bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison Between the Veillon and the Symons–Fanning CT Classification Systems for Otosclerosis
Authors: Pinto João Viana , Almeida Ana Isabel , Andrade António , Vales Fernando , Moura Carla Pinto , Marques Pedro
Published: September 2024

Objective

To analyze the correlation between outcomes of stapes surgery and preoperative and postoperative audiometric results with different radiological staging classifications such as the Veillon classification (VC) and the Symons–Fanning classification (SFC).

Study Design

Retrospective observational study.

Setting

One tertiary hospital center.

Patients

Adult patients submitted to stapes surgery due to otosclerosis from January 2017 to December 2022.

Intervention

Evaluation of different radiological classifications such as the VC and SFC.

Main Outcome Measures

Preoperative and postoperative pure-tone audiometric data, outcomes of stapes surgery success (closure of the ABG, rates of AC threshold less than or equal to 30 dB), and postoperative sensorineural hearing loss.

Results

A total of 87 patients and 97 operated ears were included. The SFC was associated with preoperative BC (p = 0.041) and AC (p = 0.018) and postoperative BC (p = 0.026) with an increase in thresholds with higher radiological stages. The VC was associated with postoperative AC (p = 0.045) with an increase in AC thresholds with increasing radiological stages. Lastly, both the VC (p = 0.032) and the SFC (p = 0.023) were associated with a decrease in rates of postoperative AC thresholds ≤30 dB with higher radiological stages.

Conclusions

The SFC seems to be more useful to predict preoperative AC and BC and postoperative BC. On the contrary, the VC was more useful to predict postoperative AC. Both scales were similarly associated with the rate of AC thresholds ≤30 dB.
When to Start Computer-Based Auditory Training After Cochlear Implantation: Effects on Quality of Life and Speech Recognition
Authors: Dornhoffer James R. , Shannon Christian , Hernandez-Herrara Gabriel A. , Schvartz-Leyzac Kara C. , Dubno Judy R. , McRackan Theodore R.
Published: September 2024

Objective

Computer-based auditory training (CBAT) has been shown to improve outcomes in adult cochlear implant (CI) users. This study evaluates in new CI users whether starting CBAT within 3 months of activation or later impacts CI outcomes.

Study Design

Prospective natural experiment.

Setting

Tertiary academic medical center.

Patients

Sixty-five new adult CI users.

Interventions

CBAT use over the first-year postactivation.

Main Outcome Measures

Speech recognition scores and CIQOL-35 Profile score improvements between CI recipients who started CBAT resources early (<3 mo) and late (3–12 mo) postactivation.

Results

A total of 43 CI recipients started using CBAT within 3 months postactivation (early) and 22 after 3 months (late). Patients who used CBAT within 3 months postactivation showed significantly greater improvement in consonant-nucleus-consonant words (CNCw) (48.3 ± 24.2% vs 27.8 ± 24.9%; d = 0.84), AzBio Sentences in quiet (55.1 ± 28.0% vs 35.7 ± 36.5%; d = 0.62), and CIQOL-35 listening domain scores (18.2 ± 16.3 vs 6.9 ± 12.9, d = 0.73 [0.023, 1.43]), at 3 months postactivation, compared to those who had not yet initiated CBAT. However, by 12 months postactivation, after which all CI recipients had started CBAT, there were no differences observed between patients who started CBAT early or late in speech recognition scores (CNCw: d = 0.26 [−0.35, 0.88]; AzBio: d = 0.37 [−0.23, 0.97]) or in any CIQOL global or domain score (d-range = 0.014–0.47).

Conclusions

Auditory training with self-directed computer software (CBAT) may yield speech recognition and quality-of-life benefits for new adult CI recipients. While early users showed greater improvement in outcomes at 3 months postactivation than users who started later, both groups achieved similar benefits by 12 months postactivation.
Correlation between 18F-FDG PET/CT metabolic parameters and microvascular invasion before liver transplantation in patients with hepatocellular carcinoma
Authors: Wu Fan , Cao Guohong , Lu Jinlan , Ye Shengli , Tang Xin
Published: September 2024

Background

Microvascular infiltration (MVI) before liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is associated with postoperative tumor recurrence and survival. MVI is mainly assessed by pathological analysis of tissue samples, which is invasive and heterogeneous. PET/computed tomography (PET/CT) with 18F-labeled fluorodeoxyglucose (18F-FDG) as a tracer has been widely used in the examination of malignant tumors. This study investigated the association between 18F-FDG PET/CT metabolic parameters and MVI before LT in HCC patients.

Methods

About 124 HCC patients who had 18F-FDG PET/CT examination before LT were included. The patients’ clinicopathological features and 18F-FDG PET/CT metabolic parameters were recorded. Correlations between clinicopathological features, 18F-FDG PET/CT metabolic parameters, and MVI were analyzed. ROC curve was used to determine the optimal diagnostic cutoff value, area under the curve (AUC), sensitivity, and specificity for predictors of MVI.

