ResearchPad - 16 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice]]> https://www.researchpad.co/article/N4cdc74ff-002c-45bb-8f1d-ad7f957c837c Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

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<![CDATA[Letter: Neurosurgical Management of Spinal Pathology Via Telemedicine During the COVID-19 Pandemic: Early Experience and Unique Challenges]]> https://www.researchpad.co/article/N50a23e0c-05be-46bd-bd67-48f60a990c47 <![CDATA[Evolution in the Debian GNU/Linux software network: analogies and differences with gene regulatory networks]]> https://www.researchpad.co/article/N36ed7a4d-f37c-42e3-b0e5-334f53109fd2

Biological networks exhibit intricate architectures deemed to be crucial for their functionality. In particular, gene regulatory networks, which play a key role in information processing in the cell, display non-trivial architectural features such as scale-free degree distributions, high modularity and low average distance between connected genes. Such networks result from complex evolutionary and adaptive processes difficult to track down empirically. On the other hand, there exists detailed information on the developmental (or evolutionary) stages of open-software networks that result from self-organized growth across versions. Here, we study the evolution of the Debian GNU/Linux software network, focusing on the changes of key structural and statistical features over time. Our results show that evolution has led to a network structure in which the out-degree distribution is scale-free and the in-degree distribution is a stretched exponential. In addition, while modularity, directionality of information flow, and average distance between elements grew, vulnerability decreased over time. These features resemble closely those currently shown by gene regulatory networks, suggesting the existence of common adaptive pathways for the architectural design of information-processing networks. Differences in other hierarchical aspects point to system-specific solutions to similar evolutionary challenges.

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<![CDATA[How the thermal environment shapes the structure of termite mounds]]> https://www.researchpad.co/article/N31476f69-0900-4f3b-925c-832a14722245

A computational model has been developed to predict the role of environment in the forms and functions of termite mounds. The proposed model considers the most relevant forces involved in the heat transfer process of termite mounds, while also reflecting their gas-exchange function. The method adopts a system configuration procedure to determine thermally optimized mound structures. The model successfully predicts the main architectural characteristics of typical Macrotermes michaelseni mounds for the environmental conditions they live in. The results indicate that the mound superstructure and internal condition strongly depend on the combined effect of environmental forces. It is noted that mounds being exposed to higher solar irradiances develop intricate lateral channels, inside, and taller and more pronounced spire tilt towards the Sun, outside. It is also found that the mounds' spire tilt angle depends on the geographical location, following the local average solar zenith angle for strong irradiances. Although wind does not influence the overall over-ground mound shape, it significantly affects the mound internal condition. The results of this study resonate with what is seen in nature. The proposed approach provides a broader view of the factors that are effective in the form and function of a naturally made structure.

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<![CDATA[Beauty in artistic expressions through the eyes of networks and physics]]> https://www.researchpad.co/article/N034345df-04aa-4302-808a-d26b534fce2a

Beauty is subjective, and as such it, of course, cannot be defined in absolute terms. But we all know or feel when something is beautiful to us personally. And in such instances, methods of statistical physics and network science can be used to quantify and to better understand what it is that evokes that pleasant feeling, be it when reading a book or looking at a painting. Indeed, recent large-scale explorations of digital data have lifted the veil on many aspects of our artistic expressions that would remain forever hidden in smaller samples. From the determination of complexity and entropy of art paintings to the creation of the flavour network and the principles of food pairing, fascinating research at the interface of art, physics and network science abounds. We here review the existing literature, focusing in particular on culinary, visual, musical and literary arts. We also touch upon cultural history and culturomics, as well as on the connections between physics and the social sciences in general. The review shows that the synergies between these fields yield highly entertaining results that can often be enjoyed by layman and experts alike. In addition to its wider appeal, the reviewed research also has many applications, ranging from improved recommendation to the detection of plagiarism.

