bluuebunny/crossref_metadata_2025 huggingface dataset:
Right Ventricular Failure and  Cor Pulmonale
Authors: Frantz Robert P. , Murphy Joseph G.
Published: January 2025

Right-sided heart failure, or right ventricular failure, is a clinical syndrome that is often challenging to diagnose and treat. Right ventricular failure is the inability of the right ventricle to pump an adequate amount of blood to the lungs without an increased central venous filling pressure. Right ventricular dysfunction as seen on cardiac imaging studies may be asymptomatic, particularly at rest, and is not synonymous with right-sided heart failure. Right ventricular failure should not be considered a freestanding diagnosis but instead should lead to a search for an underlying disease; it most often occurs secondary to pulmonary hypertension, congenital heart disease, or left-sided heart failure, for which it often predicts a poor prognosis. Causes of isolated right ventricular failure include congenital heart disease, severe tricuspid incompetence, pulmonary embolism, acute respiratory distress syndrome, right ventricular infarction, and, rarely, arrhythmogenic right ventricular cardiomyopathy.
Intellectualization Limits Your Compassion
Authors: Friedland Robert P.
Published: January 2025

Intellectualization is when you allow thoughts to repress feelings.
Learn from Clinical Experience (but Not Too Much)
Authors: Friedland Robert P.
Published: January 2025

Clinical experience is valuable but it is always incomplete.
Tell the Truth Whenever Possible
Authors: Friedland Robert P.
Published: January 2025

Truth telling is desirable whenever possible. If the patient will be harmed by truth telling it may be desirable to not to be completely truthful.
Experimenter Bias
Authors: Friedland Robert P.
Published: January 2025

Experimental design and data collection may be influenced by the researcher’s bias.
Being Smart Is Not Enough
Authors: Friedland Robert P.
Published: January 2025

“Imagination is more important than knowledge” A. Einstein.
Learn How to Learn and Enhance Your Learning Capacity
Authors: Friedland Robert P.
Published: January 2025

It is valuable to be aware of the best ways you learn.
Find Out Where You Find Meaning
Authors: Friedland Robert P.
Published: January 2025

Finding meaning in life is important at every stage. Where meaning is found is different in each person.
Look Beyond the Easiest Options and Pursue the Best Resources Possible
Authors: Friedland Robert P.
Published: January 2025

Seek out the best educational and research experiences possible.
Do Not Be Intimidated by Accomplished Persons in Medicine and Science
Authors: Friedland Robert P.
Published: January 2025

Do not be afraid to contact scientific leaders for advice.
Accept the Help of Others
Authors: Friedland Robert P.
Published: January 2025

Accepting the help of others through collaboration may be a valuable way to make progress.
Learn from the History of Medicine and Science
Authors: Friedland Robert P.
Published: January 2025

Our intellectual ancestors have many lessons of value to us.
Learn To Be a Salesperson
Authors: Friedland Robert P.
Published: January 2025

Medical and scientific written and verbal communications are forms of salesmanship.
Learn How To Learn from Bad Example
Authors: Friedland Robert P.
Published: January 2025

It is best to learn from good example but often necessary to learn as well from bad example.
The Need To Believe in the Guilty Victim
Authors: Friedland Robert P.
Published: January 2025

Do not assume that suffering persons are responsible for their illness.
Compassion Is Part of Our Fundamental Nature
Authors: Friedland Robert P.
Published: January 2025

Natural selection has fostered the development of compassion as part of our fundamental nature. “Joy is compassion turned inward”.
How does regulation influence euthanasia practice in Belgium? A qualitative exploration of involved doctors’ and nurses’ perspectives
Authors: Archer Madeleine , Willmott Lindy , Chambaere Kenneth , Deliens Luc , White Ben P
Published: January 2025

Euthanasia has been legal in Belgium since 2002. Despite extensive research exploring Belgian euthanasia practice, investigations into its governing regulatory framework are limited. Existing studies that consider regulation take a ‘siloed’ approach, generally considering sources of regulation individually, including euthanasia legislation and euthanasia policies. This study obtains insights from providing health professionals on how the Belgian euthanasia regulatory landscape influences their euthanasia practice. We conducted semi-structured, in-depth interviews from September 2022 to March 2024 with eligible physicians and nurses and analysed them using a reflexive approach to thematic analysis. We generated three overarching themes describing the influence of regulation on euthanasia practice: the Act is a valuable, boundary-setting instrument; but the Act is limited, leaving space for gap filling and other forms of regulation; and relying on professional judgment can make practitioners feel vulnerable. Key findings include that practitioners respond to the Act’s non-prescriptiveness and regulatory lacunae by relying on their professional judgment, and that the efficacy of the retrospective euthanasia oversight model depends on physicians’ good faith participation. Policymakers in Belgium and internationally are encouraged to reflect on the implications of Belgium’s euthanasia regulatory model for the consistency, quality, and control of euthanasia practice.
SN 2021foa: the bridge between SN IIn and Ibn
Authors: Gangopadhyay Anjasha , Dukiya Naveen , Moriya Takashi J , Tanaka Masaomi , Maeda Keiichi , Howell D Andrew , Singh Mridweeka , Singh Avinash , Sollerman Jesper , Kawabata Koji S , Brennan Seán J , Pellegrino Craig , Dastidar Raya , Nakaoka Tatsuya , Kawabata Miho , Misra Kuntal , Schulze Steve , Chandra Poonam , Taguchi Kenta , Sahu Devendra K , McCully Curtis , Bostroem K Azalee , Gonzalez Estefania Padilla , Newsome Megan , Hiramatsu Daichi , Takei Yuki , Yamanaka Masayuki , Tajitsu Akito , Isogai Keisuke
Published: January 2025

