bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Mediterranean Dietary Education on Symptoms for Adults at Risk for Nonalcoholic Fatty Liver Disease
Authors: Jerome Nirupama Esther , Edwards Nancy E. , Ding Qinglan (Priscilla)
Published: August 2023

This 2-month quasi-experimental study focused on the impact of education regarding the Mediterranean diet on symptoms for adults who are at risk for nonalcoholic fatty liver disease (NAFLD). The study was conducted on a sample of 28 adults who presented to Pinnacle clinical research for NAFLD screening via a fibroscan. These individuals who are at risk for NAFLD received a single 15-minute one-on-one in person education regarding the Mediterranean diet. The diet encourages fruits, vegetables, whole grains, legumes, nuts, seeds, fish, and olive oil. The results of the study showed that the Mediterranean diet education was associated with significant improvement of abdominal symptoms (t = 3.34, p = .03), improvement of fatigue symptoms (t = 5.88, p < .001), and decrease in hepatic steatosis (t = 5.77, p < .001). Our study suggests that the education on the Mediterranean diet may be associated with improvement of self-reported abdominal symptoms, fatigue, and steatosis score.
Immune checkpoint inhibitors induced side effects of the peripheral nervous system
Authors: Hundsberger Thomas , Schreiner Bettina , Roth Patrick
Published: August 2023

Purpose of review

This review highlights recent knowledge on the diagnosis and treatment of immune checkpoint inhibitor-induced neurological side effects (irNAE) focussing on the neuromuscular system.

Recent findings

irNAEs mainly resemble sporadic neuromuscular autoimmune diseases and paraneoplastic neurological syndromes. However, neurological symptoms may be unspecific (muscle weakness, fatigue) in the oncological setting and carry the risk of misdiagnosis and delayed therapeutic intervention. The role of disease-specific neuromuscular autoantibodies in the diagnosis is controversial as preexisting autoantibodies may otherwise be present before immune checkpoint inhibitor (ICI) treatment without clinical symptoms and may not develop in case of irNAE manifestation. A new necrotising form of myositis (irMyositis) has been described presenting with facial weakness and ptosis mimicking myasthenia gravis. It comes along with a high rate of severe myocarditis accounting for a triad overlap syndrome (myasthenia/myositis/myocarditis). The role of modern biologicals in the treatment of irNAEs has to be determined.

irNAEs are rare but carry the risk of permanent morbidity and mortality. Early suspicion and diagnosis are key to prevent neurological sequelae. Beyond interruption of ICI administration, treatment corresponds to sporadic autoimmune diseases. The myasthenia/myositis/myocarditis overlap syndrome deserves special attention as it carries the highest risk of mortality. The role of neurotoxic pretreatment regimens, preexisting subclinical neurological autoimmune diseases and the risk of ICI-re-challenge after irNAEs has to be further investigated.
Frailty is related to serum inflammageing markers: results from the VITAL study
Authors: van Sleen Yannick , Shetty Sudarshan A , van der Heiden Marieke , Venema Milou CA , Gutierrez-Melo Nicolas , Toonen Erik JM , van Beek Josine , Buisman AnneMarie M , van Baarle Debbie , Sauce Delphine
Published: August 2023

Frailty describes an age-associated state in individuals with an increased vulnerability and less resilience against adverse outcomes. To score frailty, studies have employed the questionnaires, such as the SF-36 and EQ-5D-3L, or the Frailty Index, a composite score based on deficit accumulation. Furthermore, ageing of the immune system is often accompanied by a state of low-grade inflammation (inflammageing). Here, we aimed to associate 29 circulating markers of inflammageing with frailty measures in a prospective cohort study to understand the mechanisms underlying ageing.

Frailty measures and inflammageing markers were assessed in 317 participants aged 25-90. We determined four different measures of frailty: the Frailty Index based on 31 deficits, the EQ-5D-3L and two physical domains of the SF-36. Serum/plasma levels of inflammageing markers and CMV/EBV seropositivity were measured using different techniques: Quanterix, Luminex or ELISA.

All four measures of frailty strongly correlated with age and BMI. Nineteen biomarkers correlated with age, some in a linear fashion (IL-6, YKL-40), some only in the oldest age brackets (CRP), and some increased at younger ages and then plateaued (CCL2, sIL-6R). After correcting for age, biomarkers, such as IL-6, CRP, IL-1RA, YKL-40 and elastase, were associated with frailty. When corrected for BMI, the number of associations reduced further.

In conclusion, inflammageing markers, particularly markers reflecting innate immune activation, are related to frailty. These findings indicate that health decline and the accumulation of deficits with age is accompanied with a low-grade inflammation which can be detected by specific inflammatory markers.
Evaluation of a Large Language Model to Identify Confidential Content in Adolescent Encounter Notes
Authors: Rabbani Naveed , Brown Conner , Bedgood Michael , Goldstein Rachel L. , Carlson Jennifer L. , Pageler Natalie M. , Morse Keith E.
Published: August 2023

Introduction

In adolescent care, information sharing through patient portals can lead to unintentional disclosures to patients’ guardians around protected health topics such as mental health, sexual health, and substance use. A persistent challenge facing pediatric health systems is configuring systems to withhold confidential information recorded as free text in encounter notes. This study evaluates the accuracy of a proprietary large language model (LLM) in identifying content relating to adolescent confidentiality in such notes.

