bluuebunny/crossref_metadata_2025 huggingface dataset:
Eredményesen oktatjuk-e azt, amit fontosnak tartunk? Ahogy az orvosképzés oktatói látják
Authors: Varga Zsuzsanna , Pótó Zsuzsanna , Csathó Árpád , Füzesi Zsuzsanna
Published: April 2022

Magyarországon az általános orvostudományi szakra vonatkozó Képzési és Ki­me­neti Köve­tel­mények határozzák meg, hogy a végzett orvostanhallgatóknak milyen tudással, va­lamint jártasságokkal, készségek­kel, képességekkel, azaz kompetenciával kell rendelkezniük. Kutatásunkban egyrészt azt vizsgáltuk, hogy az orvosképzéshez a Képzési és Ki­meneti Követelményekben megfogalmazott kompetenciák fontosságát hogyan ítélik meg az oktatók, másrészt, hogy ezeket milyen mértékben közvetítik oktatói tevékenységük során. Az empirikus kutatást 2017 őszén végeztük négy magyarországi orvosképző intéz­mény­ben, saját fejlesztésű kérdőív használatával. Az elemzéshez GAP-analízist, Wil­coxon-próbát, faktoranalízist alkalmaztunk. Kérdőívünket a négy orvosképző intézmény összes oktatójához eljuttattuk (1790 fő), közülük 439-en töltötték ki a nyomtatványt (24,5%). A kutatási eredmények azt mutatják, hogy az oktatók a képzés során egyetlen kompetenciát sem közvetítettek olyan mértékben oktatási gyakorlatukban, mint amennyire azokat fontosnak tartották (egy kivételével). A fontosság és a közvetítés mértéke között – kompetenciánként eltérő mértékű – statisztikailag is igazol­ható negatív rés (GAP) található. A vizsgált kompetenciák jól azonosítható faktorokba sorolhatók, melyek megfelelnek a nemzetközi szakirodalomban elfogadott háromkörös modellnek. A kutatás rámutatott arra, hogy az or­vos­képzésben – a szűkebben vett orvosszakmai ismeretek mellett – további fejlesztési és fejlődési lehetőségek rejlenek, amelyek fontosságát az oktatási folyamat végrehajtói, az oktatók is megerősítették. A hiányok és a szükségletek felismerése mellett ezek megvalósításához az oktatók saját készségeinek fejlesztése is fontos, köztük a pedagógiai, módszertani ismereteké is.
Basın Suçlarında Ceza Sorumluluğu
Authors: GÜNDÜZ Hakan
Published: April 2022

İletişimin gerçekleşmesine aracılık eden kitle iletişim araçları içerisinde hiç şüphesiz basının önemi büyüktür. Basının kitleler üzerindeki etkisine atfedilen öneme binaen Anayasa’nın 28 ilâ 30. maddeleri arasında basın özgürlüğü ve süreli-süresiz yayın hakkına münhasır ayrıntılı düzenlemelere yer verilmiştir. Anayasal düzenlemelerde bu denli önem atfedilen basın özgürlüğünün kötüye kullanılması idari yaptırım yoluyla cezalandırıldığı gibi, haksızlık içeriği daha ağır olan bu nitelikteki bazı fiiller basın yoluyla işlenen suçlarla yaptırıma bağlanmıştır. Eser sahibi, sorumlu müdür, yayımcı, basımcı gibi pek çok kişinin kollektif çalışması sonucunda meydan getirilen basılmış eser yoluyla işlenen suçlarda ceza kanunlarının sorumluluğa ilişkin genel hükümlerinin yeterli olmayacağı ve suça iştirake ilişkin genel hükümler basın suçu açısından da uygulandığında, faillerin cezasız kalabileceği, kitleler üzerinde bu denli etkili olan basının suç işlenmesinde araç olarak kullanılmasının cezasız kalmasının toplumsal açıdan, diğer suçların doğurduğu etkiye nazaran daha ağır sonuçlar doğurabileceği gerekçeleriyle, ülkelerin mevzuatında basılmış eserler yoluyla işlenen suçlar açısından ceza sorumluluğunun genel ilkelerinden ayrık özel sorumluluk sistemlerine yer verilebilmektedir. Bu kapsamda, 5187 sayılı Basın Kanunu’nun “Cezai sorumluluk” başlıklı 11. maddesinde de basılmış eser yoluyla işlenen suçlar açısından Türk Ceza Kanunu’nun ceza sorumluluğuna ilişkin genel hükümlerinden farklı, özel bir sorumluluk sistemine yer verilmiştir. Çalışmada, Basın Kanunu’nda düzenlenen bu özel sorumluluk sistemi, ceza hukukunun genel ilkeleri açısından değerlendirilmiştir.
The Independent Parasite: Mosca’s Theatrical Service in Volpone
Authors: Gutiérrez-Popoca Emiliano
Published: April 2022

This article explores the relationship between Volpone and Mosca as a master-servant bond grounded on roleplaying and theatricality. I argue that Mosca’s growing importance as an actor within Volpone’s theatrical schemes for wealth acquisition lead Mosca to envision detachment from his master and to gain an independent self. Mosca’s independence is legally recognized by the Venetian authorities only for a moment in the final act before he is discovered and punished. Notwithstanding its conservative ending, the play reveals paths of advancement for the parasite through deceit and theatricality. In addition, Mosca’s soliloquies reveal an introspective mind that delights in his role of parasite. I relate this introspection to a form of subjectivity arising from the precarious employment of household servants in early modern London, which prompted their adaptation to a variety of roles. My argument examines early modern texts that put forth an ideology of service and that discuss duplicity and the parasite. I specifically delve into the figure of the parasite in Gervase Markham’s A health to the gentlemanly profession of seruingmen and in Jonson’s Discoveries as well as into the the concept of “eye-service” and parasitical service in William Gouge’s Of Domesticall Duties to draw connections between the anxiety of social mobility found in these texts and the rise of Mosca in Jonson’s play. Through Mosca’s rise and fall in the play, Jonson, I argue, shows the possibilities but also the limits of social mobility for servants in the transitional period of early-seventeenth-century London.
Italy in Philip Massinger’s The Maid of Honour
Authors: Paravano Cristina
Published: April 2022

