9,798 research outputs found
Inferior Alveolar Canal Automatic Detection with Deep Learning CNNs on CBCTs: Development of a Novel Model and Release of Open-Source Dataset and Algorithm
Featured Application Convolutional neural networks can accurately identify the Inferior Alveolar Canal, rapidly generating precise 3D data. The datasets and source code used in this paper are publicly available, allowing the reproducibility of the experiments performed. Introduction: The need of accurate three-dimensional data of anatomical structures is increasing in the surgical field. The development of convolutional neural networks (CNNs) has been helping to fill this gap by trying to provide efficient tools to clinicians. Nonetheless, the lack of a fully accessible datasets and open-source algorithms is slowing the improvements in this field. In this paper, we focus on the fully automatic segmentation of the Inferior Alveolar Canal (IAC), which is of immense interest in the dental and maxillo-facial surgeries. Conventionally, only a bidimensional annotation of the IAC is used in common clinical practice. A reliable convolutional neural network (CNNs) might be timesaving in daily practice and improve the quality of assistance. Materials and methods: Cone Beam Computed Tomography (CBCT) volumes obtained from a single radiological center using the same machine were gathered and annotated. The course of the IAC was annotated on the CBCT volumes. A secondary dataset with sparse annotations and a primary dataset with both dense and sparse annotations were generated. Three separate experiments were conducted in order to evaluate the CNN. The IoU and Dice scores of every experiment were recorded as the primary endpoint, while the time needed to achieve the annotation was assessed as the secondary end-point. Results: A total of 347 CBCT volumes were collected, then divided into primary and secondary datasets. Among the three experiments, an IoU score of 0.64 and a Dice score of 0.79 were obtained thanks to the pre-training of the CNN on the secondary dataset and the creation of a novel deep label propagation model, followed by proper training on the primary dataset. To the best of our knowledge, these results are the best ever published in the segmentation of the IAC. The datasets is publicly available and algorithm is published as open-source software. On average, the CNN could produce a 3D annotation of the IAC in 6.33 s, compared to 87.3 s needed by the radiology technician to produce a bidimensional annotation. Conclusions: To resume, the following achievements have been reached. A new state of the art in terms of Dice score was achieved, overcoming the threshold commonly considered of 0.75 for the use in clinical practice. The CNN could fully automatically produce accurate three-dimensional segmentation of the IAC in a rapid setting, compared to the bidimensional annotations commonly used in the clinical practice and generated in a time-consuming manner. We introduced our innovative deep label propagation method to optimize the performance of the CNN in the segmentation of the IAC. For the first time in this field, the datasets and the source codes used were publicly released, granting reproducibility of the experiments and helping in the improvement of IAC segmentation
Mitochondria: It is all about energy
Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases
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Ensuring Access to Safe and Nutritious Food for All Through the Transformation of Food Systems
Examples of works to practice staccato technique in clarinet instrument
Klarnetin staccato tekniğini güçlendirme aşamaları eser çalışmalarıyla uygulanmıştır. Staccato
geçişlerini hızlandıracak ritim ve nüans çalışmalarına yer verilmiştir. Çalışmanın en önemli amacı
sadece staccato çalışması değil parmak-dilin eş zamanlı uyumunun hassasiyeti üzerinde de
durulmasıdır. Staccato çalışmalarını daha verimli hale getirmek için eser çalışmasının içinde etüt
çalışmasına da yer verilmiştir. Çalışmaların üzerinde titizlikle durulması staccato çalışmasının ilham
verici etkisi ile müzikal kimliğe yeni bir boyut kazandırmıştır. Sekiz özgün eser çalışmasının her
aşaması anlatılmıştır. Her aşamanın bir sonraki performans ve tekniği güçlendirmesi esas alınmıştır.
Bu çalışmada staccato tekniğinin hangi alanlarda kullanıldığı, nasıl sonuçlar elde edildiği bilgisine
yer verilmiştir. Notaların parmak ve dil uyumu ile nasıl şekilleneceği ve nasıl bir çalışma disiplini
içinde gerçekleşeceği planlanmıştır. Kamış-nota-diyafram-parmak-dil-nüans ve disiplin
kavramlarının staccato tekniğinde ayrılmaz bir bütün olduğu saptanmıştır. Araştırmada literatür
taraması yapılarak staccato ile ilgili çalışmalar taranmıştır. Tarama sonucunda klarnet tekniğin de
kullanılan staccato eser çalışmasının az olduğu tespit edilmiştir. Metot taramasında da etüt
çalışmasının daha çok olduğu saptanmıştır. Böylelikle klarnetin staccato tekniğini hızlandırma ve
güçlendirme çalışmaları sunulmuştur. Staccato etüt çalışmaları yapılırken, araya eser çalışmasının
girmesi beyni rahatlattığı ve istekliliği daha arttırdığı gözlemlenmiştir. Staccato çalışmasını yaparken
doğru bir kamış seçimi üzerinde de durulmuştur. Staccato tekniğini doğru çalışmak için doğru bir
kamışın dil hızını arttırdığı saptanmıştır. Doğru bir kamış seçimi kamıştan rahat ses çıkmasına
bağlıdır. Kamış, dil atma gücünü vermiyorsa daha doğru bir kamış seçiminin yapılması gerekliliği
vurgulanmıştır. Staccato çalışmalarında baştan sona bir eseri yorumlamak zor olabilir. Bu açıdan
çalışma, verilen müzikal nüanslara uymanın, dil atış performansını rahatlattığını ortaya koymuştur.