Result

In total 72 (58.06%) patients were detected with MVI among the 124 HCC patients. Univariate analysis showed that tumor size (P = 0.001), T stage (P < 0.001), maximum standardized uptake value (SUVmax) (P < 0.001), minimum standardized uptake value (SUVmin) (P = 0.031), mean standardized uptake value (SUVmean) (P = 0.001), peak standardized uptake value (SUVpeak) (P = 0.001), tumor-to-liver ratio (SUVratio) (P = 0.010), total lesion glycolysis (TLG) (P = 0.006), metabolic tumor volume (MTV) (P = 0.011) and MVI were significantly different. Multivariate logistic regression showed that tumor size (P = 0.018), T stage (P = 0.017), TLG (P = 0.023), and MTV (P = 0.015) were independent predictors of MVI. In the receiver operating characteristic curve, TLG predicted MVI with an AUC value of 0.645. MTV predicted MVI with an AUC value of 0.635. Patients with tumor size ≥5 cm, T3-4, TLG > 400.67, and MTV > 80.58 had a higher incidence of MVI.

Conclusion

18F-FDG PET/CT metabolic parameters correlate with MVI and may be used as a noninvasive technique to predict MVI before LT in HCC patients.
The Diagnostic Performance of Large Language Models and General Radiologists in Thoracic Radiology Cases
Authors: Gunes Yasin Celal , Cesur Turay
Published: September 2024

Purpose:

To investigate and compare the diagnostic performance of 10 different large language models (LLMs) and 2 board-certified general radiologists in thoracic radiology cases published by The Society of Thoracic Radiology.

Materials and Methods:

We collected publicly available 124 “Case of the Month” from the Society of Thoracic Radiology website between March 2012 and December 2023. Medical history and imaging findings were input into LLMs for diagnosis and differential diagnosis, while radiologists independently visually provided their assessments. Cases were categorized anatomically (parenchyma, airways, mediastinum-pleura-chest wall, and vascular) and further classified as specific or nonspecific for radiologic diagnosis. Diagnostic accuracy and differential diagnosis scores (DDxScore) were analyzed using the χ2, Kruskal-Wallis, Wilcoxon, McNemar, and Mann-WhitneyUtests.

Results:

Among the 124 cases, Claude 3 Opus showed the highest diagnostic accuracy (70.29%), followed by ChatGPT 4/Google Gemini 1.5 Pro (59.75%), Meta Llama 3 70b (57.3%), ChatGPT 3.5 (53.2%), outperforming radiologists (52.4% and 41.1%) and other LLMs (P<0.05). Claude 3 Opus DDxScore was significantly better than other LLMs and radiologists, except ChatGPT 3.5 (P<0.05). All LLMs and radiologists showed greater accuracy in specific cases (P<0.05), with no DDxScore difference for Perplexity and Google Bard based on specificity (P>0.05). There were no significant differences between LLMs and radiologists in the diagnostic accuracy of anatomic subgroups (P>0.05), except for Meta Llama 3 70b in the vascular cases (P=0.040).

Conclusions:

Claude 3 Opus outperformed other LLMs and radiologists in text-based thoracic radiology cases. LLMs hold great promise for clinical decision systems under proper medical supervision.
A review on the pathogenesis theory of cancerous toxin from the viewpoint of system theory
Authors: Guo Tianhao , Zhou Hongguang , Chen Fangping , Gu Yutian , Li Liu , Cheng Haibo
Published: September 2024

In recent years, traditional Chinese medicine (TCM) has made great progress in the prevention and treatment of cancer. It has gradually revealed its characteristics and advantages in clinical practice, including alleviating clinical symptoms, prolonging survival time, decreasing the adverse effects of chemotherapy, and improving living quality. However, clinical TCM treatment of cancer lacks systematic theoretical guidance, because ancient TCM has not formed a recognized theoretical system of cognitive cancer, and there still are different opinions on the pathogenesis of cancer. Due to the complexity of cancer, the essence of cancer pathogenesis has not been described accurately by using common pathogenic factors, such as pathogenic wind, cold, dampness, summer heat, dryness, and fire. Ancient and modern TCM physicians have a similar understanding that the occurrence of cancer is related to toxin. In the 1990s, the thought of cancerous toxin was first proposed by Prof Zhou Zhongying, a TCM master based on more than 60 years of clinical practice, who used “pandemic Qi (Li-Qi) is a specific pathogenic factor of epidemic disease” in Wenyi Lun (Treatise on Pestilence) for references. The pathogenesis theory of cancerous toxin was gradually established under the guidance of the thought of cancerous toxin. It holds that the cancerous toxin, a special pathogenic factor of cancer, is the key pathogenesis of the occurrence of malignant tumors. According to the pathogenesis theory of cancerous toxin, the basic pathogenesis of malignant tumors is the accumulation of pathogenic factors and cancerous toxin, and the deficiency of the vital Qi (Zheng-Qi). Therefore, the treatment principle involves eliminating pathogenic factors, resolving cancerous toxin, and supporting the vital Qi. The anticancer detoxification methods and the classification of Chinese medicinal herbs with anticancer detoxification effects were put forward. System theory has much in common with the concepts in the theory system of TCM, such as the universal relation theory, asking for a concrete analysis of concrete conditions, the humanism thought, and so on. This article aims to describe, review, and analyze the pathogenesis theory of cancerous toxin based on system theory for clinical practices.
Comparison of thoracic epidural catheter and continuous peripheral infusion for management of traumatic rib fracture pain
Authors: Beyene Robel T. , Wallace Marshall W. , Statzer Nicholas , Hamblin Susan E. , Woo Edward , Nelson Scott D. , Allen Brian F.S. , McEvoy Matthew D. , Riffert Derek A. , Wesoloski Amber N. , Ye Fei , Irlmeier Rebecca , Fiorentino Michele , Dennis Bradley M.
Published: September 2024