Methods

A random sample of 300 notes were selected from outpatient adolescent encounters performed at an academic pediatric health system. The notes were manually reviewed by a group of pediatricians to identify confidential content. A proprietary LLM, GPT-3.5 (OpenAI, San Francisco, CA), was prompted using a “few-shot learning” method to identify the confidential content within these notes. Two primary outcomes were considered: (1) the ability of the LLM to determine whether a progress note contains confidential content and (2) its ability to identify the specific confidential content within the note.

Results

Of the 300 sampled notes, 91 (30%) contained confidential content. The LLM was able to classify whether an adolescent progress note contained confidential content with a sensitivity of 97% (88/91), specificity of 18% (37/209), and positive predictive value of 34% (88/260). Only 40 of the 306 manually reviewed excerpts (13%) were accurately derived from the original note (ie. contained no hallucinations), 22 (7%) of which represented the note’s actual confidential content.

Discussion

A proprietary LLM achieved a high sensitivity in classifying whether adolescent encounter notes contain confidential content. However, its low specificity and poor positive predictive value limit its usefulness. Furthermore, an alarmingly high fraction of confidential note excerpts proposed by the model contained hallucinations. In its current form, GPT-3.5 cannot reliably identify confidential content in free-text adolescent progress notes.
Immature platelet dynamics are associated with clinical outcomes after major trauma
Authors: Schofield Henry , Rossetto Andrea , Armstrong Paul C , Allan Harriet E , Warner Timothy D , Brohi Karim , Vulliamy Paul
Published: August 2023

Background

Major trauma results in dramatic changes in platelet behavior. Newly-formed platelets are more reactive than older platelets, but their contributions to hemostasis and thrombosis after severe injury have not been previously evaluated.

Objectives

To determine the relationship between immature platelet metrics and circulating drivers of platelet production with clinical outcomes after major injury.

Methods

Prospective observational cohort study of adult trauma patients. Platelet counts and the immature platelet fraction (IPF) were measured at admission, 24 hours, 72 hours and 7 days post-injury. Plasma proteins involved in thrombopoiesis were quantified at admission. The primary outcome was in-hospital mortality; secondary outcomes were venous thromboembolic events (VTE) and organ failure.

Results

At two hours post-injury, immature platelet counts (IPC) were significantly lower in non-survivors (n=40) compared to survivors (n=236; 7.3x109/L vs 10.6x109/L, p=0.009). Similarly, impaired platelet function on thromboelastometry was associated with a lower admission IPC (9.1x109/L vs 11.9x109/L, p<0.001). However, at later timepoints we observed a significantly higher IPF and IPC in patients who developed VTE (21.0x109/L vs 11.1x109/L, p=0.02) and prolonged organ dysfunction (20.9 x109/L vs 11x109/L, p=0.003) compared to those who did not develop complications. Plasma levels of thrombopoietin at admission were significantly lower in in non-survivors (p<0.001), in patients with organ failure (p<0.001) and in those who developed VTE (p=0.04).

Conclusions

Immature platelet depletion in the acute phase after major injury is associated with increased morality, whereas excessive immature platelet release at later timepoints may predispose to thrombosis and organ dysfunction.

ESSENTIALS

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Newly-formed platelets are highly active, but their role in outcomes after major trauma is unknown

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Immature platelets were quantified in a cohort of 276 severely injured patients

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Early depletion of immature platelets is associated with increased mortality and coagulopathy

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Raised immature platelet at later timepoints increases the risk of thrombosis and organ failure
Serologic biomarkers and scoring systems for hepatic fibrosis in obese children with nonalcoholic steatohepatitis
Authors: Joo Jung Yeon , Yoo In Hyuk , Yang Hye Ran
Published: August 2023

Objectives

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing with the increasing prevalence of childhood obesity. Although NASH has a high risk of progression to liver fibrosis and cirrhosis, few studies have reported on noninvasive markers for predicting hepatic fibrosis in children. This study aimed to evaluate and compare the diagnostic accuracy of serologic biomarkers and scoring systems for hepatic fibrosis in obese children with NASH.

Methods

A total of 99 children were diagnosed with NASH based on liver biopsy findings, and divided into two groups according to the degree of liver fibrosis: mild (stage 0-1) or advanced (stage 2-4). Clinical and laboratory parameters and serum levels of hyaluronic acid and type IV collagen were measured. Moreover, the aspartate aminotransferase/platelet ratio index (APRI) and fibrosis-4 (FIB-4) score were calculated.