We present the long-term photometric and spectroscopic analysis of a transitioning SN IIn/Ibn from –10.8 d to 150.7 d post V-band maximum. SN 2021foa shows prominent He i lines comparable in strength to the H $\alpha$ line around peak, placing SN 2021foa between the SN IIn and SN Ibn populations. The spectral comparison shows that it resembles the SN IIn population at pre-maximum, becomes intermediate between SNe IIn/Ibn, and at post-maximum matches with SN IIn 1996al. The photometric evolution shows a precursor at –50 d and a light curve shoulder around 17 d. The peak luminosity and colour evolution of SN 2021foa are consistent with most SNe IIn and Ibn in our comparison sample. SN 2021foa shows the unique case of an SN IIn where the narrow P-Cygni in H $\alpha$ becomes prominent at 7.2 d. The H $\alpha$ profile consists of a narrow (500–1200 km s$^{-1}$) component, intermediate width (3000–8000 km s$^{-1}$) and broad component in absorption. Temporal evolution of the H $\alpha$ profile favours a disc-like CSM geometry. Hydrodynamical modelling of the light curve well reproduces a two-component CSM structure with different densities ($\rho \propto$ r$^{-2}$–$\rho \propto$ r$^{-5}$), mass-loss rates (10$^{-3}$–10$^{-1}$ M$_{\odot }$ yr$^{-1}$) assuming a wind velocity of 1000 km s$^{-1}$ and having a CSM mass of 0.18 M$_{\odot }$. The overall evolution indicates that SN 2021foa most likely originated from an LBV star transitioning to a WR star with the mass-loss rate increasing in the period from 5 to 0.5 yr before the explosion or it could be due to a binary interaction.
GBMPurity: A Machine Learning Tool for Estimating Glioblastoma Tumour Purity from Bulk RNA-seq Data
Authors: Thomas Morgan P H , Ajaib Shoaib , Tanner Georgette , Bulpitt Andrew J , Stead Lucy F
Published: January 2025

Background

Glioblastoma (GBM) presents a significant clinical challenge due to its aggressive nature and extensive heterogeneity. Tumour purity, the proportion of malignant cells within a tumour, is an important covariate for understanding the disease, having direct clinical relevance or obscuring signal of the malignant portion in molecular analyses of bulk samples. However, current methods for estimating tumour purity are non-specific and technically demanding. Therefore, we aimed to build a reliable and accessible purity estimator for GBM.

Methods

We developed GBMPurity, a deep-learning model specifically designed to estimate the purity of IDH-wildtype primary GBM from bulk RNA-seq data. The model was trained using simulated pseudobulk tumours of known purity from labelled single-cell data acquired from the GBmap resource. The performance of GBMPurity was evaluated and compared to several existing tools using independent datasets.

Results

GBMPurity outperformed existing tools, achieving a mean absolute error of 0.15 and a concordance correlation coefficient of 0.88 on validation datasets. We demonstrate the utility of GBMPurity through inference on bulk RNA-seq samples and observe reduced purity of the Proneural molecular subtype relative to the Classical, attributed to the increased presence of healthy brain cells.

Conclusions

GBMPurity provides a reliable and accessible tool for estimating tumour purity from bulk RNA-seq data, enhancing the interpretation of bulk RNA-seq data and offering valuable insights into GBM biology. To facilitate the use of this model by the wider research community, GBMPurity is available as a web-based tool at: https://gbmdeconvoluter.leeds.ac.uk/.
ATP-CITRATE LYASEB1 supplies materials for sporopollenin biosynthesis and microspore development in Arabidopsis
Authors: Ma Chang-Kai , Wang Sheng-Hong , Shi Qiang-Sheng , Guo Meng-Die , Yang Yan-Ming , Fu Jia , Chen Xiao , Mao Yi-Chen , Huang Xue-Hui , Zhu Jun , Yang Zhong-Nan
Published: January 2025

Acetyl-CoA is the main substrate of lipid metabolism and functions as an energy source for plant development. In the cytoplasm, acetyl-CoA is mainly produced by ATP-citrate lyase (ACL), which is composed of ACLA and ACLB subunits. In this study, we isolated the restorer-4 (res4) of the thermo-sensitive genic male sterile mutant reversible male sterile-2 (rvms-2) in Arabidopsis (Arabidopsis thaliana). RES4 encodes ACLB1, and res4 harbors a point mutation (Gly584 to Arg) in the citryl-CoA lyase domain. Both the ACLA and ACLB subunits are expressed in the tapetal layer of anthers. RES4 is regulated by MS188, and the res4 point mutation leads to pollen with a defective exine structure. In res4, lipid accumulation was significantly reduced within the tapetum and locules. These results indicate that acetyl-CoA synthesized by ACL is used for sporopollenin biosynthesis in the tapetum. Microspore diameter was significantly smaller in res4 than in wild type, indicating that acetyl-CoA from the tapetum supplies microspore development. Previous studies have shown that delayed degradation of the tetrad wall in res2 and res3 provides additional protection for rvms-2 microspores. The reduced volume of res4 microspores may lessen the requirement for cell wall protection to restore rvms-2 fertility. This study reveals the function of ACL in anther development and the mechanisms of fertility restoration in photoperiod- and thermo-sensitive genic male sterile lines.
Are clinical, psychophysical, or psychological variables helpful for discriminating patients with tension type headache? A diagnostic accuracy study
Authors: Cigarán-Mendez Margarita , Pacho-Hernández Juan C , Tejera-Alonso Angela , Fernández-Palacios Francisco G , Valera-Calero Juan Antonio , Gómez Cristina , Fernández-de-las-Peñas César
Published: January 2025

Importance

Diagnosis of tension-type headache (TTH) is a challengue for clinicians.