BACKGROUND

Thoracic epidural catheters (TECs) are useful adjuncts to multimodal pain regimens in traumatic rib fractures. However, TEC placement is limited by contraindications, patient risk profile, and provider availability. Continuous peripheral infusion of ketamine and/or lidocaine is an alternative that has a modest risk profile and few contraindications. We hypothesized that patients with multiple traumatic rib fractures receiving TECs would have better pain control, in terms of daily morphine milligram equivalents (MMEs) and mean pain scores (MPSs) when compared with continuous peripheral infusions of ketamine and/or lidocaine.

METHODS

We retrospectively analyzed traumatic rib fracture admissions to a level 1 trauma center between January 2018 and December 2020. We evaluated two treatment groups: TEC only and continuous infusion only (drip only). A linear mixed-effects model evaluated the association of MME with treatment group. An interaction term of treatment group by time (days 1–7) was included to allow estimating potential time-dependent treatment effect on MME. A zero-inflated Poisson mixed-effects model evaluated the association of treatment with MPS. Both models adjusted for confounders.

RESULTS

A total of 1,647 patients were included. After multivariable analysis, a significant, time-varying dose-response relationship between treatment group and MME was found, indicating an opioid-sparing effect favoring the TEC-only group. The opioid-sparing benefit for TEC-only therapy was most prominent at day 3 (27.4 vs 36.5 MME) and day 4 (27.3 vs 36.2 MME) (p < 0.01). The drip-only group had 1.21 times greater MPS than patients with TEC only (p < 0.001).

CONCLUSION

Drip-only analgesia is associated with higher daily MME use and MPS, compared with TEC only. The maximal benefit of TEC therapy appears to be on days 3 and 4. Prospective, randomized comparison between groups is necessary to evaluate the magnitude of the treatment effect.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Real-time attending trauma surgeon assessment of direct-to-operating room trauma resuscitations: Results from a prospective observational study
Authors: Lee Heewon , Dilday Joshua , Johnson Amelia , Kuchler Andrea , Rott Michael , Cole Frederick , Barbosa Ronald , Long William , Martin Matthew J.
Published: September 2024

BACKGROUND

Direct-to-operating room (DOR) resuscitation expedites interventions for trauma patients. Perceived benefit from the surgeon's perspective is not well known. This study assesses the integration of a real-time surgeon assessment tool into a DOR protocol.

METHODS

Surgeon assessment tool results from a prospective study of DOR cases were analyzed. Analysis assessed patient factors and surgeon perception for appropriateness and benefit of DOR. Multivariate analysis identified independent factors associated with perceived DOR benefit.

RESULTS

A total of 104 trauma patients underwent DOR resuscitation; 84% were perceived as appropriate triage, and 48% as beneficial. Patients with Injury Severity Score of >15 (50% vs. 28%), systolic blood pressure of <90 mm Hg (24% vs. 9%), and severe abdominal injury (28% vs. 9%) had higher perceived DOR benefits (all p < 0.05). Patients deemed to benefit from DOR underwent more emergent interventions or truncal surgery (44% vs. 92%, p < 0.01). No difference in benefit was seen based on age, sex, Glasgow Coma Scale score of <9, or injury mechanism. Forty-four percent had perceived benefit from DOR resuscitation despite requiring imaging after initial evaluation. Patients with perceived benefit had a higher rate of unplanned return to the operating room (16% vs. 2%, p < 0.05), but no differences in complication rates, Glasgow Outcome Score, or mortality. Injury Severity Score of >15 was the only independently associated variable with a perceived benefit on surgeon assessment tool (odds ratio, 3.5; p < 0.05).