Results

Among the noninvasive markers, only serum type IV collagen level and FIB-4 revealed significant differences between the two fibrosis groups. The area under the receiver operating curve of each biomarker and scoring system was 0.80 (95% confidence interval [CI]: 0.70-0.90) for type IV collagen at an optimal cutoff of 148 ng/mL (sensitivity 69.8%, specificity 84.6%), followed by 0.69 (95% CI: 0.57-0.83) for APRI, 0.68 (95% CI: 0.56-0.80) for FIB-4, and 0.65 (95% CI: 0.53-0.77) for hyaluronic acid.

Conclusions

Type IV collagen as a single noninvasive serologic biomarker for hepatic fibrosis and FIB-4 as a hepatic fibrosis score are beneficial in predicting advanced hepatic fibrosis, and in determining proper diagnosis and treatment strategies before fibrosis progresses in obese children with NASH.

Why was this study done?

With the increase of the obese population of children and adolescents, the prevalence of nonalcoholic fatty liver disease is increasing. Non-alcoholic steatohepatitis has a high risk of developing liver fibrosis and cirrhosis. However, a single non-invasive serological marker that can predict fatty liver fibrosis in children and adolescents has not been clearly presented.

What did the researchers do and find?

We evaluate diagnostic accuracy of serological biomarkers and scoring systems for hepatic fibrosis in obese children with NASH.

What do these findings mean?

Type IV collagen is a useful single noninvasive serological biomarker for hepatic fibrosis. Therefore, it is useful in making appropriate diagnosis and treatment decisions before fibrosis progresses in obese children with non-alcoholic steatohepatitis.
A Comparative Analysis of In-Hospital Outcomes and Care Cost Between Surgical and Transcatheter Valve Replacement for Aortic Stenosis: Insights From the U.S Nationwide Inpatient Sample Database
Authors: Uwumiro Fidelis E. , Bojerenu Michael , Ogbodo Charles T. , Okpujie Victory O. , Nwabueze Cherechi O. , Otabor Emmanuel O. , Shielu Muhammed L. , Nwume Chuka G. , Oshodi Omolade J. , Alemenzohu Hillary , Abesin Olawale O.
Published: August 2023

Background/objectives

Transcatheter aortic valve replacement (TAVR) has emerged as a preferred alternative to surgical aortic valve replacement (SAVR) for symptomatic aortic stenosis. This study aimed to compare the clinical outcomes and care costs of TAVR and SAVR to medical management using five years of inpatient data.

Methods

Adult hospitalizations with a principal diagnosis of aortic stenosis were analyzed from the Nationwide Inpatient Sample database (2016-2020). Diagnosis and procedure variables, as well as confounders and comorbidities, were identified using the International Classification of Diseases (ICD-10) codes. Multivariable regression models were utilized to assess mortality odds, length of stay (LOS), periprocedural complications, and care costs.

Results

Among the 364,515 admissions for aortic stenosis analyzed, the mean age was 76 ± 0.5 years, with a majority of male patients (57.8%) and White Americans comprising 85.5% of the population. SAVR was performed in 29.3% of cases, and TAVR in 50.8%. TAVR demonstrated significantly lower in-hospital mortality compared to SAVR (aOR: 0.463; 95% CI: 0.366-0.587; P < 0.001), whereas SAVR did not show a significant difference (aOR: 0.786; 95% CI: 0.601-1.029; P = 0.079). TAVR also resulted in a significantly shorter mean LOS compared to SAVR (adjusted mean LOS: 2.37; 95% CI: 2.12-2.63; P < 0.001 vs. 6.25; 95% CI: 6.00-6.50; P < 0.001). While TAVR patients had a lower likelihood of complications, they incurred higher hospital costs.

Conclusion

TAVR demonstrated significantly lower odds of in-hospital mortality and shorter length of stay compared to medical management or SAVR. However, TAVR patients incurred higher hospital costs despite a lower likelihood of complications.
Decoding EEG for optimizing naturalistic memory
Authors: Rudoler J.H. , Bruska J.P. , Chang W. , Dougherty M.R. , Katerman B.S. , Halpern D.J. , Diamond N.B. , Kahana M.J.
Published: August 2023

Background

Spectral features of human electroencephalographic (EEG) recordings during learning predict subsequent recall variability.

New method

Capitalizing on these fluctuating neural features, we develop a non-invasive closed-loop (NICL) system for real-time optimization of human learning. Participants play a virtual navigation and memory game; recording multi-session data across days allowed us to build participant-specific classification models of recall success. In subsequent closed-loop sessions, our platform manipulated the timing of memory encoding, selectively presenting items during periods of predicted good or poor memory function based on EEG features decoded in real time.

Results

We observed greater memory modulation (difference between recall rates when presenting items during predicted good vs. poor learning periods) for participants with higher out-of-sample classification accuracy.