Objective

The aims of this study were: (1) to determine the ability of pain thresholds to differentiate between subjects with and without TTH; and (2) to determine the capability of clinical, psychological and psychophysical variables to differentiate between individuals with frequent episodic (FETTH) or chronic (CTTH) tension-type headache.

Design

A diagnostic accuracy study.

Setting

An urban hospital in Madrid (Spain).

Participants

One hundred (n = 100) individuals with TTH and 50 comparable non-headache subjects.

Main Outcomes

Pressure pain threshold (PPTs) over the temporalis muscle, cervical spine, second metacarpal, and tibialis anterior muscle and dynamic pain thresholds (DPT) were bilaterally assessed. Clinical headache parameters (headache diary), headache-associated burden (HDI), anxiety and depressive levels (HADS), sleep quality (PSQI), and state (STAI-S)—trait (STAI-T) anxiety levels were also evaluated. The area under the receiver operating characteristic (ROC) curve, optimal cut-off point, sensitivity, specificity, and positive and negative likelihood ratios (LR) for each variable were calculated.

Results

Individuals with TTH exhibited lower PPTs and DPT than those without TTH. No significant differences in PPTs and DPT were found between FETTH and CTTH individuals. Overall, no clinical, psychological or psychophysical variable exhibited an acceptable ROC value (≥0.7) for identifying between TTH patients and non-headache controls or between subjects with FETTH and CTTH.

Conclusion

Although individuals with TTH exhibit widespread pressure pain hyperalgesia, neither clinical nor psychological nor psychophysical variable had proper diagnostic accuracy to discriminate between individuals with/without TTH or between those with FETTH and CTTH.

Relevance

Pressure pain thresholds should not be used at this stage as diagnostic tool for TTH. Further studies should clarify the clinical relevance of these findings.
The development and application of a bibliometric strength, potential and risk analysis for research strategy in a University Medical Center
Authors: Iping Rik , van Leeuwen Thed N , Noyons Ed , Burdorf Alex , Mathijssen Irene M J , van Leeuwen Johannes P T M , Cohen Adrian M
Published: January 2025

This paper describes the development of a bibliometric strength, potential and risk analysis tool, and its applications for research strategy and evaluation. We focus specifically on the motivation, organizational strategic needs, the development and evaluation of the tool. Furthermore, we highlight the co-creation process of the tool and discuss the methodology behind the tool, how it works and initial feedback on how insights from the tool can be applied for research strategy and evaluation.
Transcriptomic analysis in liver spheroids identifies a dog-specific mechanism of hepatotoxicity for amcenestrant
Authors: Bajaj Piyush , Brennan Richard J , Laurent Sébastien , Sauzeat Sylvie , Dufault Michael , Richards Brenda , Adkins Karissa
Published: January 2025

Therapeutic drugs can sometimes cause adverse effects in a nonclinical species that do not translate to other species, including human. Species-specific (rat, dog, and human) in vitro liver spheroids were employed to understand the human relevance of cholestatic liver injury observed with a selective estrogen receptor degrader (amcenestrant) in dog, but not in rat, during preclinical development. Amcenestrant showed comparable cytotoxicity in liver spheroids from all 3 species; however, its M5 metabolite (RA15400562) showed dog preferential cytotoxicity after 7 days of treatment. Whole genome transcript profiles generated from liver spheroids revealed downregulation of genes related to bile acid synthesis and transport indicative of strong farnesoid X receptor (FXR) antagonism following treatment with both amcenestrant and its M5 metabolite in the dog but not in rat or human. In human spheroids, upregulation of genes for detoxification enzymes indicative of pregnane X receptor (PXR) agonism was observed following amcenestrant treatment, whereas in the dog these genes were downregulated. The M5 metabolite showed gene dysregulation indicating PXR agonism in both rat and human, and antagonism in dog. Analysis of liver samples from a 3-mo dog toxicity study conducted with amcenestrant showed downregulation of several genes associated with PXR and FXR, corroborating the in vitro results. These results support the hypothesis that dogs are uniquely susceptible to cholestatic hepatotoxicity following administration of amcenestrant due to species-specific antagonism of FXR and highlight the value of in vitro liver spheroids to investigating mechanisms of toxicity and possible species differences.
The Diagnostic Utility of Host RNA Biosignatures in Adult Patients With Sepsis: A Systematic Review and Meta-Analysis
Authors: Loi Mervin V. , Sultana Rehena , Nguyen Tuong Minh , Tia Shi Ting , Lee Jan Hau , O’Connor Daniel
Published: January 2025

OBJECTIVES:

Sepsis is a life-threatening medical emergency, with a profound healthcare burden globally. Its pathophysiology is complex, heterogeneous and temporally dynamic, making diagnosis challenging. Medical management is predicated on early diagnosis and timely intervention. Transcriptomics is one of the novel “-omics” technologies being evaluated for recognition of sepsis. Our objective was to evaluate the performance of host gene expression biosignatures for the diagnosis of all-cause sepsis in adults.