This article discusses Philip Massinger’s The Maid of Honour, showing how this tragicomedy set in Italy is resonant of stories, ideas, theories and characters from the Italian literary and cultural tradition. On the one hand, I will shed light on Massinger’s use of an Italian ambience, concentrating on the choice of Palermo and Siena as a setting. The pseudo-historic setting of the play may be seen as a pretext to dramatize the author’s moral needs and convey a form of political ideology, which reflects the social tensions and the political concerns of the period. On the other hand, I will discuss the different forms of legacy from the Italian world, focusing on the cultural forces, and the moral and ideological motivations behind the playwright’s choice of the genre of his play, the changes concerning plot, setting and the characters’ names in the original Italian text on which the tragicomedy is based. Moreover, this tragicomedy, characterized by a profound didactic and moral intent, also seems to combine some elements of the late 16th century commedia grave, mainly in the presence of an exemplary female protagonist, Camiola, who embodies the providential spirit of the Counter-Reformist attitudes in vogue in the period. Finally, I will examine the way an image of Italy is portrayed through language, analyzing the very marginal occurrence of the Italian language and the presence of Latin words and tags.
KERISTENAN DI KOTA RAHA: 1909-1950
Authors: Samrila Lili , Fatma Fatma
Published: April 2022

Masalah penelitian ini adalah: (1) Apa yang melatar belakangi kekristenan di Kota Raha pada 1909-1950? (2) Bagaimana perkembangan kekristenan di Kota Raha pada 1909-1950? (3) Apa saja dampak Kekristenan di Kota Raha pada 1909-1950? Metode yang digunakan dalam penelitian ini adalah metode sejarah yang terdiri dari lima tahap kegiatan yaitu, sebagai berikut: (1) Pemilihan Topik, (2) Heuristik Sumber, (3) Verifikasi Sumber, (4) Interpretasi Sumber, (5) Historiografi. Hasil penelitian menunjukkan bahwa: (1) Kekristenan di Kota Raha dilatarbelakangi oleh datangnya pastor P.I Onel sebagai langkah awal untuk memberikan pelayanan pada masyarakat yang kurang mampu berupa bantuan sandang dan pangan. Jalur penyebaran agama Kristen di pulau Muna berawal dari penyebaran ajaran Kristen oleh Pastor Asselberg yang menjadi pastor pertama di Makassar serta beberapa pembaptisan pada 1912 oleh seorang Putra dari David Salmon Pella, seorang pendiri organisator dan koordinator umat Katolik di Raha; (2)  Perkembangan Agama Katolik di Kota Raha pada 1909-1942 terbagi menjadi tiga periode, yaitu (a) 1909-1930 saat Kristen Katolik diizinkan untuk melakukan misi di Pulau Muna, (b) 1942-1945 saat masa pendudukan Jepang, dan (c) 1945-1950 yang ditandai oleh penyebaran Kristen di luar Kota Raha melalui jalur pendidikan dan kesehatan; (3) Kekristenan di Kota Raha berdampak pada aspek sosial dan kebudayaan setempat.
PERJUANGAN MASSALINRI DAENG MALLIRA DALAM MENENTANG BELANDA DI KERAJAAN TELLU LIMPOE: 1861-1871
Authors: Yanti Yelda , Arman Arman
Published: April 2022

Penelitian ini bertujuan untuk (1) Menjelaskan latar belakang masuknya Belanda di Kerajaan Tellu Limpoe, (2) Menjelaskan alasan Massalinri Daeng Mallira menentang Kolonial Belanda di Kerajaan Tellu Limpoe pada tahun 1861-1871, (3) Menjelaskan strategi Massalinri Daeng Mallira dalam menentang Kolonial Belanda di Kerajaan Tellu Limpoe. Penelitian ini menggunakan metode sejarah dengan tahapan-tahapan kerja sebagai berikut: (1) pemilihan topik, (2) pengumpulan sumber, (3) kritik sumber, (4) Interpretasi sumber, (5) Historiografi. Hasil penelitian menunjukkan bahwa (1) Belanda masuk di Sinjai pada tahun 1636 melalui ekspansi wilayah dengan menjalankan politik devide et impera (politik pecah belah). Kerajaan-kerajaan di Sinjai menentang upaya Belanda untuk memisahkan hubungan persatuan antarkerajaan yang ada di Sulawesi Selatan. Rakyat Sinjai tetap berupaya berpegang pada perjanjian Topekkong. Kolonial Belanda kemudian menyerang Kerajaan Tellu Limpoe dan berhasil menguasainya. Pasukan Sinjai pada masa itu dipimpin oleh Andi Mandasini dan Baso Kalaka pada tahun 1859. (2) Alasan Massalinri Daeng Mallira menentang Belanda di Kerajaan Tellu Limpoe karena tidak tahan dengan perlakuan Belanda terhadap rakyat Tellu Limpoe, selain  karena faktor siri, faktor agama dan faktor ekonomi, Belanda juga menngganti sistem pemerintahan tradisional menjadi sistem pemerintahan Kolonial, mengadakan pemecatan raja-raja dan mengadakan pembuatan jalan yang dikerjakan oleh rakyat Tellu Limpoe dengan upah rendah, (3) Strategi yang ditempuh Massalinri Daeng Mallira dalam menentang Belanda di kerajaan Tellu Limpoe yakni bergerilya. Massalinri juga melakukan penyerangan selama tiga kali. Pada tahun 1863 perang yang dilakukan akhirnya menewaskan Raja Bulo-bulo yaitu Abd. Ganing yang diangkat oleh Belanda. Massalinri juga berhasil melumpuhkan pasukan Belanda dalam penyerangannya di Cakeppong. Penyerangan kedua dilakukan pada tahun 1870 dengan cara bergerilya dan berhasil melumpuhkan pasukan Belanda di tempat pangkalan militer yaitu di gerbang Benteng Balangnipa. Perang ketiga terjadi pada tahun 1871 dan merupakan akhir perjuangan Massalinri. Pada perang ketiga, pasukan Belanda berhasil melumpuhkan pasukan Massalinri dan menewaskan Massalinri Daeng Mallira tepatnya di Cappa Galung (diujung sawah) Bola Roman, Bikeru.
Solar System Wave Function
Authors: Soltani Abolfazl
Published: April 2022