Comparison with Existing Methods

This study demonstrates greater-than-chance memory decoding from EEG recordings in a naturalistic virtual navigation task with greater real-world validity than basic word-list recall paradigms. Here we modulate memory by timing stimulus presentation based on noninvasive scalp EEG recordings, whereas prior closed-loop studies for memory improvement involved intracranial recordings and direct electrical stimulation. Other noninvasive studies have investigated the use of neurofeedback or remedial study for memory improvement.

Conclusions

These findings present a proof-of-concept for using non-invasive closed-loop technology to optimize human learning and memory through principled stimulus timing, but only in those participants for whom classifiers reliably predict out-of-sample memory function.
Decreased accuracy of forensic DNA mixture analysis for groups with lower genetic diversity
Authors: Flores Maria , Ly Cara , Ho Evan , Ceberio Niquo , Felix Kamillah , Thorner Hannah Mariko , Guardado Miguel , Paunovich Matt , Godek Chris , Kalaydjian Carina , Rohlfs Rori
Published: August 2023

Forensic investigation of DNA samples from multiple contributors has become commonplace. These complex analyses use statistical frameworks accounting for multiple levels of uncertainty in allelic contributions from different individuals, particularly for samples containing few molecules of DNA. These methods have been thoroughly tested along some axes of variation, but less attention has been paid to accuracy across human genetic variation. Here, we quantify the accuracy of DNA mixture analysis over 244 human groups. We find higher false inclusion rates for mixtures with more contributors, and for groups with lower genetic diversity. Even for two-contributor mixtures where one contributor is known and the reference group is correctly specified, false inclusion rates are 1e-5 or higher for 56 out of 244 groups. This means that, depending on multiple testing, some false inclusions may be expected. These false positives could be lessened with more selective and conservative use of DNA mixture analysis.

HIGHLIGHTS

Groups with lower genetic diversity have higher mixture analysis false positive rates.

Analyses with mis-specified references have somewhat higher false positive rates.

Mixture analysis accuracy decreases with more mixture contributors.

GRAPHICAL ABSTRACT
Uncovering the molecular signatures of russet skin formation in Niagara grapevine (Vitis vinifera x Vitis labrusca)
Authors: Niederauer Guilherme Francio , de Oliveira Geovani Luciano , Aono Alexandre Hild , Graciano Diego da Silva , Carmello-Guerreiro Sandra Maria , Moura Mara Fernandes , de Souza Anete Pereira
Published: August 2023

Grape breeding programs are mostly focused on developing new varieties with high production volume, sugar contents, and phenolic compound diversity combined with resistance and tolerance to the main pathogens under culture and adverse environmental conditions. The ‘Niagara’ variety (Vitis labruscaxVitis vinifera) is one of the most widely produced and commercialized table grapes in Brazil. In this work, we selected three Niagara somatic variants with contrasting berry phenotypes and performed morphological and transcriptomic analyses of their berries. Histological sections of the berries were also performed to understand anatomical and chemical composition differences of the berry skin between the genotypes. An RNA-Seq pipeline was implemented, followed by global coexpression network modeling. ‘Niagara Steck’, an intensified russet mutant with the most extreme phenotype, showed the largest difference in expression and showed selection of coexpressed network modules involved in the development of its russet-like characteristics. Enrichment analysis of differently expressed genes and hub network modules revealed differences in transcription regulation, auxin signaling and cell wall and plasmatic membrane biogenesis. Cutin- and suberin-related genes were also differently expressed, supporting the anatomical differences observed with microscopy.
Using a multiscale lidar approach to determine variation in canopy structure from African forest elephant trails
Authors: Keany Jenna M. , Burns Patrick , Abraham Andrew J. , Jantz Patrick , Makaga Loic , Saatchi Sassan , Maisels Fiona , Abernethy Katharine , Doughty Christopher
Published: August 2023

Recently classified as a unique species by the IUCN, African forest elephants (Loxodonta cyclotis) are critically endangered due to severe poaching. With limited knowledge about their ecological role due to the dense tropical forests they inhabit in central Africa, it is unclear how the Afrotropics would change if forest elephants were to go extinct. Although their role as seed dispersers is well known, they may also drive large-scale processes that determine forest structure, through the creation of elephant trails and browsing the understory and allowing larger, carbon-dense trees to succeed. Multiple scales of lidar were collected by NASA in Lopé National Park, Gabon from 2015-2022. Utilizing two airborne lidar datasets and one spaceborne lidar in an African forest elephant stronghold, detailed canopy structural information was used in conjunction with elephant trail data to determine how forest structure varies on and off trails. Forest above elephant trails displayed different structural characteristics than forested areas off trails, with lower canopy height, canopy cover, and different vertical distribution of plant mass. Less plant area density was found on trails at 1 m in height, while more vegetation was found at 12 m, compared to off trail locations. Trails with previous logging history had lower plant area in the top of the canopy.
Tryptophan wasting and disease activity as a systems phenomenon in inflammation – an analysis across 13 chronic inflammatory diseases
Authors: Harris Danielle MM , Szymczak Silke , Schuchardt Sven , Labrenz Johannes , Tran Florian , Welz Lina , Graßhoff Hanna , Zirpel Henner , Sümbül Melike , Oumari Mhmd , Engelbogen Nils , Junker Ralf , Conrad Claudio , Thaçi Diamant , Frey Norbert , Franke Andre , Weidinger Stephan , Rosenstiel Philip , Hoyer Bimba , Waschina Silvio , Schreiber Stefan , Aden Konrad
Published: August 2023