DATA SOURCES:

PubMed/Ovid Medline, Ovid Embase, and Cochrane databases from inception to June 2023.

STUDY SELECTION:

We included studies evaluating the performance of host gene expression biosignatures in adults who were diagnosed with sepsis using existing clinical definitions. Controls where applicable were patients without clinical sepsis.

DATA EXTRACTION:

Data including population demographics, sample size, study design, tissue specimen, type of transcriptome, health status of comparator group, and performance of transcriptomic biomarkers were independently extracted by at least two reviewers.

DATA SYNTHESIS:

Meta-analysis to describe the performance of host gene expression biosignatures for the diagnosis of sepsis in adult patients was performed using the random-effects model. Risk of bias was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 117 studies (n = 17,469), comprising 132 separate patient datasets, were included in our final analysis. Performance of transcriptomics for the diagnosis of sepsis against pooled controls showed area under the receiver operating characteristic curve (AUC, 0.86; 95% CI, 0.84–0.88). Studies using healthy controls showed AUC 0.87 (95% CI, 0.84–0.89), while studies using controls with systemic inflammatory response syndrome (SIRS) had AUC 0.84 (95% CI, 0.78–0.90). Transcripts with excellent discrimination against SIRS controls include UrSepsisModel, a 210 differentially expressed genes biosignature, microRNA-143, and Septicyte laboratory.

CONCLUSIONS:

Transcriptomics is a promising approach for the accurate diagnosis of sepsis in adults and demonstrates good discriminatory ability against both healthy and SIRS control subjects.
Development of machine learning-based models for vault prediction in implantable collamer lens surgery according to implant orientation
Authors: González-Cruces Timoteo , Aguilar-Salazar Francisco Javier , Tort Jordi Marfany , Sánchez-Ventosa Álvaro , Villarrubia Alberto , Mateu Jose Lamarca , Barraquer Rafael I. , Pardina Sergio , Palacios David Cerdán , Cano-Ortiz Antonio
Published: January 2025

Purpose:

The main objective was to develop a prediction model based on machine learning to calculate the postoperative vault as well as the ideal implantable collamer lens (ICL) size, considering for the first time the implantation orientation in a Caucasian population.

Setting:

Arruzafa Ophthalmological Hospital (Cordoba, Spain) and Barraquer Ophthalmology Center (Barcelona, Spain)

Design:

Multicenter, randomized, retrospective study.

Methods:

Anterior segment biometric data from 235 eyes of patients who underwent ICL lens implantation surgery were collected using the anterior segment optical coherence tomography (AS-OCT) CASIA II, to train and validate five types of multiple regression models based on advanced machine learning techniques. To perform an external validation a dataset of 45 observations was used.

Results:

The Pearson correlation coefficient between observed and predicted values was similar in the five models in the external validation, with least absolute shrinkage and selection operator (LASSO) regression being the highest (r = 0.62, p < 0.001), followed by random forest regression model (r = 0.60, p < 0.001) and backward stepwise regression (r = 0.58, ρ < 0.001). In addition, the predictions generated by the different models showed closer agreement with the actual vault compared with the Nakamura formulas. Using the new methods, about 70% of the observations had a prediction error below 150 µm.

Conclusions:

Advanced forms of regressions models based on machine learning allow satisfactory calculation of the ideal lens size, offering greater precision to surgeons customizing surgery according to implant orientation.
Outcomes of Zero Power Intraocular Lenses: Insights into the Keratometric Index and Axial Length
Authors: Melles Ronald B. , Cooke David L. , Olsen Thomas
Published: January 2025

Purpose:

We analyzed intraocular lens (IOL) power calculation in a series of patients with a zero diopter power implant. The idea was to bypass the Estimated Lens Plane (ELP), an important variable in normal IOL calculation.

Setting:

Large multi-center group practice.

Design:

Retrospective, observational study.

Methods:

A consecutive series of patients undergoing cataract surgery after optical biometry and implantation of a zero (0.0 D) power IOL were studied. Complete biometry was performed with an optical low coherence optical biometer. The predicted refraction was calculated with and without recalibrating the axial length (AL) using a Sum-Of-Segments (SOS) approach with the Hoffer Q, Holladay 1, SRK/T, Haigis, Barrett Universal II, and Olsen formulas. A ray tracing model to back-calculate the corneal power from the observed postoperative refraction and AL was also included.

Results:

In 52 eyes of 52 patients, mean prediction errors for the Hoffer Q, Holladay 1, SRK/T, Haigis, Barrett Universal II, and the Olsen formulas were +1.48, +1.15, +0.91, +0.65, +0.15 and +0.11 D respectively using standard AL and after SOS correction of the AL the mean errors changed to +1.08, +0.75, +0.52, +0.26, -0.25, and -0.27 D respectively. The mean back-calculated corneal power was 1.25 D lower than the mean keratometer reading using the standard keratometric index of 1.3375 and corresponded to an effective index of 1.328.

Conclusions:

The hyperopic error commonly seen in highly myopic eyes with classical thin-lens formulas is only partly corrected by SOS recalibration of the AL. We suggest the source of the residual error is an incorrect keratometric index.
Exploring the role of sex in hospitalizations among people with and without HIV in British Columbia, Canada
Authors: Naidu Nicholas , Kooij Katherine W. , Budu Michael , Ye Monica , Lu Michelle , Ding Erin , Mcclean Alison , Guillemi Silvia , Hull Mark , Barrios Rolando , Montaner Julio S.G. , Hogg Robert S.
Published: January 2025

Objective:

We assessed sex differences in hospitalization rates among people with HIV (PWH) and people without HIV (PWoH) in British Columbia (BC).