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<![CDATA[Imaging unlabeled proteins on DNA with super-resolution]]> https://www.researchpad.co/article/N22442a84-cdb5-4341-9fbd-48a5adeebd15

Abstract

Fluorescence microscopy is invaluable to a range of biomolecular analysis approaches. The required labeling of proteins of interest, however, can be challenging and potentially perturb biomolecular functionality as well as cause imaging artefacts and photo bleaching issues. Here, we introduce inverse (super-resolution) imaging of unlabeled proteins bound to DNA. In this new method, we use DNA-binding fluorophores that transiently label bare DNA but not protein-bound DNA. In addition to demonstrating diffraction-limited inverse imaging, we show that inverse Binding-Activated Localization Microscopy or ‘iBALM’ can resolve biomolecular features smaller than the diffraction limit. The current detection limit is estimated to lie at features between 5 and 15 nm in size. Although the current image-acquisition times preclude super-resolving fast dynamics, we show that diffraction-limited inverse imaging can reveal molecular mobility at ∼0.2 s temporal resolution and that the method works both with DNA-intercalating and non-intercalating dyes. Our experiments show that such inverse imaging approaches are valuable additions to the single-molecule toolkit that relieve potential limitations posed by labeling.

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<![CDATA[Psychometric properties of the Friedreich Ataxia Rating Scale]]> https://www.researchpad.co/article/Nd7fbac11-63bd-4c2f-a9a2-3b4c14e6afbb

Objective

To investigate the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination.

Methods

Based on cross-sectional FARS data from the FA–Clinical Outcome Measures cohort, we conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs.

Results

The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS.

Conclusions

A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

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<![CDATA[Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2]]> https://www.researchpad.co/article/N0016e68f-10c6-41a2-a3e7-8df34418bdc9

Objective

To report the presence of a new neuronal surface antibody against the metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in 2 patients with paraneoplastic cerebellar ataxia.

Methods

mGluR2-Abs were initially characterized by immunohistochemistry on the rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluRs, expression of mGluR2 in patients' tumors, and the effects of mGluR2-Abs on cultures of rat hippocampal neurons.

Results

Patient 1 was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients' serum and CSF showed a characteristic immunostaining of the hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients' antibodies only recognized mGluR2. mGluR2-Abs were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias, and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters.

Conclusions

mGluR2-Abs are a novel biomarker of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by downregulation or internalization of neuronal surface mGluR2.

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<![CDATA[Virus-induced transposable element expression up-regulation in human and mouse host cells]]> https://www.researchpad.co/article/Ndbdd434c-7f8d-4bb3-8cc0-b6af110392c2

Genome-wide transposon expression up-regulation in host cells regardless of virus, species, and host cell tissue types occurs early during viral infection and likely contributes to promoting the host innate immune response.

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<![CDATA[Segregation and polarization in urban areas]]> https://www.researchpad.co/article/Nda11ba35-af2a-41e8-bf00-ec341e795810

Social behaviours emerge from the exchange of information among individuals—constrained by and reciprocally influencing the structure of information flows. The Internet radically transformed communication by democratizing broadcast capabilities and enabling easy and borderless formation of new acquaintances. However, actual information flows are heterogeneous and confined to self-organized echo-chambers. Of central importance to the future of society is understanding how existing physical segregation affects online social fragmentation. Here, we show that the virtual space is a reflection of the geographical space where physical interactions and proximity-based social learning are the main transmitters of ideas. We show that online interactions are segregated by income just as physical interactions are, and that physical separation reflects polarized behaviours beyond culture or politics. Our analysis is consistent with theoretical concepts suggesting polarization is associated with social exposure that reinforces within-group homogenization and between-group differentiation, and they together promote social fragmentation in mirrored physical and virtual spaces.