Chronic inflammatory diseases (CID) are systems disorders affecting various organs including the intestine, joint and skin. The essential amino acid tryptophan (Trp) is not only used for protein synthesis but can also be catabolized to various bioactive derivatives that are important for cellular energy metabolism and immune regulation. Increased Trp catabolism via the kynurenine pathway is seen across individual CID entities1–5. Here, we assessed the levels of Trp and tryptophan derivatives across 13 CID to investigate the extent and nature of Trp wasting as a systems phenomenon in CID. We found reduced serum Trp levels across the majority of CID and a prevailing negative relationship between Trp and systemic inflammatory marker C-reactive protein (CRP). Increases in the kynurenine-to-Trp ratio (Kyn:Trp) indicate that the kynurenine pathway is a major route for CID-related Trp wasting. However, the extent of Trp depletion and its relationship with disease activity varies by disease, indicating potential differences in Trp metabolism. In addition, we find that amino acid catabolism in chronic inflammation is specific to tryptophan wasting, whereas other proteinogenic amino acids are not affected. Hence, our results suggest that increased Trp catabolism is a common metabolic occurrence in CID that may directly affect systemic immunity.

Grant support

This work was supported by the DFG Cluster of Excellence 1261 “Precision medicine in chronic inflammation” (KA, SSchr, PR, BH, SWa), the BMBF (e:Med Juniorverbund “Try-IBD” 01ZX1915A and 01ZX2215, the e:Med Network iTREAT 01ZX2202A, and GUIDE-IBD 031L0188A), DFG RU5042 (PR, KA), and Innovative Medicines Initiative 2 Joint Undertakings (“Taxonomy, Treatments, Targets and Remission”, No. 831434, “ImmUniverse”, grant agreement No. 853995, “BIOMAP”, grant agreement No. 821511).
Glymphatic Inhibition Exacerbates Tau Propagation in an Alzheimer’s Disease Model
Authors: Lopes Douglas M , Wells Jack A , Ma Da , Wallis Lauren , Park Daniel , Llewellyn Sophie K , Ahmed Zeshan , Lythgoe Mark F , Harrison Ian F
Published: August 2023

Background

The aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins.

Methods

In this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brainin vivoprior to brain extraction for immunohistochemical characterisation.

Results

Our findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus and cortex following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the aforementioned alterations were attenuated.

Conclusions

These results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.
Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion
Authors: Kudo Rei , Safonov Anton , Silva Edaise da , Li Qing , Shao Hong , Will Marie , Fushimi Atsushi , Nakshatri Harikrishna , Reis-Filho Jorge S. , Goel Shom , Koff Andrew , Weigelt Britta , Khan Qamar J. , Razavi Pedram , Chandarlapaty Sarat
Published: August 2023

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a clinically-annotated cohort of patients with metastatic HR+ breast cancer, we identifiedTP53loss (28.8%) andMDM2amplification (6.7%) to be associated with lack of long-term disease control. Human breast cancer models revealed that p53 loss did not affect CDK4/6 activity or G1-blockade, but instead promoted drug-insensitive p130 phosphorylation by CDK2. Persistence of phospho-p130 prevented DREAM complex assembly, enabling cell cycle reentry and tumor progression. Inhibitors of CDK2 could overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically-diverse HR+ breast cancers.
Stromal signals dominate gene expression signature scores that aim to describe cancer-intrinsic stemness or mesenchymality characteristics
Authors: Kreis Julian , Aybey Bogac , Geist Felix , Brors Benedikt , Staub Eike
Published: August 2023

Purpose

Epithelial-to-mesenchymal transition (EMT) in cancer cells confers migratory ability, a crucial aspect of tumor metastasis that frequently leads to death. In multiple studies, authors proposed gene expression signatures for EMT, stemness, and mesenchymality (EMT-related) characteristics of tumors based on bulk tumor expression profiling. However, recent studies have suggested that non-cancerous cells in the tumor micro- or macroenvironment heavily influence individual signature profiles.

Experimental Design

We analyzed scores of 11 published and frequently referenced gene expression signatures in bulk, single cell, and pseudo bulk expression data across multiple cancer types.

Results

Our study strengthens and extends the influence of non-cancerous cells on signatures that were proposed to describe EMT-related (EMT, mesenchymal, or stemness) characteristics in various cancer types. The cell type composition, especially the amount of tumor cells, of a tumor sample frequently dominates EMT-related signature scores. Additionally, our analyses revealed that stromal cells, most often fibroblasts, are the main drivers of the EMT-related signature scores.