Pluto, Ceres and all planets of solar system except Neptune, with a high approximation, follow a law called Titius-Bode law (TBL) or Bode law, which can by no means be considered as a stochastic event. This law shows that the distance of the planets from the sun in Solar system is regulated. Here, we prove that, probably, the existence of a standing and cosine wave packet in solar system, with the wavelength λ = 0.6 AU (AU represents the distance of earth from the sun) and the phase constant ∅0=π/6, is the reason for TBL. In this article we will obtain the equation of this wave packet empirically. Finally, we will prove that without solar system wave function, it is not possible to reach to the TBL from the protoplanetary disk of solar system. Here we prove that the nebular theory without our wave theory is an incomplete theory.
Robin's criterion on divisibility
Authors: Vega Frank
Published: April 2022

Robin's criterion states that the Riemann hypothesis is true if and only if the inequality $\sigma(n)5040$, where $\sigma(n)$ is the sum-of-divisors function of $n$ and $\gamma\approx 0.57721$ is the Euler-Mascheroni constant. We show that the Robin inequality is true for all natural numbers $n>5040$ that are not divisible by some prime between $2$ and $1771559$. We prove that the Robin inequality holds when $\frac{\pi^{2}}{6}\times\log\log n' \leq\log\log n$ for some $n>5040$ where $n'$ is the square free kernel of the natural number $n$. The possible smallest counterexample $n>5040$ of the Robin inequality implies that $q_{m}>e^{31.018189471}$, $1<\frac{(1+\frac{1.2762}{\log q_{m}})\times \log(2.82915040011)}{\log\log n}+\frac{\log N_{m}}{\log n}$, $(\log n)^{\beta}<1.03352795481\times\log(N_{m})$ and $n<(2.82915040011)^{m}\times N_{m}$, where $N_{m}=\prod_{i = 1}^{m} q_{i}$ is the primorial number of order $m$, $q_{m}$ is the largest prime divisor of $n$ and $\beta=\prod_{i = 1}^{m}\frac{q_{i}^{a_{i}+1}}{q_{i}^{a_{i}+1}-1}$ when $n$ is an Hardy-Ramanujan integer of the form $\prod_{i=1}^{m}q_{i}^{a_{i}}$.
Infiltración linfocitaria tumoral como factor de buen pronóstico de supervivencia en pacientes con cáncer gástrico localmente avanzado
Authors: Castillo José , Caballero Henry , Tapia Verónica
Published: April 2022

Introducción: La relación entre supervivencia e infiltración linfocitaria en el cáncer gástrico se ha determinado como factor pronóstico beneficioso, este estudio local tiene como objetivo determinar la probabilidad de supervivencia en los pacientes con cáncer gástrico estadios IB al IIIC de acuerdo con el porcentaje de infiltración linfocitaria.

Metodología: El presente estudio longitudinal se realizó en el Hospital Oncológico Solón Espinosa Ayala Solca-Núcleo de Quito. El período de estudio de enero del 2013 a enero del 2016, el tiempo de seguimiento terminó en diciembre del 2018. El cálculo muestral fue no probabilístico en donde se incluyeron casos de pacientes mayores a 18 años con diagnóstico de cáncer gástrico con estadios clínicos IB al IIIC, que contaron con una muestra histopatológica de gastrectomías. Se usó la variable: “Porcentaje de infiltración” para el análisis la muestra y se dividió en 3 grupos: G1: infiltración linfocitaria leve, G2: moderada y G3: intensa. Las estimaciones de supervivencia se calcularon utilizando el método de Kaplan-Meier y la comparación entre los grupos con la prueba log-rank.

Resultados: 173 pacientes con cáncer gástrico con estadios clínicos IB al IIIC, seguidos a 72 meses, el 60 % son hombres y el 40 % mujeres. Según el porcentaje de infiltración linfocitaria, el 52 % reportaron un porcentaje de infiltración leve, el 21 % moderada y el 27 % intensa. A los 72 meses de seguimiento la supervivencia en G1 fue del 31 %, en G2 fue del 48 %, y en G3 fue del 77 % (P= 0.001).