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<![CDATA[Serum levels of L1-ORF1p and airflow limitation]]> https://www.researchpad.co/article/N8d8b1971-c580-436e-8f83-cd026ca0859b

LINE-1 (long interspersed nuclear element-1) is a group of polymorphic DNA sequences in the human genome that mobilise via RNA binding proteins, reverse transcriptase and endonuclease to alter the host genome via mutational insertions, chromosomal rearrangements and reprogramming of gene expression (reviewed by Ramos et al. [1]). Full-length LINE-1 sequences encode two proteins: L1-ORF1p, a 40-kDa protein with nucleic acid binding activity; and L1-ORF2p, a 150-kDa protein with endonuclease and reverse transcriptase activities. The activity of LINE-1 is repressed in somatic tissues via DNA methylation and covalent protein modifications, and reactivated by displacement of retinoblastoma-associated proteins from the regulatory region [2]. Recent studies in our laboratory have implicated LINE-1 as a master regulator of human bronchial epithelial cell phenotypes in experimental in vitro and in vivo models [3].

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<![CDATA[Atti del 52° Congresso Nazionale]]> https://www.researchpad.co/article/N40742df4-0c85-42be-960e-c80df7e02214

Nel promuovere e gestire i cambiamenti necessari per coniugare pratiche sicure ed efficaci con l’efficienza, l’equità e la sostenibilità dei servizi sanitari, essenziale è la conoscenza, la diffusione e l’adesione alle raccomandazioni per la pratica professionale derivanti da linee guida (LG). In Italia la Legge 24/2017 (“Disposizioni in materia di sicurezza delle cure e della persona assistita, nonché in materia di responsabilità professionale degli esercenti le professioni sanitarie”), stabilendo che “gli esercenti le professioni sanitarie, nell’esecuzione delle prestazioni sanitarie con finalità preventive, diagnostiche, terapeutiche, palliative, riabilitative e di medicina legale, si attengono, salve le specificità del caso concreto, alle raccomandazioni previste dalle linee guida pubblicate ed elaborate da enti e istituzioni pubblici e privati nonché dalle società scientifiche e dalle associazioni tecnico-scientifiche delle professioni sanitarie iscritte in apposito elenco”, ha rinnovato l’impulso legislativo, culturale, professionale e scientifico alla diffusione delle LG nel Servizio Sanitario Nazionale. L’attuale quadro regolamentare italiano prevede che la loro produzione venga garantita sulla base degli standard di predisposizione e valutazione della qualità metodologica definiti dal Centro Nazionale per l’Eccellenza Clinica (CNEC) dell’Istituto Superiore di Sanità, punto di riferimento per l’attuazione del nuovo Sistema Nazionale Linee Guida (istituito con il DM 27 febbraio 2018) (https://snlg.iss.it).

Secondo la vigente definizione adottata dal CNEC, le LG sono uno “strumento di supporto decisionale finalizzato a consentire che, fra opzioni alternative, sia adottata quella che offre un migliore bilancio fra benefici ed effetti indesiderati, tenendo conto della esplicita e sistematica valutazione delle prove disponibili, commisurandola alle circostanze peculiari del caso concreto e condividendola-laddove possibile-con il paziente o i caregiver”. Le linee guida servono dunque a supportare i processi decisionali che connotano la pratica professionale preventiva, diagnostica, terapeutica e assistenziale, ma anche le scelte manageriali e le politiche sanitarie. Ai diversi livelli del sistema sanitario, infatti, la disponibilità di LG è fondamentale per contrastare alcune delle criticità sistemiche della sanità connesse, tra l’altro, all’erogazione di cure di qualità sub-ottimale, alla variazione ingiustificata di pratiche ed esiti e alle diseguaglianze, in un quadro di risorse limitate.