Conclusions

We call attention to the risk of false conclusions about tumor properties when interpreting EMT-related signatures, especially in a clinical setting: high patient scores of EMT-related signatures or calls of “stemness subtypes” often result from low tumor cell content in tumor biopsies rather than cancer cell-specific stemness or mesenchymality/EMT characteristics.
A low-cost and open-source imaging platform reveals spatiotemporal insight intoArabidopsisleaf elongation and movement
Authors: Oskam Lisa , Snoek Basten L. , Pantazopoulou Chrysoula K. , van Veen Hans , Matton Sanne E. A. , Dijkhuizen Rens , Pierik Ronald
Published: August 2023

Plant organs move throughout the diurnal cycle, changing leaf and petiole positions to balance light capture, leaf temperature and water loss under dynamic environmental conditions. Upward movement of the petiole, called hyponasty, is one of several traits of the shade avoidance syndrome (SAS). SAS traits are elicited upon perception of vegetation shade signals such as far-red light (FR) and improve light capture in dense vegetation. Monitoring plant movement at a high temporal resolution allows studying functionality, as well as molecular regulation of hyponasty. However, high temporal resolution imaging solutions are often very expensive, making this unavailable to many researchers. Here, we present a modular and low-cost imaging set-up, based on small Raspberry Pi computers, that can track leaf movements and elongation growth with high temporal resolution. We also developed an open-source, semi-automated image analysis pipeline. Using this setup we followed responses to FR enrichment, light intensity and their interactions. Tracking both elongation and angle of petiole, lamina and entire leaf revealed insight into R:FR sensitivities of leaf growth and movement dynamics, and its interactions with background light intensity. We also identified spatial separation in hyponastic response regulation for the petiole and the lamina of the leaf, depending on the light conditions.
Constructing networks for comparison of collagen types
Authors: Wesp Valentin , Scholz Lukas , Ziermann-Canabarro Janine M. , Schuster Stefan , Stark Heiko
Published: August 2023

Collagens are structural proteins that are predominantly found in the extracellular matrix of multicellular animals, where they are mainly responsible for the stability and structural integrity of various tissues. All collagens contain polypeptide strands (ɑ-chains). There are several types of collagens, some of which differ significantly in form, function, and tissue specificity. Because of their importance in clinical research, they are grouped into subdivisions, the so-called collagen families, and their sequences are often analysed. However, problems arise with highly homologous sequence segments. To increase the accuracy of collagen classification and prediction of their functions, the structure of these collagens and their expression in different tissues could result in a better focus on sequence segments of interest. Here, we analyse collagen families with different levels of conservation. As a result, clusters with high interconnectivity can be found, such as the fibrillar collagens, the COL4 network-forming collagens, and the COL9 FACITs. Furthermore, a large cluster between network-forming, FACIT, and COL28a1 ɑ-chains is formed with COL6a3 as a major hub node. The formation of clusters also signifies, why it is important to always analyse the ɑ-chains and why structural changes can have a wide range of effects on the body.
Integration of graph neural networks and genome-scale metabolic models for predicting gene essentiality
Authors: Hasibi Ramin , Michoel Tom , Oyarzún Diego A.
Published: August 2023

Genome-scale metabolic models are powerful tools for understanding cellular physiology. Flux balance analysis (FBA), in particular, is a popular optimization approach for predicting metabolic phenotypes under genetic and environmental perturbations. In model microbes such asEscherichia coli, FBA has been successful at predicting essential genes, i.e. those genes that impair survival when deleted. A central assumption in this approach, however, is that both wild type and deletion strains optimize the same fitness objective. While the optimality assumption may hold for the wild type metabolic network, deletion strains are not subject to the same evolutionary pressures and knock-out mutants may steer their metabolism to meet other objectives for survival. Here, we present FlowGAT, a hybrid FBA-machine learning strategy for predicting essentiality directly from wild type metabolic phenotypes. The approach is based on graph-structured representation of metabolic fluxes predicted by FBA, where nodes correspond to enzymatic reactions and edges quantify the propagation of metabolite mass flow between a reaction and its neighbours. We integrate this information into a graph neural network that can be trained on knock-out fitness assay data. Comparisons across different model architectures reveal that FlowGAT predictions forE. coliare close to those of FBA for several growth conditions. This suggests that gene essentiality can be accurately predicted by exploiting the network structure of metabolism, without additional assumptions beyond optimality of the wild type. Our approach demonstrates the benefits of combining the mechanistic insights afforded by genome-scale models with the ability of deep learning models to extract patterns from complex data.
Infection with the chytrid fungus (Batrachochytrium dendrobatidis) may distort sex ratio via sex reversal but not sex-dependent mortality in a common Eurasian amphibian
Authors: Ujszegi János , Ujhegyi Nikolett , Balogh Emese , Mikó Zsanett , Kásler Andrea , Hettyey Attila , Bókony Veronika
Published: August 2023

