinical trials suggest the use and beneficial effects of antidepressants among AD+P patients. This motivates our rationale for exploring their potential as a novel combination therapy option amongst these patients.

Methods

We included University of Pittsburgh Medical Center (UPMC) electronic medical records (EMRs) of 10,260 AD patients from January 2004 and October 2019 in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. To provide more valuable insights on the hidden mechanisms of the combinatorial therapy, a protein-protein interaction (PPI) network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. An indicator score combining the measurements on the separation between drugs and the proximity between the drugs and AD+P was used to measure the effect of an antipsychotic-antidepressant drug pair against AD+P.

Results

Our survival analyses replicated that antipsychotic usage is strongly associated with increased mortality in AD patients while the co-administration of antidepressants with antipsychotics showed a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar proximity scores to AD+P. Eight drug pairs, including some popular recommendations like Aripiprazole/Sertraline and other pairs not reported previously like Iloperidone/Maprotiline showed higher than average indicator scores which suggest their potential in treating AD+P via strong synergetic effects as seen in our study.

Conclusion

Our proposed combinations of antipsychotics and antidepressants therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.
Five years of Hospital at Home adoption in Catalonia: impact and challenges
Authors: Gonzalez-Colom Ruben , Carot-Sans Gerard , Vela Emili , Espallargues Mireia , Hernandez Carme , Jimenez Francesc Xavier , Nicolas David , Suarez Montserrat , Torne Elvira , Villegas-Bruguera Eulalia , Ozores Fernando , Cano Isaac , Piera-Jimenez Jordi , Roca Josep
Published: January 2023

Background: Hospital at home (HaH), either admission avoidance (AA) or early supported discharge (ESD), was increasingly implemented in Catalonia (7.7 M, Spain) for selected patients, achieving regional adoption within the 2011-2015 Health Plan. This study aimed to assess population-wide HaH outcomes over five years (2015-2019) in a consolidated regional HaH program and provide context-independent recommendations for service quality assurance. Methods: A mixed-methods approach was adopted, combining population-based retrospective analyses of registry information with qualitative research. AA and ESD were separately compared with conventional hospitalization groups using propensity score matching techniques. In the analysis, we evaluated the 12-month period before the acute episode, the admission, and use of healthcare resources at 30 and 90 days after discharge. A panel of experts discussed the results and provided recommendations for monitoring HaH services. Results: The adoption of AA steadily increased from 5,185 to 8,086 episodes/year (total episodes 31,901; mean age 73 (SD 17) years; 79% high-risk patients), whereas ESD remained stable over the study period, averaging 5,329 episodes per year (total episodes 26,646; mean age 68 (SD 16) years; 71% high-risk patients). Mortality rates were similar in HaH and conventional hospitalization within the episode (AA: 0.31% vs. 0.45%; ESD: 0.18% vs. 0.45%) and at 30-days (AA: 3.94% vs. 3.24%; ESD: 4.50% vs. 4.07%). Likewise, the frequency of patients requiring hospital re-admissions or ER visits 30 days after discharge was similar in HaH (AA and ESD) and the corresponding controls. The 27 healthcare providers assessed showed high variability in patients age, multimorbidity, severity of episodes, recurrences, and length of stay of AA episodes. Recommendations aiming at enhancing service delivery were produced. Conclusions: Besides confirming safety and value generation of AA, we found that this service is delivered in a case-mix of diferent scenarios, encouraging provider-profiled monitoring of the service, particularly for ESD modalities. Keywords: Hospital at Home, Admission Avoidance, Early Supported Discharge, Implementation Science, Integrated Care.
Differential patterns of automatic segmentation of 3T and 7T MRI: Implications in neuropsychiatric disease
Authors: Verma Gaurav , Choi Ki Sueng , Mayberg Helen , Balchandani Priti
Published: January 2023

Automatic segmentation was performed on T1-MPRAGE structural MRI data acquired at 3T and 7T from 37 and 69 distinct healthy controls, respectively. Additionally, segmentation was performed on imaging acquired from 215 major depressive disorder (MDD) patients at 3T and 40 MDD patients at 7T. Of 259 segmentation-derived imaging features evaluated, 120 showed significant 3T vs. 7T differences among controls, and 153 among patients. 7T imaging metrics showed consistently lower cortical thickness and cortical gray/white matter ratios. Subcortical and cortical volumes measured at 7T were more mixed, with 7T images showing greater frontal lobe volume, but lower cortical volumes elsewhere.
Comorbidities, Behaviors, and Socioeconomic Factors and Mortality from Diseases of the Heart in New Jersey
Authors: Guariglia Matthew , Poos Stephen , Gawash Ahmed , Lo David F.
Published: January 2023