CONCLUSION

The majority of DOR resuscitations were deemed as appropriately triaged, and approximately half had a perceived benefit. Benefit was associated with higher injury severity and the need for urgent interventions but was not predicted by injury mechanism or other triage variables.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Nutrient starvation activates ECM remodeling gene enhancers associated with inflammatory bowel disease risk in fibroblasts
Authors: Secchia Stefano , Beilinson Vera , Chen Xiaoting , Yang Zi F. , Wayman Joseph A. , Dhaliwal Jasbir , Jurickova Ingrid , Angerman Elizabeth , Denson Lee A. , Miraldi Emily R. , Weirauch Matthew T. , Ikegami Kohta
Published: September 2024

Nutrient deprivation induces a reversible cell cycle arrest state termed quiescence, which often accompanies transcriptional silencing and chromatin compaction. Paradoxically, nutrient deprivation is associated with activated fibroblast states in pathological microenvironments in which fibroblasts drive extracellular matrix (ECM) remodeling to alter tissue environments. The relationship between nutrient deprivation and fibroblast activation remains unclear. Here, we report that serum deprivation extensively activates transcription of ECM remodeling genes in cultured fibroblasts, despite the induction of quiescence. Starvation-induced transcriptional activation accompanied large-scale histone acetylation of putative distal enhancers, but not promoters. The starvation-activated putative enhancers were enriched for non-coding genetic risk variants associated with inflammatory bowel disease (IBD), suggesting that the starvation-activated gene regulatory network may contribute to fibroblast activation in IBD. Indeed, the starvation-activated genePLAU, encoding uPA serine protease for plasminogen and ECM, was upregulated in inflammatory fibroblasts in the intestines of IBD patients. Furthermore, the starvation-activated putative enhancer atPLAU, which harbors an IBD risk variant, gained chromatin accessibility in IBD patient fibroblasts. This study implicates nutrient deprivation in transcriptional activation of ECM remodeling genes in fibroblasts and suggests nutrient deprivation as a potential mechanism for pathological fibroblast activation in IBD.

HIGHLIGHTS

- Serum starvation transcriptionally activates ECM remodeling genes in fibroblasts.

- Fibroblast starvation activates putative distal enhancers associated with ECM remodeling genes.

- Starvation-activated putative enhancers are enriched for inflammatory bowel disease (IBD) risk variants.

-PLAUenhancer and expression are activated in IBD intestinal fibroblasts, as in starved fibroblasts.
EmbSAM: Cell boundary localization and Segment Anything Model for fast images of developing embryos
Authors: Zhao Cunmin , Li Zelin , Zhang Pei , Chen Yixuan , Ye Pohao , Wong Ming-Kin , Chan Lu-Yan , Yan Hong , Tang Chao , Guan Guoye , Zhao Zhongying
Published: September 2024

Cellular shape dynamics are critical for understanding cell fate determination and organogenesis during development. However, fluorescence live-cell images of cell membranes frequently suffer from a low signal-to-noise ratio, especially during long-duration imaging with high spatiotemporal resolutions. This is caused by phototoxicity and photobleaching, which limit laser power and hinder effective time-lapse cell shape reconstruction, particularly in rapidly developing embryos. Here, we devised a new computational framework, EmbSAM, that incorporates a deep-learning-based cell boundary localization algorithm and the Segment Anything Model. EmbSAM enables accurate and robust three-dimensional (3D) cell membrane segmentation for roundworm Caenorhabditis elegans embryos imaged every 10 seconds. The cell shape data prior to gastrulation quantitatively characterizes a series of cell-division-coupled morphodynamics associated with cell position, cell identity, lineage, and fate, and can be accessed locally and online. The framework also exhibits potential in segmenting and quantifying the fluorescence labeling various cell-membraned-attached molecules in both wild-type and RNAi-treated embryos.
Non-canonical IL-22 receptor signaling remodels the mucosal barrier during fungal immunosurveillance
Authors: Millet Nicolas , Sekar Jinendiran , Solis Norma V. , Millet Antoine , Aggor Felix E.Y. , Wildeman Asia , Lionakis Michail S. , Gaffen Sarah L. , Jendzjowsky Nicholas , Filler Scott G. , Swidergall Marc
Published: September 2024

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatalCandida albicanscolonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.
A chromosome level reference genome of Diviners sage (Salvia divinorum) provides insight into salvinorin A biosynthesis
Authors: Ford Scott A. , Ness Rob W. , Kwon Moonhyuk , Ro Dae-Kyun , Phillips Michael A.
Published: September 2024

Background: Diviners sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human kappa opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date. Results: To facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment. Conclusions: This genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential.
Phylogeny-based selection of representative variants with Navargator: Proof of principle using humoral cross-reactivity data from two immunization studies
Authors: Curran David M. , Ng Dixon , Parkinson John , Moraes Trevor F. , Gray-Owen Scott D. , Fegan Jamie E.
Published: September 2024

Background

The accessibility to the immune system of bacterial surface proteins makes them attractive targets for subunit vaccines. However, this same property also means they tend to exhibit high sequence variability. Achieving broad cross-protection usually necessitates that antigens from multiple isolates are included, but the choice of sequence variant is a non-trivial problem. Visual inspection of phylogenetic trees is the norm, but this is subjective and can be greatly influenced by the choice of viewing software. This has real-world implications, as groups have shown that the selection of non-optimal antigens likely led to lower cross-protection in the commercially available vaccines againstNeisseria meningitidisserogroup B.