Se dunque oggi il valore delle linee guida per la pratica clinica è indiscutibile in tutti gli ambiti disciplinari della medicina, peculiare è il significato, professionale e organizzativo, che le stesse possono assumere nello sviluppo e nella specifica applicazione alla sanità pubblica. In particolare, la sanità pubblica si caratterizza per: la forte eterogeneità nelle evidenze scientifiche disponibili (non di rado costituite solamente da studi osservazionali), l’adozione di un approccio di population health e la frequente individuazione di target costituiti da persone sane, la molteplicità (anche in relazione all’importanza attribuita dagli stakeholder coinvolti) degli ambiti di produzione di linee guida (www.who.int/publications/guidelines), degli interventi sanitari e degli outcome individuati nei contesti reali (e non di ricerca), condizionati da una molteplicità di variabili culturali, organizzative, socio-economiche e ambientali.

Spesso le raccomandazioni prodotte in sanità pubblica sono destinate ad avere un impatto quali-quantitativamente molto rilevante sul sistema sanitario e necessitano di modelli in grado di prevederne l’implementazione, non sempre agevolmente correlabili alle evidenze scientifiche disponibili a priori. Altresì, il percorso di costruzione del consenso e implementazione degli interventi è articolato e complesso. In misura maggiore rispetto ad altre discipline mediche, i comportamenti degli operatori non si basano solo sulle conoscenze tecnico-scientifiche disponibili (talora limitate e non sempre esplicitamente generalizzabili), ma risentono e sono condizionati da dettati normativi, meccanismi di consenso locale, eterogeneità di strutture erogatrici e risorse (professionali, organizzative e tecnologiche), nonché da relazioni con una molteplicità di portatori di interesse dentro e fuori il sistema sanitario (che a loro volta esprimono valori e preferenze anche contrastanti).

Il metodo scelto dal CNEC (e adottato anche dall’Agenzia Italiana del Farmaco per le valutazioni di propria competenza) per la produzione di linee guida è il metodo GRADEGrading of Recommendations Assessment, Development and Evaluation – che costituisce oggi la principale cornice riferimento per la valutazione di affidabilità delle prove scientifiche e per la formulazione di raccomandazioni cliniche basate sulle evidenze in sanità: viene utilizzato da più di 100 organizzazioni in tutto il mondo comprendenti anche l’Organizzazione Mondiale della Sanità e il National Institute for Health and Care Excellence (www.gradeworkinggroup.org). Il GRADE assicura standardizzazione e trasparenza della procedura con cui viene valutata la qualità delle prove disponibili e la forza delle raccomandazioni per la produzione di linee guida, favorendo una valutazione integrata della qualità metodologica delle prove disponibili con altri aspetti che devono essere considerati per sviluppare e stabilire la forza di una raccomandazione, mediante i cosiddetti Evidence to Decision Framework, quali: priorità della problematica trattata (es. impatto sanitario, variabilità, costi), benefici e rischi attesi, valori e preferenze dei pazienti, costo-efficacia, accettabilità, fattibilità ed equità. Il GRADE offre un approccio flessibile e pragmatico che può essere applicato sia alla produzione di una linea guida ex novo che all’adattamento di linee guida già esistenti, per le quali si applicano gli schemi di GRADE-ADOLOPMENT, calibrati su un determinato contesto culturale e organizzativo. Il panel di esperti (gruppi di lavoro multidisciplinari e multistakeholder che sistematicamente devono coinvolgere anche utenti/cittadini) definisce chiaramente la domanda di ricerca, il protocollo condiviso secondo l’acronimo PICO (Patient-Intervention-Comparator-Outcome) per l’analisi della qualità delle prove di evidenza ed esprimere giudizi sui diversi criteri di valutazione necessari alla formulazione e valutazione della forza delle raccomandazioni. Mediante una gestione trasparente (e una particolare attenzione alla disclosure e alla gestione dei conflitti di interesse dei membri dei panel), fortemente ancorata al mondo reale, con il processo di “evidence to decision” il GRADE si pone l’obiettivo di ordinare per gradi la forza delle raccomandazioni espresse dai panel di esperti in modo da offrire strumenti interpretativi e decisionali per pazienti/utenti, clinici e decisori sanitari. La rappresentatività e il coinvolgimento con modalità strutturate di tutte le figure competenti e rilevanti per i quesiti e sulle raccomandazioni in oggetto costituisce un aspetto fondamentale di qualità e credibilità della linea guida.

