The SHV β-lactamases (BLs) have undergone strong allele diversification that changed their substrate specificities. Based on 147 NCBI entries for SHV alleles, in silico mathematical models predicted five positions as relevant for the β-lactamase inhibitor (BLI) resistant (2br) phenotype, 12 as relevant for the extended-spectrum BL (ESBL) (2be) phenotype, and two positions were related to solely the narrow spectrum (2b) phenotype. These positions and additional 6 positions described in other studies (including one promoter mutation), were systematically substituted and investigated for their substrate specificities in a BL-free E. coli background, representing, to our knowledge, the most comprehensive substrate and substitution analysis for SHV alleles to date. An in vitro analysis confirmed the essentiality of the positions 238 and 179 for the 2be phenotype and 69 for the 2br phenotype. The substitutions E240K and E240R, which do not occur alone in known 2br SHV variants, led to a 2br phenotype, indicating a latent BLI-resistance potential of these substitutions. The substitutions M129V, A234G, S271I and R292Q conferred latent resistance to cefotaxime. In addition, 7 positions that were found to be not always associated with the ESBL phenotype resulted in increased resistance to ceftaroline. We also observed that coupling of a strong promoter (IS26) to a A146V mutant with the 2b phenotype resulted in a highly increased resistance to BLIs, cefepime and ceftaroline but not to 3^rd generation cephalosporins, indicating that SHV enzymes represent an underestimated risk for empirical therapies that use piperacillin/tazobactam or cefepime to treat different infectious diseases caused by gram-negatives.

Szymon Talaga and Andrzej Nowak: Real-world social networks often exhibit high levels of clustering, positive degree assortativity, short average path lengths (small-world property) and right-skewed but rarely power law degree distributions. On the other hand homophily, defined as the propensity of similar agents to connect to each other, is one of the most fundamental social processes observed in many human and animal societies. In this paper we examine the extent to which homophily is sufficient to produce the typical structural properties of social networks. To do so, we conduct a simulation study based on the Social Distance Attachment (SDA) model, a particular kind of Random Geometric Graph (RGG), in which nodes are embedded in a social space and connection probabilities depend functionally on distances between nodes. We derive the form of the model from first principles based on existing analytical results and argue that the mathematical construction of RGGs corresponds directly to the homophily principle, so they provide a good model for it. We find that homophily, especially when combined with a random edge rewiring, is sufficient to reproduce many of the characteristic features of social networks. Additionally, we devise a hybrid model combining SDA with the configuration model that allows generating homophilic networks with arbitrary degree sequences and we use it to study interactions of homophily with processes imposing constraints on degree distributions. We show that the effects of homophily on clustering are robust with respect to distribution constraints, while degree assortativity can be highly dependent on the particular kind of enforced degree sequence.

Data-driven businesses use technology as an insight platform to empower nontechnical users.

The post Data-driven to business insights appeared first on The Data Roundtable.

Jim Harris shows how data, analytics and humans work together to form the "insight equation."

The post Data, analytics and humans: The insight equation appeared first on The Data Roundtable.

Dr. Catherine Knupp, executive vice president and president of Research and Development at Zoetis, shares her insights on the value of innovation to both animal and human health.

If I talk about my life, it was much simpler when I used to live with my parents. They took good care of whatever I wanted - in fact, they still do. But now, I am living alone, and sometimes I buy...

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You must deal with many reports in your daily life – for your health, financial accounts, credit, your child’s academic records, and the count goes on. Ever noticed that these reports contain many details, most of which you don’t wa...(read more)

Imagine you are on a vacation with your family, and suddenly, your phone starts buzzing. You pick it up and what are you looking at is a bunch of pending, unanswered e-mails. You start recollecting the checklist you had made before taking off only to realize that you haven’t put on the automatic replies! (read more)

What is a Power Distribution Network (PDN) after all but resistance, inductance, and capacitance in the PCB and components? And, of course, it is there to deliver the right current and voltage to each component on your PCB. But is that all? Are there oth...(read more)

So, what if you can figure out all that can go wrong when your product is being assembled early on? Not guess but know and correct at an early stage – not wait for the fabricator or manufacturer to send you a long report of what needs to change. That’s why Design for Assembly (DFA) rules(read more)

Brexit; It’s been the buzz word dominating the media recently and it’s likely to continue for some time. The UK’s decision to leave the EU has left both supporting sides of the ‘leave’ and ‘remain’ campaign in a somewhat collective state of uncertainty as to how this decision will impact the country right now and in the future years.