Mortality from diseases of the heart claimed the lives of 186,074 New Jerseyans from 2010 to 2019. This study aims to establish correlations between each of health-related risk factors and death from heart disease in each of the six New Jersey counties. Each of the counties ranked by age-adjusted mortality per 100,000 from diseases of the heart. The six counties were divided by the least (Hunterdon, Somerset, Bergen) and greatest (Cape May, Salem, and Cumberland) mortality rates from heart disease. Additionally, this data was broken down into three main categories that include comorbidities, socioeconomic status, and behavior patterns. Each main category is further broken down into subcategories that provide further evidence of how mortality from heart disease impacts the garden state. The main outcome of death in adults over 25 from heart disease from 2010 to 2019 was correlated to 28 health factors including comorbidities, behaviors, and socioeconomic factors. An R squared value was calculated to evaluate the strength of the correlation between each factor and the outcome of mortality from disease of the heart.
Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution
Authors: Bartos Laura M , Kirchleitner Sabrina V , Kolabas Zeynep Ilgin , Quach Stefanie , Blobner Jens , Mueller Stephan A , Ulukaya Selin , Hoeher Luciano , Horvath Izabela , Wind-Mark Karin , Holzgreve Adrien , Ruf Viktoria C , Gold Lukas , Kunze Lea H , Kunte Sebastian T , Beumers Philipp , Antons Melissa , Zatcepin Artem , Briel Nils , Hoermann Leonie , Messerer Denise , Bartenstein Peter , Riemenschneider Markus J , Lindner Simon , Ziegler Sibylle , Herms Jochen , Lichtenthaler Stefan F , Ertürk Ali , Tonn Joerg C , Baumgarten Louisa von , Albert Nathalie L , Brendel Matthias
Published: January 2023

Various cellular sources hamper interpretation of positron-emission-tomography (PET) biomarkers in the tumor microenvironment (TME). We developed immunomagnetic cell sorting afterin vivoradiotracer injection (scRadiotracing) in combination with 3D-histology via tissue clearing to dissect the cellular allocation of PET signals in the TME. In SB28 glioblastoma mice, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs). Cellular radiotracer uptake was validated by proteomics and confirmed forin vitrosamples of patients with glioblastoma. Regional agreement between PET signals and single cell tracer uptake predicted the individual cell distribution in 3D-histology. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma, however proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D-histology facilitates precise allocation of complex PET signal sources and will serve to validate novel TAM-specific radioligands.
Multi-omics data integration approach identifies potential biomarkers for Prostate cancer
Authors: Chikwambi Zedias , Hidjo Marie , Chikondowa Pageneck , Jayeoba Glory , Aketch Vincent , Afolabi Lawrence , Awe Olaitan I. , Enoma David
Published: January 2023

Prostate cancer (PCa) is one of the most common malignancies, and many studies have shown that PCa has a poor prognosis, which varies across different ethnicities. This variability is caused by genetic diversity. High-throughput omics technologies have identified and shed some light on the mechanisms of its progression and finding new biomarkers. Still, a systems biology approach is needed for a holistic molecular perspective. In this study, we applied a multi-omics approach to data analysis using different publicly available omics data sets from diverse populations to better understand the PCa disease etiology. Our study used multiple omic datasets, which included genomic, transcriptomic and metabolomic datasets, to identify drivers for PCa better. Individual omics datasets were analysed separately based on the standard pipeline for each dataset. Furthermore, we applied a novel multi-omics pathways algorithm to integrate all the individual omics datasets. This algorithm applies the p-values of enriched pathways from unique omics data types, which are then combined using the MiniMax statistic of the PathwayMultiomics tool to prioritise pathways dysregulated in the omics datasets. The single omics result indicated an association between up-regulated genes in RNA-Seq data and the metabolomics data. Glucose and pyruvate are the primary metabolites, and the associated pathways are glycolysis, gluconeogenesis, pyruvate kinase deficiency, and the Warburg effect pathway. From the interim result, the identified genes in RNA-Seq single omics analysis are linked with the significant pathways from the metabolomics analysis. The multi-omics pathway analysis will eventually enable the identification of biomarkers shared amongst these different omics datasets to ease prostate cancer prognosis.
Heparan sulfates regulate axonal excitability and context generalization through Ca2+/calmodulin-dependent protein kinase II
Authors: Song Inseon , Kuznetsova Tatiana , Baidoe-Ansah David , Mirzapourdelavar Hadi , Senkov Oleg , Hayani Hussam , Mironov Andrey , Kaushik Rahul , Druzin Michael , Johansson Staffan , Dityatev Alexander
Published: January 2023

Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and elevated Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 hours after injection in mice. Patch-clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 hours after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting a key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.
The Hidradenitis Suppurativa ‘Omics Database (HS-OmicsDB)
Authors: Dimitrion Peter , Loveless Ian , Zhou Li , Mi Qing-Sheng , Adrianto Indra
Published: January 2023

Large scale meta-analyses of genomics and genetics have spurred research in a number of fields, such as cancer, genetics and immunology. Publicly available ‘omics databases provide valuable hypothesis generating and validation tools. To date, no such initiative has been undertaken for Hidradenitis Suppurativa (HS), an inflammatory skin disease of unknown etiology. We present here, a longitudinal initiative seeking to aggregate publicly available ‘omics data to enhance research efforts in HS. In its first iteration, we include bulk and single-cell RNA sequencing data from untreated HS patients. Our data, aggregated from publicly available GEO datasets provides a tool to profile gene expression in specific tissue types (i.e. lesional, perilesional, nonlesional and healthy skin) as well as map cell-specific gene expression on single-cell data from HS lesions.
Spatial Multimodal Analysis of Transcriptomes and Metabolomes in Tissues
Authors: Vicari Marco , Mirzazadeh Reza , Nilsson Anna , Shariatgorji Reza , Bjärterot Patrik , Larsson Ludvig , Lee Hower , Nilsson Mats , Foyer Julia , Ekvall Markus , Czarnewski Paulo , Zhang Xiaoqun , Svenningsson Per , Andrén Per E. , Lundeberg Joakim
Published: January 2023

We present a spatial omics approach that merges and expands the capabilities of independently performedin situassays on a single tissue section. Our spatial multimodal analysis combines histology, mass spectrometry imaging, and spatial transcriptomics to facilitate precise measurements of mRNA transcripts and low-molecular weight metabolites across tissue regions. We demonstrate the potential of our method using murine and human brain samples in the context of dopamine and Parkinson’s disease.
Behavioural individuality determines infection risk in clonal ant colonies
Authors: Li Z. , Frank E.T. , Oliveira-Honorato T. , Azuma F. , Bachmann V. , Parker D. J. , Schmitt T. , Economo E. , Ulrich Y.
Published: January 2023

In social groups, disease risk is not distributed evenly across group members. Individual behaviour is a key source of variation in infection risk, yet its effects are difficult to separate from those of other factors. Here, we combine long-term epidemiological experiments and automated tracking in clonal raider ant colonies, where behavioural individuality emerges among identical workers. We find that: 1) division of labour determines the distribution of parasitic nematodes (Diploscapter) among hosts, showing that differences in infection can emerge from behavioural variation alone, 2) infections affect colony social organisation by causing infected workers to stay in the nest. By disproportionally infecting some workers and shifting their spatial distribution, infections reduce division of labour and increase spatial overlap between hosts, which is expected to facilitate parasite transmission. Thus, division of labour, a defining feature of many societies, not only shapes infection risk and distribution but can also be modified by parasites.
decOM: Similarity-based microbial source tracking of ancient oral samples using k-mer-based methods
Authors: González Camila Duitama , Vicedomini Riccardo , Lemane Téo , Rascovan Nicolas , Richard Hugues , Chikhi Rayan
Published: January 2023

Background

The analysis of ancient oral metagenomes from archaeological human and animal samples is largely confounded by contaminant DNA sequences from modern and environmental sources. Existing methods for Microbial Source Tracking (MST) estimate the proportions of environmental sources, but do not perform well on ancient metagenomes. We developed a novel method called decOM for Microbial Source Tracking and classification of ancient and modern metagenomic samples using k-mer matrices.

Results

We analysed a collection of 360 ancient oral, modern oral, sediment/soil and skin metagenomes, using stratified five-fold cross-validation. decOM estimates the contributions of these source environments in ancient oral metagenomic samples with high accuracy, outperforming two state-of-the-art methods for source tracking, FEAST and mSourceTracker.