One of the major factors driving the currently ongoing biodiversity crisis is the anthropogenic spread of infectious diseases. Diseases can have conspicuous consequences, such as mass mortality events, but may also exert covert but similarly severe effects, such as sex ratio distortion via sex-biased mortality or sex reversal. Chytridiomycosis, caused by the fungal pathogenBatrachochytrium dendrobatidis(Bd) is among the most important threats to amphibian biodiversity. Yet, whether Bd infection can skew sex ratios in amphibians is currently unknown, although such a hidden effect may cause the already dwindling amphibian populations to collapse. To investigate this possibility, we collected common toad (Bufo bufo) tadpoles from a natural habitat in Hungary, and continuously treated them until metamorphosis with sterile Bd culture medium (control), or a liquid culture of a Hungarian or a Spanish Bd isolate. Three months after metamorphosis we dissected the individuals and diagnosed their phenotypic and genetic sex. Bd prevalence was high in animals that died during the experiment but was almost zero at sexing. Survival was generally low in the control group, but it was further lowered by the Bd treatments. We did not observe sex-dependent mortality in either treatment. However, treatment with the Spanish Bd isolate significantly increased the frequency of sex reversal: 3 out of 9 genetic females developed into phenotypic males. Based on our results, Bd infection may have the potential to affect sex ratio in common toads through female-to-male sex reversal, but future research is needed to ascertain the generality of these findings.
Uncertainty propagation in matrix population models: gaps, importance, and guidelines
Authors: Simmonds Emily G. , Jones Owen R.
Published: August 2023

Matrix population models (MPMs), which describe the demographic behaviour of a population based on age or stage through discrete time, are popular in ecology, evolutionary biology, and conservation biology. MPMs provide a tool for guiding management decisions and can give insight into life history trade-offs, patterns of senescence, transient dynamics, and population trajectories. These models are parameterised with estimates of vital rates (e.g. survival and reproduction) and can have multiple layers of underlying statistical analyses, all of which introduce uncertainty. For accurate and transparent results, this uncertainty should be propagated through to quantities derived from the MPMs. However, full propagation is not always achieved, leading to omitted uncertainty, and negative consequences for the reliability of inferences drawn.

We summarised the state-of-the-art regarding vital rate uncertainty reporting and propagation, by reviewing papers using MPMs from 2010-2019. We then used reported uncertainties as the basis for a simulation study to explore the impact of uncertainty omission on inferences drawn from the analysis of MPMs. We simulated four scenarios of vital rate propagation and evaluated their impact on population growth rate estimates.

Although around 78% of MPM papers report some kind of uncertainty in their findings, only half of those report uncertainty in all aspects. Additionally, only 31% of papers fully propagate uncertainty through to derived quantities. Our simulations demonstrate that, even under a median uncertainty level, incomplete propagation introduces bias. Omitting uncertainty may substantially alter conclusions, particularly for results showing small changes in population size. Biased conclusions were most common when uncertainty in the most influential vital rates for population growth were omitted.

We suggest comprehensive guidelines for reporting and propagating uncertainty in MPMs. Standardising methods and reporting will increase the reliability of MPMs and enhance the comparability of different models. These guidelines will improve the accuracy, transparency, and reliability of population projections, increasing our confidence in results that can inform conservation efforts, ultimately contributing to biodiversity preservation.
Loss of NMDA receptor function during development results in decreased KCC2 expression and increased neurons in the zebrafish forebrain
Authors: Napoli Amalia J. , Laderwager Stephanie , Zoodsma Josiah D. , Biju Bismi , Mucollari Olgerta , Schubel Sarah K. , Aprea Christieann , Sayed Aaliya , Morgan Kiele , Napoli Annelysia , Flanagan Stephanie , Wollmuth Lonnie P. , Sirotkin Howard I.
Published: August 2023

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1-/-) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors. Focusing on the forebrain, we find that these fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis, but which extends to all forebrain regions during postembryonic neurogenesis. This enhanced neuron population does not arise directly from increased numbers or mitotic activity of radial glia cells, the principal neural stem cells. Rather, it stems from a lack of timely maturation of transit-amplifying neuroblasts into post-mitotic neurons, as indicated by a decrease in expression of the ontogenetically-expressed chloride transporter, KCC2. Pharmacological blockade with MK-801 recapitulates thegrin1-/-supernumerary neuron phenotype, indicating a requirement for ionotropic signaling. Thus, NMDA receptors are required for suppression of indirect, transit amplifying cell-driven neurogenesis by promoting maturational termination of mitosis. Loss of suppression results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in pathogenesis of neurodevelopmental disorders caused by NMDA receptor dysfunction.
Estimating the number of breeders from helminth larvae with genomic data
Authors: Dennis Tristan. P. W. , Sands William , Opoku Millicent , Debrah Alex , Batsa Linda , Pfarr Kenneth , Klarmann-Schulz Ute , Hoerauf Achim , Specht Sabine , Scandale Ivan , Ranford-Cartwright Lisa C. , Lamberton Poppy H. L.
Published: August 2023