Government support for Australia’s defence industries is on the increase, as two government agencies extend collaboration.

India has moved up 14 places to be 63rd among 190 nations for ease of doing business, in the World Bank’s Doing Business 2020 report, released on 24 October.

Across the world, the pace of innovation is increasing and transforming the way services are delivered and goods produced.

The use of innovative technology in agriculture – agtech – has fundamentally disrupted conventional production techniques and market linkages in the Indian agricultural sector.

Perceptions of political uncertainty and community opposition continue to weigh heavily on Mexico’s mining sector.

Australian food businesses will find a warm reception in India, where the expanding middle-class population, modern retail formats and entry of international e-commerce platforms are driving growth in the country’s food and beverage (F&B) retail sector.

In a country with a population of 1.3 billion and where around 700 million people are above the legal drinking age – a number growing by 19 million a year – India is a market with many opportunities for Australia’s winemakers.

Like many countries, Japan is undertaking a significant renewal and upgrade of its defence and security capabilities. The Japanese Government is spending just under A$370 billion on defence up until early 2024. With the industry gradually opening to collaborations with overseas partners, this presents many opportunities for Australian businesses.

While the China market has been a miracle for Australian food exporters, the data belies many of the operating challenges individual Australian firms face.

Australian table grape exports to Korea have continuously increased year on year, with a three-fold increase each year from 162 tonnes in 2017; 776 tons in 2018 and 3,224 tons in 2019.

India’s consumers have embraced online retail, creating a market worth A$52 billion that is expected to reach over A$100 billion by 2026. With a fast-growing ecommerce sector, India is creating major new market opportunities for Australian companies.

As many Australian clients know, India announced a 21-day lockdown across the entire country, commencing on March 24. At this point, this is the largest lockdown in the world affecting more than a billion people. On April 14, this lockdown was extended until May 3.

With e-commerce accelerating in cities across India, it’s easy to miss how consumer behaviour is changing right across the South Asia region.

A strong and trusted partnership between a Wuhan based distributor of Australian beef and their Australian supplier ensured shipments continued during the worst of the pandemic crisis.

Recent changes in the Indian Government’s approach to mining has opened up opportunities for private sector involvement in the sector, including international METS firms.

A strong and trusted partnership between a Wuhan based distributor of Australian beef and their Australian supplier ensured shipments continued during the worst of the pandemic crisis.

Recent changes in the Indian Government’s approach to mining has opened up opportunities for private sector involvement in the sector, including international METS firms.

Brexit; It’s been the buzz word dominating the media recently and it’s likely to continue for some time. The UK’s decision to leave the EU has left both supporting sides of the ‘leave’ and ‘remain’ campaign in a somewhat collective state of uncertainty as to how this decision will impact the country right now and in the future years.

On 20th March, we held the 'Coronavirus Insights and practical solutions for landlords' webinar. 

On 20th March, we held the 'Coronavirus Insights and practical solutions for landlords' webinar.  In this webinar, our speakers discussed how the outbreak of Covid-19 and the subsequent political and economic impact is having a signific...

In this session we answered some of the most common questions clients have asked us over recent weeks as well as digging into more detail around how your business should proceed with specific legal and technical challenges according to French, Germa...

The law on force majeure differs from country to country, not least between common law and civil law jurisdictions. We have produced a both a Global Guide to Force Majeure and an Asia-Pacific Guide to Force Majeure that provides some preliminary ad...