Aim / Methods

To address this problem, we have developed Navargator, bioinformatics software that takes a phylogenetic tree as input and identifies the variants that are the most similar to the greatest number of other sequences. The underlying premise is that cross-reactivity will be correlated with phylogenetic distances extracted from the tree; this was validated by several rodent immunization studies with the proteins transferrin-binding protein B and factor H binding protein fromN. meningitidisandN. gonorrhoeae, measuring antibody-based cross-reactivity between an antigen panel using a custom high-throughput ELISA.

Results

Navargator has been made freely available both as an online tool and as source code for local installation. We implemented several different clustering methods, with exact algorithms for smaller datasets, and heuristics suitable for large trees of thousands of sequences. Our immunization studies have shown that this approach is sound, and that cross-reactivity is predicted well by phylogenetic distances in a sigmoidal manner.

Conclusions

The complexity of vaccine development rises sharply with each additional antigen included, so using the minimal number required is an important consideration. Navargator attempts to facilitate this in a systematic and generalizable manner. The user can run the analysis by selecting their desired number of representatives, or they can provide any form of cross-reactivity data and have the program identify a minimum reactivity threshold via correlation with the phylogenetic tree. The program will then identify the smallest number of representatives required to satisfy this threshold.
genomesizeR: An R package for genome size prediction
Authors: Mercier Celine , Elleouet Joane , Garrett Loretta , Wakelin Steve A
Published: September 2024

The genome size of organisms present in an environment can provide many insights into evolutionary and ecological processes at play in that environment. The genomic revolution has enabled a rapid expansion of our knowledge of genomes in many living organisms, and most of that knowledge is classified and readily available in the databases of the National Center for Biotechnology Information (NCBI). ThegenomesizeRtool leverages the wealth of taxonomic and genomic information present in NCBI databases to infer the genome size of Archeae, Bacteria, or Eukaryote organisms identified at any taxonomic level. This R package uses statistical modelling on data from the most up-to-date NCBI databases and provides three statistical methods for genome size prediction of a given taxon, or group of taxa. A straightforward ‘weighted mean’ method identifies the closest taxa with available genome size information in the taxonomic tree, and averages their genome sizes using weights based on taxonomic distance. A frequentist random effect model uses nested genus and family information to output genome size estimates. Finally a third option provides predictions from a distributional Bayesian multilevel model which uses taxonomic information from genus all the way to superkingdom, therefore providing estimates and uncertainty bounds even for under-represented taxa.

All three methods use:

A list of queries; a query being a taxon or a list of several taxa. The package was designed to make it easy to use with data coming from environmental DNA experiments, but works with any table of taxa.

A reference database containing all the known genome sizes, built from the NCBI databases, with associated taxa, provided in an archive to download.

A taxonomic tree structure as built by the NCBI, provided in the same archive.

genomesizeRretrieves the taxonomic classification of input queries, estimates the genome size of each query, and provides 95% confidence intervals for each estimate.
Mutations inPSEN1predispose inflammation in an astrocyte model of familial Alzheimer’s disease through disrupted regulated intramembrane proteolysis
Authors: Ziff Oliver J. , Jolly Sarah , Casey Jackie M. , Granat Lucy , Samra Satinder , Seto-Salvia Nuria , Alatza Argyro , Phadke Leela , Galet Benjamin , Ravassard Philippe , Potier Marie-Claude , Fox Nick C. , Hardy John , Salih Dervis , Whiting Paul , Ducotterd Fiona , Patani Rickie , Wray Selina , Arber Charles
Published: September 2024

Mutations inPSEN1cause familial Alzheimer’s disease with almost complete penetrance. Age at onset is highly variable between differentPSEN1mutations and even within families with the same mutation. Current research into late onset Alzheimer’s disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of γ-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations inPSEN1impact inflammatory responses in astrocytes, thereby contributing to disease progression.

Here, using iPSC-astrocytes, we show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathologicalPSEN1mutations. Using transcriptomic analyses, we demonstrate thatPSEN1mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with an upregulation of genes coding for regulated intramembrane proteolytic and robust activation of JAK-STAT signalling. Using JAK-STAT2 as an example signalling pathway, we show altered phosphorylation cascades inPSEN1mutant astrocytes, reinforcing the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of γ-secretase to confirm a role for PSEN1/γ-secretase in regulating the astrocytic response to inflammatory stimuli.