Effective control of helminth infections requires the application of mathematical models to inform control efforts and policy, the development of product profiles for new drugs, and the monitoring of existing drugs for resistance. Key to the success of these approaches is accurately estimating the number of worms within a host, as well as distinguishing, in drug efficacy trials and monitoring, between adults surviving treatment and adults who have reinfected a host following drug treatment. In practice, observing adult worms is often extremely challenging in a patient, as many adult helminths are embedded deep in host tissues. Genetic approaches to infer kinship between larvae or eggs offer a solution to establish adult worm burdens, and to distinguish between treatment failure or treatment success followed by reinfection. Here, we use low-coverage whole-genome, and mitochondrial sequencing, ofOnchocerca volvuluslarvae to estimate the number of adults contributing to pools of offspring of known and unknown parentage. lcWGS reconstructs full-sibling relationships, resolving the number of unique adult worms contributing to a pool of offspring. Mitochondrial genotyping reconstructs maternal sib-ship, thus estimating the minimum number of adult females within a patient. Further development will improve these techniques for evaluating adult worm burden and trial outcome.
Praziquantel activates a native cation current inSchistosoma mansoni
Authors: Chulkov Evgeny G. , Rohr Claudia M. , Marchant Jonathan S.
Published: August 2023

Praziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms – rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target mediating these effects has been intimated as a Ca2+-permeable ion channel, but native currents evoked by PZQ have not been reported in any schistosome cell type. The properties of the endogenous PZQ activated conductance therefore remain unknown. Here, invasive electrophysiology was used to probe for responses to PZQ from different locales in a living schistosome worm. No direct response was seen in tegument-derived vesicles, or from the sub-tegumental muscle layer despite the presence of voltage-operated currents. However, PZQ rapidly triggered a sustained, non-selective cation current in recordings from neuronal tissue, targeting both the anterior ganglion and the main longitudinal nerve cord. The biophysical signature of this PZQ-evoked current resolved at single channel resolution matched that of a transient receptor potential ion channel named TRPMPZQ, recently proposed as the molecular target of PZQ. The endogenous PZQ-evoked current was also inhibited by a validated TRPMPZQantagonist. PZQ therefore is a neuroactive anthelmintic, effecting a robust, depolarization through ion channels with the characteristics of TRPMPZQ.

Key Findings / Scope Statement

Responses to the anthelmintic drug, praziquantel (PZQ), were examined using invasive electrophysiology in a living schistosome worm.

PZQ evoked a cation current in recordings from neuronal tissue

The biophysical and pharmacological characteristics of the native PZQ current matched the properties of TRPMPZQ.
Reengineering of a flavin-binding fluorescent protein using ProteinMPNN
Authors: Nikolaev Andrey , Kuzmin Alexander , Markeeva Elena , Kuznetsova Elizaveta , Semenov Oleg , Anuchina Arina , Remeeva Alina , Gushchin Ivan
Published: August 2023

Recent advances in machine learning techniques have led to development of a number of protein design and engineering approaches. One of them, ProteinMPNN, predicts an amino acid sequence that would fold and match user-defined backbone structure. In this short report, we test whether ProteinMPNN can be used to reengineer a flavin-binding fluorescent protein, CagFbFP. We fixed the native backbone conformation and the identity of 20 amino acids interacting with the chromophore (flavin mononucleotide, FMN), while letting ProteinMPNN predict the rest of the sequence. The software package suggested replacing 36-48 out of the remaining 86 amino acids. The three designs that we tested experimentally displayed different expression levels, yet all were able to bind FMN and displayed fluorescence, thermal stability and other properties similar to those of CagFbFP. Our results demonstrate that ProteinMPNN can be used to generate diverging unnatural variants of fluorescent proteins, and, more generally, to reengineer proteins without losing their ligand-binding capabilities.
Border-forming wound repair astrocytes
Authors: O’Shea Timothy M. , Ao Yan , Wang Shinong , Ren Yilong , Cheng Amy , Kawaguchi Riki , Swarup Vivek , Sofroniew Michael V.
Published: August 2023

Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes. Fundamental features of these cells are poorly understood. Here, we show that 90% of border-forming astrocytes derive from proliferating Aldh1l1-expressing local astrocytes, and 10% from Pdgfra-expressing oligodendrocyte progenitors in mice. Temporal transcriptome analysis, snRNAseq and immunohistochemistry showed that after CNS injury, local mature astrocytes dedifferentiated, proliferated, and became transcriptionally reprogrammed to permanently altered new functional states, with persisting downregulation of molecules associated with astrocyte-neuron interactions, and upregulation of molecules associated with wound healing, microbial defense, and interactions with stromal and immune cells. Our findings show that at CNS injury sites, local mature astrocytes proliferate and adopt canonical features of essential wound repair cells that persist in adaptive states and are the predominant source of neuroprotective borders that re-establish CNS integrity by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.