The afc antifungal activity cluster, which is under tight regulatory control of ShvR, is essential for transition from intracellular persistence of Burkholderia cenocepacia to acute pro-inflammatory infection.

The opportunistic pathogen Burkholderia cenocepacia is particularly life-threatening for cystic fibrosis (CF) patients. Chronic lung infections with these bacteria can rapidly develop into fatal pulmonary necrosis and septicaemia. We have recently shown that macrophages are a critical site for replication of B. cenocepacia K56-2 and the induction of fatal pro-inflammatory responses using a zebrafish infection model. Here, we show that ShvR, a LysR-type transcriptional regulator that is important for biofilm formation, rough colony morphotype and inflammation in a rat lung infection model, is also required for the induction of fatal pro-inflammatory responses in zebrafish larvae. ShvR was not essential, however, for bacterial survival and replication in macrophages. Temporal, rhamnose-induced restoration of shvR expression in the shvR mutant during intramacrophage stages unequivocally demonstrated a key role for ShvR in transition from intracellular persistence to acute fatal pro-inflammatory disease. ShvR has been previously shown to tightly control the expression of the adjacent afc gene cluster, which specifies the synthesis of a lipopeptide with antifungal activity. Mutation of afcE, encoding an acyl-CoA dehydrogenase, has been shown to give similar phenotypes as the shvR mutant. We found that, like shvR, afcE is also critical for the switch from intracellular persistence to fatal infection in zebrafish. The closely related B. cenocepacia H111 has been shown to be less virulent than K56-2 in several infection models, including Galleria mellonella and rats. Interestingly, constitutive expression of shvR in H111 increased virulence in zebrafish larvae to almost K56-2 levels in a manner that absolutely required afc. These data confirm a critical role for afc in acute virulence caused by B. cenocepacia that depends on strain-specific regulatory control by ShvR. We propose that ShvR and AFC are important virulence factors of the more virulent Bcc species, either through pro-inflammatory effects of the lipopeptide AFC, or through AFC-dependent membrane properties

Case report: A combination of nitroglycerin and adenosine proves effective in repairing a cerebral arteriovenous malformation

Hemorrhage secondary to rupture of a brain arteriovenous malformations (AVM) is one of the initial manifestations, and the main cause of, morbidity and mortality in patients with this condition. Current treatment strategies include endovascular embolization with the goal of AVM obliteration and neurological preservation. In the transvenous endovascular embolization procedure, adenosine is the preferred agent to induce temporary hypotension and allow adequate AVM embolization. We describe the intraoperative management of an adenosine-resistant 38 year-old male who underwent a successful intracranial AVM embolization after concomitant administration of gradually increasing doses of nitroglycerin. This report suggests that nitroglycerin infusion can be combined with adenosine boluses to create a pronounced and dose-dependent hypotension in patients partially unresponsive to adenosine alone

Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo

Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Importancia Científica de las Oxifotobacterias del Género Nostoc sp.: una revisión sistemática

Antecedentes: Nostoc sp. es un alga que se encuentra en los lagos o ríos de diversas localidades. Esta presenta compuestos químicos con múltiples actividades farmacológicas, en la cual, posee gran valor nutricional en diferentes partes del mundo. Objetivo: Realizar una revisión sistemática de la importancia científica de la Oxifotobacteria Nostoc sp. Materiales y métodos: Se recolectaron investigaciones referentes a esta especie, provenientes de la base de datos, ScienceDirect, Scielo, Core y PubMed, búsqueda realizada con términos Nostoc sp. en base a características etnobotánicas, composición fitoquímica, actividad farmacológica y actividad toxicológica. Resultados: Tras la ardua indagación realizada con el término Nostoc sp. para características etnobotánicas se logró encontrar diecisiete artículos enfocados a diversos usos culinarios que se le brinda. También diecisiete artículos se evidenciaron en base a su composición fitoquímica, en la cual, permitió identificar compuestos como Nostoflan, compuesto capaz de actuar como antiviral. Mientras que veinte fueron los artículos encontrados para la actividad farmacológica como; antimicrobianos, antiulcerosos, antiinflamatorios y hasta reductores del envejecimiento. Por último, solo ocho artículos demostraron actividad toxicológica provenientes de aguas contaminadas. Conclusiones: Esta revisión sistemática se ha basado en sesenta y dos artículos en base a las variables de investigación, donde indica el uso que se le da a cushuro en diferentes poblaciones. Desde actividades medicinales y lo nocivo que puede ser; por ende, se ínsita a realizar más estudios detallados de esta especie porque presenta muchas bondades y son fácilmente adaptables