Together, these data suggest that mutations inPSEN1enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution ofPSEN1mutations to fAD pathogenesis, not only impacting APP and Aβ processing but also altering the cellular response to inflammation.
Burst firing optimizes invariant coding of natural communication signals by electrosensory neural populations
Authors: Metzen Michael G. , Akhshi Amin , Bashivan Pouya , Khadra Anmar , Chacron Maurice J.
Published: September 2024

Accurate perception of objects within the environment independent of context is essential for an organism’s survival. While neurons that respond in an invariant manner to identity-preserving transformations of objects are thought to provide a neural correlate of context-independent perception, how these emerge in the brain remains poorly understood. Here we demonstrate that burst firing in neural populations can give rise to an invariant representation of highly heterogeneous natural communication stimuli. Multi-unit recordings from central sensory neural populations showed that considering burst spike trains led to invariant representations at the population but not the single neuron level. Computational modeling further revealed that optimal invariance is achieved for levels of burst firing seen experimentally. Taken together, our results demonstrate a novel function for burst firing towards establishing invariant representations of sensory input in neural populations.
Inferring cell differentiation maps from lineage tracing data
Authors: Sashittal Palash , Zhang Richard Y. , Law Benjamin K. , Strzalkowski Alexander , Schmidt Henri , Bolondi Adriano , Chan Michelle M. , Raphael Benjamin J.
Published: September 2024

During development, mulitpotent cells differentiate through a hierarchy of increasingly restricted progenitor cell types until they realize specialized cell types. A cell differentiation map describes this hierarchy, and inferring these maps is an active area of research spanning traditional single marker lineage studies to data-driven trajectory inference methods on single-cell RNA-seq data. Recent high-throughput lineage tracing technologies profile lineages and cell types at scale, but current methods to infer cell differentiation maps from these data rely on simple models with restrictive assumptions about the developmental process. We introduce a mathematical framework for cell differentiation maps based on the concept of potency, and develop an algorithm,Carta, that infers an optimal cell differentiation map from single-cell lineage tracing data. The key insight inCartais to balance the trade-off between the complexity of the cell differentiation map and the number of unobserved cell type transitions on the lineage tree. We show thatCartamore accurately infers cell differentiation maps on both simulated and real data compared to existing methods. In models of mammalian trunk development and mouse hematopoiesis,Cartaidentifies important features of development that are not revealed by other methods including convergent differentiation of specialized cell types, progenitor differentiation dynamics, and the refinement of routes of differentiation via new intermediate progenitors.

Code availability

Cartasoftware is available athttps://github.com/raphael-group/CARTA
CNValidatron, automated validation of CNV calls using computer vision
Authors: Montalbano Simone , Walters G. Bragi , Jonsson Gudbjorn F. , Gådin Jesper R. , Werge Thomas , Stefansson Hreinn , Stefánsson Kári , Ingason Andrés
Published: September 2024

Motivation

For more than a decade, running PennCNV on SNP array data has been the gold standard for detecting Copy Number Variants (CNVs, deletions and duplications). It is generally assumed that PennCNV has high sensitivity but poor specificity, leading to a large portion of CNV calls being false positives. Researchers often rely on manual inspection of the raw data to validate CNV calls. However, this approach is not feasible for more than a handful of loci in large collections.

Results

Here we present an R package implementing a convolutional neural network capable of automating CNV validation with an accuracy comparable to a trained human analyst. We also present an in-depth analysis into PennCNV false positive and false negative rates. Finally, we propose an algorithm to simplify the analysis of genome-wide CNV calls computing CNV regions.

Availability and implementation

The code is available on GitHubhttps://github.com/SinomeM/CNValidatron_fl.
Expansion of functional human salivary acinar cell spheroids with reversible thermo-ionically crosslinked 3D hydrogels
Authors: Munguia-Lopez Jose G. , Pillai Sangeeth , Zhang Yuli , Gantz Amatzia , Camasao Dimitria B. , Nazhat Showan N. , Kinsella Joseph M. , Tran Simon D.
Published: September 2024

Xerostomia (dry mouth) is frequently experienced by patients treated with radiotherapy for head and neck cancers or with Sjögren’s syndrome, with no permanent cure existing for this debilitating condition. To this end,in vitroplatforms are needed to test therapies directed at salivary (fluid-secreting) cells. However, since these are highly differentiated secretory cells, the maintenance of their differentiated state while expanding in numbers is challenging. In this study, the efficiency of three reversible thermo-ionically crosslinked gels: 1) alginate-gelatin (AG), 2) collagen-containing AG (AGC), and 3) hyaluronic acid-containing AG (AGHA), to recapitulate a native-like environment for human salivary gland (SG) cell expansion and 3D spheroid formation was compared. Although all gels were of mechanical properties comparable to human SG tissue (∼11 kPa) and promoted the formation of 3D spheroids, AGHA gels produced larger (>100 cells/spheroid), viable (>93%), proliferative, and well-organized 3D SG spheroids while spatially and temporally maintaining the high expression of key SG proteins (aquaporin-5, NKCC1, ZO-1, α-amylase) for 14 days in culture. Moreover, the spheroids responded to agonist-induced stimulation by increasing α-amylase secretory granules. Here, we propose alternative low-cost, reproducible, and reversible AG-based 3D hydrogels that allow the facile and rapid retrieval of intact, highly viable 3D-SG spheroids for downstream applications.
Identification of novel myokines and putative protein targets that mediate functional adaptations in response to chronic contractile activity induced skeletal muscle-extracellular vesicle treatment
Authors: Obi Patience O. , Souza Tamiris F. G. , Lao Ying , McManus Kirk J. , Gordon Joseph W. , LeDuc Richard , Zahedi René P. , Saleem Ayesha
Published: September 2024