Gelecek nesillere edinilen bilgi ve birikimlerin aktarılması ve geliştirici olması teşvik edilmiştir.
Çıkacak eserlerin nasıl çözüleceği, staccato tekniğinin nasıl üstesinden gelinebileceği anlatılmıştır.
Staccato tekniğinin daha kısa sürede çözüme kavuşturulması amaç edinilmiştir. Parmakların
yerlerini öğrettiğimiz kadar belleğimize de çalışmaların kaydedilmesi önemlidir. Gösterilen azmin ve
sabrın sonucu olarak ortaya çıkan yapıt başarıyı daha da yukarı seviyelere çıkaracaktır
Receptor–ligand pair typing and prognostic risk model of response or resistance to immune checkpoint inhibitors in lung adenocarcinoma
IntroductionCurrently, programmed cell death-1 (PD-1)-targeted treatment is ineffective for a sizable minority of patients, and drug resistance still cannot be overcome.MethodsTo explore the mechanisms of immunotherapy and identify new therapeutic opportunities in lung adenocarcinoma (LUAD), data from patients who did and did not respond to the anti-PD-1 treatment were evaluated using single-cell RNA sequencing, and bulk RNA sequencing were collected.ResultsWe investigated the gene expression that respond or not respond to immunotherapy in diverse cell types and revealed transcriptional characteristics at the single-cell level. To ultimately explore the molecular response or resistance to anti-PD-1 therapy, cell-cell interactions were carried out to identify the different LRIs (ligand-receptor interactions) between untreated patients vs. no-responders, untreated patients vs. responders, and responders vs. non-responders. Next, two molecular subgroups were proposed based on 73 LRI genes, and subtype 1 had a poor survival status and was likely to be the immunosuppressive tumor subtype. Furthermore, based on the LASSO Cox regression analysis results, we found that TNFSF13, AXL, KLRK1, FAS, PROS1, and CDH1 can be distinct prognostic biomarkers, immune infiltration levels, and responses to immunotherapy in LUAD.DiscussionAltogether, the effects of immunotherapy were connected to LRIs scores, indicating that potential medications targeting these LRIs could contribute to the clinical benefit of immunotherapy. Our integrative omics analysis revealed the mechanisms underlying the anti-PD-1 therapy response and offered abundant clues for potential strategies to improve precise diagnosis and immunotherapy
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico
Valve replacement remains as the standard therapeutic option for aortic
stenosis patients, aiming at abolishing pressure overload and triggering
myocardial reverse remodeling. However, despite the instant hemodynamic
benefit, not all patients show complete regression of myocardial hypertrophy,
being at higher risk for adverse outcomes, such as heart failure. The current
comprehension of the biological mechanisms underlying an incomplete reverse
remodeling is far from complete. Furthermore, definitive prognostic tools and
ancillary therapies to improve the outcome of the patients undergoing valve
replacement are missing. To help abridge these gaps, a combined myocardial
(phospho)proteomics and pericardial fluid proteomics approach was followed,
taking advantage of human biopsies and pericardial fluid collected during
surgery and whose origin anticipated a wealth of molecular information
contained therein.
From over 1800 and 750 proteins identified, respectively, in the myocardium
and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated
proteins were detected. Gene annotation and pathway enrichment analyses,
together with discriminant analysis, are compatible with a scenario of increased
pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by
complement activity and other extrinsic factors, such as death receptor
activators), acute-phase response, immune system activation and fibrosis.
Specific validation of some targets through immunoblot techniques and
correlation with clinical data pointed to complement C3 β chain, Muscle Ring
Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation
regulated kinase 1A (DYRK1A) as potential markers of an incomplete
response. In addition, kinase prediction from phosphoproteome data suggests
that the modulation of casein kinase 2, the family of IκB kinases, glycogen
synthase kinase 3 and DYRK1A may help improve the outcome of patients
undergoing valve replacement. Particularly, functional studies with DYRK1A+/-
cardiomyocytes show that this kinase may be an important target to treat
cardiac dysfunction, provided that mutant cells presented a different response
to stretch and reduced ability to develop force (active tension).