Accanto alla chiara affinità tra metodo GRADE e logiche epidemiologiche e di centralità di un approccio multidimensionale, multidisciplinare e inter-professionale che caratterizza il processo decisionale in sanità pubblica, è interessante evidenziare l’opportunità della promozione dell’applicazione del GRADE per gli igienisti sia nella veste di proponenti, esperti per gli ambiti tecnico-scientifici di propria competenza e destinatari “professionali” delle raccomandazioni, che in qualità di manager e decisori che possono essere coinvolti nei panel (anche su pratiche di non esclusiva pertinenza della sanità pubblica), nonché, naturalmente di metodologi, parte dei team di revisione della letteratura e a supporto dell’utilizzo del metodo stesso che richiede una specifica formazione e competenza.

Gli indirizzi sulle LG comprendono anche la fase di implementazione attinente come a partire dalle raccomandazioni prodotte e diffuse si riesce ad incidere sui comportamenti professionali, ovvero colmare il gap tra ricerca e pratica professionale. Questo richiede leadership e facilitazione del giusto mix di interventi (preferibilmente multifattoriali) di supporto al cambiamento (audit & feedback, interventi formativi mirati, processi di consenso locali, uso di strumenti di comunicazione, ecc), calibrati su ostacoli e fattori favorenti l’adozione delle linee guida. L’implementazione di LG promuove la gestione e la condivisione di informazioni, conoscenze e pratiche che favoriscono un approccio trasversale rispetto alle funzioni e ai team di lavoro che promuove l’integrazione (sia all’interno che con l’esterno delle organizzazioni sanitarie) e può assicurare processi decisionali più affidabili ed efficienti.

La coerenza tra raccomandazioni per l’ottimizzazione dell’efficacia e altre dimensioni della qualità dell’intervento sanitario (quali sicurezza, accessibilità ed equità) con le esigenze di efficienza e razionalità organizzativa dei servizi configura un importante ancoraggio delle LG al paradigma emergente del valore in sanità. Costruire una sanità basata sul valore implica una chiara analisi del profilo di efficacia degli interventi sanitari e la disponibilità di robusti strumenti valutativi e infrastrutture digitali di supporto alla misurazione accurata e tempestiva dei dati epidemiologici della popolazione, da trasformare in informazioni cliniche rilevanti per integrare e analizzare tutti i passaggi (e i risultati ottenuti) del ciclo di assistenza in oggetto e da correlare costantemente con i costi sostenuti dal sistema sanitario. Massimizzare il valore, ovvero gli esiti prodotti in relazione alle risorse a disposizione, per gli individui e le popolazioni presuppone l’adozione di criteri di finanziamento e di gestione delle risorse (umane e organizzative) e soluzioni tecnologiche che facilitino la costruzione di reti e percorsi, da coniugare con la capacità di tradurre i risultati della ricerca sanitaria e le best practice in raccomandazioni. D’altro canto, la diffusione di pratiche sicure, efficaci e appropriate consente di concorrere in maniera determinante all’uniformità di tassonomia, modelli e comportamenti professionali in contesti decisionali affini, ovvero di contribuire a standardizzare l’operatività dei servizi, aspetto quest’ultimo rilevante nel contesto della sanità pubblica italiana e delle sue articolazioni operative territoriali.