Psychiatric and Medical Profiles of Autistic Adults in the SPARK Cohort

This study examined lifetime medical and psychiatric morbidity reported by caregivers of 2917 autistic adults participating in the US research cohort SPARK. Participants were 78.4% male, 47.3% had intellectual disability, and 32.1% had persistent language impairments. Childhood language disorders (59.7%), speech/articulation problems (32.8%), sleep (39.4%) and eating problems (29.4%), motor delays (22.8%) and history of seizure (15.5%) were the most frequently reported clinical features. Over two thirds (67.2%) had been diagnosed with at least one psychiatric disorder (anxiety disorders: 41.1%; ADHD: 38.7%). Compared to verbally fluent participants, those with language impairments had lower frequencies of almost all psychiatric disorders. Female sex and older age were associated with higher medical and psychiatric morbidity

Matrix metalloproteinase degradable, in situ photocrosslinked nanocomposite bioinks for bioprinting applications

The development of suitable bioinks with high printability, mechanical strength, biodegradability, and biocompatibility is a key challenge for the clinical translation of 3D constructs produced with bioprinting technologies. In this work, we developed a new type of nanocomposite bioinks containing thiolated mesoporous silica nanoparticles (MSN) that act as active fillers within norbornene-functionalized hydrogels. The MSNs could rapidly covalently crosslink the hydrogels upon exposure to UV light. The mechanical properties of the gels could be modulated from 9.3 to 19.7 kPa with increasing concentrations of MSN. The ability of the MSN to covalently crosslink polymeric networks was, however, significantly influenced by polymer architecture and the number of functional groups. Modification of the outer surface of MSNs with matrix metalloproteinase (MMP) sensitive peptides (MSN-MMPs) resulted in proteinase K and MMP-9 enzyme responsive biodegradable bioinks. Additional cysteine modified RGD peptide incorporation enhanced cell-matrix interactions and reduced the gelation time for bioprinting. The nanocomposite bioinks could be printed by using extrusion-based bioprinting. Our nanocomposite bioinks preserved their shape during in vitro studies and encapsulated MG63 cells preserved their viability and proliferated within the bioinks. As such, our nanocomposite bioinks are promising bioinks for creating bioprinted constructs with tunable mechanical and degradation properties

Marketing high quality Thai organic products in Europe? An exploratory approach

In an international trade context, environmental elements (e.g. the introduction of organic agriculture) and the role of the country of origin could influence the demand in the market of destination. This study aims at describing how qualitative research methods may help deepen knowledge regarding interest towards organic products imported from Thailand, specifically Kamut® wheat, Organic Rice and Tapioca. In the case of Kamut-based-products 21 individual interviews were conducted with Italian large scale retailers, whereas in the case of products based on Thai rice and Tapioca, 4 focus groups comprising of European consumers from Germany, Greece, Italy, and Scotland were administered. The individual and group interviews were recorded, transcribed and analysed using a qualitative approach. In both cases a list of semantic categories was created, explained and supported by analysing the discussions using content analysis techniques. According to these results, survey participants did not know much about these products, especially about tapioca. In general, Thai Organic rice was perceived by the interviewed consumers as a “different type” of rice and tapioca as a “new food product”. Kamut® wheat was also perceived by the interviewed retailers as a “new product”. The survey participants tend to favour the product’s nutritional aspects, as the most relevant attributes followed by taste and smell, as well as a series of social and environmental benefits. The information obtained could be useful in further exploration of this topic, but it needs to be tested with a quantitative approach