Conclusión: Se encontró que el grado de infiltración linfocitaria intensa en los pacientes con cáncer gástrico estuvo asociado a una mejor supervivencia en el seguimiento a 72 meses.
PENGEMBANGAN DAN IMPLEMENTASI PANDUAN MENDESAIN PEMBELAJARAN DARING DENGAN PLATFORM SEDERHANA UNTUK GURU-GURU
Authors: Devitama Karina Almira , Siregar Eveline , Nursetyo Kunto Imbar
Published: April 2022

This research is a development research that aims to facilitate teachers to be able to design online learning at this time, by utilizing certain application platforms that suit their learning needs. Through this research, a Digital Guide is produced that can be used by teachers, so that in carrying out online learning or learning from home (BDR) for their students, they will be helped in using a platform that is simple and easy, but can create fun and meaningful learning. In this product development process, the Derek Rowntree development model is used, which consists of three main stages, namely 1) planning, 2) writing preparation, 3) writing and editing. At the writing and editing stage, after the product prototype is produced, expert review is carried out by material experts, media experts, and learning design experts. After experiencing improvement, the product is tested on users in a training which is designed for teachers at Tenjo Village, Bogor. The training is held in order to execute community service of Educational Technology Master Program UNJ. The test results indicated that the product is feasible to use and is very good at facilitating teachers who will design online learning, as well as selecting and using certain appropriate application platforms.
Public Volume Electron Microscopy Data: An Essential Resource to Study the Brain Microvasculature
Authors: Bonney Stephanie K. , Coelho-Santos Vanessa , Huang Sheng-Fu , Takeno Marc , Kornfeld Joergen , Keller Annika , Shih Andy Y.
Published: April 2022

Electron microscopy is the primary approach to study ultrastructural features of the cerebrovasculature. However, 2D snapshots of a vascular bed capture only a small fraction of its complexity. Recent efforts to synaptically map neuronal circuitry using volume electron microscopy have also sampled the brain microvasculature in 3D. Here, we perform a meta-analysis of 7 data sets spanning different species and brain regions, including two data sets from the MICrONS consortium that have made efforts to segment vasculature in addition to all parenchymal cell types in mouse visual cortex. Exploration of these data have revealed rich information for detailed investigation of the cerebrovasculature. Neurovascular unit cell types (including, but not limited to, endothelial cells, mural cells, perivascular fibroblasts, microglia, and astrocytes) could be discerned across broad microvascular zones. Image contrast was sufficient to identify subcellular details, including endothelial junctions, caveolae, peg-and-socket interactions, mitochondria, Golgi cisternae, microvilli and other cellular protrusions of potential significance to vascular signaling. Additionally, non-cellular structures including the basement membrane and perivascular spaces were visible and could be traced between arterio-venous zones along the vascular wall. These explorations revealed structural features that may be important for vascular functions, such as blood-brain barrier integrity, blood flow control, brain clearance, and bioenergetics. They also identified limitations where accuracy and consistency of segmentation could be further honed by future efforts. The purpose of this article is to introduce these valuable community resources within the framework of cerebrovascular research. We do so by providing an assessment of their vascular contents, identifying features of significance for further study, and discussing next step ideas for refining vascular segmentation and analysis.
Paxillin: A Hub for Mechano-Transduction from the β3 Integrin-Talin-Kindlin Axis
Authors: Ripamonti Marta , Wehrle-Haller Bernhard , de Curtis Ivan
Published: April 2022

Focal adhesions are specialized integrin-dependent adhesion complexes, which ensure cell anchoring to the extracellular matrix. Focal adhesions also function as mechano-signaling platforms by perceiving and integrating diverse physical and (bio)chemical cues of their microenvironment, and by transducing them into intracellular signaling for the control of cell behavior. The fundamental biological mechanism of creating intracellular signaling in response to changes in tensional forces appears to be tightly linked to paxillin recruitment and binding to focal adhesions. Interestingly, the tension-dependent nature of the paxillin binding to adhesions, combined with its scaffolding function, suggests a major role of this protein in integrating multiple signals from the microenvironment, and accordingly activating diverse molecular responses. This minireview offers an overview of the molecular bases of the mechano-sensitivity and mechano-signaling capacity of core focal adhesion proteins, and highlights the role of paxillin as a key component of the mechano-transducing machinery based on the interaction of cells to substrates activating the β3 integrin-talin1-kindlin.
SLC38A10 Regulate Glutamate Homeostasis and Modulate the AKT/TSC2/mTOR Pathway in Mouse Primary Cortex Cells
Authors: Tripathi Rekha , Aggarwal Tanya , Lindberg Frida A. , Klemm Anna H. , Fredriksson Robert
Published: April 2022

Glutamate acts as a critical regulator of neurotransmitter balance, recycling, synaptic function and homeostasis in the brain and glutamate transporters control glutamate levels in the brain. SLC38A10 is a member of the SLC38 family and regulates protein synthesis and cellular stress responses. Here, we uncover the role of SLC38A10 as a transceptor involved in glutamate-sensing signaling pathways that control both the glutamate homeostasis and mTOR-signaling. The culture of primary cortex cells from SLC38A10 knockout mice had increased intracellular glutamate. In addition, under nutrient starvation, KO cells had an impaired response in amino acid-dependent mTORC1 signaling. Combined studies from transcriptomics, protein arrays and metabolomics established that SLC38A10 is involved in mTOR signaling and that SLC38A10 deficient primary cortex cells have increased protein synthesis. Metabolomic data showed decreased cholesterol levels, changed fatty acid synthesis, and altered levels of fumaric acid, citrate, 2-oxoglutarate and succinate in the TCA cycle. These data suggests that SLC38A10 may act as a modulator of glutamate homeostasis, and mTOR-sensing and loss of this transceptor result in lower cholesterol, which could have implications in neurodegenerative diseases.
Long COVID: The Nature of Thrombotic Sequelae Determines the Necessity of Early Anticoagulation
Authors: Wang Chengyue , Yu Chengyuan , Jing Haijiao , Wu Xiaoming , Novakovic Valerie A. , Xie Rujuan , Shi Jialan
Published: April 2022