We have previously shown that skeletal muscle-derived extracellular vesicles (EVs) released post-chronic contractile activity (CCA) increased mitochondrial biogenesis in murine myoblasts, and decreased cell viability and induced apoptosis and senescence in non-small cell lung cancer cells. While the underlying mechanisms are unknown, the effects perpetuated were dependent on membrane-bound proteins. Here, we performed an extensive LC-MS/MS proteomic analysis on EVs from control and CCA myotubes. A total of 2900 proteins were identified in CON-EVs and CCA-EVs, including EV-associated proteins such as TSG101, tetraspanins (CD9, CD81, and CD63), flotillin-1, and annexins. Of these, 856 proteins are novel and not listed in EV databases (ExoCarta and Vesiclepedia), indicating that myotube-EVs harbor proteins not yet identified in EVs of different origin. Additionally, we identified 2062 unique proteins that have not yet been previously reported in myotube-EVs to date. Remarkably, of the 2900 total proteins identified, we observed 46 upregulated, and 25 downregulated differentially expressed proteins (DEPs) in CCA-EVsvs. control-EVs. Most of upregulated DEPs include EV-associated proteins. Comparing the 71 DEPs with proteins expressed in skeletal muscle indicated 61 of these as potential myokines. We identified actin cytoskeleton signaling, integrin signaling and muscle contraction as the most enriched pathways among the DEPs using different databases/software including FunRich, KEGG, STRING and Ingenuity Pathway Analysis. Using a relevance score that prioritized membrane-bound proteins with known function in mitochondrial biogenesis and inhibition of cancer growth, we identified top-scoring highly enriched DEPs of interest: IGF1R, ATP7A, PFN1, GJA1, PRKCA and ITGA6. We confirmed upregulation of these targets in EVs using immunoblotting. Among these top-scoring DEPs, PFN1, and ITGA6 are associated with EVs, with expression upregulated following acute exercise. In summary, we report the first comprehensive analysis of skeletal muscle-EV proteome following CCA, with identification of putative protein targets and signaling pathways that may execute the pro-metabolic and anti-tumorigenic effects of CCA-EVs.
An endogenous peptide PEP2 modulates Iron-deficiency signalling and root growth in Arabidopsis.
Authors: Shikha Deep , Mishra Sanskar , Satbhai Santosh B
Published: September 2024

Iron (Fe) is an essential element for most of the living organisms including plants and humans, where plants serve as the primary source of our dietary iron intake. The availability of Fe determines plant fitness and yield. Thus, understanding of iron uptake, its acquisition and utilization is of critical importance to reap nutritional benefits from plant breeding. Despite significant progress in uncovering how iron homeostasis is regulated by transcription factors and phytohormones, molecular pathways that mediate Fe deficiency through the action of signalling peptides remain elusive. In this work, we reported the role of PROPEP2 (Plant Elicitor Peptide 2) and PEPR (Perception of Arabidopsis danger signal peptide receptor) in regulating plant growth and development under Fe-deprived conditions. We revealed that a Damage Associated Molecular Pattern (DAMP) such as PROPEP2 is significantly induced under Fe deficiency. We also show that PEP2 modulates the expression of Iron Regulated Transporter 1 (IRT1) and Ferric-Reduction Oxidase (FRO2) under Fe deficiency. Furthermore, we showed that PEPR2 perceives PEP2 to positively regulate reactive oxygen species (ROS) content and negatively regulate the primary root growth, iron content and rhizosphere acidification. Our findings reveal the complex interplay between Fe and DAMP signalling pathways in plants.
Deficits in the knowledge of social norms and their underlying mechanisms in Alzheimer’s disease
Authors: Carrier Thomas , Rouleau Isabelle , St-Georges Marie-Anne , Montembeault Maxime
Published: September 2024

Background

Compared to other components of social cognition, knowledge of social norms has received less attention, even more so in Alzheimer’s disease (AD). While semantic memory deficits have been identified early in the course of AD, no study has delved into the knowledge of social norms at these preliminary stages, although evidence suggests it shares common ground with semantic memory. In addition, it is unclear whether the knowledge of social norms in AD is associated socioemotional deficits, as seen in the behavioral variant of frontotemporal dementia (bvFTD). Finally, how social norms knowledge impairments predict behaviours in real-world settings remains unknown in the context of AD.

Methods

This study included 286 participants with mild cognitive impairment (MCI), 157 with AD, 285 with bvFTD along with 384 older healthy controls. All participants were selected from the National Alzheimer’s Coordinating Center. They completed the Social Norms Questionnaire, which assesses the tendency to break or overadhere to social norms. They also completed tests assessing executive, semantic and socioemotional functions, along with tests measuring spontaneous interpersonal behaviours.

Results

Between-group comparisons show that individuals with AD and MCI break and overadhere to social norms significantly more than HC, while they perform better than individuals with bvFTD. Knowledge of social norms was mainly associated with semantic knowledge across groups, and predicted insensitivity and disinhibition severity in patients.