Conclusions

decOM is a high-accuracy microbial source tracking method, suitable for ancient oral metagenomic data sets. The decOM method is generic and could also be adapted for MST of other ancient and modern types of metagenomes. We anticipate that decOM will be a valuable tool for MST of ancient metagenomic studies.
Niche conservatism in a generalist felid: low differentiation of the climatic niche among subspecies of the leopard(Panthera pardus)
Authors: Leedham Sidney , Paijmans Johanna L. A. , Manica Andrea , Leonardi Michela
Published: January 2023

Aim

Species distribution modelling can be used to reveal if the ecology of a species varies across its range, to investigate if range expansions entailed niche shifts, and to help assess ecological differentiation: the answers to such questions are vital for effective conservation. The leopard (Panthera pardus spp.) is a generalist species composed of one African and eight Asian subspecies, reflecting dispersal from an ancestral African range. This study uses species distribution models to compare the niches of leopard subspecies, to investigate if they conserved their niches when moving into new territories or adapted to local conditions and shifted niche.

Location

Africa and Eurasia

Methods

We assembled a database ofP. pardus spp. presences. We then associated them with bioclimatic variables to identify which are relevant in predicting the distribution of the leopard. We then constructed a species distribution model and compared the distribution predicted from models based on presences from all subspecies versus the ones built only using African leopards. Finally, we used multivariate analysis to visualise the niche occupied by each subspecies in the climate space, and to compare niche overlaps to assess ecological differentiation.

Results

Niche comparisons and model predictions suggest a general lack of niche separation between all subspecies. Most Asian subspecies have overlapping niches and occupy subsets of the niche of the African leopard. Nevertheless, we found the Persian leopardPanthera pardus saxicolorto have the most distinct niche, giving some evidence for niche expansion in more Northern Asian subspecies.

Main conclusions

These results suggest little ecological differentiation among leopard subspecies and a lack of adaptation to novel climates after dispersal from Africa. This finding complements recent genetic studies in implying that the taxonomy of Asian leopards may not reflect biological differentiation, an issue that is important to resolve due to its relevance for the conservation of the species.
N-arylpyrazole NOD2 agonists promote immune checkpoint inhibitor therapy
Authors: Griffin Matthew E. , Tsukidate Taku , Hang Howard C.
Published: January 2023

The characterization of microbiota mechanisms in health and disease has reinvigorated pattern recognition receptors as prominent targets for immunotherapy. Notably, our recent studies onEnterococcusspecies revealed peptidoglycan remodeling and activation of NOD2 as key mechanisms for microbiota enhancement of immune checkpoint inhibitor therapy. Inspired by this work and other studies of NOD2 activation, we performedin silicoligand screening and developedN-arylpyrazole dipeptides as novel NOD2 agonists. Importantly, ourN-arylpyrazole NOD2 agonist is enantiomer-specific, effective at promoting immune checkpoint inhibitor therapy and requires NOD2 for activityin vivo. Given the significant functions of NOD2 in innate and adaptive immunity, these next-generation agonists afford new therapeutic leads and adjuvants for a variety of NOD2-responsive diseases.
The nanoscale organization of reticulon 4 shapes local endoplasmic reticulum structurein situ
Authors: Fuentes Lukas A. , Marin Zach , Tyson Jonathan , Baddeley David , Bewersdorf Joerg
Published: January 2023

The endoplasmic reticulum’s (ER) structure is directly linked to the many functions of the ER but its formation is not fully understood. We investigate how the ER-membrane curving protein reticulon 4 (Rtn4) localizes to and organizes in the membrane and how that affects local ER structure. We show a strong correlation between the local Rtn4 density and the local ER membrane curvature. Our data further reveal that the typical ER tubule possesses an elliptical cross-section with Rtn4 enriched at either end of the major axis. Rtn4 oligomers are linear-shaped, contain about five copies of the protein, and preferentially orient parallel to the tubule axis. Our observations support a mechanism in which oligomerization leads to an increase of the local Rtn4 concentration with each molecule increasing membrane curvature through a hairpin wedging mechanism. This quantitative analysis of Rtn4 and its effects on the ER membrane result in a new model of tubule shape as it relates to Rtn4.