Many discharged COVID-19 patients affected by sequelae experience reduced quality of life leading to an increased burden on the healthcare system, their families and society at large. Possible pathophysiological mechanisms of long COVID include: persistent viral replication, chronic hypoxia and inflammation. Ongoing vascular endothelial damage promotes platelet adhesion and coagulation, resulting in the impairment of various organ functions. Meanwhile, thrombosis will further aggravate vasculitis contributing to further deterioration. Thus, long COVID is essentially a thrombotic sequela. Unfortunately, there is currently no effective treatment for long COVID. This article summarizes the evidence for coagulation abnormalities in long COVID, with a focus on the pathophysiological mechanisms of thrombosis. Extracellular vesicles (EVs) released by various types of cells can carry SARS-CoV-2 through the circulation and attack distant tissues and organs. Furthermore, EVs express tissue factor and phosphatidylserine (PS) which aggravate thrombosis. Given the persistence of the virus, chronic inflammation and endothelial damage are inevitable. Pulmonary structural changes such as hypertension, embolism and fibrosis are common in long COVID. The resulting impaired lung function and chronic hypoxia again aggravates vascular inflammation and coagulation abnormalities. In this article, we also summarize recent research on antithrombotic therapy in COVID-19. There is increasing evidence that early anticoagulation can be effective in improving outcomes. In fact, persistent systemic vascular inflammation and dysfunction caused by thrombosis are key factors driving various complications of long COVID. Early prophylactic anticoagulation can prevent the release of or remove procoagulant substances, thereby protecting the vascular endothelium from damage, reducing thrombotic sequelae, and improving quality of life for long-COVID patients.
Responsible Research and Innovation Associated With Risk Communication and Public Engagement on Health Emergency Preparedness at the Local Level
Authors: Possenti Valentina , De Mei Barbara , Kurchatova Anna , Green Manfred , Drager Kåre Harald , Villa Roberta , d'Onofrio Alberto , Saadatian-Elahi Mitra , Moore Vanessa , Brattekas Kjersti , Karnaki Pania , Beresniak Ariel , Popa Mircea I. , Greco Donato
Published: April 2022

Responsible Research and Innovation (RRI) associated with public health emergency preparedness (PHEP) and response pose major challenges to the scientific community and civil society because a multistakeholder and interdisciplinary methodology is needed to foster public engagement. In 2017, within “Action plan on Science in Society related issues in Epidemics and Total pandemics”, twenty-three initiatives in eleven cities—Athens, Brussels, Bucharest, Dublin, Geneva, Haifa, Lyon, Milan, Oslo, Rome, and Sofia—represented effective opportunities for Mobilization and Mutual Learning on RRI issues in the matter of PHEP with different community-level groups. These experiences show that to effectively address a discourse on RRI-related issues in PHEP it is necessary to engage the local population and stakeholders, which is challenging because of needed competencies and resources. Under coronavirus disease 2019 (COVID-19) pandemic, we are proven that such a diversified multistakeholder engagement on RRI related to PHEP locally needs further elaboration and practical development.
Assessment of Myocardial Microstructure in a Murine Model of Obesity-Related Cardiac Dysfunction by Diffusion Tensor Magnetic Resonance Imaging at 7T
Authors: Lohr David , Thiele Arne , Stahnke Max , Braun Vera , Smeir Elia , Spranger Joachim , Brachs Sebastian , Klopfleisch Robert , Foryst-Ludwig Anna , Schreiber Laura M. , Kintscher Ulrich , Beyhoff Niklas
Published: April 2022

Background

Obesity exerts multiple deleterious effects on the heart that may ultimately lead to cardiac failure. This study sought to characterize myocardial microstructure and function in an experimental model of obesity-related cardiac dysfunction.

Methods

Male C57BL/6N mice were fed either a high-fat diet (HFD; 60 kcal% fat, n = 12) or standard control diet (9 kcal% fat, n = 10) for 15 weeks. At the end of the study period, cardiac function was assessed by ultra-high frequency echocardiography, and hearts were processed for further analyses. The three-dimensional myocardial microstructure was examined ex vivo at a spatial resolution of 100 × 100 × 100 μm3 by diffusion tensor magnetic resonance imaging (DT-MRI) at 7T. Myocardial deformation, diffusion metrics and fiber tract geometry were analyzed with respect to the different myocardial layers (subendocardium/subepicardium) and segments (base/mid-cavity/apex). Results were correlated with blood sample analyses, histopathology, and gene expression data.

Results

HFD feeding induced significantly increased body weight combined with a pronounced accumulation of visceral fat (body weight 42.3 ± 5.7 vs. 31.5 ± 2.2 g, body weight change 73.7 ± 14.8 vs. 31.1 ± 6.6%, both P < 0.001). Obese mice showed signs of diastolic dysfunction, whereas left-ventricular ejection fraction and fractional shortening remained unchanged (E/e’ 41.6 ± 16.6 vs. 24.8 ± 6.0, P < 0.01; isovolumic relaxation time 19 ± 4 vs. 14 ± 4 ms, P < 0.05). Additionally, global longitudinal strain was reduced in the HFD group (−15.1 ± 3.0 vs. −20.0 ± 4.6%, P = 0.01), which was mainly driven by an impairment in basal segments. However, histopathology and gene expression analyses revealed no myocardial fibrosis or differences in cardiomyocyte morphology. Mean diffusivity and eigenvalues of the diffusion tensor were lower in the basal subepicardium of obese mice as assessed by DT-MRI (P < 0.05). The three-dimensional fiber tract arrangement of the left ventricle (LV) remained preserved.