L’adozione di linee guida ovviamente presenta anche aspetti di criticità, legati all’effettiva traduzione dei risultati della ricerca e dell’innovazione in comportamenti professionali diffusi e virtuosi; ma anche all’adeguatezza delle LG e dei correlati processi decisionali di fronte a quesiti o target di popolazione per loro natura complessi, come quelli che si incontrano per esempio nel produrre indirizzi che siano effettivamente rispondenti alle esigenze di prevenzione e personalizzazione dell’assistenza del “paziente complesso”. A ciò vanno aggiunte alcune difficoltà organizzative e professionali che connotano l’odierna fase di avvio della concreta applicazione del metodo GRADE allo sviluppo delle raccomandazioni per la pratica clinica proposto nel “nuovo Sistema Nazionale Linee Guida”. Per esempio, rispetto alla sanità pubblica, pur esistendo oggi molte LG autorevoli e di diffusa applicazione, queste spesso risultano essere datate e realizzate con meccanismi di consenso e formulazione delle raccomandazioni di tipo tradizionale, rendendo dunque necessari aggiornamenti e adattamenti secondo le menzionate modalità di lavoro proposte a livello nazionale e internazionale per produrre linee guida di alta qualità.

Per operare nel quadro della nuova cornice metodologica sulle LG, ai medici e agli altri professionisti sanitari, ai manager e ai policy maker della sanità, al mondo accademico e alle società scientifiche è richiesto un investimento prioritario nella gestione di conoscenze fondate su un approccio scientifico, strutturato e trasparente alla definizione dell’efficacia e dell’appropriatezza degli interventi medici. In questo contesto nazionale, per gli igienisti in collaborazione con tutti gli attori della Sanità Pubblica, è strategico un impegno permanente sulla tematica delle linee guida, da sostenere anche mediante azioni di formazione, condivisione di conoscenza e di comunicazione. Valorizzare l’applicazione critica di strumenti per governare i processi decisionali secondo logiche di partecipazione e fiducia reciproca tra gli stakeholder è fondamentale per il perseguimento degli obiettivi di ottimizzazione della qualità e della sostenibilità nel Servizio Sanitario Nazionale, a beneficio dei cittadini-pazienti e della società nella sua globalità.

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<![CDATA[Clinical performance of Anyplex II HPV28 by human papillomavirus type and viral load in a referral population]]> https://www.researchpad.co/article/5c5217cad5eed0c4847945b2

Anyplex II HPV28 (`Anyplex`) is a semi-quantitative DNA PCR assay divided into set A, comprising 14 high risk (hr)HPV types; and set B, comprising 5 possibly hrHPV types and 9 low risk (lr)HPV types. We compared the ability of Anyplex to that of Hybrid Capture 2 (HC2) and PreTect HPV-Proofer (`Proofer`) to detect cervical intraepithelial neoplasia grade two or worse (CIN2+) by HPV types and viral load. This cross-sectional study included 296 women referred to colposcopy with abnormal cervical cytology and/or persistent HPV infection. CIN2+ was identified in 175/296 women. Liquid based cytology samples were used to perform HPV testing. The sensitivity of Anyplex to detect CIN2+ was 98.9% (95% CI 95.9–99.9) and specificity 43.0% (95% CI 34.0–52.3). Restricting to medium and high viral loads in Anyplex set A, sensitivity and specificity were 97.1% (95% CI 93.5–99.1) and 59.5% (95% CI 50.2–68.3) with positive (PPV) and negative predictive value (NPV) 77.6% and 93.5%, respectively, comparable to HC2. Restricting Anyplex to the hrHPV types in Proofer, HPV16, 18, 31, 33 and 45, sensitivity and specificity for CIN2+ were 85.1% (95% CI 79.0–90.1) and 71.1% (95% CI 62.1–79.0), comparable to Proofer`s. When adding HPV52 and 58, the sensitivity for CIN2+ was 92.6% (95% CI 87.6–96.0) and CIN3+ 96.5% (95% CI 92.0–98.8). No value of Anyplex set B was found in detecting CIN2+. In conclusion, the clinical performance of medium and high viral loads in Anyplex set A was comparable to HC2. Restricting the test to the 7 hrHPV types included in the 9-valent HPV-vaccine, HPV16, 18, 31, 33, 45, 52 and 58, satisfies the international criteria for cervical cancer screening with relative sensitivity compared to HC2 for CIN2+ and CIN3+ of 0.98 and 1.01, respectively. Detecting all 28 Anyplex HPV types adds no benefit in a referral population.