This study opens many avenues in post-aortic valve replacement reverse
remodeling research. In the future, gain-of-function and/or loss-of-function
studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic
targets. Besides, clinical studies in larger cohorts will bring definitive proof of
complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de
referência para doentes com estenose aórtica e visa a eliminação da
sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica.
Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os
mecanismos biológicos subjacentes a uma remodelagem reversa incompleta
ainda não são claros. Além disso, não dispomos de ferramentas de
prognóstico definitivos nem de terapias auxiliares para melhorar a condição
dos pacientes indicados para substituição da válvula. Para ajudar a resolver
estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica
para a caracterização, respetivamente, do miocárdio e do líquido pericárdico
foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio
e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteínas desreguladas foram detetadas. As análises de anotação de genes,
de enriquecimento de vias celulares e discriminativa corroboram um cenário de
aumento da expressão de genes pro-hipertróficos e de síntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrínsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos específicos através de immunoblot e correlação
com dados clínicos apontou para a cadeia β do complemento C3, a Muscle
Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation
regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta
incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma,
sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a
glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição
dos pacientes indicados para intervenção. Em particular, a avaliação funcional
de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo
importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes
responderam de forma diferente ao estiramento e mostraram uma menor
capacidade para desenvolver força (tensão ativa).
Este estudo levanta várias hipóteses na investigação da remodelagem reversa.
No futuro, estudos de ganho e/ou perda de função realizados em
cardiomiócitos isolados ou em modelos animais de banding-debanding da
aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos
encontrados. Além disso, estudos clínicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
Development of in-vitro in-silico technologies for modelling and analysis of haematological malignancies
Worldwide, haematological malignancies are responsible for roughly 6% of all the cancer-related deaths. Leukaemias are one of the most severe types of cancer, as only about 40% of the patients have an overall survival of 10 years or more. Myelodysplastic Syndrome (MDS), a pre-leukaemic condition, is a blood disorder characterized by the presence of dysplastic, irregular, immature cells, or blasts, in the peripheral blood (PB) and in the bone marrow (BM), as well as multi-lineage cytopenias.
We have created a detailed, lineage-specific, high-fidelity in-silico erythroid model that incorporates known biological stimuli (cytokines and hormones) and a competing diseased haematopoietic population, correctly capturing crucial biological checkpoints (EPO-dependent CFU-E differentiation) and replicating the in-vivo erythroid differentiation dynamics. In parallel, we have also proposed a long-term, cytokine-free 3D cell culture system for primary MDS cells, which was firstly optimized using easily-accessible healthy controls. This system enabled long-term (24-day) maintenance in culture with high (>75%) cell viability, promoting spontaneous expansion of erythroid phenotypes (CD71+/CD235a+) without the addition of any exogenous cytokines. Lastly, we have proposed a novel in-vitro in-silico framework using GC-MS metabolomics for the metabolic profiling of BM and PB plasma, aiming not only to discretize between haematological conditions but also to sub-classify MDS patients, potentially based on candidate biomarkers. Unsupervised multivariate statistical analysis showed clear intra- and inter-disease separation of samples of 5 distinct haematological malignancies, demonstrating the potential of this approach for disease characterization.
The work herein presented paves the way for the development of in-vitro in-silico technologies to better, characterize, diagnose, model and target haematological malignancies such as MDS and AML.Open Acces
Varastest embrüotest pärit ekstratsellulaarsed vesiikulid: potentsiaal embrüokvaliteedi markeritena ja roll embrüo-emaka suhtluses
Väitekirja elektrooniline versioon ei sisalda publikatsiooneViljatus on globaalne rahvatervise probleem, mis mõjutab miljoneid inimesi. Abistav reproduktiivtehnoloogia, sealhulgas in vitro viljastamine, on aidanud mitmeid viljatuid inimesi. Küll on sellel metoodikal üheks kitsaskohaks implantatsiooni ebaõnnestumine isegi morfoloogiliselt parimate embrüotega. Seetõttu toimuvad jätkuvalt uuringud tuvastamaks paremaid meetodeid, mis hindavad embrüo kvaliteeti ja ennustavad siirdamise edukust, olles peamiselt embrüokasvusöötme baasil.
Rakuvälised ehk ekstratsellulaarsed vesiikulid (EV) on membraaniga ümbritsetud nanoosakesed, mida toodavad peaaegu kõik rakutüübid erinevates füsioloogilistes ja patoloogilistes konditsioonides. Nende kaudu toimub rakuvaheline suhtlus. Mitmed uuringud, eriti vähi korral, on uurinud EVde potentsiaali biomarkerina ja ravimkandursüsteemina.