Conclusion

Fifteen weeks of high-fat diet induced alterations in myocardial diffusion properties in mice, whereas no remodeling of the three-dimensional myofiber arrangement of the LV was observed. Obese mice showed reduced longitudinal strain and lower mean diffusivity predominantly in the left-ventricular base, and further investigation into the significance of this regional pattern is required.
High-Dimensional DNA Methylation Mediates the Effect of Smoking on Crohn’s Disease
Authors: Wang Tingting , Xia Pingtian , Su Ping
Published: April 2022

Epigenome-wide mediation analysis aims to identify high-dimensional DNA methylation at cytosine–phosphate–guanine (CpG) sites that mediate the causal effect of linking smoking with Crohn’s disease (CD) outcome. Studies have shown that smoking has significant detrimental effects on the course of CD. So we assessed whether DNA methylation mediates the association between smoking and CD. Among 103 CD cases and 174 controls, we estimated whether the effects of smoking on CD are mediated through DNA methylation CpG sites, which we referred to as causal mediation effect. Based on the causal diagram, we first implemented sure independence screening (SIS) to reduce the pool of potential mediator CpGs from a very large to a moderate number; then, we implemented variable selection with de-sparsifying the LASSO regression. Finally, we carried out a comprehensive mediation analysis and conducted sensitivity analysis, which was adjusted for potential confounders of age, sex, and blood cell type proportions to estimate the mediation effects. Smoking was significantly associated with CD under odds ratio (OR) of 2.319 (95% CI: 1.603, 3.485, p < 0.001) after adjustment for confounders. Ninety-nine mediator CpGs were selected from SIS, and then, seven candidate CpGs were obtained by de-sparsifying the LASSO regression. Four of these CpGs showed statistical significance, and the average causal mediation effects (ACME) were attenuated from 0.066 to 0.126. Notably, three significant mediator CpGs had absolute sensitivity parameters of 0.40, indicating that these mediation effects were robust even when the assumptions were slightly violated. Genes (BCL3 and FKBP5) harboring these four CpGs were related to CD. These findings suggest that changes in methylation are involved in the mechanism by which smoking increases risk of CD.
What Is Long-Term Survival and Which First-Line Immunotherapy Brings Long-Term Survival for Advanced Wild-Type Non-Small Cell Lung Cancer: A Network Meta-Analysis Based on Integrated Analysis
Authors: Zhang Xue , Xu Qian , Yu Xuejun , Huang Miao , Li Song , Sheng Lei , Dai Xin , Huang Kai , Wang Jian , Liu Lian
Published: April 2022

Background

Immune checkpoint inhibitors (ICIs) have significantly improved survival for advanced wild-type non-small cell lung cancer, but there is no direct comparison to confirm which first-line treatment may lead to the longest overall survival. What qualifies as long-term survival (LS) is even unclear.

Methods

By searching PubMed, Embase, and the Cochrane Central Register of Controlled Trials from January 2005 to December 2020, we included randomized controlled trials (RCTs) of first-line ICI-containing treatments to perform an integrated analysis (IA) to determine the criterion of LS and then screened regimens with LS for network meta-analysis (NMA). The main outcomes for NMA were median overall survival (mOS), 1-year survival rate (1ySR), and 2-year survival rate (2ySR); those for IA were the pooled mOS (POS), 1ySR (P1SR), and 2ySR (P2SR).

Results

By IA of 16 first-line ICIs from 20 RCTs, the POS was 16.20 (95% CI 14.79–17.60) months, with P1SR of 63% (95% CI 59–66%) and P2SR of 37% (33–41%). Thus, we defined LS as mOS ≥ POS (16.20 m) for regimens and screened for RCTs with outcomes meeting this criterion. Eleven ICI-based regimens can bring LS for the overall population, among which ICI with bevacizumab and chemotherapy achieved the longest POS of 19.50 m (16.90–22.10 m) and the highest P1SR (74%, 61%–87%) and P2SR (49%, 38%–61%). Pembrolizumab with chemotherapy ranked first in mOS and 1ySR, while atezolizumab plus bevacizumab and chemotherapy ranked first in 2ySR.

Conclusions

Through the IA of first-line treatment regimens, a POS of 16.20 m can be determined as the LS standard. Further considering 1ySR and 2ySR, atezolizumab combined with bevacizumab and chemotherapy or pembrolizumab plus chemotherapy are likely to bring the longest LS in the overall population, while single ICI may be adequate for patients with a high PD-L1 expression. ICIs with bevacizumab and chemotherapy may be the best combination for LS for its further advantage over time.
Validity of Machine Learning in Predicting Giant Cell Arteritis Flare After Glucocorticoids Tapering
Authors: Venerito Vincenzo , Emmi Giacomo , Cantarini Luca , Leccese Pietro , Fornaro Marco , Fabiani Claudia , Lascaro Nancy , Coladonato Laura , Mattioli Irene , Righetti Giulia , Malandrino Danilo , Tangaro Sabina , Palermo Adalgisa , Urban Maria Letizia , Conticini Edoardo , Frediani Bruno , Iannone Florenzo , Lopalco Giuseppe
Published: April 2022

Background

Inferential statistical methods failed in identifying reliable biomarkers and risk factors for relapsing giant cell arteritis (GCA) after glucocorticoids (GCs) tapering. A ML approach allows to handle complex non-linear relationships between patient attributes that are hard to model with traditional statistical methods, merging them to output a forecast or a probability for a given outcome.

Objective

The objective of the study was to assess whether ML algorithms can predict GCA relapse after GCs tapering.

Methods

GCA patients who underwent GCs therapy and regular follow-up visits for at least 12 months, were retrospectively analyzed and used for implementing 3 ML algorithms, namely, Logistic Regression (LR), Decision Tree (DT), and Random Forest (RF). The outcome of interest was disease relapse within 3 months during GCs tapering. After a ML variable selection method, based on a XGBoost wrapper, an attribute core set was used to train and test each algorithm using 5-fold cross-validation. The performance of each algorithm in both phases was assessed in terms of accuracy and area under receiver operating characteristic curve (AUROC).