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<![CDATA[Episodic ataxia in CASPR2 autoimmunity]]> https://www.researchpad.co/article/5c5f19ced5eed0c484699d48 ]]> <![CDATA[Viperin controls chikungunya virus–specific pathogenic T cell IFNγ Th1 stimulation in mice]]> https://www.researchpad.co/article/5c5afb62d5eed0c48425feed

This study shows that Viperin controls the microenvironment pro-inflammatory response and CD4 T cell–mediated pathogenesis during anti-chikungunya virus immune response in mice.

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<![CDATA[The tumor-suppressive function of miR-1296-5p by targeting EGFR and CDK6 in gastric cancer]]> https://www.researchpad.co/article/5c4b9418d5eed0c48487dd54

We aimed to confirm the role of miR-1296-5p in gastric cancer and to identify its target genes. The expression of miR-1296-5p was measured in gastric cancer tissues and cell lines. The function of miR-1296-5p was examined by the overexpression and inhibition of its expression in typical gastric cell lines as well as SGC-7901 and MGC-803 cells. The targets of miR-1296-5p were identified by a luciferase activity assay. We found that miR-1296-5p was down-regulated in gastric cancer tissue and cell lines, and low expression levels of miR-1296-5p were associated with advanced clinical stage. Moreover, miR-1296-5p inhibited cell proliferation, migration, and invasion in SGC-7901 and MGC-803 cells. Then, we identified CDK6 and EGFR as novel targets of miR-1296-5p by a luciferase activity assay. Furthermore, the overexpression of miR-1296-5p suppressed the expression of CDK6 and EGFR. Our results indicated a tumor-suppressive role of miR-1296-5p through the translational repression of oncogenic CDK6 and EGFR in gastric cancer.

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<![CDATA[MiRNA-575 suppresses angiogenesis by targeting Rab5-MEK-ERK pathway in endothelial cells]]> https://www.researchpad.co/article/5c4b941cd5eed0c48487de14

Hypertension is a major risk factor for the development of atherosclerosis. Increased carotid intima-media thickness (CIMT) is generally considered as an early marker of atherosclerosis. Recently, circulating miRNAs have been implicated both as sensitive biomarkers and key regulators in the development of atherosclerosis. However, the biological functions and molecular regulatory mechanisms for miR-575 on angiogenesis remain unknown. In our study, we first identified up-regulation of circulating miR-575 in plasma of essential hypertensive patients with increased CIMT (iCIMT) compared with those patients with normal CIMT (nCIMT). Furthermore, the overexpression of miR-575 in human umbilical vein endothelial cells (HUVECs) by its mimics significantly inhibited migration and proliferation as well as induction of apoptosis of HUVECs. Inhibition of miR-575 performed the reverse effects of HUVECs. We further suggested Rab5B was the downstream target of miR-575 and knockdown of Rab5B significantly inhibited migration and proliferation of HUVECs. Overexpression of Rab5B largely rescued the miR-575-mediated impairment of angiogenesis processes including: cell proliferation, migration, and apoptosis as well as activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK) signaling. Therefore, our results uncover a novel role of miR-575 in endothelial cells, implying a potential biomarker and clinical target for atherosclerosis in hypertensive patients.