Methods:

PWH and a 10% random sample of PWoH in BC aged ≥19 were followed from 04/01/2002 to 03/31/2020, using linked administrative Comparative Outcomes and Service Utilization Trends (COAST) study data. Hospitalizations were categorized by discharge diagnosis, using broad International Classification of Diseases-classes. Using Poisson regression, we modelled the association between sex, HIV-status, their interaction, and hospitalization rates adjusting for confounders.

Results:

Among 12,635 PWH (17.81% females) and 548,992 PWoH (49.34% females), age-adjusted hospitalization rates per 100 person-years were highest among females with HIV (incidence rate [IR] 34.25), followed by males with HIV (IR 21.49), females (IR 7.10), and males (IR 7.06) without HIV. Hospitalization rates for all causes declined from 2002-2022 across all subgroups but remained consistently higher among females with HIV, except for circulatory diseases and neoplasms. Adjusted for socio-structural factors, being male (rate ratio [RR] 1.92) or female with HIV (RR 2.66) was significantly associated with a higher hospitalization rate compared to males without HIV. Among PWH, female sex remained significantly associated with a higher hospitalization rate, after adjusting for HIV- and disease-related factors.

Conclusions:

We found a higher hospitalization rate among PWH than PWoH in BC, with the highest rate among females with HIV. This could partially be explained by socio-structural factors. Addressing these disparities and improving our understanding of the underlying mechanisms is critical to enhance health outcomes for women with HIV.
Clinical and sociodemographic characteristics of alzheimer's disease and related dementias (AD/ADRD) among people living with HIV: a cross-sectional analysis
Authors: Brown Monique J. , Murtala Nyame Mustapha , Amoatika Daniel , Kaur Amandeep , Addo Prince Nii Ossah , Osinubi Medinat Omobola , Miller Maggi , Ingram Lucy A.
Published: January 2025

Introduction:

Alzheimer's disease and related dementias (AD/ADRD) continue to be a public health challenge. People living with HIV (PLWH) are at risk for neurocognitive disorders and may be at risk for AD/ADRD. However, studies examining clinical and sociodemographic factors associated with AD/ADRD among PLWH are lacking. Therefore, the aim of this cross-sectional study was to determine the association between selected sociodemographic (age, gender, race and rurality) and clinical (depression and encephalopathy) factors with (AD/ADRD) among PLWH.

Methods:

Data were obtained from the South Carolina Revenue and Fiscal Affairs (RFA) Office and the South Carolina Alzheimer's Disease Registry (N = 13,390). Multivariable logistic regression models were used to determine the association between age, gender, race, rurality, depression and encephalopathy, and AD/ADRD among PLWH.

Results:

Among the study population (N = 13,390), 5% (n = 601) were found to have AD/ADRD. There was a dose-response relationship between age group and AD/ADRD whereas the age group increased, the association increased. For example, those who were aged 80 years and older were 80 times more likely to have AD/ADRD compared to those aged 18–29 years (aOR: 80.4; 95% CI: 40.2–160.8). Additionally, male sex (aOR: 1.3; 95% CI: 1.9–1.6) and encephalopathy (aOR: 2.4; 95% CI: 1.9–3.2) were positively associated with AD/ADRD for PLWH.

Conclusion:

AD/ADRD interventions may be warranted among PLWH, especially among older adults, men, and those with encephalopathy. Future studies should examine potential pathways between clinical and sociodemographic characteristics and AD/ADRD among PLWH.
Senotherapy: Implications for Transplantation
Authors: Jaros Martin , Melk Anette
Published: January 2025

Cellular senescence has been identified as a potential driver of age-associated loss of organ function and as a mediator of age-related disease. Novel strategies in targeting senescent cells have shown promise in several organ systems to counteract functional decline, chronic inflammation, and age-dependent loss of repair capacity. Transgenic models have provided proof of principle that senolysis, the elimination of senescent cells, is an attractive strategy to overcome many age-related pathologies. The translation into clinical application is now possible with the emergence of drug-based senotherapies. In this review, we will discuss different senotherapeutic approaches and their modes of action. Senolytics eliminate senescent cells preferentially through the induction of apoptosis in senescent but not in normal cells, whereas senomorphics rather interact with the proinflammatory profile present in senescent cells. In the context of transplantation, the natural clearance of senescent cells might be reduced because of dysfunctional immune surveillance under immunosuppression. The transplantation setting allows for different applications of senotherapies. Conditioning donor organs before and during the ex situ phase offers the opportunity to interfere with accumulating senescence, ultimately reducing the burden of life-limiting comorbidities in chronically ill recipients.
Campylobacter fetus subspecies fetus; an unforeseen cause of abortion in Regional Australia.
Authors: Owusu-Ansa Immanuella , Ramadas Manjeera , Jacob Nikhitha , Ayeni Femi E.
Published: January 2025