Results

The dataset consisted of 107 GCA patients (73 women, 68.2%) with mean age ( ± SD) 74.1 ( ± 8.5) years at presentation. GCA flare occurred in 40/107 patients (37.4%) within 3 months after GCs tapering. As a result of ML wrapper, the attribute core set with the least number of variables used for algorithm training included presence/absence of diabetes mellitus and concomitant polymyalgia rheumatica as well as erythrocyte sedimentation rate level at GCs baseline. RF showed the best performance, being significantly superior to other algorithms in accuracy (RF 71.4% vs LR 70.4% vs DT 62.9%). Consistently, RF precision (72.1%) was significantly greater than those of LR (62.6%) and DT (50.8%). Conversely, LR was superior to RF and DT in recall (RF 60% vs LR 62.5% vs DT 47.5%). Moreover, RF AUROC (0.76) was more significant compared to LR (0.73) and DT (0.65).

Conclusions

RF algorithm can predict GCA relapse after GCs tapering with sufficient accuracy. To date, this is one of the most accurate predictive modelings for such outcome. This ML method represents a reproducible tool, capable of supporting clinicians in GCA patient management.
Ocean Currents May Influence the Endolithic Bacterial Composition in Coral Skeletons
Authors: Liu Po-Yu , Yang Sung-Yin , Lu Chih-Ying , Wada Naohisa , De Palmas Stéphane , Yeh Shu-Shuo , Yamashiro Hideyuki , Tang Sen-Lin , Yang Shan-Hua
Published: April 2022

Coral endolithic microbes can be an important nutrients support for hosts while under stresses. Previous studies have found that the endolithic microbial composition of a single coral species can be biogeographical diverse. However, the potential environmental factors, such as salinity, temperature, pH, and nutrient, that might influence the composition of the endolithic microbes remain unclear. In this study, we used both amplicon sequence variants (ASV) and a kmer-based taxonomic unit (KTU) to characterize the endolithic bacterial constitution of Isopora spp. located in the western Pacific Ocean—where it is subjected to the Kuroshio Current (in Okinawa, Japan and Green Island, Taiwan)—and the South China Sea (Dongsha Atoll). The endolithic bacterial community compositions showed a significant geographical difference, and we suggest that the ocean current and primary productivity are the most essential environmental factors influencing the bacterial communities in the skeleton of Isopora spp. In addition, our results showed that, technically, compared to ASV, bacterial composition based on KTU avoids extreme data, making it a suitable tool for explaining the associations between microbes and environmental factors.
Genetic Screening of Candida albicans Inactivation Mutants Identifies New Genes Involved in Macrophage-Fungal Cell Interactions
Authors: Godoy Pablo , Darlington Peter John , Whiteway Malcolm
Published: April 2022

Candida albicans, an important fungal pathogen of humans, displays different morphologies, such as yeast, pseudo-hyphae and hyphae, which are recognized unequally by phagocytic cells of the innate immune response. Once C. albicans cells invade host tissues, immune cells such as macrophages are attracted to the site of infection and activated to recognize, engulf and kill the pathogen. We have investigated this fungal cell-macrophage interface by using high-throughput screening of the C. albicans GRACE library to identify genes that can influence this interaction and modify the kinetics of engulfment. Compared with the wild-type (WT) strain, we identified generally faster rates of engulfment for those fungal strains with constitutive pseudo-hyphal and hyphal phenotypes, whereas yeast-form-locked strains showed a reduced and delayed recognition and internalization by macrophages. We identified a number of GRACE strains that showed normal morphological development but exhibited different recognition and engulfment kinetics by cultured macrophages and characterized two mutants that modified interactions with the murine and human-derived macrophages. One mutant inactivated an uncharacterized C. albicans open reading frame that is the ortholog of S. cerevisiae OPY1, the other inactivated CaKRE1. The modified interaction was monitored during a 4 h co-culture. Early in the interaction, both opy1 and kre1 mutant strains showed reduced recognition and engulfment rates by macrophages when compared with WT cells. At fungal germ tube initiation, the engulfment kinetics increased for both mutants and WT cells, however the WT cells still showed a higher internalization by macrophages up to 2 h of interaction. Subsequently, between 2 and 4 h of the interaction, when most macrophages contain engulfed fungal cells, the engulfment kinetics increased for the opy1 mutant and further decreased for the kre1 mutant compared with Ca-WT. It appears that fungal morphology influences macrophage association with C. albicans cells and that both OPY1 and KRE1 play roles in the interaction of the fungal cells with phagocytes.
Long-Term Effect of Acetylcholinesterase Inhibitors on the Dorsal Attention Network of Alzheimer’s Disease Patients: A Pilot Study Using Resting-State Functional Magnetic Resonance Imaging
Authors: Yamashita Ken-ichiro , Uehara Taira , Taniwaki Yoshihide , Tobimatsu Shozo , Kira Jun-ichi
Published: April 2022

Background

Alzheimer’s disease (AD) is the most common condition of all neurodegenerative diseases and is characterized by various cognitive dysfunctions. Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have revealed the physiological dynamics of functionally connected brain networks, which are called resting-state networks (RSNs). Associations between impairments of RSNs and various neuropsychiatric diseases, such as AD, have been reported. Acetylcholinesterase inhibitors (AChEIs) have been used as a pharmacological treatment for mild-to-moderate moderate AD, and short-term improvements in cognitive functions and RSNs in restricted areas have been reported.

Objective

We aimed to characterize AChEI-related RSN changes by acquiring two sets of rs-fMRI data separated by approximately 3 to 6 months.