Listen as our panel answer some of the most common questions clients have asked us over recent weeks as well as digging into more detail around how your business should proceed with specific legal and technical challenges. A recording of the session...

Hyundai Merchant Marine is pushing forward with a plan to attract an investment of up to 1 trillion won from BlackRock, the world's largest asset management firm. According to investment banking industry and shipping industry sources on August 20, the company is currently in talks with BlackRock to bring in an investment of 600 billion won to 1 trillion won. The investment will be made in the form of BlackRock taking part in a capital increase by Hyundai. Once the deal is successful, the equi...

ABSTRACT

Burkholderia pseudomallei, the founding member of the B. pseudomallei complex (Bpc), is a biothreat agent and causes melioidosis, a disease whose treatment mainly relies on ceftazidime and meropenem. The concern is that B. pseudomallei could enhance its drug resistance repertoire by the acquisition of DNA from resistant near-neighbor species. Burkholderia ubonensis, a member of the B. cepacia complex (Bcc), is commonly coisolated from environments where B. pseudomallei is present. Unlike B. pseudomallei, in which significant primary carbapenem resistance is rare, it is not uncommon in B. ubonensis, but the underlying mechanisms are unknown. We established that carbapenem resistance in B. ubonensis is due to an inducible class A PenB β-lactamase, as has been shown for other Bcc bacteria. Inducibility is not sufficient for high-level resistance but also requires other determinants, such as a PenB that is more robust than that present in susceptible isolates, as well as other resistance factors. Curiously and diagnostic for the two complexes, both Bpc and Bcc bacteria contain distinct annotated PenA class A β-lactamases. However, the protein from Bcc bacteria is missing its essential active-site serine and, therefore, is not a β-lactamase. Regulated expression of a transcriptional penB'-lacZ (β-galactosidase) fusion in the B. pseudomallei surrogate B. thailandensis confirms that although Bpc bacteria lack an inducible β-lactamase, they contain the components required for responding to aberrant peptidoglycan synthesis resulting from β-lactam challenge. Understanding the diversity of antimicrobial resistance in Burkholderia species is informative about how the challenges arising from potential resistance transfer between them can be met.

IMPORTANCE Burkholderia pseudomallei causes melioidosis, a tropical disease that is highly fatal if not properly treated. Our data show that, in contrast to B. pseudomallei, B. ubonensis β-lactam resistance is fundamentally different because intrinsic resistance is mediated by an inducible class A β-lactamase. This includes resistance to carbapenems. Our work demonstrates that studies with near-neighbor species are informative about the diversity of antimicrobial resistance in Burkholderia and can also provide clues about the potential of resistance transfer between bacteria inhabiting the same environment. Knowledge about potential adverse challenges resulting from the horizontal transfer of resistance genes between members of the two complexes enables the design of effective countermeasures.

Objective

To specifically report on ataxic-hypotonic cerebral palsy (CP) using registry data and to directly compare its features with other CP subtypes.

The Bcl-2 (B cell lymphoma 2)-related protein Nr-13 plays a major role in the regulation of cell death in developing avian B cells. With over 65% sequence similarity to the chicken Nr-13, herpesvirus of turkeys (HVT) vNr-13, encoded by the HVT079 and HVT096 genes, is the first known alphaherpesvirus-encoded Bcl-2 homolog. HVT-infected cells were reported to be relatively more resistant to serum starvation, suggested that vNr-13 could be involved in protecting the cells. Here, we describe CRISPR/Cas9-based editing of exon 1 of the HVT079 and HVT096 genes from the HVT genome to generate the mutant HVT-vNr-13 to gain insights into its functional roles. Overall, wild-type HVT and HVT-vNr-13 showed similar growth kinetics; however, at early time points, HVT-vNr-13 showed 1.3- to 1.7-fold-lower growth of cell-associated virus and 3- to 6.2-fold-lower growth of cell-free virus. In transfected cells, HVT vNr-13 showed a mainly diffuse cytoplasmic distribution with faint nuclear staining. Further, vNr-13 localized to the mitochondria and endoplasmic reticulum (ER) and disrupted mitochondrial network morphology in the transfected cells. In the wild-type HVT-infected cells, vNr-13 expression appeared to be directly involved in the disruption of the mitochondrial network, as the mitochondrial network morphology was substantially restored in the HVT-vNr-13-infected cells. IncuCyte S3 real-time apoptosis monitoring demonstrated that vNr-13 is unequivocally involved in the apoptosis inhibition, and it is associated with an increase of PFU, especially under serum-free conditions in the later stages of the viral replication cycle. Furthermore, HVT blocks apoptosis in infected cells but activates apoptosis in noninfected bystander cells.