Campylobacter fetus (C.fetus) subspecies fetus, a gram-negative bacterium, is an established cause of abortion and infertility in cattle, sheep and goats. Human infections have been rarely reported. In contrast to TORCH infections, this campylobacter species is hardly recognised as a cause of abortion in humans. Since 1947 after the first case report in France, there are only 11 reported cases in pregnant women worldwide and no published reports in Australia, pregnant or otherwise. The case in this study was compared to the first reported infection of C.fetus in 1947 to raise awareness and educate doctors and midwives, subsequently impacting prenatal and antenatal counselling in these regions.  
A Venn diagram was constructed to highlight the similarities between this and the index case. The similarities found included the clinical state of the patient post-abortion and the all-important history of exposure to farm animals that suffered recent deaths on the farms of both patients. Some of the differences included the time of onset of symptoms to the time of abortion, the choice of antibiotics by both treating teams and the presentation of sepsis, suggesting the importance of Campylobacter fetus subspecies fetus as a perinatal infection.
scAGG: Sample-level embedding and classification of Alzheimer’s disease from single-nucleus data
Authors: Verlaan T. , Bouland G. , Mahfouz A. , Reinders M.J.T.
Published: January 2025

Identifying key cell types and genes in Alzheimer’s Disease (AD) is crucial for understanding its pathogenesis and discovering therapeutic targets. Single cell RNA sequencing technology (scRNAseq) has provided unprecedented opportunities to study the molecular mechanisms that underlie AD at the cellular level. In this study, we address the problem of sample-level classification of AD using scRNAseq data, where we predict the disease status of entire samples from the gene expression profiles of their cells, which are not necessarily all affected by the disease. We introduce scAGG, a sample-level classification model which uses a sample-level pooling mechanism to aggregate single-cell embeddings, and show that it can accurately classify AD individuals and healthy controls. We then investigate the latent space learnt by the model and find that the model learns an ordering of the cells corresponding to disease severity. Genes associated with this ordering are enriched in AD-linked pathways, including cytokine signalling, apoptosis, and metal ion response. We also evaluate two attention-based models that perform on par with scAGG, but entropy analysis of their attention scores reveals limited interpretability value. As scRNAseq is increasingly applied to large cohorts, our approach provides a way to link individual phenotypes to single-cell measurements. Our cell- and sample-level severity scores may enable identification of AD-associated cell subtypes, paving the way for targeted drug development and personalized treatment strategies in AD.

A Python implementation of scAGG is available athttp://github.com/timoverlaan/scAGG
Distinct localization patterns of actin microfilaments during early cell plate formation in plants through deep learning-based image restoration
Authors: Kikuchi Suzuka , Kotaka Takumi , Hanaki Yuga , Ueda Minako , Higaki Takumi
Published: January 2025

Phragmoplasts are plant-specific intracellular structures composed of microtubules, actin microfilaments (AFs), membranes, and associated proteins. Importantly, they are involved in the formation and expansion of cell plates that partition daughter cells during cell division. While previous studies have revealed the important role of cytoskeletal dynamics in the proper functioning of the phragmoplast, the localization and role of AFs in the initial phase of cell plate formation remain controversial. Here, we used deep learning-based image restoration to achieve high-resolution 4D imaging with minimal laser-induced damage, enabling us to investigate the dynamics of AFs during the initial phase of cell plate formation in transgenic tobacco BY-2 cells labeled with Lifeact-RFP or RFP-ABD2 (actin binding domain 2). This computational approach overcame the limitation of conventional imaging, namely laser-induced photobleaching and phototoxicity. The restored images indicated that RFP-ABD2 labeled AFs were predominantly localized near the daughter nucleus, whereas Lifeact-RFP labeled AFs were found not only near the daughter nucleus but also around the initial cell plate. These findings, validated by imaging with a long exposure time, highlight distinct localization patterns between the two AF probes and suggest that Lifeact-RFP labeled AFs play a role in initiating cell plate formation.
An integrative molecular systems approach unravels mechanisms underlying biphasic nitrate uptake by plant nitrate transporter NRT1.1
Authors: Subhadarshini Seemadri , Sahoo Sarthak , Jolly Mohit Kumar , Rashid Mubasher
Published: January 2025

Elucidating the mechanisms of transport kinetics in plants is crucial to develop crops that can use nutrients efficiently. The plant nitrate transporter NRT1.1 rapidly switches between high- and low-affinity transport modes to maintain an optimal uptake amidst fluctuations in nitrate levels. This functional switch is regulated by NRT1.1 phosphorylation, but the precise mechanisms remain poorly understood. Here, using an integrated molecular and systems-level modeling, we identify mechanisms underlying biphasic behaviour of NRT1.1. Phosphorylation of NRT1.1 and its binding to nitrate impacts its overall flexibility and synergistically modulates its global conformation, impacting the nitrate transport rate. Integrating these observations with a regulatory network involving kinases CIPK8/CIPK23 and calcium binding proteins CBL1/9, reveals that in high nitrate conditions, CIPK8-mediated sequestration of CBL1 disrupts the CIPK23-CBL complex required for NRT1.1 phosphorylation, switching NRT1.1 to a low-affinity mode. Together, our findings untangle the molecular complexity enabling NRT1.1 phosphorylation switch with broader implications in nitrate sensing and molecular-level adaption to fluctuating external nutrient levels.
Functional Modulation of Retrotrapezoid Neurons Drives Fentanyl-Induced Respiratory Depression
Authors: Moreira Thiago S. , Burgraff Nicholas J. , Takakura Ana C. , Oliveira Luiz M. , Araujo Emmanuel V. , Guan Steven , Ramirez Jan-Marino
Published: January 2025