Methods

Seventeen patients with AD and nine healthy subjects participated in this study. Independent component analysis was performed on the rs-fMRI data of AChEI-responsive and non-responsive AD patients, stratified according to change in Mini-Mental State Examination (MMSE) scores after 3 to 6 months of AChEI therapy. In addition, a region of interest-based analysis of the rs-fMRI data before therapy was performed to explore the functional connectivity (FC) changes associated with AchEI therapy.

Results

Responders showed a significantly greater increase in MMSE scores, especially for orientation for time, than that of non-responders following AChEI therapy. A subtraction map of MMSE score differences (responders minus non-responders) in the independent component analysis revealed higher FC of the dorsal attention network in responders compared with that in non-responders. Moreover, in the region of interest analysis of untreated status data, the dorsal attention network showed significant negative FC with the right planum temporale, which belongs to the ventral attention network, proportional to MMSE score change.

Conclusion

The negative correlation of the FC of the dorsal attention network and right planum temporale before AChEI therapy and MMSE score change may be a biomarker of the therapeutic effect of AChEIs for AD.
Neural Hyperactivity Is a Core Pathophysiological Change Induced by Deletion of a High Autism Risk Gene Ash1L in the Mouse Brain
Authors: Gao Yuen , Aljazi Mohammad B. , He Jin
Published: April 2022

ASH1L is one of the highest risk genes associated with autism spectrum disorder (ASD) and intellectual disability (ID). Our recent studies demonstrate that loss of Ash1l in the mouse brain is sufficient to induce ASD/ID-like behavioral and cognitive deficits, suggesting that disruptive ASH1L mutations are likely to have a positive correlation with ASD/ID genesis. However, the core pathophysiological changes in the Ash1l-deficient brain remain largely unknown. Here we show that loss of Ash1l in the mouse brain causes locomotor hyperactivity, high metabolic activity, and hyperactivity-related disturbed sleep and lipid metabolic changes. In addition, the mutant mice display lower thresholds for the convulsant reagent-induced epilepsy and increased neuronal activities in multiple brain regions. Thus, our current study reveals that neural hyperactivity is a core pathophysiological change in the Ash1l-deficient mouse brain, which may function as a brain-level mechanism leading to the Ash1l-deletion-induced brain functional abnormalities and autistic-like behavioral deficits.
At the Crossroad Between Resiliency and Fragility: A Neurodevelopmental Perspective on Early-Life Experiences
Authors: Chelini Gabriele , Pangrazzi Luca , Bozzi Yuri
Published: April 2022

Postnatal development of the brain is characterized by sensitive windows during which, local circuitry are drastically reshaped by life experiences. These critical periods (CPs) occur at different time points for different brain functions, presenting redundant physiological changes in the underlying brain regions. Although circuits malleability during CPs provides a valuable window of opportunity for adaptive fine-tuning to the living environment, this aspect of neurodevelopment also represents a phase of increased vulnerability for the development of a variety of disorders. Consistently, accumulating epidemiological studies point to adverse childhood experience as a major risk factor for many medical conditions, especially stress- and anxiety-related conditions. Thanks to creative approaches to manipulate rodents’ rearing environment, neurobiologist have uncovered a pivotal interaction between CPs and early-life experiences, offering an interesting landscape to improve our understanding of brain disorders. In this short review, we discuss how early-life experience impacts cellular and molecular players involved in CPs of development, translating into long-lasting behavioral consequences in rodents. Bringing together findings from multiple laboratories, we delineate a unifying theory in which systemic factors dynamically target the maturation of brain functions based on adaptive needs, shifting the balance between resilience and vulnerability in response to the quality of the rearing environment.
Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases
Authors: Zhang Shuyuan , Zhao Juan , Quan Zhenzhen , Li Hui , Qing Hong
Published: April 2022

The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles—especially mitochondria—in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.
The Prognostic Signature of Head and Neck Squamous Cell Carcinoma Constructed by Immune-Related RNA-Binding Proteins
Authors: Ming Ruijie , Li Xiangrui , Wang Enhao , Wei Jiahui , Liu Bo , Zhou Peng , Yu Wenting , Zong Shimin , Xiao Hongjun
Published: April 2022

Purpose

This study aimed to construct a prognostic signature consisting of immune-related RNA-binding proteins (RBPs) to predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) effectively.

Methods

The transcriptome and clinical data of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, we ascertained the immunological differences in HNSCC, through single-sample gene set enrichment analysis, stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE), and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) deconvolution algorithm. Then we used univariate proportional hazards (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to screen immune-related RBPs and acquire the risk score of each sample. Subsequently, we further investigated the difference in prognosis, immune status, and tumor mutation burden in high- and low-risk groups. Finally, the efficacy of immunotherapy was measured by the tumor immune dysfunction and exclusion (TIDE) score.

Results

We derived 15 immune-related RBPs, including FRMD4A, ASNS, RAB11FIP1, FAM120C, CFLAR, CTTN, PLEKHO1, SELENBP1, CHCHD2, NPM3, ATP2A3, CFDP1, IGF2BP2, NQO1, and DENND2D. There were significant differences in the prognoses of patients in the high- and low-risk groups in the training set (p < 0.001) and the validation set (p < 0.01). Furthermore, there were statistical differences between the high-risk group and low-risk group in immune cell infiltration and pathway and tumor mutation load (p < 0.001). In the end, we found that patients in the low-risk group were more sensitive to immunotherapy (p < 0.001), and then we screened 14 small-molecule chemotherapeutics with higher sensitivity to the high-risk group (p < 0.001).

Conclusion

The study constructed a prognostic signature of HNSCC, which might guide clinical immunotherapy in the future.