Antud doktoritöö uuris implantatsiooni-eelse perioodi embrüost vabanenud EVde potentsiaali embrüokvaliteedi markerina ja embrüo-emaka suhtluse vahendajana. Katsed viidi läbi kasutades veise-embrüoid ja inimrakukultuuride põhiseid eksperimentaalmudeleid. Esimene uuring tõestas, et individuaalselt kasvatatud implantatsiooni-eelse perioodi veise-embrüod eritavad EVsid kasvusöötmesse ning nende kontsentratsiooni- ja suurusprofiil sõltub embrüo kvaliteedist ja arengustaadiumist. Järgnevalt katsetati munajuharakkudel implantatsiooni-eelse perioodi embrüost pärit EVde funktsionaalsust. Katse käigus selgus, et EVd kõrge kvaliteediga embrüotest muutsid munajuharakkude geeniekspressiooni, mida aga ei teinud halva kvaliteediga embrüote EVd. Suurenenud ekspressiooniga geenide hulgas olid mitmed interferoon-τ raja interferooni stimuleerivad geenid. Interferoon-τ peetakse mäletsejaliste tiinuse tuvastusmolekuliks. See leid viitab, et munajuha tunneb ära kvaliteetse embrüo. Viimaseks uuriti embrüo EVde funktsionaalsuse spetsiifilisust. Leiti, et endomeetrium reageerib vaid embrüo päritolu EVdele. Uuringute käigus tuvastati embrüost vabanenud EVde potentsiaal ja spetsiifilisus embrüokvaliteedi biomarkerina.Infertility is a global public health problem that affects millions of people in their reproductive life. Assisted reproductive technologies (ARTs) such as in-vitro fertilization have enabled many patients to overcome this issue. However, a bottleneck in ART success is the implantation failure even after the transfer of morphologically best embryos. Hence, investigations continue to identify better or complementary methods of assessing embryo quality and predicting transfer success, mainly based on the embryo culture media.
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by almost all types of cells under different physiological and pathological conditions. They mediate intercellular communication. Many studies, especially related to cancer, have investigated EVs' potential as biomarkers and therapeutic drug delivery systems.
This project investigated preimplantation embryo-derived extracellular vesicles as a potential embryo quality marker and a mediator of embryo-maternal communication. Experiments were performed using bovine embryos and human cell-culture based experimental models. The first study showed that individually cultured preimplantation bovine embryos release EVs to their culture media, and their concentration and size profile are dependent on the quality and development stage of embryos. Subsequently, the functionality of preimplantation embryo-derived EVs were tested in the oviduct. It was observed that EVs from good quality embryos, but not the EVs from embryos of low developmental potential quality, could alter the gene expression of the oviduct. Among the up-regulated genes, many were interferon-stimulated genes of the interferon-τ pathway. Interferon-τ is considered the pregnancy recognition molecule in ruminant pregnancy. This finding suggests that the oviduct can serve as a biosensor of embryo quality. Finally, the functional specificity of embryonic EVs were investigated. It was observed that endometrium only react to embryonic EVs but not to the non-embryonic EVs. All these studies support the potential and specificity of embryo-derived EVs as a biomarker of embryo quality.https://www.ester.ee/record=b548409
Statistical Learning for Gene Expression Biomarker Detection in Neurodegenerative Diseases
In this work, statistical learning approaches are used to detect biomarkers for neurodegenerative diseases (NDs). NDs are becoming increasingly prevalent as populations age, making understanding of disease and identification of biomarkers progressively important for facilitating early diagnosis and the screening of individuals for clinical trials. Advancements in gene expression profiling has enabled the exploration of disease biomarkers at an unprecedented scale. The work presented here demonstrates the value of gene expression data in understanding the underlying processes and detection of biomarkers of NDs. The value of novel approaches to previously collected -omics data is shown and it is demonstrated that new therapeutic targets can be identified. Additionally, the importance of meta-analysis to improve power of multiple small studies is demonstrated. The value of blood transcriptomics data is shown in applications to researching NDs to understand underlying processes using network analysis and a novel hub detection method. Finally, after demonstrating the value of blood gene expression data for investigating NDs, a combination of feature selection and classification algorithms were used to identify novel accurate biomarker signatures for the diagnosis and prognosis of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Additionally, the use of feature pools based on previous knowledge of disease and the viability of neural networks in dimensionality reduction and biomarker detection is demonstrated and discussed. In summary, gene expression data is shown to be valuable for the investigation of ND and novel gene biomarker signatures for the diagnosis and prognosis of PD and AD
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