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), characterized by severe suppression of respiratory rate, destabilized breathing patterns, hypercapnia, and heightened risk of apnea. The retrotrapezoid nucleus (RTN), a critical chemosensitive brainstem region in the rostral ventrolateral medullary reticular formation contains Phox2b+/Neuromedin-B (Nmb) propriobulbar neurons. These neurons, stimulated by CO2/H+, regulate breathing to prevent respiratory acidosis. Since the RTN shows limited expression of opioid-receptors, we expected that opioid-induced hypoventilation should activate these neurons to restore ventilation and stabilize arterial blood gases. However, the ability of the RTN to stimulate ventilation during OIRD has never been tested. We used optogenetic and pharmacogenetic approaches, to activate and inhibit RTN Phox2B+/Nmb+neurons before and after fentanyl administration. As expected, fentanyl (500 µg/kg, ip) suppressed respiratory rate and destabilized breathing. Before fentanyl, optogenetic stimulation of Phox2b+/Nmb+or chemogenetic inhibition ofNmb+cells increased and decreased breathing activity, respectively. Surprisingly, optogenetic stimulation after fentanyl administration caused a significantly greater increase in breathing activity compared to pre-fentanyl levels. By contrast chemogenetic ablation of RTNNmbneurons caused profound hypoventilation and breathing instability after fentanyl. The results suggest that fentanyl does not inhibit the ability of Phox2b+/Nmb+cells within the RTN region to stimulate breathing. Thus, this study highlights the potential of stimulating RTN neurons as a therapeutic approach to restore respiratory function in cases of OIRD.
Inferring active and passive mechanical drivers of epithelial convergent extension
Authors: Anjum Sommer , Vijayraghavan Deepthi , Fernandez-Gonzalez Rodrigo , Sutherland Ann , Davidson Lance
Published: January 2025

What can we learn about the mechanical processes that shape tissues by simply watching? Several schemes suggest that static cell morphology or junctional connectivity can reveal where chains of cells transmit force or where force asymmetries drive cellular rearrangements. We hypothesize that dynamic cell shape changes from time lapse sequences can be used to distinguish specific mechanisms of tissue morphogenesis. We refer to this as 'mechanism inference'. Convergent extension (CE) is a crucial developmental motif wherein a planar tissue narrows in one direction and lengthens in the other. It is tempting to assume that forces driving CE reside within cells of the deforming tissue, but CE may reflect a variety of active processes or passive responses to forces generated by adjacent tissues. In this work, we first construct a simple model of epithelial cells capable of passive CE in response to external forces. We adapt this framework to simulate CE from active anisotropic processes in three different modes: crawling, contraction, and capture. We develop an image analysis pipeline for analysis of morphogenetic changes in both live cells and simulated cells using a panel of mechanical and statistical approaches. Our results allow us to identify how each simulated mechanism uniquely contributes to tissue morphology and provide insight into how force transmission is coordinated. We construct a MEchanism Index (MEI) to quantify how similar live CE is to simulated CE modes. Applying these analyses to timelapse data of Xenopus neural CE reveals features of both passive motion and active forces. Furthermore, we find spatial variation across the neural plate. We compare the inferred mechanisms in the frog midline to tissues undergoing CE in both the mouse and fly. We find that distinct active modes may have different prevalences depending on the model system. Our modeling framework allows us to gain insight from tissue timelapse images and assess the relative contribution of specific cellular mechanisms to observed tissue phenotypes. This approach can be used to guide further experimental inquiry into how mechanics influences the shaping of tissues and organs during development.
Complex exchanges among plasmids and clonal expansion of lineages shape the population structure and virulence ofBorrelia burgdorferi
Authors: Laing Rachel A. , Foster Michael J. , Hassani M. Amine , Kotzen Benjamin , Huang Weihua , Shea Terrence , Schaffner Stephen F. , Cerar Tjasa , Freimark Lisa , Ruzic-Sabljic Eva , Liveris Dionysios , Reed Kurt D. , Branda John A. , Steere Allen C. , Wormser Gary P. , Strle Franc , Sabeti Pardis C. , Earl Ashlee , Schwartz Ira , Strle Klemen , Lemieux Jacob E.
Published: January 2025

Background

In the United States,Borrelia burgdorferi(Bb) is the principal etiologic agent of Lyme disease. The complex structure ofBbgenomes has posed challenges for genomic studies because homology among the bacterium’s many plasmids, which account for ∼40% of the genome by length, has made them difficult to sequence and assemble.

Results

We used long-read sequencing to generate near-complete assemblies of 62 isolates of human-derivedBband collected public genomes with plasmid sequences. We characterized genetic diversity and population structure in the resulting set of 82 plasmid-completeBorrelia burgdorferisensu stricto genomes. TheBbcore genome is encoded by a chromosome and the conserved plasmids cp26, lp54, and lp17; the accessory genome is encoded by all other plasmids and the distal arm of the chromosome. Near-complete genomes reveal that the most granularBbgenotypes are clonal expansions of complex rearrangements among accessory genome elements. Ribosomal spacer types (RST) represent multiple collections of such genotypes, whereas OspC types are usually clonal. Structural rearrangements are non-randomly distributed throughout the genome, with cp32 plasmids undergoing dense exchanges and most linear plasmids, except lp54, sharing blocks among themselves and with the distal arm of the chromosome. OspC type A strains, known to possess greater virulence in humans, are distinguished by the presence of lp28-1 and lp56. Rearrangements among plasmids tended to preserve gene content, suggesting functional constraints among gene networks. Using k-partite graph decompositions, we identified gene sets with correlation patterns suggestive of conserved functional modules.