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<![CDATA[QRREM method for the isolation of high-quality RNA from the complex matrices of coconut]]> https://www.researchpad.co/article/5c4b93ebd5eed0c48487d4af

Complex plant tissues vary in hardness, i.e. some are succulent, while others are complex to break. Besides, plant metabolites, such as polysaccharides, proteins, polyphenols and lipids, can greatly interfere with the RNA extraction. So, in order to obtain a high-quality RNA from the complex tissues (like coconut endosperm, coconut apple and coconut leaf bud) rich in secondary metabolites, a robust method is demanded. Several methods (MRIP, CTAB and TRIZOL) have been used previously for the isolation of quality RNA from the coconut tissues, but without any success. The present study will provide with the details of a new method (Quick and Reliable RNA Extraction Method or QRREM), which have efficiently isolated the intact RNA form the complex tissues of coconut compared with CTAB, Trizol and RNA plant. The method has been validated for the isolation of high-quality intact RNA from the other available plant species (Areca/betel nut, mint and spring onion). The method has various advantages over the other methods in terms of time and cost effectiveness. Furthermore, the resulted RNA from various tissues of coconut performed well in the downstream experiments, i.e. reverse transcription and PCR for the production and amplification of cDNA.

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<![CDATA[Building the space elevator: lessons from biological design]]> https://www.researchpad.co/article/5c1acd4bd5eed0c484078c34

One of the biggest perceived challenges in building megastructures, such as the space elevator, is the unavailability of materials with sufficient tensile strength. The presumed necessity of very strong materials stems from a design paradigm which requires structures to operate at a small fraction of their maximum tensile strength (usually, 50% or less). This criterion limits the probability of failure by giving structures sufficient leeway in handling stochastic components, such as variability in material strength and/or external forces. While reasonable for typical engineering structures, low working stress ratios—defined as operating stress as a fraction of ultimate tensile strength—in the case of megastructures are both too stringent and unable to adequately control the failure probability. We draw inspiration from natural biological structures, such as bones, tendons and ligaments, which are made up of smaller substructures and exhibit self-repair, and suggest a design that requires structures to operate at significantly higher stress ratios, while maintaining reliability through a continuous repair mechanism. We outline a mathematical framework for analysing the reliability of structures with components exhibiting probabilistic rupture and repair that depend on their time-in-use (age). Further, we predict time-to-failure distributions for the overall structure. We then apply this framework to the space elevator and find that a high degree of reliability is achievable using currently existing materials, provided it operates at sufficiently high working stress ratios, sustained through an autonomous repair mechanism, implemented via, e.g. robots.

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<![CDATA[Renal miR-148b is associated with megalin down-regulation in IgA nephropathy]]> https://www.researchpad.co/article/5c15d68cd5eed0c484287e37

Megalin is essential for proximal tubule reabsorption of filtered proteins, hormones, and vitamins, and its dysfunction has been reported in IgA nephropathy (IgAN). miR-148b has been shown to regulate renal megalin expression in vitro and in animal models of kidney disease. We examined a potential role of miR-148b and other miRNAs in regulating megalin expression in IgAN by analyzing the association between megalin and miR-148b, miR-21, miR-146a, and miR-192 expression. Quantitative PCR (qPCR) analysis identified a marked increase in renal levels of several miRNAs, including miR-148b, miR-21, miR-146a, and a significant decrease in megalin mRNA levels in IgAN patients when compared with normal controls. By multiple linear regression analysis, however, only renal miR-148b was independently associated with megalin mRNA levels in IgAN. Proximal tubule megalin expression was further evaluated by immunofluorescence labeling of biopsies from the patients. The megalin expression was significantly lower in patients with highest levels of renal miR-148b compared with patients with lowest levels. To examine the direct effects of the miRNAs on megalin and other membrane proteins expression, proximal tubule LLC-PK1 cells were transfected with miR-148b, miR-21, miR-146a, or miR-192 mimics. Transfection with miR-148b mimic, but not the other three miRNA mimics inhibited endogenous megalin mRNA expression. No significant effect of any of the four miRNA mimics was observed on cubilin or aquaporin 1 (AQP1) mRNA expression. The findings suggest that miR-148b negatively regulates megalin expression in IgAN, which may affect renal uptake and metabolism of essential substances.

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