IMPORTANCE B cell lymphoma 2 (Bcl-2) family proteins play important roles in regulating apoptosis during homeostasis, tissue development, and infectious diseases. Several viruses encode homologs of cellular Bcl-2-proteins (vBcl-2) to inhibit apoptosis, which enable them to replicate and persist in the infected cells and to evade/modulate the immune response of the host. Herpesvirus of turkeys (HVT) is a nonpathogenic alphaherpesvirus of turkeys and chickens that is widely used as a live vaccine against Marek’s disease and as recombinant vaccine viral vectors for protecting against multiple avian diseases. Identical copies of the HVT genes HVT079 and HVT096 encode the Bcl-2 homolog vNr-13. While previous studies have identified the potential ability of vNr-13 in inhibiting apoptosis induced by serum deprivation, there have been no detailed investigations on the functions of vNr-13. Using CRISPR/Cas9-based ablation of the vNr-13 gene, we demonstrated the roles of HVT vNr-13 in early stages of the viral replication cycle, mitochondrial morphology disruption, and apoptosis inhibition in later stages of viral replication.

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism <50% had hemolysis (reticulocytosis) and higher HbS than their donor. Four of them had donor chimerism <30%, including a patient with AA donor (hemoglobin >10 g/dL) and three with AS donors (hemoglobin <10 g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with the lowest chimerism, the donor engraftment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for SCD, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent a vaso-occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels (i.e. ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.

Manoella Gemaque Cavalcante, Cleusa Yoshiko Nagamachi, Julio Cesar Pieczarka, and Renata Coelho Rodrigues Noronha

Eukaryotic genomes exhibit substantial accumulation of repetitive DNA sequences. These sequences can participate in chromosomal reorganization events and undergo molecular cooption to interfere with the function and evolution of genomes. In turtles, repetitive DNA sequences appear to be accumulated at probable break points and may participate in events such as non-homologous recombination and chromosomal rearrangements. In this study, repeated sequences of 5S rDNA, U2 snRNA and Tc1/Mariner transposons were amplified from the genomes of the turtles, Podocnemis expansa and Podocnemis unifilis, and mapped by fluorescence in situ hybridization. Our data confirm the 2n=28 chromosomes for these species (the second lowest 2n in the order Testudines). We observe high conservation of the co-located 5S rDNA and U2 snRNA genes on a small chromosome pair (pair 13), and surmise that this represents the ancestral condition. Our analysis reveals a wide distribution of the Tc1/Mariner transposons and we discuss how the mobility of these transposons can act on karyotypic reorganization events (contributing to the 2n decrease of those species). Our data add new information for the order Testudines and provide important insights into the dynamics and organization of these sequences in the chelonian genomes.

The Early Career Members Committee (ECMC) of the European Respiratory Society (ERS) consists of 14 members, one Early Career Member (ECM) representative per assembly. In September 2019, seven recently elected representatives joined the ECMC. An overview is given of the tasks performed by each representative within the ECMC (table 1). In addition, a short summary about the content of these tasks is provided.

Purpose:

Preclinical data demonstrating androgen receptor (AR)–positive (AR⁺) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR⁺ (≥10%) breast cancer.