Rtn4 forms linear-shaped oligomers that contain an average of five Rtn4 proteins, localize to the sides of elliptical tubules, prefer orientations near parallel to the tubule axis, and increase local curvature of the ER membrane by increasing local Rtn4 density.
Structure of human NaV1.6 channel reveals Na+selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
Authors: Li Yue , Yuan Tian , Huang Bo , Zhou Feng , Peng Chao , Li Xiaojing , Qiu Yunlong , Yang Bei , Zhao Yan , Huang Zhuo , Jiang Daohua
Published: January 2023

The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. In the apo-form structure, two potential Na+binding sites were revealed in the selectivity filter, suggesting a possible mechanism for Na+selectivity and conductance. In the 4,9-ah-TTX-bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na+binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into NaV1.6 structure, ion conductance, and inhibition.
SeqPanther: Sequence manipulation and mutation statistics toolset
Authors: San James Emmanuel , Van Wyk Stephanie , Tegally Houriiyah , Eche Simeon , Wilkinson Eduan , Kanzi Aquillah M. , de Oliveira Tulio , Kiran Anmol M.
Published: January 2023

Pathogen genomes harbor critical information necessary to support genomic investigations that inform public health interventions such as treatment, control, and eradication. To extract this information, their sequences are analysed to identify structural variations such as single nucleotide polymorphisms (SNPs) and insertions and deletions (indels) that may be associated with phenotypes of interest. Typically, this involves generating a consensus sequence from raw reads, aligning it to a reference and identifying positions where variations occur. Several pipelines exist to map raw reads and assemble whole genomes for downstream analysis. However, there is no easy to use, freely available bioinformatics quality control (QC) tool to explore mappings for both positional codons and nucleotide distributions in mapped short reads of microbial genomes. To address this problem, we have developed a fast and accurate tool to summarise read counts associated with codons, nucleotides, and indels in mapped next-generation sequencing (NGS) short reads. The tool, developed in Python, also provides a visualization of the genome sequencing depth and coverage. Furthermore, the tool can be run in single or batch mode, where several genomes need to be analysed. Our tool produces a text-based report that enables quick review or can be imported into any analytical tool for upstream analysis. Additionally, the tool also provides functionality to modify the consensus sequences by adding, masking, or restoring to wild type mutations specified by the user.

Availability

SeqPanther is available athttps://github.com/codemeleon/seqPanther, along with the necessary documentation for installation and usage.
The intrinsic clock of the hippocampal subfield CA3 rescues limbic seizures in a biohybrid graft-host interaction in vitro
Authors: Caron Davide , Buccelli Stefano , Canal-Alonso Ángel , Hernández Marco , Pruzzo Giacomo , Corchado Juan Manuel , Chiappalone Michela , Panuccio Gabriella
Published: January 2023

Hippocampal dysfunction is the hallmark of mesial temporal lobe epilepsy (MTLE), the most common epileptic syndrome in adults and the most often refractory to medical therapy. Deep brain stimulation (DBS) may ameliorate drug-refractory MTLE, but it still cannot guarantee a seizure-free life. One major drawback is that the stimulation policy is informed by trial-and-error rather than by the operating mode of the brain. Thus, optimizing DBS parameters is still an unmet clinical need.

Here, we propose the deployment of hippocampal interictal activity in a biohybrid approach to control limbic ictogenesis. Specifically, an electronic bridge establishes a graft-host interaction between the hippocampal subfield CA3 (graft) and the parahippocampal cortex (CTX – host) of distinct rodent brain slices, both treated with 4-aminopyridine; the electronic bridge relays the graft interictal events to the host via electrical pulses. We show that interictal activity generated by the graft CA3 controls limbic ictogenesis in the host CTX even in the absence of feedback from it, thus likely reflecting an intrinsic anti-ictogenic clock of this brain region.

This work opens a translational perspective for MTLE treatment via biohybrid neuroprostheses relying on the intrinsic clock of incorporated hippocampal cells.
Cell cycle oscillations driven by two interlinked bistable switches
Authors: Parra-Rivas Pedro , Ruiz-Reynés Daniel , Gelens Lendert
Published: January 2023

Regular transitions between interphase and mitosis during the cell cycle are driven by changes in the activity of the enzymatic protein complex cyclin B with cyclin-dependent kinase 1 (Cdk1). At the most basic level, this cell cycle oscillator is driven by negative feedback: active cyclin B Cdk1 activates the Anaphase-Promoting Complex - Cyclosome, which triggers the degradation of cyclin B. Such cell cycle oscillations occur fast and periodically in the early embryos of the frogXenopus laevis, where several positive feedback loops leading to bistable switches in parts of the regulatory network have been experimentally identified. Here, we build cell cycle oscillator models to show how single and multiple bistable switches in parts of the underlying regulatory network change the properties of the oscillations and how they can confer robustness to the oscillator. We present a detailed bifurcation analysis of these models.