Conclusions

This study suggests that declines in semantic memory likely play a key role in social norms knowledge decreases and that these decreases predict behavioural tendencies.
Timely vaccine strain selection and genomic surveillance improves evolutionary forecast accuracy of seasonal influenza A/H3N2
Authors: Huddleston John , Bedford Trevor
Published: September 2024

For the last decade, evolutionary forecasting models have influenced seasonal influenza vaccine design. These models attempt to predict which genetic variants circulating at the time of vaccine strain selection will be dominant 12 months later in the influenza season targeted by vaccination campaign. Forecasting models depend on hemagglutinin (HA) sequences from the WHO’s Global Influenza Surveillance and Response System to identify currently circulating groups of related strains (clades) and estimate clade fitness for forecasts. However, the average lag between collection of a clinical sample and the submission of its sequence to the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database is ∼3 months. Submission lags complicate the already difficult 12-month forecasting problem by reducing understanding of current clade frequencies at the time of forecasting. These constraints of a 12-month forecast horizon and 3-month average submission lags create an upper bound on the accuracy of any long-term forecasting model. The global response to the SARS-CoV-2 pandemic revealed that modern vaccine technology like mRNA vaccines can reduce how far we need to forecast into the future to 6 months or less and that expanded support for sequencing can reduce submission lags to GISAID to 1 month on average. To determine whether these recent advances could also improve long-term forecasts for seasonal influenza, we quantified the effects of reducing forecast horizons and submission lags on the accuracy of forecasts for A/H3N2 populations. We found that reducing forecast horizons from 12 months to 6 or 3 months reduced average absolute forecasting errors to 25% and 50% of the 12-month average, respectively. Reducing submission lags provided little improvement to forecasting accuracy but decreased the uncertainty in current clade frequencies by 50%. These results show the potential to substantially improve the accuracy of existing influenza forecasting models by modernizing influenza vaccine development and increasing global sequencing capacity.
Pyjacker identifies enhancer hijacking events in acute myeloid leukemia includingMNX1activation via deletion 7q
Authors: Sollier Etienne , Riedel Anna , Toprak Umut H. , Wierzbinska Justyna A. , Weichenhan Dieter , Schmid Jan Philipp , Hakobyan Mariam , Touzart Aurore , Jahn Ekaterina , Vick Binje , Brown-Burke Fiona , Kelly Katherine , Kelekci Simge , Pejkovska Anastasija , Goyal Ashish , Bähr Marion , Breuer Kersten , Chen Mei-Ju May , Llamazares-Prada Maria , Hartmann Mark , Schönung Maximilian , Correia Nádia , Trumpp Andreas , Abdullah Yomn , Klingmüller Ursula , Mughal Sadaf S. , Brors Benedikt , Westermann Frank , Schlesner Matthias , Vosberg Sebastian , Herold Tobias , Greif Philipp A. , Pfeifer Dietmar , Lübbert Michael , Fischer Thomas , Heidel Florian H. , Gebhard Claudia , Walter Wencke , Haferlach Torsten , Eisfeld Ann-Kathrin , Mrózek Krzysztof , Nicolet Deedra , Bullinger Lars , Smeenk Leonie , Erpelinck Claudia , Mulet-Lazaro Roger , Delwel Ruud , Ernst Aurélie , Scherer Michael , Lutsik Pavlo , Jeremias Irmela , Döhner Konstanze , Döhner Hartmut , Lipka Daniel B. , Plass Christoph
Published: September 2024

Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequentTP53mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identifiedmotor neuron and pancreas homeobox 1(MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of aCDK6enhancer.MNX1-activated cases show significant co-occurrence withBCORmutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated thatMNX1is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.

Statement of significance

This study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML.MNX1overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.
Timing of starvation determines its effects on susceptibility to infection inDrosophila melanogasterfemales independent of host evolutionary history
Authors: Basu Aabeer , Singh Aparajita , Prasad Nagaraj Guru
Published: September 2024

An organism’s susceptibility to pathogens is contingent on various environmental factors, including the availability of nutrition. Starvation can alter host susceptibility to infections, either directly via depletion of resources essential for proper functioning of the immune system, or indirectly via the various physiological changes it induces within the host body. We tested if the susceptibility ofDrosophila melanogasterpopulations toEnterococcus faecalisinfection is affected by (a) whether the hosts are starved before or after the infection, and (b) the evolutionary history of the host. Hosts from laboratory fly populations that have been experimentally evolved to be more resistant toE. faecalis, and their corresponding control populations, were subjected to infection with or without being starved prior to and after being infected. We found that the effect of starvation on susceptibility toE. faecalischanged with the timing of starvation: starvation after infection improved survival of infected hosts, irrespective of how they were treated before infection, while starving only prior to infection (and not after) compromised post-infection survival. The changes in infection susceptibility were uniform in both the evolved and the control populations, suggesting that the effects of starvation are not dependent on pre-existing resistance to the infecting pathogen.