Conclusions

Long-read assemblies reveal thatBbpopulation genetic structure results from clonal expansion of lineages that have undergone complex rearrangements among plasmid-encoded accessory genome elements. Genetic structure is preserved among genes even when plasmid rearrangements occur, suggesting that selection among epistatic loci maintains functional genetic networks. The analysis of near-complete genomes assembled using long-read sequencing methods advances our understanding ofBbbiology and Lyme disease pathogenesis by providing the first detailed view of population variation in previously inaccessible areas of theBbgenome.
ChiraKit, an online tool for the analysis of circular dichroism spectroscopy data
Authors: Burastero Osvaldo , Jones Nykola C. , Defelipe Lucas A. , Zavrtanik Uroš , Hadži San , Hoffmann Søren Vrønning , Garcia-Alai Maria M.
Published: January 2025

Circular dichroism (CD) spectroscopy is an established biophysical technique to study chiral molecules. CD allows investigating conformational changes under varying experimental conditions and has been used to understand secondary structure, folding and binding of proteins and nucleic acids. Here, we present ChiraKit, a user-friendly, online, open-source tool to process raw CD data and perform advanced analysis. ChiraKit features include the calculation of protein secondary structure with the SELCON3 and SESCA algorithms, estimation of peptide helicity using the helix-ensemble model, the fitting of thermal/chemical unfolding or user-defined models, and the decomposition of spectra through singular value decomposition (SVD) or principal component analysis (PCA). ChiraKit can be accessed athttps://spc.embl-hamburg.de/.
Single-AAV CRISPR editing of skeletal muscle in non-human primates with NanoCas, an ultracompact nuclease
Authors: Rauch Benjamin J. , DeLoughery Aaron , Sper Renan , Chen Sean , Yunanda Sophia , Masnaghetti Megan , Chai Ning , Lin Jason Chen , Neckelmann Alexander , Bjornson Ymer , Espino David Paez , Sancio Alyssa , Schmitt Christopher , Scholes Clarissa , Shah Ria , Narendra Pooja Kyatsandra , Ansaloni Sara , Tan SiuSze , Rukmini Subhadra Jayaraman , Somaiah Sahana , Suresh Shravanti , Minami Shiaki , Tymoshenko Stepan , Wright Will , Xu Siming , Broughton James , Retwitzer Matan Drory , Bobbin Maggie , Yuan Dave , Abe Keith , DeWitt Mark , Zhang Bohong , Harrington Lucas B.
Published: January 2025

CRISPR gene editing is a transformative technology for addressing genetic diseases, but delivery constraints have largely limited its therapeutic applications to liver-targeted andex vivotherapies. Here, we present the discovery and engineering of NanoCas, an ultracompact CRISPR nuclease capable of extending CRISPR’s reachin vivobeyond liver targets. We experimentally screened 176 ultracompact CRISPR systems found in metagenomic data and applied protein engineering approaches to enhance the editing efficiency of NanoCas. The optimized NanoCas exhibits potent editing capabilities across various cell systems and tissuesin vivowhen administered via adeno-associated viral (AAV) vectors. This is accomplished despite NanoCas being approximately one-third the size of conventional CRISPR nucleases. In proof-of-concept experiments, we observed robust editing with our optimized NanoCas in mouse models targeting Pcsk9, a gene involved in cholesterol regulation, and targeting exon splice sites in dystrophin to address Duchenne muscular dystrophy (DMD) mutations. We further tested the efficacy of our NanoCas systemin vivoin non-human primates (NHPs) resulting in editing levels above 30% in muscle tissues. The compact size of NanoCas, in combination with robust nuclease editing, opens the door for single-AAV editing of non-liver tissuesin vivo, including the use of newer editing modalities such as reverse transcriptase (RT) editing, base editing, and epigenetic editing.
Three-dimensional cellularization in chytrid fungi uses distinct mechanisms from those driving one- and two-dimensional cytokinesis in animals and yeast
Authors: Medina Edgar M , Elting Mary W , Fritz-Laylin Lillian
Published: January 2025

Chytrid fungi offer a unique opportunity to study three-dimensional cellularization, where nuclei that start out homogeneously distributed throughout the cytoplasm are synchronously compartmentalized into daughter cells. This process addresses geometric challenges not encountered in conventional cytokinesis, where nuclei are organized in a one-dimensional line, or inDrosophilacellularization, which is organized in a two-dimensional plane—both of which allow nuclei direct access to cytokinetic cues placed at the plasma membrane. Here, we show that three-dimensional cellularization in the chytridSpizellomyces punctatusproceeds through a stepwise program, beginning with the transient migration of nuclei and their associated centrosomes to the plasma membrane. At this point, centrosome-associated vesicles form and initiate membrane invagination, establishing tubular furrows that expand and branch, ultimately creating a foam-like tessellation of tightly packed polyhedral compartments, each containing a single nucleus and bearing a cilium. Using a combination of small molecule inhibitors and laser ablation, we demonstrate that, similar to cytokinesis andDrosophilacellularization, chytrid cellularization is powered by actomyosin networks. We also show that while microtubules are important for patterning, they appear dispensable for cellularization. Finally, we suggest that chytrids may have incorporated mechanisms associated with ciliogenesis in animals to coordinate the association of internal nuclei with actomyosin networks and membranes. These data highlight the value of using chytrid fungi to study the unique geometric problems associated with three-dimensional cellularization.